@article {pmid40267187,
year = {2025},
author = {Guillaud, L and Garanzini, A and Zakhia, S and De la Fuente, S and Dimitrov, D and Boerner, S and Terenzio, M},
title = {Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.},
journal = {Science advances},
volume = {11},
number = {17},
pages = {eadq6077},
doi = {10.1126/sciadv.adq6077},
pmid = {40267187},
issn = {2375-2548},
mesh = {*Adenosine Triphosphate/metabolism ; Humans ; Animals ; *Protein Aggregation, Pathological/metabolism/pathology ; Mice ; *Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Axons/metabolism ; Viscosity ; Mitochondria/metabolism ; Protein Aggregates ; Parkinson Disease/metabolism/pathology ; DNA-Binding Proteins/metabolism ; Alzheimer Disease/metabolism/pathology ; },
abstract = {Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.},
}

*Adenosine Triphosphate/metabolism
Humans
Animals
*Protein Aggregation, Pathological/metabolism/pathology
Mice
*Neurons/metabolism
Induced Pluripotent Stem Cells/metabolism
Amyotrophic Lateral Sclerosis/metabolism/pathology
*Axons/metabolism
Viscosity
Mitochondria/metabolism
Protein Aggregates
Parkinson Disease/metabolism/pathology
DNA-Binding Proteins/metabolism
Alzheimer Disease/metabolism/pathology

@article {pmid40262868,
year = {2025},
author = {Shi, Y and Wu, Z and Cheng, R and Zhang, L and Guo, X and Li, X and Bi, Y},
title = {The Trp-574-Leu mutations together with enhanced metabolism contribute to cross-resistance to ALS inhibiting herbicides in Fimbristylis littoralis.},
journal = {Pesticide biochemistry and physiology},
volume = {210},
number = {},
pages = {106385},
doi = {10.1016/j.pestbp.2025.106385},
pmid = {40262868},
issn = {1095-9939},
abstract = {Fimbristylis littoralis Gaudich., an important weed in Chinese paddy fields, has caused significant yield losses in rice and other crops. Acetolactate synthase (ALS) inhibitors, such as halosulfuron-methyl, are widely used for weed control. This study identified a highly resistant population (R23-1) of F. littoralis to halosulfuron-methyl, with an exceptionally high resistance index (RI) of 3441.66. The resistant mechanisms of F. littoralis to ALS inhibitors have not been reported previously. We employed a comprehensive approach to address this, including whole-plant bioassay, ALS target gene sequencing, molecular docking, synergistic tests with metabolic enzyme inhibitors, glutathione S-transferases (GSTs) activity assays, and cross-resistance testing. The results revealed the first report of a Trp-574-Leu mutation in the ALS gene of the R23-1 population, which significantly increased binding energy, as shown by molecular docking analysis. Synergistic tests demonstrated that the cytochrome P450 monooxygenase (P450) inhibitor piperonyl butoxide (PBO) and the GSTs inhibitor 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) markedly enhanced the sensitivity of the R23-1 population to halosulfuron-methyl, with synergistic ratios of 4.11 and 8.15, respectively, while malathion had no effect. GST activity decreased in both populations after halosulfuron-methyl treatment, with the R23-1 population consistently showing significantly higher levels, peaking on day five. Furthermore, the R23-1 population demonstrated cross-resistance to multiple ALS inhibitors. These findings provide novel insights into the resistance mechanisms of F. littoralis and lay a theoretical foundation for developing effective strategies to mitigate or delay the evolution of resistance.},
}

@article {pmid40262277,
year = {2025},
author = {Turner, N and Palmer, J and Faull, C and Davidson, S and Turner, MR and Wilson, E},
title = {Tracheostomy ventilation in ALS: healthcare practitioner perspectives on quality of life and implications for decision-making.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/21678421.2025.2495014},
pmid = {40262277},
issn = {2167-9223},
abstract = {Objectives: This qualitative study aimed to increase understanding of how healthcare practitioners (HCPs) perceive quality of life for people with ALS who use tracheostomy ventilation (TV) and the extent to which such views inform discussions regarding future treatment and care. Methods: A thematic analysis was applied to data derived from online semi-structured interviews with a professionally diverse group of 24 HCPs with experience of supporting people with ALS to use TV. Results: Four main themes relating to TV use emerged: i) Positive benefits; ii) Risks and challenges; iii) Factors influencing HCP perspectives; iv) Concepts informing HCP discussions. HCPs acknowledged that TV has the potential to extend life but were concerned with prolonging a serious decline in physical and cognitive functioning. HCPs tried to identify the 'tipping point' between quantity and quality of life for the individual and their family, taking into account the likelihood of a higher burden of care. HCPs drew on prior experience to assess anticipated quality of life, yet most HCPs in the UK have limited experience of TV for this group. HCPs also drew on principles of person-centered care, patient autonomy and value for money to guide their approach to discussing TV. Conclusions: HCP experience of positive outcomes of TV can foster a more proactive approach to initiating conversations about its potential use. Sharing best practice and improving guidance for HCPs may support early and on-going future care planning and enable people with ALS to make choices which are informed and in their best interests.},
}

@article {pmid40261116,
year = {2025},
author = {Shneider, NA and Nesta, AV and Rifai, OM and Yasek, J and Elyaman, W and Aziz-Zaman, S and Lyu, MA and Levy, SHS and Hoover, BN and Vlad, G and Huang, M and Zeng, K and Sadeghi, T and Reddy, A and Flowers, CR and Parmar, S},
title = {Clinical Safety and Preliminary Efficacy of Regulatory T Cells for ALS.},
journal = {NEJM evidence},
volume = {4},
number = {5},
pages = {EVIDoa2400249},
doi = {10.1056/EVIDoa2400249},
pmid = {40261116},
issn = {2766-5526},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Middle Aged ; *T-Lymphocytes, Regulatory/transplantation ; Female ; Male ; Aged ; Adult ; Biomarkers/blood ; Treatment Outcome ; Neurofilament Proteins/blood ; },
abstract = {BACKGROUND: Peripheral and neuroinflammation have been previously associated with progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving progressive loss of motor neurons. We hypothesize that regulatory T cell (Treg) therapy can resolve inflammation and preserve function in those patients with ALS.

METHODS: Participants with ALS received infusions of a fixed dose (100×10[6] cells) of umbilical cord blood-derived, allogeneic, nonhuman leukocyte antigen-matched, cryopreserved Treg product (TREG), administered as four weekly infusions followed by six monthly infusions. No lymphodepletion, immunosuppression, or interleukin 2 was administered. The primary outcome was dose-limiting toxicity, including infusion reaction within 24 hours (as graded by National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 4.0) and/or regimen-related death, or grade 3 or 4 cytokine release syndrome within 14 days postinfusion. We measured clinical response using the Revised ALS Functional Rating Scale (ALSFRS-R; range 0 to 48, with lower numbers indicating lower functional ability). Exploratory analyses measured serum and plasma neurofilament light (NfL) and inflammatory biomarkers.

RESULTS: Six participants with a median age of 48.5 years (range 27 to 66 years) and baseline ALSFRS-R score of 31.5 (range 23 to 43) were treated with a median of 11 (range 6 to 22) TREG infusions in an ambulatory setting. No dose-limiting toxicity was observed. In participants with sufficient data points (n=4), the mean ALSFRS-R slope of decline was -1.66±1.03 points/month before treatment, -0.41±0.45/month during treatment, and -0.60±0.59/month posttreatment. Biomarkers including NfL and inflammatory markers MIP-1δ (macrophage inflammatory protein-1 delta), CTACK (cutaneous T cell-attracting chemokine), and GROα (growth-regulated oncogene alpha) exhibited different relationships with ALSFRS-R score between participants.

CONCLUSIONS: This study demonstrates the preliminary safety of "off-the-shelf", allogeneic Treg-cell therapy.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy
Middle Aged
*T-Lymphocytes, Regulatory/transplantation
Female
Male
Aged
Adult
Biomarkers/blood
Treatment Outcome
Neurofilament Proteins/blood

@article {pmid40255098,
year = {2025},
author = {Regnault, R and Kouach, M and Goossens, L and Thuru, X and Bailly, C and Goossens, JF},
title = {HR-MS Analysis of the Covalent Binding of Edaravone to 5-Formylpyrimidine Bases and a DNA Oligonucleotide Containing a 5-Formylcytidine Residue.},
journal = {Rapid communications in mass spectrometry : RCM},
volume = {39},
number = {14},
pages = {e10050},
doi = {10.1002/rcm.10050},
pmid = {40255098},
issn = {1097-0231},
support = {//Comité de l'Oise de la Ligue Contre le Cancer/ ; //French Ligue Against Cancer/ ; },
mesh = {Edaravone/chemistry ; *Mass Spectrometry/methods ; *Oligonucleotides/chemistry/metabolism ; *Pyrimidines/chemistry ; *DNA/chemistry ; *Cytidine/chemistry/analogs & derivatives ; Cytosine/analogs & derivatives ; },
abstract = {RATIONALE: Edaravone (EDA) is a radical scavenger and an antioxidant drug approved to treat amyotrophic lateral sclerosis and used as a research tool to explore treatment of neurodegenerative diseases and cancers. It is also a reactive agent, known as PMP (1-phenyl-3-methyl-5-pyrazolone), used for the analysis of polysaccharides composition. EDA can react with sugars and aromatic aldehydes. In this context, we have investigated the reactivity of EDA toward the biologically relevant formylated nucleobases, nucleosides, and an oligonucleotide containing a formylated residue.

METHODS: The formation of both mono- and bis-adducts between EDA and the formylated nucleobases (5-formyluracil (5fU) and 5-formylcytosine (5fC)) or the corresponding nucleosides 5-fdU and 5-fdC was characterized using high-resolution mass spectrometry (HR-MS). Similarly, the covalent binding of EDA to an 8-mer palindromic oligonucleotide d (TATG[*C]ATA) containing a single 5-fdC residue [*C] under physiological conditions was investigated using mass spectrometry.

RESULTS: For the first time, EDA is shown to react with formylated pyrimidines. Covalent and stable adducts were identified. EDA was found to react efficiently with the formylated oligonucleotide to generate mono- and bis-adducts. The rate of formation of the mono-adduct was five times higher than that of the bis-adduct. The reaction of EDA with aldehydic DNA modifications such as 5fU/5fC may have important consequences in terms of gene expression.

CONCLUSIONS: These observations raise implications for an epigenetic contribution to the mechanism of action of EDA. The biological implications of our in vitro results are discussed, notably in the frame of neurodegenerative diseases and cancers.},
}

Edaravone/chemistry
*Mass Spectrometry/methods
*Oligonucleotides/chemistry/metabolism
*Pyrimidines/chemistry
*DNA/chemistry
*Cytidine/chemistry/analogs & derivatives
Cytosine/analogs & derivatives

@article {pmid40251832,
year = {2025},
author = {Bresque, M and Esteve, D and Balmer, G and Hamilton, HL and Stephany, JS and Pehar, M and Vargas, MR},
title = {FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.},
journal = {Glia},
volume = {},
number = {},
pages = {},
doi = {10.1002/glia.70023},
pmid = {40251832},
issn = {1098-1136},
support = {R01NS122973/NH/NIH HHS/United States ; R01NS132760/NH/NIH HHS/United States ; },
abstract = {Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.},
}

@article {pmid40250093,
year = {2025},
author = {Casiraghi, V and Pellegrini, E and Brusati, A and Peverelli, S and Invernizzi, S and Santangelo, S and Colombrita, C and Verde, F and Ticozzi, N and Silani, V and Ratti, A},
title = {Characterization of human healthy i[3] lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype.},
journal = {Journal of the neurological sciences},
volume = {473},
number = {},
pages = {123508},
doi = {10.1016/j.jns.2025.123508},
pmid = {40250093},
issn = {1878-5883},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. Neurodegeneration in ALS might be driven by proteotoxicity or neuroinflammation, which have also been proposed to be promoted by toxic components of the cerebrospinal fluid (CSF). We investigated the possible toxicity of ALS CSF on healthy induced pluripotent stem cells (iPSC)-derived integrated, inducible, and isogenic lower motor neurons (i[3]LMNs). CSFs were obtained from ALS patients homozygous for the risk UNC13A rs12608932 single nucleotide polymorphism (CC) and for the corresponding major allele (AA), ALS patients with C9ORF72 hexanucleotide repeat expansion, and individuals affected by normal pressure hydrocephalus as non-disease controls (ND). A chronic and low-dose sodium arsenite (ARS) treatment was used as positive control of oxidative stress. We found that 10 % ALS CSF treatment for 48 h was not sufficient to induce significant alterations in viability, autophagic flux, axonal degeneration, DNA damage, and Golgi apparatus integrity in healthy i[3]LMNs, in contrast to ARS treatment. Only UNC13A CC CSF significantly increased protein aggregation and Golgi apparatus fragments dimension. RNA-sequencing revealed that all ALS and ND CSFs induced expression changes of few genes, while chronic ARS deregulated the expression of thousands of genes, mostly involved in inflammation and synapse biology. In this work, we demonstrated that in our experimental settings only CSF from UNC13A CC patients induced some ALS-associated pathological features in healthy i[3]LMNs. Further studies will be required to elucidate the mechanistic link between the risk UNC13A genotype and CSF composition and toxicity.},
}

@article {pmid40244061,
year = {2025},
author = {Tseriotis, VS and Liampas, A and Lazaridou, IZ and Karachrysafi, S and Vavougios, GD and Hadjigeorgiou, GM and Papamitsou, T and Kouvelas, D and Arnaoutoglou, M and Pourzitaki, C and Mavridis, T},
title = {Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
doi = {10.3390/ijms26073221},
pmid = {40244061},
issn = {1422-0067},
mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Nerve Tissue Proteins/metabolism/antagonists & inhibitors/genetics ; *GPI-Linked Proteins/metabolism/antagonists & inhibitors/genetics ; Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; },
abstract = {Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa's responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.},
}

Humans
Animals
*Nervous System Diseases/metabolism/drug therapy
*Nerve Tissue Proteins/metabolism/antagonists & inhibitors/genetics
*GPI-Linked Proteins/metabolism/antagonists & inhibitors/genetics
Molecular Targeted Therapy
Neurodegenerative Diseases/metabolism/drug therapy

@article {pmid40237254,
year = {2025},
author = {Russek, M and Peltner, J and Haenisch, B},
title = {Supplementing Single-Arm Trials with External Control Arms-Evaluation of German Real-World Data.},
journal = {Clinical pharmacology and therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1002/cpt.3684},
pmid = {40237254},
issn = {1532-6535},
abstract = {As single-arm trials (SATs) are increasingly used in pharmaceutical research, the validity of such study designs needs to be critically assessed. We characterize the feasibility of supplementing SATs with real-world data (RWD)-derived external control arms by determining the proportion of SATs on breast cancer and amyotrophic lateral sclerosis (ALS) for which an external control arm based on RWD can be constructed. The main outcome measure is the number and percentage of trials for which all important eligibility criteria and at least one primary endpoint could be identified in one of five German RWD sources. We surveyed all SATs concerning breast cancer or ALS treatment registered in the European Union's clinical trial registers between 2004 and 2023. Ten out of 379 breast cancer SATs and 2 of 11 ALS SATs could feasibly be supplemented with RWD-derived external control arms, if all important eligibility criteria and a primary endpoint have to be identifiable in the RWD source. Ninety-three breast cancer trials had at least one outcome ascertainable in a RWD source, and 35 trials had all important eligibility criteria recorded in a RWD source. Nine ALS trials had at least one primary endpoint ascertainable in RWD sources, and 2 had all important eligibility criteria recorded in a RWD source. Our study shows that SATs with RWD-derived external control arms will rarely be suitable to establish treatment effects of medicines in the current setting for the investigated phenotypes and that SATs should be designed with limitations of the source of external controls in mind.},
}

@article {pmid40235867,
year = {2025},
author = {Sundararaju, U and Rajakumar, HK},
title = {Prognostic value of neutrophil-to-lymphocyte ratio in gastric cancer: Enhancing clinical relevance.},
journal = {World journal of gastrointestinal oncology},
volume = {17},
number = {4},
pages = {103128},
pmid = {40235867},
issn = {1948-5204},
abstract = {Gastric cancer (GC) is a leading cause of cancer-related deaths, highlighting the need for reliable prognostic biomarkers to guide treatment. Wei et al's systematic review and meta-analysis evaluates the neutrophil-to-lymphocyte ratio (NLR) as a potential biomarker for GC patients undergoing neoadjuvant chemotherapy. NLR is a simple and cost-effective measure of systemic inflammation that shows promise in predicting treatment response and survival outcomes, including overall survival and progression-free survival. However, variations in NLR thresholds and timing of measurements affect its accuracy and clinical utility. Moreover, the studies reviewed primarily involved Asian populations, which may limit the generalizability of the findings. To improve NLR's clinical relevance, future research should focus on standardizing NLR thresholds, refining measurement timing, and incorporating additional inflammatory markers like platelet-to-lymphocyte ratio and Glasgow prognostic score. Addressing confounders and including diverse patient populations will help improve NLR's reliability as a prognostic marker for GC.},
}

@article {pmid40229540,
year = {2025},
author = {Ghimire, S and Kreilaus, F and Rosa Porto, R and Anderson, LL and Yerbury, JJ and Arnold, JC and Karl, T},
title = {Behavioural effects of oral cannabidiol (CBD) treatment in the superoxide dismutase 1 G93 A (SOD1[G93 A]) mouse model of amyotrophic lateral sclerosis.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40229540},
issn = {1432-2072},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting voluntary muscle movement as well as cognitive and other behavioural domains at later disease stages. No effective treatment for ALS is currently available. Elevated neuroinflammation, oxidative stress and alterations to the endocannabinoid system are evident in ALS. The phytocannabinoid cannabidiol (CBD) has anti-inflammatory and anti-oxidant properties. Thus, we evaluated the remedial effects of chronic oral cannabidiol (CBD) treatment on ALS-relevant behavioural domains in the copper-zinc superoxide dismutase 1 (SOD1) mouse model of ALS that carries a G93A mutation (SOD1[G93A]).

METHODS: Male and female SOD1[G93A] and wild type-like (WT) littermates were fed either a control (CHOW) or CBD-enriched chow diet (equivalent to a dose of 36 mg/kg per day) beginning from 10 weeks of age. Bodyweight and motor performance were recorded weekly from 11 to 19 weeks and open field behaviours at 12 and 18 weeks. Mice were also tested for prepulse inhibition (PPI), social behaviours, as well as fear-associated memory.

RESULTS: CBD treatment ameliorated the bodyweight loss in female SOD1[G93A] mice, tended to reinstate sociability in SOD1[G93A] males, strengthened social recognition memory in SOD1[G93A] females, and improved the PPI response in younger SOD1[G93A] females at higher prepulse intensities. CBD had no effect on motor impairments but instead reversed the anxiolytic-like phenotype of 12-week-old male SOD1[G93A] mice and decreased the acoustic startle response and strengthened cue freezing in male mice.

CONCLUSION: Thus, the current remedial oral dose of CBD delayed disease progression (inferred by bodyweight) in both male and female mice and improve specific cognitive deficits of SOD1[G93A] mice in a sex specific manner without altering the motor phenotype.},
}

@article {pmid40226510,
year = {2025},
author = {Ufarry Alvarado, AJ and Zaidi Pons, MA and Plaza Hernández, J and Torres Ortiz, C},
title = {Improvements of Paraquat Treatment in Liquid Media for Behavior and Neurodegenerative Tests.},
journal = {microPublication biology},
volume = {2025},
number = {},
pages = {},
pmid = {40226510},
issn = {2578-9430},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a disease characterized by misfolded and aggregated proteins that have toxic effects on motor neurons. The missense mutation, G85R, of the sod-1 gene associated with ALS displays locomotor impairments in Caenorhadbitis elegans (C. elegans). We treated the sod-1 (G85R) strain with 0 and 2.5 mM Paraquat treatments in a liquid M9 buffer for 4 hours and in solid NGM media for 18 hours. In both methodologies, the locomotion defects and neurodegeneration were significantly increased with 2.5 mM Paraquat. Our work provides evidence of methodology that is more cost effective, rapid and reproducible to perform behavior and neurodegenerative assay in worms.},
}

@article {pmid40222103,
year = {2025},
author = {Lum, JS and Brown, ML and Farrawell, NE and Bartlett, R and Chisholm, CG and Gorman, J and Dosseto, A and Dux, F and McInnes, LE and Ecroyd, H and McAlary, L and Crouch, PJ and Donnelly, PS and Yerbury, JJ},
title = {A polytherapy approach demonstrates therapeutic efficacy for the treatment of SOD1 associated amyotrophic lateral sclerosis.},
journal = {EBioMedicine},
volume = {115},
number = {},
pages = {105692},
doi = {10.1016/j.ebiom.2025.105692},
pmid = {40222103},
issn = {2352-3964},
abstract = {BACKGROUND: SOD1 mutations are a significant contributor of familial amyotrophic lateral sclerosis (ALS) cases. SOD1 mutations increase the propensity for the protein to misfold and aggregate into insoluble proteinaceous deposits within motor neurons and neighbouring cells. The small molecule, CuATSM, has repeatedly shown in mouse models to be a promising therapeutic treatment for SOD1-associated ALS and is currently in Phase II/III clinical trials for the treatment of ALS. We have previously shown CuATSM stabilises various ALS-associated variants of the SOD1 protein, reducing misfolding and toxicity. Two additional FDA-approved small molecules, ebselen and telbivudine, have also been identified to reduce mutant SOD1 toxicity, providing additional potential therapeutic candidates that could be used in combination with CuATSM. Here, we aimed to investigate if CuATSM, ebselen and telbivudine (CET) polytherapy could improve on the therapeutic efficacy of CuATSM monotherapy for the treatment of SOD1-associated ALS.

METHODS: We utilised a 3D checkerboard approach to investigate whether a matrix of different concentrations CuATSM, ebselen and telbivudine could provide therapeutic improvements on cell survival, SOD1 folding and aggregation in SOD1[G93A]-transfected NSC-34 cells, compared to CuATSM alone. To progress the preclinical development of CET polytherapy, we evaluated the bioavailability and safety of in vivo polytherapy administration. Furthermore, we assessed and compared the effects of CET- and CuATSM-treatment on disease onset, motor function, survival and neuropathological features in SOD1[G93A] mice.

FINDINGS: CET polytherapy reduced inclusion formation and increased cell survival of NSC-34 cells overexpressing SOD1[G93A] compared to higher concentrations of CuATSM monotherapy. In addition, CET administration was bioavailable and tolerable in mice. CET treatment in SOD1[G93A] mice delayed disease onset, reduced motor impairments, and increased survival compared to vehicle- and CuATSM-treated mice. In line with these findings, biochemical analysis of lumbar spinal cords showed CET administration improved SOD1 folding, decreased misfolded SOD1 accumulation, and reduced motor neuron loss.

INTERPRETATION: These findings support CET polytherapy as an advantageous alternative compared to CuATSM monotherapy and highlight the potential of utilising small molecules targeting SOD1 as a polytherapy avenue for the treatment of SOD1-associated ALS.

FUNDING: This work was supported by a FightMND Drug Development Grant, an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (No. 1194872) and a Motor Neuron Disease Research Institute of Australia Bill Gole Postdoctoral Fellowship.},
}

@article {pmid40216746,
year = {2025},
author = {Rezaei, A and Kocsis-Jutka, V and Gunes, ZI and Zeng, Q and Kislinger, G and Bauernschmitt, F and Isilgan, HB and Parisi, LR and Kaya, T and Franzenburg, S and Koppenbrink, J and Knogler, J and Arzberger, T and Farny, D and Nuscher, B and Katona, E and Dhingra, A and Yang, C and Gouna, G and LaClair, KD and Janjic, A and Enard, W and Zhou, Q and Hagan, N and Ofengeim, D and Beltrán, E and Gokce, O and Simons, M and Liebscher, S and Edbauer, D},
title = {Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {3442},
pmid = {40216746},
issn = {2041-1723},
support = {390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 407495230//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 423957469//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 101057649//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; 101117710//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; },
mesh = {Animals ; Female ; Mice ; *Oligodendroglia/metabolism/drug effects ; *Lipid Metabolism/drug effects/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/pathology ; *C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; Male ; Cholesterol/metabolism ; Humans ; *2-Hydroxypropyl-beta-cyclodextrin/pharmacology ; Mice, Transgenic ; Myelin Sheath/metabolism ; Spinal Cord/metabolism/pathology ; Longevity/drug effects/genetics ; },
abstract = {Clinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-Camk2a GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an adaptive response to cholesterol overload. Consequently, we assessed the efficacy of the cholesterol-binding drug 2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing C9orf72 ALS mouse model with extensive poly-GA expression and myelination deficits. CD treatment normalized cholesteryl ester levels, lowered neurofilament light chain levels, and prolonged lifespan in female but not male GA-Nes mice, without impacting poly-GA aggregates. Single nucleus transcriptomics indicated that CD primarily affected oligodendrocytes, significantly restored myelin gene expression, increased density of myelinated axons, inhibited the disease-associated oligodendrocyte response, and downregulated the lipid-associated genes Plin4 and ApoD. These results suggest that reducing excess free cholesterol in the CNS could be a viable ALS treatment strategy.},
}

Animals
Female
Mice
*Oligodendroglia/metabolism/drug effects
*Lipid Metabolism/drug effects/genetics
*Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/pathology
*C9orf72 Protein/genetics/metabolism
Disease Models, Animal
Male
Cholesterol/metabolism
Humans
*2-Hydroxypropyl-beta-cyclodextrin/pharmacology
Mice, Transgenic
Myelin Sheath/metabolism
Spinal Cord/metabolism/pathology
Longevity/drug effects/genetics

@article {pmid40213632,
year = {2025},
author = {Dezawa, M},
title = {Macrophage- and pluripotent-like reparative Muse cells are unique endogenous stem cells distinct from other somatic stem cells.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {13},
number = {},
pages = {1553382},
pmid = {40213632},
issn = {2296-4185},
abstract = {Muse cells are endogenous reparative stem cells with dual characteristics: pluripotent-like and macrophage-like. They can be identified by the pluripotent surface marker stage-specific embryonic antigen-3-positive (SSEA-3 (+)) cells in the bone marrow, peripheral blood, and various organs, including the umbilical cord and amnion. Muse cells can differentiate into ectodermal, endodermal, and mesodermal lineage cells, self-renew, and selectively migrate to damaged sites by sensing one of the universal tissue damage signals, sphingosine-1-phosphate (S1P). At these sites, they phagocytose damaged/apoptotic cells and differentiate into the same cell type as the phagocytosed cells. In this manner, Muse cells replace damaged/apoptotic cells with healthy, functioning cells, thereby repairing tissues. Due to their specific immunosuppressive and immunotolerant mechanism, clinical trials have been conducted for acute myocardial infarction (AMI), subacute ischemic stroke, epidermolysis bullosa, amyotrophic lateral sclerosis (ALS), cervical spinal cord injury, neonatal hypoxic-ischemic encephalopathy (HIE), and COVID-19 acute respiratory distress syndrome. These trials involved the intravenous injection of ∼1.5 × 10[7] donor Muse cells without human leukocyte antigen (HLA) matching or immunosuppressant treatment, and they demonstrated safety and therapeutic efficacy. Thus, donor Muse cell treatment does not require gene manipulation, differentiation induction, or surgical intervention. These unique characteristics distinguish Muse cells from other somatic stem cells, such as mesenchymal stem cells, VSEL stem cells, and marrow-isolated adult multi-lineage inducible (MIAMI) cells.},
}

@article {pmid40209696,
year = {2025},
author = {Hawas, Y and Hamad, AA and Meshref, M and Elbehary, M and Mohamed, RG and Elshahat, A and Mabrouk, MA and Nashwan, AJ and Fouda, BH},
title = {Clinical Features, Diagnostic Implications, And Outcomes of Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Systematic Review.},
journal = {Medical principles and practice : international journal of the Kuwait University, Health Science Centre},
volume = {},
number = {},
pages = {1-18},
doi = {10.1159/000545806},
pmid = {40209696},
issn = {1423-0151},
abstract = {OBJECTIVE: This review aims to summarize the current evidence of reported myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) overlap syndrome regarding clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision.

METHODS: Recently, a few cases of an unusual association between both diseases have been reported. PubMed, Scopus, and Web of Science were searched from inception until May 2024 to identify eligible studies. After the screening and data extraction, 20 studies with 42 cases suffering from ALS and MG were included.

RESULTS: 42 cases were categorized into four groups as follows: The first group had 26 cases with MG onset (range 26-82 years) preceding ALS (range 46-83 years). The second group had 9 cases with ALS (range 34-89) preceding MG (range 40-89 years). The third group comprised 5 cases of ALS with positive acetylcholine receptor antibodies but without clinical manifestations of MG. The fourth group involved 2 cases of ALS with initial ocular symptoms that were unresponsive to MG treatments.

CONCLUSION: The onset of new ptosis or diplopia in ALS patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment.},
}

@article {pmid40209306,
year = {2025},
author = {Meanti, R and Bresciani, E and Rizzi, L and Molteni, L and Coco, S and Omeljaniuk, RJ and Torsello, A},
title = {Cannabinoid Receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {186},
number = {},
pages = {118044},
doi = {10.1016/j.biopha.2025.118044},
pmid = {40209306},
issn = {1950-6007},
abstract = {The endocannabinoid system (ECS) is a ubiquitous physiological system that plays a crucial role in maintaining CNS homeostasis and regulating its functions. It includes cannabinoid receptors (CBRs), endogenous cannabinoids (eCBs), and the enzymes responsible for their synthesis and degradation. In recent years, growing evidence has highlighted the therapeutic potential of the ECS and CBRs, in a wide range of severe diseases and pathological conditions, including Alzheimer's and Parkinson's diseases, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington's Disease, HIV-1 associated neurocognitive disorders, neuropathic pain and migraine. Targeting the cannabinoid type 2 receptor (CB2R) has gained attention due to its ability to (i) mitigate neuroinflammatory responses, (ii) regulate mitochondrial function and (iii) provide trophic support, all without eliciting the psychotropic actions associated with CB1R activation. This review aims to explore the potential of CB2R modulation as a strategy for the prevention and treatment of neurologic disorders, exploring both preclinical and clinical findings.},
}

@article {pmid40205152,
year = {2025},
author = {Mohan, M and Mannan, A and Singh, TG},
title = {Unravelling the role of protein kinase R (PKR) in neurodegenerative disease: a review.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {377},
pmid = {40205152},
issn = {1573-4978},
mesh = {Humans ; *eIF-2 Kinase/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Parkinson Disease/metabolism/genetics ; Huntington Disease/genetics/metabolism ; Alzheimer Disease/metabolism/genetics ; Mitochondria/metabolism ; },
abstract = {Protein Kinase R is an essential regulator of many cell activities and belongs to one of the largest and most functionally complex gene families. These are found all over the body, and by adding phosphate groups to the substrate proteins, they regulate their activity and coordinate the action of almost all cellular processes. Recent research has illuminated the involvement of PKR in the pathogenesis of neurodegenerative disorders (NDs), thereby expanding our understanding of intricate molecular mechanisms underlying disease progression. Through their inhibition or activation, they hold potential therapeutic targets for the pathogenesis or protection of NDs. In the case of AD (AD), PKR contributes to the protection or elevation of Aβ accumulation, neuroinflammation, synaptic plasticity alterations, and neuronal excitability. Similarly, in Parkinson's disease (PD), PKR again has a dual role in dopaminergic neuronal loss, gene mutations, and mitochondrial dysfunction via various pathways. Notably, neuronal excitotoxicity, as well as genetic mutations, have been linked to ALS. In Huntington's disease (HD), PKR is associated with decreased or increased mutated genes, striatal neuron degeneration, neuroinflammation, and excitotoxicity. This review emphasizes strategies that target PKR for the treatment of neurodegenerative disorders. Doing so offers valuable insights that can guide future research endeavors and the development of innovative therapeutic approaches.},
}

Humans
*eIF-2 Kinase/metabolism/genetics
*Neurodegenerative Diseases/metabolism/genetics
Animals
Parkinson Disease/metabolism/genetics
Huntington Disease/genetics/metabolism
Alzheimer Disease/metabolism/genetics
Mitochondria/metabolism

@article {pmid40200577,
year = {2025},
author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Perez, KD and Li, D and Cheung, VG and Grunseich, C},
title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.},
journal = {HGG advances},
volume = {},
number = {},
pages = {100435},
doi = {10.1016/j.xhgg.2025.100435},
pmid = {40200577},
issn = {2666-2477},
abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope-tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels while having minimal effect on the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference.},
}

@article {pmid40198473,
year = {2025},
author = {Seok, HY},
title = {Critical issues in the use of edaravone for the treatment of amyotrophic lateral sclerosis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40198473},
issn = {1590-3478},
abstract = {Edaravone, along with riluzole, is a key treatment for amyotrophic lateral sclerosis (ALS), with evidence supporting its efficacy in slowing disease progression, particularly in patients with early-stage ALS. Despite its approval and increasing clinical use, several critical questions about its use remain unanswered: Can edaravone be effective as monotherapy? Is it beneficial for patients who fall outside the inclusion criteria of pivotal trials? What is the optimal duration of treatment as ALS progresses? In addition, does edaravone provide clinical benefit to patients with familial ALS? Answering these questions is essential to optimize the use of edaravone in clinical practice and to further our understanding of its role in the treatment of ALS. This review synthesizes the current evidence to address these questions and identifies areas that require further investigation.},
}

@article {pmid40196899,
year = {2025},
author = {Li, S and Pandat, T and Chi, B and Moon, D and Mas, M},
title = {Management Approaches to Spastic Gait Disorders.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28402},
pmid = {40196899},
issn = {1097-4598},
abstract = {Spastic gait presents clinically as the net mechanical consequence of neurological impairments of spasticity, weakness, and abnormal synergies and their interactions with the ground reaction force in patients with upper motor neuron syndromes and with some neuromuscular diseases. It is critical to differentiate whether the primary problem is weakness or spasticity, thus better understanding different phenotypes of spastic gait disorders. Pelvic girdle abnormality plays a pivotal role in determining the clinical presentation of gait disorders, since it determines the body vector and compensatory kinetic chain reactions in the knee and ankle joints. Knee joint abnormality can be a mechanical compensation for hip and/or ankle and foot abnormality. Diagnostic nerve blocks and instrumented gait analysis may be needed for diagnosing the underlying problems and developing an individualized plan of care. A wide spectrum of treatment options has been used to manage spastic gait disorders. Some are in early and investigational stages, such as neuromodulation modalities, while others are well-developed, such as therapeutic exercise, ankle-foot orthoses, botulinum toxin treatment, and surgical interventions. Physicians and other healthcare providers who manage spastic gait disorders should be familiar with these treatment options and should employ appropriate interventions concurrently rather than serially. The most effective treatments can be selected based on careful evaluation, inputs from patients, family, and therapists, along with appropriate goal setting. Treatment plans need to be re-evaluated for effectiveness, relevance, and in concordance with disease progress. This is particularly important for patients with progressive neuromuscular diseases such as amyotrophic lateral sclerosis.},
}

@article {pmid40196013,
year = {2025},
author = {Viteri, JA and Kerr, NR and Brennan, CD and Kick, GR and Wang, M and Ketabforoush, A and Snyder, HK and Moore, PJ and Darvishi, FB and Dashtmian, AR and Ayyagari, SN and Rich, K and Zhu, Y and Arnold, WD},
title = {Targeting senescence in Amyotrophic Lateral Sclerosis: senolytic treatment improves neuromuscular function and preserves cortical excitability in a TDP-43Q331K mouse model.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6081213/v1},
pmid = {40196013},
issn = {2693-5015},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron degeneration in the primary motor cortex (PMC) and spinal cord. Aging is a key factor in ALS onset and progression, with evidence suggesting that biological aging-a process involving cellular decline- far outpaces chronological aging in ALS. This promotes senescent cell accumulation-marked by irreversible cell-cycle arrest, impaired apoptosis, and chronic inflammation-disrupting tissue homeostasis and impairing neuronal support functions. Thus, targeting senescence presents a novel therapeutic strategy for ALS. Here, we investigated the senolytic combination Dasatinib and Quercetin (D&Q) in TDP-43 [Q331K] ALS mice. D&Q improved neuromuscular function and reduced plasma neurofilament light chain, a biomarker of axonal damage. The most pronounced improvement was the improved cortical excitability, accompanied by reductions in senescence and TDP-43 in the PMC. These findings highlight the potential of senolytics to mitigate ALS-related dysfunction, supporting their viability as a therapeutic strategy. *Jose A. Viteriab, Nathan R. Kerrab, and Charles D. Brennana are co-first authors.},
}

@article {pmid40188375,
year = {2025},
author = {Prajapati, JL and Dhurandhar, Y and Singh, AP and Gupta, DK and Baghel, VS and Kushwaha, U and Namdeo, KP},
title = {Redox chemical delivery system: an innovative strategy for the treatment of neurodegenerative diseases.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2025.2489558},
pmid = {40188375},
issn = {1744-7593},
abstract = {INTRODUCTION: It is anticipated that the prevalence of illnesses affecting the central nervous system (CNS) will rise significantly due to longer lifespans and changing demography. Age-related decline in brain function and neuronal death are features of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, which provide formidable treatment challenges. Because most therapeutic drugs cannot pass across the blood-brain barrier (BBB) to reach the brain, there are still few treatment alternatives available despite a great deal of research.

AREAS COVERED: This study explores the role of redox chemical delivery systems in CNS drug delivery and addresses challenges associated with neurodegenerative disease (ND). Redox Chemical Delivery System offers a promising approach to enhancing leveraging redox reactions that facilitate the transport of therapeutic agents across the BBB. Through the optimization of medication delivery pathways to the brain, this technology has the potential to greatly improve the treatment of ND.

EXPERT OPINION: As our understanding of the biological underpinnings of ND deepens, the potential for effective interventions increases. Refining drug delivery strategies, such as RCDS, is essential for advancing CNS therapies from research to clinical practice. These advancements could transform the management of ND, improving both treatment efficacy and patient outcomes.},
}

@article {pmid40187044,
year = {2025},
author = {Fu, Y and Zhang, J and Qin, R and Ren, Y and Zhou, T and Han, B and Liu, B},
title = {Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.},
journal = {Pharmacological reviews},
volume = {77},
number = {3},
pages = {100053},
doi = {10.1016/j.pharmr.2025.100053},
pmid = {40187044},
issn = {1521-0081},
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.},
}

@article {pmid40185536,
year = {2025},
author = {Uzgiris, AJ and Ladic, LA and Pfister, SX},
title = {Advances in neurofilament light chain analysis.},
journal = {Advances in clinical chemistry},
volume = {126},
number = {},
pages = {31-71},
doi = {10.1016/bs.acc.2025.01.006},
pmid = {40185536},
issn = {2162-9471},
mesh = {*Neurofilament Proteins/analysis ; Humans ; Biomarkers/analysis ; *Nervous System Diseases/diagnosis/metabolism ; },
abstract = {This chapter provides a comprehensive summary of clinical laboratory testing for neurofilament light chain (NfL) in neurologic disease. A primer on the NfL structure and function is presented with its potential use as a biomarker. The most widely utilized methods for NfL in biologic samples are highlighted and examined. Limitations of current knowledge are considered, as are outstanding questions related to dissemination and standardization of testing. Herein we focus on methods available today and those in development for clinical use. In the final section, a broad vision is presented of how NfL may be utilized in the future to improve diagnosis and treatment of neurologic diseases as well as for maintaining health.},
}

*Neurofilament Proteins/analysis
Humans
Biomarkers/analysis
*Nervous System Diseases/diagnosis/metabolism

@article {pmid40181198,
year = {2025},
author = {Manolopoulos, A and Yao, PJ and Kapogiannis, D},
title = {Extracellular vesicles: translational research and applications in neurology.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {40181198},
issn = {1759-4766},
abstract = {Over the past few decades, extensive basic, translational and clinical research has been devoted to deciphering the physiological and pathogenic roles of extracellular vesicles (EVs) in the nervous system. The presence of brain cell-derived EVs in the blood, carrying diverse cargoes, has enabled the development of predictive, diagnostic, prognostic, disease-monitoring and treatment-response biomarkers for various neurological disorders. In this Review, we consider how EV biomarkers can bring us closer to understanding the complex pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis and multiple sclerosis. We describe how translational research on EVs might unfold bidirectionally, proceeding from basic to clinical studies but also in the opposite direction, with biomarker findings in the clinic leading to novel hypotheses that can be tested in the laboratory. We demonstrate the potential value of EVs across all stages of the therapeutic development pipeline, from identifying therapeutic targets to the use of EVs as reporters in model systems and biomarkers in clinical research. Finally, we discuss how the cargo and physicochemical properties of naturally occurring and custom-engineered EVs can be leveraged as novel treatments and vehicles for drug delivery, potentially revolutionizing neurotherapeutics.},
}

@article {pmid40180646,
year = {2025},
author = {Temiz, K and Gul, A and Gov, E},
title = {5-Repurposed Drug Candidates Identified in Motor Neurons and Muscle Tissues with Amyotrophic Lateral Sclerosis by Network Biology and Machine Learning Based on Gene Expression.},
journal = {Neuromolecular medicine},
volume = {27},
number = {1},
pages = {24},
pmid = {40180646},
issn = {1559-1174},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Humans ; *Machine Learning ; *Motor Neurons/metabolism/drug effects ; *Drug Repositioning/methods ; Transcriptome ; Gene Expression Profiling ; *Muscle, Skeletal/metabolism ; Gene Regulatory Networks ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to motor neuron degeneration, muscle weakness, and respiratory failure. Despite ongoing research, effective treatments for ALS are limited. This study aimed to apply network biology and machine learning (ML) techniques to identify novel repurposed drug candidates for ALS. In this study, we conducted a meta-analysis using 4 transcriptome data in ALS patients (including motor neuron and muscle tissue) and healthy controls. Through this analysis, we uncovered common shared differentially expressed genes (DEGs) separately for motor neurons and muscle tissue. Using common DEGs as proxies, we identified two distinct clusters of highly clustered differential co-expressed cluster genes: the 'Muscle Tissue Cluster' for muscle tissue and the 'Motor Neuron Cluster' for motor neurons. We then evaluated the performance of the nodes of these two modules to distinguish between diseased and healthy states with ML algorithms: KNN, SVM, and Random Forest. Furthermore, we performed drug repurposing analysis and text-mining analyses, employing the nodes of clusters as drug targets to identify novel drug candidates for ALS. The potential impact of the drug candidates on the expression of cluster genes was predicted using linear regression, SVR, Random Forest, Gradient Boosting, and neural network algorithms. As a result, we identified five novel drug candidates for the treatment of ALS: Nilotinib, Trovafloxacin, Apratoxin A, Carboplatin, and Clinafloxacin. These findings highlight the potential of drug repurposing in ALS treatment and suggest that further validation through experimental studies could lead to new therapeutic avenues.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/genetics
Humans
*Machine Learning
*Motor Neurons/metabolism/drug effects
*Drug Repositioning/methods
Transcriptome
Gene Expression Profiling
*Muscle, Skeletal/metabolism
Gene Regulatory Networks

@article {pmid40176466,
year = {2025},
author = {Zhang, Y and Robinson, K and Xia, Y and Sun, J},
title = {Synergistic Effects of Riluzole and Sodium Butyrate on Barrier Function and Disease Progression of Amyotrophic Lateral Sclerosis Through the Gut-Neuron Axis.},
journal = {Comprehensive Physiology},
volume = {15},
number = {2},
pages = {e70009},
pmid = {40176466},
issn = {2040-4603},
support = {R01DK114126/NH/NIH HHS/United States ; R01DK105118/NH/NIH HHS/United States ; R01DK134343/NH/NIH HHS/United States ; I01BX004824-06//U.S. Department of Veterans Affairs/ ; },
mesh = {Animals ; *Riluzole/pharmacology/therapeutic use/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Mice ; *Butyric Acid/pharmacology/therapeutic use ; Disease Progression ; *Neuroprotective Agents/pharmacology ; Male ; Mice, Transgenic ; Drug Synergism ; Disease Models, Animal ; *Neurons/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; },
abstract = {Emerging evidence has shown that gut-brain barrier dysfunction occurs at the early stages of ALS. Previous studies demonstrated that sodium butyrate significantly prolonged the life span of ALS mice. Riluzole is the first FDA-approved drug for ALS treatment. We hypothesize that Riluzole and sodium butyrate combined treatment further decreases aggregation of the h-SOD1[G93A], restores the gut-brain barrier function, and delays ALS progression. SOD1[G93A] mice (9-10-week-old) were treated with Riluzole (10 mg/kg, I.P. daily), sodium butyrate (2% in drinking water), or Riluzole and sodium butyrate combination for 6 weeks. The Riluzole/butyrate combination showed a significantly longer rotarod time, increased grip strength, and enhanced intestinal barrier, as compared with Riluzole or sodium butyrate-only treatment. More reduction of h-SOD1[G93A] aggregation was observed in the colon, spinal cord lumbar, and brain cortex with Riluzole and sodium butyrate combination, compared with Riluzole or sodium butyrate-only treatment. Tight junction proteins (ZO-1 and Claudin-5) significantly increased in the colon, spinal cord lumbar, and brain cortex of mice with Riluzole and sodium butyrate treatment. The Riluzole and sodium butyrate combination reduced serum lipopolysaccharides and h-SOD1[G93A] aggregation, and inflammatory cytokines more than those in Riluzole or sodium butyrate-only treatment. Overall, Riluzole and sodium butyrate treatment is more effective than either Riluzole or sodium butyrate-only in delaying ALS progress. It provides a potential therapeutic strategy and mechanism by restoring barrier function through the gut-brain axis for ALS.},
}

Animals
*Riluzole/pharmacology/therapeutic use/administration & dosage
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology
Mice
*Butyric Acid/pharmacology/therapeutic use
Disease Progression
*Neuroprotective Agents/pharmacology
Male
Mice, Transgenic
Drug Synergism
Disease Models, Animal
*Neurons/drug effects
Superoxide Dismutase-1/genetics/metabolism

@article {pmid40170672,
year = {2025},
author = {Schneck, D and Arguedas, A and Xenopoulos-Oddsson, A and Arcila-Londono, X and Lunetta, C and Wymer, J and Olney, N and Gwathmey, K and Ajroud-Driss, S and Hayat, G and Heiman-Patterson, T and Cerri, F and Fournier, C and Glass, J and Sherman, A and Fiecas, M and Walk, D},
title = {Time-to-event prediction in ALS using a landmark modeling approach, using the ALS Natural History Consortium dataset.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2482943},
pmid = {40170672},
issn = {2167-9223},
abstract = {BACKGROUND AND OBJECTIVES: Times to clinically relevant events are a valuable outcome in observational and interventional studies, complementing linear outcomes such as functional rating scales and biomarkers. In ALS, there are several clinically relevant events. We developed dynamic prediction models for several of these times to events that can be used for clinical trial modeling and personal planning.

METHODS: Landmark time-to-event analysis was implemented to determine the effect of patient characteristics on disease progression. Longitudinal data from 1557 participants in the ALS Natural History Consortium dataset were used. Five outcomes in the ALS disease progression were considered: loss of ambulation, loss of speech, gastrostomy, noninvasive ventilation (NIV) use, and continuous NIV use. Covariates in our models include age at diagnosis, sex, onset location, riluzole use, diagnostic delay, ALSFRS-R scores at the landmark time, and ALSFRS-R rates of change from baseline. Internal and external validation techniques were used.

RESULTS: For each of our models and landmark times, we present risk prediction intervals for random sets of patient characteristics. We demonstrate our models' application for an individual's personal predicted time-to-event. Our internal and external validation metrics indicate good concordance and overall performance. The time to loss of speech models perform the best for each metric in terms of both internal and external validation.

DISCUSSION: Landmarking is an efficient, individualized risk prediction model that is intuitive for both clinicians and patients. Importantly, landmarking can be used for clinical trial modeling, personal planning, and development of real-world evidence of the impacts of treatment interventions.},
}

@article {pmid40169784,
year = {2025},
author = {Simonini, C and Zucchi, E and Martinelli, I and Gianferrari, G and Lunetta, C and Sorarù, G and Trojsi, F and Pepe, R and Piras, R and Giacchino, M and Banchelli, F and Mandrioli, J},
title = {Neurodegenerative and neuroinflammatory changes in SOD1-ALS patients receiving tofersen.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {11034},
pmid = {40169784},
issn = {2045-2322},
support = {Ricerca Corrente funding scheme of the Italian Ministry of Health//Ministero della Salute/ ; Ricerca Finalizzata bando 2021 (RF-2021-12373036)//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project)//Università Degli Studi di Modena e Reggio Emila/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; },
mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid ; Middle Aged ; *Neurofilament Proteins/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid ; *Superoxide Dismutase-1 ; *alpha 1-Antitrypsin/blood ; Disease Progression ; Aged ; Adult ; Chitinase-3-Like Protein 1/blood/cerebrospinal fluid ; Neuroinflammatory Diseases/drug therapy ; },
abstract = {The initiation of tofersen, a new specific antisense oligonucleotide (ASO) for SOD1 pathology, marked a significant turning point for SOD1-ALS patients. While clinical trials and early access program studies reported a significant reduction in plasma and cerebrospinal fluid (CSF) neurofilament levels, neuroinflammation following prolonged treatment was never assessed. In this multicenter study, we evaluated a cohort of 18 SOD1-ALS patients treated with tofersen, analyzing correlations between biomarkers of neurodegeneration/neuroinflammation and clinical variables indicative of disease progression. NfL, NfH, CHI3L1, and Serpina1 levels in serum and CSF were determined by semi-automated immunoassays (Ella™ technology). Generalized linear mixed models were employed to investigate longitudinal trends of these biomarkers. Our data highlighted a progressive decrease in CSF neurofilament levels during tofersen treatment (MR = 0.97, 95% CI 0.94-0.99, p = 0.006 and MR = 0.98, 95% CI 0.95-1.00, p = 0.076 for NfL and NfH in CSF, respectively). Conversely, CSF levels of SerpinA1 and CHI3L1 increased over time (MR = 1.12, 95% CI 1.08-1.16, p < 0.0001 and MR = 1.039, 95% CI 1.015-1.062, p = 0.001 for SerpinA1 and CHI3L1 in CSF, respectively), but these modifications were most apparent after six and twelve months of therapy, respectively. Disease progression rate did not correlate with these biomarker trends. We observed a significant decrease in neurofilament levels during Tofersen treatment, alongside an increase in neuroinflammatory markers, potentially linked to an immune response triggered by ASO treatment. Given the limited data on tofersen's long-term efficacy in ALS due to its recent introduction, identifying biomarkers that predict clinical outcomes such as diminished therapeutic response or adverse effects is crucial. These biomarkers may help to better understand the underlying pathomechanisms of ALS and tofersen's role in modulating disease progression.},
}

Humans
Male
Female
*Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid
Middle Aged
*Neurofilament Proteins/cerebrospinal fluid/blood
*Biomarkers/blood/cerebrospinal fluid
*Superoxide Dismutase-1
*alpha 1-Antitrypsin/blood
Disease Progression
Aged
Adult
Chitinase-3-Like Protein 1/blood/cerebrospinal fluid
Neuroinflammatory Diseases/drug therapy

@article {pmid40169538,
year = {2025},
author = {Iyer, KA and Tenchov, R and Sasso, JM and Ralhan, K and Jotshi, J and Polshakov, D and Maind, A and Zhou, QA},
title = {Rare Diseases, Spotlighting Amyotrophic Lateral Sclerosis, Huntington's Disease, and Myasthenia Gravis: Insights from Landscape Analysis of Current Research.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.4c00722},
pmid = {40169538},
issn = {1520-4995},
abstract = {Rare diseases are a diverse group of disorders that, despite each individual condition's rarity, collectively affect a significant portion of the global population. Currently approximately 10,000 rare diseases exist globally, with 80% of these diseases being identified as having genetic origins. In this Review, we examine data from the CAS Content Collection to summarize scientific progress in the area of rare diseases. We examine the publication landscape in the area in an effort to provide insights into current advances and developments. We then discuss the evolution of key concepts in the field, genetic associations, as well as the major technologies and development pipelines of rare disease treatments. We focus our attention on three specific rare diseases: (i) amyotrophic lateral sclerosis, a terminal neurodegenerative disease affecting the central nervous system resulting in progressive loss of motor neurons that control voluntary muscles; (ii) Huntington's disease, another terminal neurodegenerative disease that causes progressive degeneration of nerve cells in the brain, with a wide impact on a person's functional abilities; and (iii) myasthenia gravis, a chronic autoimmune synaptopathy leading to skeletal muscle weakness. While the pathogenesis of these rare diseases is being elucidated, there is neither a cure nor preventative treatment available, only symptomatic treatment. The objective of the paper is to provide a broad overview of the evolving landscape of current knowledge on rare diseases and specifically on the biology and genetics of the three spotlighted diseases, to outline challenges and evaluate growth opportunities, an aim to further efforts in solving the remaining challenges.},
}

@article {pmid40169452,
year = {2025},
author = {Hou, X and Jiang, J and Deng, M},
title = {Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {272},
number = {4},
pages = {304},
pmid = {40169452},
issn = {1432-1459},
support = {82273915//National Natural Science Foundation of China/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *Epigenesis, Genetic ; *Biomarkers/metabolism ; DNA Methylation ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. Whole-genome sequencing has identified many novel ALS-associated genes, but genetics alone cannot fully explain the onset of ALS and an effective treatment is still lacking. Moreover, we need more biomarkers for accurate diagnosis and assessment of disease prognosis. Epigenetics, which includes DNA methylation and hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs, influences gene transcription and expression by affecting chromatin accessibility and transcription factor binding without altering genetic information. These processes play a role in the onset and progression of ALS. Epigenetic targets can serve as potential biomarkers and more importantly, the reversibility of epigenetic changes supports their potential role as versatile therapeutic targets in ALS. This review summarized the alterations in different epigenetic modulations in ALS. Additionally, given the close association between aberrant metabolic profiles characterized by hypoxia and high glycolytic metabolism in ALS and epigenetic changes, we also integrate epigenetics with metabolomics. Finally, we discuss the application of therapies based on epigenetic mechanisms in ALS. Our data integration helps to identify potential diagnostic and prognostic biomarkers and support the development of new effective therapies.},
}

*Amyotrophic Lateral Sclerosis/genetics/diagnosis
Humans
*Epigenesis, Genetic
*Biomarkers/metabolism
DNA Methylation
Animals

@article {pmid40166719,
year = {2025},
author = {Xiong, J and Chen, X and Huang, K and Pan, Y},
title = {Successful Guselkumab Treatment in a Patient with Comorbid Psoriasis and Amyotrophic Lateral Sclerosis: A Case Study and Literature Review.},
journal = {Clinical, cosmetic and investigational dermatology},
volume = {18},
number = {},
pages = {735-741},
pmid = {40166719},
issn = {1178-7015},
abstract = {Psoriasis is genetically influenced and can be triggered by factors such as infections, stress, and lifestyle. Chronic plaque psoriasis, the most prevalent form, involves key roles for IL-17 and IL-23 in its pathogenesis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness and atrophy. Currently, there is no cure for ALS, and treatment is symptomatic, aimed at improving quality of life. The combination of psoriasis and ALS is relatively rare. Although biologic agents have shown remarkable efficacy in the treatment of chronic plaque psoriasis, we have not found any case reports regarding the use of biologic agents for treating psoriasis accompanied by ALS. Our study presents a patient with severe plaque psoriasis and ALS who exhibited a positive response to Guselkumab, without worsening of ALS symptoms, suggesting a promising therapeutic strategy. This could provide a treatment option for patients with psoriasis combined with ALS.We conducted a comprehensive review of the literature on the comorbidity of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ALS, with plaque psoriasis. This review highlights the differential impact of treatment modalities. Specifically, we found that TNF-α inhibitors may have adverse effects in MS but could provide protective benefits in AD and PD. In ALS patients with psoriasis, IL-17A and IL-23 inhibitors, exemplified by Guselkumab, are suggested as a more suitable alternative due to their lower risk of worsening ALS symptoms.},
}

@article {pmid40163151,
year = {2025},
author = {Wadan, AS and Shaaban, AH and El-Sadek, MZ and Mostafa, SA and Moshref, AS and El-Hussein, A and Ellakwa, DE and Mehanny, SS},
title = {Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {40163151},
issn = {1432-1912},
abstract = {Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.},
}

@article {pmid40162390,
year = {2025},
author = {Xie, Y and Xie, H and Wang, RL},
title = {Enhancing palliative care in malignant obstructive jaundice: A critical care perspective on endoscopic biliary stenting.},
journal = {World journal of gastrointestinal surgery},
volume = {17},
number = {3},
pages = {103431},
pmid = {40162390},
issn = {1948-9366},
abstract = {This letter responds to Wang et al's recent publication on endoscopic biliary stenting for malignant obstructive jaundice (MOJ) by offering constructive feedback and suggestions for future research. We commend the authors for their comprehensive study design and execution, which included a clear delineation of study groups and a robust set of outcome measures. We suggest that future studies incorporate additional biomarkers, such as serum levels of liver enzymes and bilirubin, to provide a more nuanced understanding of liver function changes post-intervention. The study's focus on short-term survival rates is appreciated, but we recommend exploring longer-term follow-up periods to capture the full spectrum of survival outcomes. Additionally, the inclusion of quality of life assessments using validated instruments could offer a more holistic view of patient outcomes. From a critical care perspective, we advocate for the integration of advanced imaging techniques to better characterize biliary anatomy and potentially predict treatment response or complications. We believe that incorporating these suggestions could enhance the understanding of endoscopic biliary stenting's role in MOJ management and its impact on patient outcomes, influencing future clinical guidelines and practice.},
}

@article {pmid40161216,
year = {2025},
author = {Scarcella, S and Brambilla, L and Quetti, L and Rizzuti, M and Melzi, V and Galli, N and Sali, L and Costamagna, G and Comi, GP and Corti, S and Gagliardi, D},
title = {Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics.},
journal = {Brain communications},
volume = {7},
number = {2},
pages = {fcaf114},
pmid = {40161216},
issn = {2632-1297},
abstract = {Amyotrophic lateral sclerosis is the most common motor neuron disease and manifests as a clinically and genetically heterogeneous neurodegenerative disorder mainly affecting the motor systems. To date, despite promising results and accumulating knowledge on the pathomechanisms of amyotrophic lateral sclerosis, a specific disease-modifying treatment is still not available. In vitro and in vivo disease models coupled with multiomics techniques have helped elucidate the pathomechanisms underlying this disease. In particular, omics approaches are powerful tools for identifying new potential disease biomarkers that may be particularly useful for diagnosis, prognosis and assessment of treatment response. In turn, these findings could support physicians in stratifying patients into clinically relevant subgroups for the identification of the best therapeutic targets. Here, we provide a comprehensive review of the most relevant literature highlighting the importance of proteomics approaches in determining the role of pathogenic misfolded/aggregated proteins and the molecular mechanisms involved in the pathogenesis and progression of amyotrophic lateral sclerosis. In addition, we explored new findings arising from metabolomic and lipidomic studies, which can aid to elucidate the intricate metabolic alterations underlying amyotrophic lateral sclerosis pathology. Moreover, we integrated these insights with microbiomics data, providing a thorough understanding of the interplay between metabolic dysregulation and microbial dynamics in disease progression. Indeed, a greater integration of these multiomics data could lead to a deeper understanding of disease mechanisms, supporting the development of specific therapies for amyotrophic lateral sclerosis.},
}

@article {pmid40157434,
year = {2025},
author = {Pu, L and Steele, JR and Phillips, CR and Violi, JP and Rodgers, KJ},
title = {The cyanobacterial toxins BMAA and 2,4-DAB perturb the l-serine biosynthesis pathway and induce systemic changes in energy metabolism in human neuroblastoma cells: A proteomic study.},
journal = {Toxicology in vitro : an international journal published in association with BIBRA},
volume = {106},
number = {},
pages = {106058},
doi = {10.1016/j.tiv.2025.106058},
pmid = {40157434},
issn = {1879-3177},
abstract = {Blue-green algae (cyanobacteria), an ancient phylum of bacteria, produce a wide array of secondary metabolites that are toxic to humans. Rapid growth of cyanobacteria in an aquatic environment can result in algal blooms capable of turning waterways green and increasing toxin levels in the environment. Cyanobacterial toxins were first linked to the high incidence of a complex neurodegenerative disorder reported on the island of Guam in the 1940s but more recently have been linked to clusters of sporadic amyotrophic lateral sclerosis (sALS) worldwide. The non-protein amino acid β-N-methylamino-L-alanine (BMAA) and its isomer L-2,4-diaminobutyric acid (2,4-DAB) are produced concurrently by most cyanobacterial species. We carried out proteomic analysis on human neuroblastoma cells treated with BMAA and 2,4-DAB to determine the underlying mechanisms of toxicity resulting from exposure to these cyanotoxins and identified significant changes in the l-serine biosynthesis pathway as well as pathways associated with energy production in the cell such as fatty acid ß-oxidation and glycolysis. The impact on the serine biosynthetic pathway was supported by demonstrating a significant decrease in both mRNA and protein levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH) the first committed step in serine biosynthesis. PHGDH uses 3-phospho-D-glycerate (3PG) an intermediate in the glycolytic pathway as a substrate, and co-incubation of cells with l-serine restored expression levels of PHGDH as did cell pre-treatment with the glycolytic product pyruvate. This is the first study to link exposure to BMAA and 2,4-DAB to impairments in the l-serine biosynthesis pathway and broad disturbances in energy metabolism.},
}

@article {pmid40153582,
year = {2025},
author = {Norata, D and Capone, F and Motolese, F and Marano, M and Rossi, M and Calandrelli, R and Sacchetti, M and Mantelli, F and Di Lazzaro, V and Pilato, F},
title = {1953-2023. Seventy Years of the Nerve Growth Factor: A Potential Novel Treatment in Neurological Diseases?.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2024.0573},
pmid = {40153582},
issn = {2152-5250},
abstract = {Rita Levi-Montalcini's 1953 discovery of nerve growth factor (NGF) in mouse sarcoma tumors marked a groundbreaking moment in neuroscience. NGF, a key signaling molecule, became the first identified neurotrophic factor, influencing the growth, differentiation, and survival of neurons in both peripheral and central nervous systems. NGF and related neurotrophic factors hold therapeutic potential for various neurological disorders, such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injuries, neuropathies, traumatic brain injuries, and stroke. However, despite promising in vitro studies and animal models findings, NGF efficacy in patients remains unproven. Indeed, its use as a therapeutic agent faces challenges in delivery and clinical translation. This review delves into these challenges, exploring ongoing research on refined delivery methods, dosages, and safety profiles. Innovative strategies, including molecular mimicking, combination therapies, gene therapy, and coupling with neuromodulation techniques like transcranial magnetic stimulation and vagal nerve stimulation, are discussed. Incorporating nerve growth factor (NGF) into a comprehensive strategy may prove beneficial, particularly in non-neurodegenerative conditions such as stroke, trauma, and neuropathies. In these instances, NGF holds promise for promoting tissue regeneration and repair. Challenges persist in addressing the complexity of neurodegenerative pathologies for a combined therapeutic approach.},
}

@article {pmid40151753,
year = {2025},
author = {Carqueja, I and Montenegro Sá, F and Monteiro, S},
title = {Ventricular Arrhythmias Caused by Left Main Coronary Artery Vasospasm: A Diagnostic Challenge in a Cardiac Arrest Victim.},
journal = {Cureus},
volume = {17},
number = {2},
pages = {e79554},
pmid = {40151753},
issn = {2168-8184},
abstract = {Sudden cardiac death (SCD) is a common cause of cardiovascular deaths. It may be caused by primary electrical diseases, cardiomyopathies, myocarditis, valvular heart diseases, or coronary artery disease (including acute coronary syndrome). Coronary artery vasospasm is defined as a transient total or subtotal coronary artery obstruction, associated with angina symptoms and ischemic findings on electrocardiogram (ECG). It is a cause of myocardial infarction, life-threatening arrhythmias, atrioventricular block, and SCD. A 55-year-old man presented to the hospital after an out-of-hospital cardiac arrest (OHCA). He had a previous history of cardiovascular risk factors, excessive alcohol intake, non-obstructive coronary artery disease, and paroxysmic atrial fibrillation. On the day of the OHCA, he had a sudden collapse while exercising, with ventricular fibrillation and return of spontaneous circulation (ROSC) after advanced life support (ALS). No ECG or echocardiographic anomalies were identified on hospital admission. The patient suffered three more episodes of cardiac arrest during the hospital stay, with atypical arrhythmic presentations. No ECG or echocardiographic abnormalities were observed after ROSC. The fourth cardiac arrest had concomitant segmental ST changes and de novoechocardiographic segmental motility abnormalities suggestive of left main coronary artery occlusion. These findings were transient, with a normal ECG and echocardiogram obtained one hour after ROSC. No electrolyte abnormalities or other causes of cardiac arrest were identified. The hypothesis of left main coronary vasospasm was raised as the likely diagnosis. Coronary artery vasospasm is a possible cause of major cardiac events. Diagnosis can be challenging due to the transient findings and varied manifestations, often in patients with normal coronary arteries. The correct diagnosis and treatment of coronary artery vasospasm can have a determinant effect on prognosis and mortality, as appropriate treatment can lead to prolonged event-free survival. Provocative coronary vasospasm tests performed in patients with atypical cardiovascular manifestations can allow for the timely diagnosis of vasospasm and avoid critical events. The authors aim to raise awareness of the different clinical presentations of coronary artery vasospasm and its consequences. The performance of provocative tests in selected patients should be considered to promote early diagnosis and potentially avoid major events.},
}

@article {pmid40151398,
year = {2025},
author = {Roy, SM and Acquarone, E and Argyrousi, EK and Zhang, H and Staniszewski, A and Inoue, A and Ziarek, JJ and Arancio, O and Watterson, DM},
title = {Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {1},
pages = {e70073},
pmid = {40151398},
issn = {2352-8737},
abstract = {INTRODUCTION: Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT2b receptor (5-HT2bR) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT2bR inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT2bR inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.

METHODS: Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT2bR activity and β-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT2bR agonist activity.

RESULTS: MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT2bR activity and β-arrestin-1 recruitment.

DISCUSSION: Selective inhibition of 5-HT2bR activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.

HIGHLIGHTS: A new highly selective 5-HT2bR antagonist, MW073, is described and used as a reference standard.MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes.Risperidone is a dose dependent inhibitor of 5-HT2bR activity and arrestin recruitment.},
}

@article {pmid40150989,
year = {2025},
author = {Matsumoto, S and Tateishi-Karimata, H and Ohyama, T and Sugimoto, N},
title = {Controlling the Local Conformation of RNA G-Quadruplex Results in Reduced RNA/Peptide Cytotoxic Accumulation Associated with C9orf72 ALS/FTD.},
journal = {Small methods},
volume = {},
number = {},
pages = {e2401630},
doi = {10.1002/smtd.202401630},
pmid = {40150989},
issn = {2366-9608},
abstract = {Repeat expansion of d(G4C2) in the noncoding region of the C9orf72 gene contributes to neurodegenerative diseases. The repeat expansion transcript r(G4C2) induces RNA/peptide accumulation, which, in turn, induces cytotoxicity and accelerates the development of neurodegenerative diseases. Such cytotoxic accumulation is triggered by peptide aggregation. Here, a technique is developed to prevent accumulation by regulating RNA interactions, assuming that RNA structure is important for peptide interactions. A screening method is used to identify compounds that suppress RNA accumulation of r(G4C2) repeats. The four compounds are identified with wide π-planes containing hydroxyl, methoxy, and cyclic ether groups that suppressed RNA accumulation. Interestingly, these compounds also suppressed RNA/peptide accumulation in neuroblastoma cells, indicating that RNA accumulation is a key regulator of RNA/peptide cytotoxic aggregate formation. In vitro and in silico physicochemical analyses reveal that these compounds bind to the loop region of the G-quadruplex via hydrogen bonds or CH-π interactions, resulting in an altered loop conformation. Importantly, these conformational changes inhibited RNA G-quadruplex associations. These results show that conformational changes are promising for controlling the interactions between G-quadruplexes and further RNA accumulation. These findings may be useful in the development of therapeutic strategies for the treatment of neurodegenerative diseases.},
}

@article {pmid40149599,
year = {2025},
author = {Yang, W and Xiao, W and Liu, X and Li, H and Huang, T and Fan, D},
title = {Testosterone Supplementation: A Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis.},
journal = {Biomedicines},
volume = {13},
number = {3},
pages = {},
pmid = {40149599},
issn = {2227-9059},
support = {82071426//National Natural Science Foundation of China/ ; },
abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by the degeneration of spinal cord and brain neurons. Proteomics combined with Mendelian randomization (MR) is an effective method for finding disease treatment targets. Methods: We aimed to seek new therapeutic targets for ALS. A large-scale GWAS on proteomics (4907 circulatory protein) with 35,559 individuals was included as the exposure data; a GWAS with 138,086 ALS patients was used as the outcome data; we found that a high level of sex hormone-binding globulin (SHBG) is a risk factor by MR analysis. Colocalization analyses were used to validate the causality between SHBG and ALS further. Functional enrichment found a high level of SHBG was associated with a low level of bioavailable testosterone. Two-sample MR confirmed the association of SHBG (400,210 samples), bioavailable testosterone (367,289 samples), and ALS. Results: A high level of SHBG, and a low level of bioavailable testosterone are risk factors for ALS. Conclusions: A low level of bioavailable testosterone is a risk factor for ALS. Although our study is relatively limited and cannot fully confirm that testosterone supplementation has a therapeutic effect on ALS, it offers a promising direction for ALS therapy.},
}

@article {pmid40148057,
year = {2025},
author = {De Marchi, F and Spinelli, EG and Bendotti, C},
title = {Neuroglia in neurodegeneration: Amyotrophic lateral sclerosis and frontotemporal dementia.},
journal = {Handbook of clinical neurology},
volume = {210},
number = {},
pages = {45-67},
doi = {10.1016/B978-0-443-19102-2.00004-1},
pmid = {40148057},
issn = {0072-9752},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/pathology ; *Neuroglia/pathology ; Animals ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases sharing significant pathologic and genetic overlap, leading to consider these diseases as a continuum in the spectrum of their pathologic features. Although FTD compromises only specific brain districts, while ALS involves both the nervous system and the skeletal muscles, several neurocentric mechanisms are in common between ALS and FTD. Also, recent research has revealed the significant involvement of nonneuronal cells, particularly glial cells such as astrocytes, oligodendrocytes, microglia, and peripheral immune cells, in disease pathology. This chapter aims to provide an extensive overview of the current understanding of the role of glia in the onset and advancement of ALS and FTD, highlighting the recent implications in terms of prognosis and future treatment options.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology
*Frontotemporal Dementia/pathology
*Neuroglia/pathology
Animals

@article {pmid40145977,
year = {2025},
author = {Zhao, W and Liu, Z and Wu, J and Liu, A and Yan, J},
title = {Potential targets of microglia in the treatment of neurodegenerative diseases: mechanism and therapeutic implications.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01343},
pmid = {40145977},
issn = {1673-5374},
abstract = {For diverse neurodegenerative disorders, microglial cells are activated. Furthermore, dysfunctional and hyperactivated microglia initiate mitochondrial autophagy, oxidative stress, and pathological protein accumulation, ending with neuroinflammation that exacerbates damage to dopaminergic neurons and contributes significantly to the pathology of neurodegenerative disorder. Microglial overactivation is closely associated with the secretion of pro-inflammatory cytokines, the phagocytosis of injured neurons, and the modulation of neurotoxic environments. This review summarizes the role of microglia neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, cortical degeneration, Lewy body dementia, and Huntington's disease. It also discusses novel forms of cell death such as ferroptosis, cuproptosis, disulfidptosis, and parthanatos (poly(adenosine diphosphate ribose) polymerase 1-dependent cell death), as well as the impact of regulatory factors related to microglial inflammation on microglial activation and neuroinflammation. The aim is to identify potential targets for microglial cell therapy in neurodegenerative diseases.},
}

@article {pmid40143051,
year = {2025},
author = {Zou, Y and Zhang, J and Chen, L and Xu, Q and Yao, S and Chen, H},
title = {Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles.},
journal = {Pharmaceutics},
volume = {17},
number = {3},
pages = {},
pmid = {40143051},
issn = {1999-4923},
support = {82100892//Hong Chen/ ; 82300929//Jing Zhang/ ; },
abstract = {Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood-brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases.},
}

@article {pmid40141987,
year = {2025},
author = {Russo, A and Putaggio, S and Tellone, E and Calderaro, A and Cirmi, S and Laganà, G and Ficarra, S and Barreca, D and Patanè, GT},
title = {Emerging Ferroptosis Involvement in Amyotrophic Lateral Sclerosis Pathogenesis: Neuroprotective Activity of Polyphenols.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {6},
pages = {},
pmid = {40141987},
issn = {1420-3049},
mesh = {*Ferroptosis/drug effects ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy/genetics ; *Polyphenols/pharmacology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Reactive Oxygen Species/metabolism ; Lipid Peroxidation/drug effects ; Oxidative Stress/drug effects ; Mitochondria/metabolism/drug effects ; Iron/metabolism ; },
abstract = {Neurodegenerative diseases are a group of diseases that share common features, such as the generation of misfolded protein deposits and increased oxidative stress. Among them, amyotrophic lateral sclerosis (ALS), whose pathogenesis is still not entirely clear, is a complex neurodegenerative disease linked both to gene mutations affecting different proteins, such as superoxide dismutase 1, Tar DNA binding protein 43, Chromosome 9 open frame 72, and Fused in Sarcoma, and to altered iron homeostasis, mitochondrial dysfunction, oxidative stress, and impaired glutamate metabolism. The purpose of this review is to highlight the molecular targets common to ALS and ferroptosis. Indeed, many pathways implicated in the disease are hallmarks of ferroptosis, a recently discovered type of iron-dependent programmed cell death characterized by increased reactive oxygen species (ROS) and lipid peroxidation. Iron accumulation results in mitochondrial dysfunction and increased levels of ROS, lipid peroxidation, and ferroptosis triggers; in addition, the inhibition of the Xc[-] system results in reduced cystine levels and glutamate accumulation, leading to excitotoxicity and the inhibition of GPx4 synthesis. These results highlight the potential involvement of ferroptosis in ALS, providing new molecular and biochemical targets that could be exploited in the treatment of the disease using polyphenols.},
}

*Ferroptosis/drug effects
Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy/genetics
*Polyphenols/pharmacology
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
Reactive Oxygen Species/metabolism
Lipid Peroxidation/drug effects
Oxidative Stress/drug effects
Mitochondria/metabolism/drug effects
Iron/metabolism

@article {pmid40140966,
year = {2025},
author = {Balaban, E and Köse, TE and Günaçar, DN and Naralan, ME and Gonca, M},
title = {Comparison of methods for detecting mandibular lingula and can antilingula be used in lingula mandibula detection?.},
journal = {BMC oral health},
volume = {25},
number = {1},
pages = {430},
pmid = {40140966},
issn = {1472-6831},
support = {02025001021255//Recep Tayyip Erdoğan University Development Foundation/ ; 02025001021255//Recep Tayyip Erdoğan University Development Foundation/ ; 02025001021255//Recep Tayyip Erdoğan University Development Foundation/ ; 02025001021255//Recep Tayyip Erdoğan University Development Foundation/ ; },
mesh = {Humans ; *Cone-Beam Computed Tomography ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; *Mandible/diagnostic imaging ; Aged ; Adolescent ; Aged, 80 and over ; Young Adult ; Orthognathic Surgical Procedures ; Anatomic Landmarks/diagnostic imaging ; Mandibular Nerve/diagnostic imaging/anatomy & histology ; },
abstract = {OBJECTIVE: The aim of this study is to evaluate the relationship between anatomical reference points used during orthognathic surgery and to minimize the risks of iatrogenic neurovascular damage.

MATERIALS AND METHODS: This retrospective study included cone-beam computed tomography (CBCT) images involving the mandible from patients who visited Recep Tayyip Erdoğan University Faculty of Dentistry between January 2018 and September 2023. The age range of the included individuals was set between 18 and 80 years. Horizontal and vertical distances between mandibular anatomical structures, such as the lingula mandibula (LM), mandibular foramen (MF), antilingula (AL), and surrounding structures were measured using CBCT software. Individuals with intraosseous pathology, insufficient image quality, or a history of surgical/orthodontic treatment were excluded from the study.

RESULTS: A total of 240 hemimandibles from 120 patients were analyzed (55.83% female, 44.17% male; mean age: 46.78 ± 15.30 years). Significant differences were identified in LM positions according to different AL types. The LM was found to be more inferior and posterior relative to hill and ridge type ALs, while it was more anterior relative to plateau type ALs. In 26.25% of mandibular rami, AL was not detected.

CONCLUSION: The position of the AL can serve as a guide in determining the osteotomy line during inferior vertical ramus osteotomy (IVRO). However, relying solely on AL as a reference point may increase the risk of inferior alveolar nerve (IAN) injury. Preoperative tomographic evaluations to determine the relationships among LM, MF, and AL can provide a safer approach in surgical planning, reduce complications, and help protect neurovascular structures.},
}

Humans
*Cone-Beam Computed Tomography
Female
Male
Retrospective Studies
Middle Aged
Adult
*Mandible/diagnostic imaging
Aged
Adolescent
Aged, 80 and over
Young Adult
Orthognathic Surgical Procedures
Anatomic Landmarks/diagnostic imaging
Mandibular Nerve/diagnostic imaging/anatomy & histology

@article {pmid40138872,
year = {2025},
author = {Liang, T and Jiang, T and Liang, Z and Li, L and Chen, Y and Chen, T and Yang, L and Zhang, N and Dong, B and Xie, X and Gu, B and Wu, Q},
title = {Gut microbiota-driven BCAA biosynthesis via Staphylococcus aureus -expressed acetolactate synthase impairs glycemic control in type 2 diabetes in South China.},
journal = {Microbiological research},
volume = {296},
number = {},
pages = {128145},
doi = {10.1016/j.micres.2025.128145},
pmid = {40138872},
issn = {1618-0623},
mesh = {*Diabetes Mellitus, Type 2/microbiology/metabolism ; *Gastrointestinal Microbiome/physiology ; *Staphylococcus aureus/enzymology/genetics/metabolism ; *Amino Acids, Branched-Chain/biosynthesis ; *Acetolactate Synthase/metabolism/genetics ; Humans ; Animals ; Mice ; China ; Male ; Insulin Resistance ; Female ; Middle Aged ; *Glycemic Control ; Blood Glucose ; Feces/microbiology ; Staphylococcal Infections/microbiology ; Metagenomics ; Prediabetic State/microbiology ; Metabolomics ; Insulin ; },
abstract = {An increase in branched-chain amino acid (BCAA) levels can result in insulin resistance at different stages of type 2 diabetes (T2D), however, the causes of this increase are unclear. We performed metagenomics and metabolomics profiling in patients with prediabetes (PDM), newly diagnosed diabetes (NDDM), and post-medication type 2 diabetes (P2DM) to investigate whether altered gut microbes and metabolites could explain the specific clinical characteristics of different disease stages of T2D. Here we identify acetolactate synthase (ALS) a BCAA biosynthesis enzyme in Staphylococcus aureus as a cause of T2D insulin resistance. Compared with healthy peoples, patients with PDM, NDDM, and P2DM groups, especially in P2DM group, have increased faecal numbers of S. aureus. We also demonstrated that insulin administration may be a risk factor for S. aureus infection in T2D. The presence of ALS-positive S. aureus correlated with the levels of BCAAs and was associated with an increased fasting blood glucose (FBG) and insulin resistance. Humanized microbiota transplantation experiment indicated that ALS contributes to disordered insulin resistance mediated by S. aureus. We also found that S. aureus phage can reduced the FBG levels and insulin resistance in db/db mice. The ALS-positive S. aureus are associated with insulin resistance in T2D, opening a new therapeutic avenue for the prevention or treatment of diabetes.},
}

*Diabetes Mellitus, Type 2/microbiology/metabolism
*Gastrointestinal Microbiome/physiology
*Staphylococcus aureus/enzymology/genetics/metabolism
*Amino Acids, Branched-Chain/biosynthesis
*Acetolactate Synthase/metabolism/genetics
Humans
Animals
Mice
China
Male
Insulin Resistance
Female
Middle Aged
*Glycemic Control
Blood Glucose
Feces/microbiology
Staphylococcal Infections/microbiology
Metagenomics
Prediabetic State/microbiology
Metabolomics
Insulin

@article {pmid40137226,
year = {2025},
author = {Stella, R and Bertoli, A and Lopreiato, R and Peggion, C},
title = {A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.},
journal = {Journal of fungi (Basel, Switzerland)},
volume = {11},
number = {3},
pages = {},
pmid = {40137226},
issn = {2309-608X},
abstract = {TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer's disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases.},
}

@article {pmid40135721,
year = {2025},
author = {Fayaz, MU and Wang, Q and Xu, M and Chen, D and Pan, F and Song, C},
title = {Compressive Strain-Induced Uphill Hydrogen Distribution in Strontium Ferrite Films.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.4c21825},
pmid = {40135721},
issn = {1944-8252},
abstract = {Hydrogen incorporation into metal oxides enhances their electrochemical properties, making them highly suitable for various energy conversion applications. The controlled distribution of hydrogen ions in material systems and their conduction at elevated temperatures have garnered significant attention for various energy storage and environmental monitoring applications, including fuel cells, smart windows, and sensor technologies. In this work, cost-effective, high-concentration hydrogen-doped SrFeO3-δ (HSrFeO3-δ) films were prepared under ambient conditions by treating Al(s)|SrFeO3-δ(s) films with KOH(aq), utilizing electron-proton codoping to investigate hydrogen distribution. The uphill hydrogen distributions in SrFeO3-δ films with compressive strain, in contrast to the density gradient behavior under tensile strain, suggest the fundamental role of the strain states in the hydrogen accommodation. Compressively strained films with a rich Al source follow an anomalous uphill feature of hydrogen distribution, highlighting their potential use as electrolyte for fuel cells. The strain significantly influences the structure, chemical lattice coupling, and consequently the ionic transport in SrFeO3-δ. Ionic conductivity measurements reveal that compressively strained HSrFeO3-δ films with uphill hydrogen distributions exhibit a significant ionic conductivity of 0.189 S/cm at 413 K, with an activation energy of approximately 0.29 eV, making them suitable for low-temperature electrochemical applications. These findings provide a promising approach for tuning material properties and valuable insights for building iontronic devices.},
}

@article {pmid40135631,
year = {2024},
author = {Novy, C and Tysnes, OB and Busk, ØL and Jaioun, K and Holmøy, T and Holla, ØL and Høyer, H},
title = {Association of UNC13A with increased amyotrophic lateral sclerosis risk, bulbar onset, and lower motor neuron involvement in a Norwegian ALS cohort.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2024.2447922},
pmid = {40135631},
issn = {2167-9223},
abstract = {Objective: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by the loss of motor neurons, has limited treatment options available. Treatments targeting specific ALS genes, including UNC13A, have attracted considerable attention. The UNC13A rs12608932 variant has been associated with an increased risk of ALS, shorter survival, and more frequent bulbar onset. Methods: In this study, we investigated the allele frequency of rs12608932 among 500 Norwegian ALS patients, divided into three groups: patients with a genetic cause, patients without a genetic cause, and the entire ALS population. The three groups were compared to two independent control groups. The patients carrying UNC13A genotypes AA, AC, and CC were further clinically characterized and compared using additive, recessive, and dominant models. Results: The frequency of the rs12608932 C allele was higher in the patients with ALS (0.438) than in the controls (0.365; p < 0.001). Among ALS patients without a known genetic cause, individuals with the CC genotype exhibited higher frequencies of bulbar onset (p = 0.015) and prominent lower motor neuron involvement (p = 0.007) than those with the AA and AC genotypes. Conclusions: The CC genotype of rs12608932 is associated with an increased risk of ALS. Additionally, it acts as a modifier of the ALS phenotype, increasing the risk of bulbar onset and dominant lower motor neuron involvement, specifically in patients without a genetic cause in known ALS genes.},
}

@article {pmid40135522,
year = {2025},
author = {Bai, D and Fang, Y and Tian, J and Liao, Y and Liu, M and Pan, L},
title = {Tribenuron-methyl resistance in Capsella bursa-pastoris: the co-existence of ALS target enzyme mutation (Pro-197-Ser) and overexpression of GSTF12 and ADP/ATP carrier protein.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.8794},
pmid = {40135522},
issn = {1526-4998},
support = {//Scientific Research Fund of Hunan Provincial Education Department/ ; //National Natural Science Foundation of China/ ; //National Key Research and Development Program of China/ ; //China Agriculture Research System/ ; //Modern Agricultural Industrial Technology System of Hunan Province/ ; },
abstract = {BACKGROUND: Capsella bursa-pastoris, a prevalent wheat-field weed in China, demonstrates substantial resistance to tribenuron-methyl, a herbicide-targeting acetolactate synthase (ALS). Understanding weed herbicide-resistance mechanisms is crucial for managing resistant weed populations. However, the genes potentially involved in nontarget-site resistance (NTSR) in herbicide-resistant C. bursa-pastoris remain poorly understood and require further investigation. This research aimed to elucidate the resistance level and underlying mechanisms of a field population (R) from Shandong Province, China, to tribenuron-methyl.

RESULTS: Whole-plant bioassays revealed that the relative resistance index (RI) of the R population was 54-fold greater than that of the tribenuron-methyl-sensitive population (S). Additionally, treatment with the cytochrome P450 (CYP450) inhibitor malathion or the glutathione S-transferase (GST) inhibitor 4-Chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) partially mitigated the resistance of the R population to tribenuron-methyl. Sequencing of the ALS target enzyme identified a substitution of proline (CCT) at position 197 with serine (TCT). RNA sequencing combined with quantitative reverse transcription polymerase chain reaction (qRT-PCR) verification identified upregulation of a candidate GST gene (GSTF12) and an ADP/ATP carrier protein in the R population. Heterologous expression of the two candidate genes in yeast cells demonstrated enhanced growth in the presence of tribenuron-methyl.

CONCLUSION: We first identified that, in tribenuron-methyl-resistant C. bursa-pastoris, the Pro-197-Ser mutation in the ALS gene, along with GSTF12 and ADP/ATP carrier protein overexpression, jointly mediate its resistance. This enhances our understanding of herbicide-resistance mechanisms and offers a novel perspective for managing tribenuron-methyl-resistant weeds in agricultural practices. © 2025 Society of Chemical Industry.},
}

@article {pmid40134643,
year = {2025},
author = {Guo, YX and Yan, X and Liu, XC and Liu, YX and Liu, C},
title = {Artificial intelligence-driven strategies for managing renal and urinary complications in inflammatory bowel disease.},
journal = {World journal of nephrology},
volume = {14},
number = {1},
pages = {100825},
pmid = {40134643},
issn = {2220-6124},
abstract = {In this editorial, we discuss the article by Singh et al published in World Journal of Nephrology, stating the need for timely adjustments in inflammatory bowel disease (IBD) patients' long-term management plans. IBD is chronic and lifelong, with recurrence and remission cycles, including ulcerative colitis and Crohn's disease. It's exact etiology is unknown but likely multifactorial. Related to gut flora and immune issues. Besides intestinal symptoms, IBD can also affect various extraintestinal manifestations such as those involving the skin, joints, eyes and urinary system. The anatomical proximity of urinary system waste disposal to that of the alimentary canal makes early detection and the differentiation of such symptoms very difficult. Various studies show that IBD and it's first-line drugs have nephrotoxicity, impacting the patients' life quality. Existing guidelines give very few references for kidney lesion monitoring. Singh et al's plan aims to improve treatment management for IBD patients with glomerular filtration rate decline, specifically those at risk. Most of IBD patients are young and they need lifelong therapy. So early therapy cessation, taking into account drug side effects, can be helpful. Artificial intelligence-driven diagnosis and treatment has a big potential for management improvements in IBD and other chronic diseases.},
}

@article {pmid40129929,
year = {2025},
author = {Liang, F and Sun, Y and Yang, J and Shen, Z and Wang, G and Zhu, J and Zhou, C and Xia, Y},
title = {Gut microbiome is associated with radiotherapy response in lung cancer patients with brain metastases.},
journal = {Frontiers in cellular and infection microbiology},
volume = {15},
number = {},
pages = {1562831},
pmid = {40129929},
issn = {2235-2988},
mesh = {Humans ; *Gastrointestinal Microbiome ; *Lung Neoplasms/radiotherapy/pathology/microbiology ; Male ; Female ; Middle Aged ; *Brain Neoplasms/secondary/radiotherapy ; Aged ; *RNA, Ribosomal, 16S/genetics ; *Feces/microbiology ; *Bacteria/classification/isolation & purification/genetics ; Treatment Outcome ; Adult ; },
abstract = {PURPOSE: To investigate the gut microbiome of lung cancer patients with brain metastases undergoing radiotherapy, identify key microorganisms associated with radiotherapy response, and evaluate their potential as biomarkers.

METHODS AND MATERIALS: This study enrolled 55 newly diagnosed lung cancer patients with brain metastases. Fecal samples were collected before radiotherapy and analyzed by 16S rRNA sequencing to assess the gut microbiome's composition and function. Patients were categorized into response (n=28) and non-response (n=27) groups based on treatment efficacy, and α-diversity, β-diversity, and functional pathways were compared between them. Linear Discriminant Analysis Effect Size was used to identify microbial features associated with treatment efficacy. Logistic regression analyses were performed to evaluate the predictive capacity of clinical and microbial factors for treatment outcomes.

RESULTS: No significant difference in α-diversity was observed between the groups (P > 0.05), but β-diversity differed significantly (P = 0.036). Twelve characteristic microorganisms were identified in the response group, including g_ Oscillibacter and g_ Blautia, and nine in the non-response group, such as f_ Desulfovibrionaceae and g_ Megamonas. Metabolic pathways associated with treatment response included ketone body metabolism and pathways related to amyotrophic lateral sclerosis. Multivariate analysis identified g_Flavonifractor (odds ratio [OR] = 6.680, P = 0.004), g_Negativibacillus (OR = 3.862, P = 0.014), C-reactive protein (OR = 1.054, P = 0.017), and systemic inflammation response index (OR = 1.367, P = 0.043) as independent predictors of radiotherapy response. The nomogram and microbiome models achieved area under the curve (AUC) values of 0.935 and 0.866, respectively, demonstrating excellent predictive performance. Decision curve analysis further confirmed these models provided significant net benefits across risk thresholds.

CONCLUSIONS: The composition and functional characteristics of the gut microbiome in lung cancer patients with brain metastases prior to radiotherapy are associated with therapeutic response and possess potential as predictive biomarkers. Further studies are warranted to validate these findings.},
}

Humans
*Gastrointestinal Microbiome
*Lung Neoplasms/radiotherapy/pathology/microbiology
Male
Female
Middle Aged
*Brain Neoplasms/secondary/radiotherapy
Aged
*RNA, Ribosomal, 16S/genetics
*Feces/microbiology
*Bacteria/classification/isolation & purification/genetics
Treatment Outcome
Adult

@article {pmid40128823,
year = {2025},
author = {Zhang, W and Huang, C and Yao, H and Yang, S and Jiapaer, Z and Song, J and Wang, X},
title = {Retrotransposon: an insight into neurological disorders from perspectives of neurodevelopment and aging.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {14},
pmid = {40128823},
issn = {2047-9158},
support = {2023TSYCCX0051//Tianshan Talent Training Program/ ; },
mesh = {Humans ; *Retroelements/genetics ; *Aging/genetics ; *Nervous System Diseases/genetics ; Animals ; },
abstract = {Neurological disorders present considerable challenges in diagnosis and treatment due to their complex and diverse etiology. Retrotransposons are a type of mobile genetic element that are increasingly revealed to play a role in these diseases. This review provides a detailed overview of recent developments in the study of retrotransposons in neurodevelopment, neuroaging, and neurological diseases. Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, and endogenous retrovirus, play important regulatory roles in the development and aging of the nervous system. They have also been implicated in the pathological processes of several neurological diseases, including Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, and schizophrenia. Retrotransposons provide a new perspective for understanding the molecular mechanisms underlying neurological diseases and provide insights into diagnostic and therapeutic strategies of these diseases.},
}

Humans
*Retroelements/genetics
*Aging/genetics
*Nervous System Diseases/genetics
Animals

@article {pmid40128246,
year = {2025},
author = {Hu, X and Wei, M and Zhang, H and Yu, M and Wang, M and Zhou, B and Luo, Y and Li, B},
title = {The experience of pain symptoms in patients with amyotrophic lateral sclerosis: a qualitative study.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {10183},
pmid = {40128246},
issn = {2045-2322},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Middle Aged ; Male ; Female ; *Pain/psychology/etiology ; *Qualitative Research ; Aged ; Adult ; Adaptation, Psychological ; Pain Management/methods ; },
abstract = {ALS is a progressive neurodegenerative disease that has a serious impact on patients and their caregivers. For a long time in the past, ALS was considered a painless disease that was largely ignored by clinicians. Describing the complexity and needs of pain symptoms from the perspective of patients can provide the most intuitive direction for future research. The purpose of our research is to explore the experience of pain symptoms in patients with amyotrophic lateral sclerosis (ALS), provide reference for better understanding of pain symptoms in ALS patients. From April 2023 to May 2023, 27 patients experiencing pain symptoms in Peking University Third Hospital who met the diagnostic criteria of "Chinese Guidelines for the Diagnosis and Treatment of amyotrophic lateral sclerosis" were interviewed by means of objective sampling. The content analysis method was used to describe the pain changes since the disease (amyotrophic lateral sclerosis), the factors that aggravate the pain, the measures to cope with the pain and the needs. The interview results included 3 themes and 11 subthemes. (1) Pain is diverse: the type of pain, the time when pain occurs, the change in pain intensity, and the factors that aggravate pain; (2) Individualized pain coping measures: posture adjustment, medication, physical therapy, warmth, emotional regulation; (3) Patients lack of understanding of pain: insufficient source of knowledge, the single orientation of the solution. The nature, location and aggravating factors of pain in amyotrophic lateral sclerosis patients in China are complicated, which should be paid attention to by clinical staff and scientific researchers. The situation of pain management is not optimistic, and the pain of the vast majority of patients has not been effectively alleviated. It is necessary to realize the importance of self-management and care of others in coping with pain, and conduct further research in the future to find a breakthrough in pain relief, so as to strengthen pain intervention in clinical practice.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/psychology
Middle Aged
Male
Female
*Pain/psychology/etiology
*Qualitative Research
Aged
Adult
Adaptation, Psychological
Pain Management/methods

@article {pmid40126464,
year = {2025},
author = {Shefner, JM and Cudkowicz, ME and Genge, A and Hardiman, O and Al-Chalabi, A and Andrews, JA and Chio, A and Corcia, P and Couratier, P and de Carvalho, M and Heiman-Patterson, T and Henderson, RD and Ingre, C and Johnston, W and Ludolph, A and Maragakis, NJ and Miller, TM and Mora, JS and Petri, S and Simmons, Z and van den Berg, LH and Zinman, L and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Rudnicki, SA and , },
title = {Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
pmid = {40126464},
issn = {2168-6157},
abstract = {IMPORTANCE: Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression.

OBJECTIVE: To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS.

A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted.

INTERVENTIONS: Oral reldesemtiv, 300 mg, or placebo twice daily.

MAIN OUTCOMES AND MEASURES: The primary end point was change in ALSFRS-R total score from baseline to week 24.

RESULTS: Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI, -2.17 to -0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11).

CONCLUSIONS AND RELEVANCE: This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04944784.},
}

@article {pmid40125959,
year = {2025},
author = {Gupta, U and Kumar, A and Alam, MI and Balaji, PG and Sharma, A and Yadav, AK},
title = {Synthesis and characterization of protein nanohybrid systems for the brain delivery of Riluzole.},
journal = {Therapeutic delivery},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/20415990.2025.2478805},
pmid = {40125959},
issn = {2041-6008},
abstract = {AIMS: Synthesis and Characterization of Protein NanoHybrid Systems for the Brain Delivery of Riluzole.

METHODS/MATERIALS: Fullerene is converted into carboxylated fullerene (CF) and then, prepared RZU-loaded BSA nanoparticles conjugated with CF.

RESULTS: The particle size and zeta potential of RZU-PNH were found to be 210 ± 1.15 nm and -18.5 ± 0.615 mV respectively, and entrapment efficiency and loading efficiency of RZU-PNH were found to be 98.8 ± 0.53% and 11.6 ± 0.43%, respectively. The XRD of the RZU-PNH shows the amorphism behavior and CD revealed that secondary structure of the protein mainly consists of α-helix andβ-sheet. The MTT assay showed 88.60% and 90.84% cell viability in both SH-SY5Yand N2a cell lines at a concentration of 20 μg/ml and also, no significant nasal ciliotoxicity was observed after incubation with RZU-PNH.

CONCLUSIONS: Obtained results indicated RZU-PNH formulation to treat amyotrophic lateral sclerosis.},
}

@article {pmid40125702,
year = {2025},
author = {Madhavan, S and Deshmukh, S and Cummings, M and Doshi, A and Rezania, K and Freels, S and Sawa, G},
title = {Home-Based Tele-tDCS in Amyotrophic Lateral Sclerosis: Feasibility, Safety, and Preliminary Efficacy.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70038},
pmid = {40125702},
issn = {2328-9503},
support = {R21HD102722//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Transcranial direct current stimulation (tDCS) shows promise as a neuromodulatory intervention in various neurological disorders, but its application in ALS, particularly in a remote, home-based format, remains underexplored. This study investigates the feasibility, safety, and preliminary efficacy of remotely supervised tele-tDCS in ALS patients.

METHODS: This double-blinded pilot study included 14 spinal-onset ALS participants randomized into two groups: the intervention group received 72 tele-tDCS sessions over 24 weeks, and the delayed-start group received 36 sham sessions followed by 36 tele-tDCS sessions. Stimulation was delivered at 2 mA for 20 min 3 times a week. Primary outcomes included feasibility, safety, and disease progression measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Adherence and adverse effects were monitored throughout.

RESULTS: Ten participants completed the study, with an overall compliance rate of 98.3%. No serious adverse events were reported, and mild side effects, like itching and tingling, were consistent with tDCS literature. The intervention group demonstrated a significantly slower decline in ALSFRS-R scores than the delayed-start group. At 24 weeks, the intervention group had a mean ALSFRS-R change of -1.7, compared to -13.6 in the delayed-start group (p = 0.0018). Additionally, the change in ALSFRS-R between pre- and mid-intervention significantly differed between groups (p = 0.0071).

INTERPRETATION: Tele-tDCS was feasible, safe, and well-tolerated in individuals with ALS. Preliminary efficacy results suggest that tele-tDCS may slow disease progression, underscoring the potential of tele-tDCS as a promising home-based neuromodulatory intervention in ALS management.

TRIAL REGISTRATION: Clinical trial registration: NCT04866771.},
}

@article {pmid40124885,
year = {2025},
author = {Dethier, C and Azirar, S and Verluyten, L and Boonen, H and Grosber, M and Gutermuth, J},
title = {Response to Fässler et al's "Successful treatment of refractory folliculitis decalvans with apremilast".},
journal = {JAAD case reports},
volume = {57},
number = {},
pages = {122-123},
pmid = {40124885},
issn = {2352-5126},
}

@article {pmid40116361,
year = {2025},
author = {Li, C and Noonan, AM and Hays, J and Roychowdhury, S and Malalur, P and Elkhatib, R and Manne, A and Mittra, A and Rahman, S and Yan, L and Hill, K and Abbott, N and Phelps, M and Na, JY and Liang, B and Storts, H and Khan, M and Zhang, EH and Miles, W and Yildiz, V and Wei, L and Wang, JJ and Jin, N},
title = {Riluzole in Combination with mFOLFOX6 and Bevacizumab in Treating Patients with Metastatic Colorectal Cancer: A Phase 1 Clinical Trial.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {},
number = {},
pages = {},
doi = {10.1158/1078-0432.CCR-24-3964},
pmid = {40116361},
issn = {1557-3265},
abstract = {BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the US. 5-fluorouracil (5-FU)-based chemotherapies in combination with targeted agents remain the standard of care in patients with metastatic or locally advanced disease. New treatment strategies are needed for metastatic CRC patients with microsatellite stable disease. Preclinical studies showed that riluzole, an oral medicine for amyotrophic lateral sclerosis, inhibits glutamate release and synergizes with 5-FU to reduce cell viability in CRC cell lines.

METHODS: In this single-arm, phase 1 trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic CRC, the riluzole dose started at 50 mg twice daily, escalating to 100 mg twice daily or de-escalating to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLOFX6/bevacizumab for 8 cycles. Patients then either continued mFOLFOX6/bevacizumab or switched therapy.

RESULTS: Twelve of the 14 patients enrolled were evaluable. All patients previously received FOLFOX, and 5 patients (41.7%) showed disease resistance to it. Two patients obtained partial responses, 9 had stable disease, and 1 had progressive disease. The objective response rate was 16.7%, and the disease control rate was 91.7%. The median duration of response was 4.9 months (95% CI 1.6-9.8). Median progression-free survival and overall survival were 4.89 and 12.98 months, respectively.

CONCLUSION: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic CRC and may have clinical activity in patients whose disease is resistant to FOLFOX.},
}

@article {pmid40116017,
year = {2025},
author = {Addy, G and Scirocco, E and Gelevski, D and Rohrer, M and Roderick, A and McCormack, M and Weiss Sadan, A and Scalia, J and Parikh, N and Giacomelli, E and Locatelli, M and Neel, DV and D'Agostino, D and Leite, A and Yu, H and Sherman, AV and Mock, J and Kalmes, A and Luppino, S and Babu, S and Berry, J and Cudkowicz, M and Paganoni, S},
title = {An Expanded Access Protocol of RNS60 in Amyotrophic Lateral Sclerosis.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28398},
pmid = {40116017},
issn = {1097-4598},
support = {//The study drug was provided at no cost by Revalesio, and program costs were covered by philanthropic donations to the Sean M. Healey & AMG Center for ALS/ ; },
abstract = {AIMS: RNS60 is an investigational product in clinical development for amyotrophic lateral sclerosis (ALS). RNS60 slowed disease progression in the ALS SOD1[G93A] mouse model and was safe and well tolerated both in an open-label pilot study and a randomized, placebo-controlled, multicenter phase 2 trial in people living with ALS. The objective of this ongoing expanded access protocol (EAP) was to provide RNS60 to people living with ALS who are ineligible for controlled clinical trials and to collect data on the safety and tolerability of dosing RNS60 via twice-daily nebulization rather than the previously studied daily nebulization with weekly intravenous administration.

METHODS: Eligible participants (≥ 18 years old, diagnosed with ALS per investigator assessment, and ineligible for an ALS clinical trial testing RNS60) were treated with twice-daily nebulization of RNS60 at home. Safety was evaluated by the assessment of adverse events and routine safety labs.

RESULTS: A total of 84 participants have been treated with RNS60 via nebulization twice daily for up to 48 months so far. The most common treatment-related adverse event was increased secretions [N = 27 (32%)]. Serious adverse events (SAEs) [69 occurrences; N = 38 (45%) with at least one SAE] and deaths [N = 24 (28%)] were deemed not related to RNS60.

DISCUSSION: This EAP supports the benign side effect profile of RNS60 when administered via twice-daily nebulization and demonstrates the feasibility of long-term EAPs as a complementary approach to controlled trials in people with advanced ALS.},
}

@article {pmid40105291,
year = {2025},
author = {Ozeki-Hayashi, R and Wilkinson, DJC},
title = {'An Unimaginable Challenge': A Cross-Cultural Qualitative Study of Ethics and Decision-Making Around Tracheostomy Ventilation in Patients with Amyotrophic Lateral Sclerosis.},
journal = {AJOB empirical bioethics},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/23294515.2025.2474928},
pmid = {40105291},
issn = {2329-4523},
abstract = {BACKGROUND: The rate of tracheostomy with invasive ventilation (TIV) for patients with Amyotrophic Lateral Sclerosis (ALS) varies widely. Previous studies have shown that doctors' values may affect decision-making. There have been no previous international qualitative comparisons of medical decision-making process for TIV or why practice varies.

METHODS: We conducted semi-structured in-depth interviews with 16 doctors actively involved in the management of ALS patients from Japan (n = 7), the UK (n = 5), and the US (n = 4). We used three hypothetical cases to explore decision-making. Conversations were transcribed and thematically analyzed.

RESULTS: Our data reveals similarities but also marked differences in views between the US, the UK and Japan. Almost all participants stated that they ought to respect patient autonomy. However, their approaches varied. British participants wanted to (and felt that they should) respect patient autonomy, but they also believed that TIV was not a realistic option. US participants were likely to prioritize patient autonomy over other ethical principles, and Japanese participants were likely to limit patient autonomy indirectly. The option of TIV appeared to be heavily influenced by the availability of healthcare resources in all three countries. The high cost, limited availability and difficulty of treatment meant that particularly in the UK and the US, it is challenging to receive TIV even if patients wanted this.

CONCLUSIONS: Our study illustrates how the emphasis on autonomy varies along with variations in the way care is organized in the setting of highly resource intensive treatment and progressive severe disabling illness. There is a need to review elements of the decision-making process in all three countries. This includes the need for transparent, ideally centralized, decision-making guidelines about the provision of TIV. Although we investigated a rare neuromuscular disease, our results will be relevant to other diseases requiring highly resource-intensive treatment toward the end of life.},
}

@article {pmid40105198,
year = {2025},
author = {Gotkine, M and Schoenfeld, DA and Cohen, I and Shefner, JM and Lerner, Y and Cohen, IR and Klein, C and Ovadia, E and Cudkowicz, ME and , },
title = {Akt Activation With IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open-Label Study.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28393},
pmid = {40105198},
issn = {1097-4598},
support = {//Immunity Pharma/ ; },
abstract = {INTRODUCTION/AIMS: Akt intracellular signal transduction pathway dysfunction has been reported in people with amyotrophic lateral sclerosis (ALS) providing a novel target for intervention in this devastating progressive disease. This first-in-human study evaluated the safety, tolerability, and preliminary efficacy of the Akt pathway activator, IPL344, in people with ALS.

METHODS: Nine participants with ALS and a progression rate > 0.55 points/month on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) received open-label IPL344 treatment (once-daily) for up to 36 months. Safety was assessed through adverse event (AE) reporting. Plasma neurofilament light chain (NfL) concentrations were measured before and after treatment. Clinical outcomes were compared to historical data.

RESULTS: The mean ± SD duration of IPL344 follow-up was 14.0 ± 12.5 months. One participant developed drug hypersensitivity, two had central venous catheter-related AEs, and two had serious pneumonia AEs. The unadjusted mean ± SE slope of decline in ALSFRS-R was -0.53 ± 0.15 (48% slower progression vs. historical controls, p = 0.028). Adjustment for disease stage and rate-indicating covariates indicated a 64% slower ALSFRS-R progression (p = 0.034), with increased rather than reduced body weight (p = 0.02). Eight of nine IPL344-treated participants had a significantly improved slope compared to the median slope of a matched control group (p = 0.04). Plasma NfL concentrations were lowered by 27% (n = 6). Unadjusted median survival for participants in the IPL344 group was 43.4 months [95% CI: 20.5, NA] compared with 19.1 months [17.4, 23.0] in the historical control group.

DISCUSSION: These preliminary data indicate that IPL344 was safe and well-tolerated, and possibly effective. Our findings may merit further investigation in a larger placebo-controlled clinical trial.},
}

@article {pmid40100917,
year = {2025},
author = {Thau-Habermann, N and Gschwendtberger, T and Bodemer, C and Petri, S},
title = {Parthenolide regulates microglial and astrocyte function in primary cultures from ALS mice and has neuroprotective effects on primary motor neurons.},
journal = {PloS one},
volume = {20},
number = {3},
pages = {e0319866},
pmid = {40100917},
issn = {1932-6203},
mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Sesquiterpenes/pharmacology ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; Mice ; *Astrocytes/drug effects/metabolism ; Cells, Cultured ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; },
abstract = {Over the last twenty years, the role of microgliosis and astrocytosis in the pathophysiology of neurodegenerative diseases has increasingly been recognized. Dysregulation of microglial and astrocyte properties and function has been described also in the fatal degenerative motor neuron disease amyotrophic lateral sclerosis (ALS). Microglia cells, the immune cells of the nervous system, can either have an immunonegative neurotoxic or immunopositive neuroprotective phenotype. The feverfew plant (Tanacetum parthenium) derived compound parthenolide has been found to be capable of interfering with microglial phenotype and properties. Positive treatment effects were shown in animal models of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Now we were able to show that PTL has a modulating effect on primary mouse microglia cells, both wild type and SOD1, causing them to adopt a more neuroprotective potential. Furthermore, we were able to show that PTL, through its positive effect on microglia, also has an indirect positive impact on motor neurons, although PTL itself has no direct effect on these primary motor neurons. The results of our study give reason to consider PTL as a drug candidate for ALS.},
}

Animals
*Microglia/drug effects/metabolism/pathology
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology
*Sesquiterpenes/pharmacology
*Motor Neurons/drug effects/metabolism/pathology
*Neuroprotective Agents/pharmacology
Mice
*Astrocytes/drug effects/metabolism
Cells, Cultured
Mice, Transgenic
Superoxide Dismutase/metabolism

@article {pmid40100796,
year = {2025},
author = {Giroud, M and Kuhn, B and Steiner, S and Westwood, P and Mendel, M and Mani, A and Pinard, E and Haap, W and Grether, U and Caramenti, P and Rombach, D and Zambaldo, C and Ritter, M and Schmid, P and Gasser, C and Aregger, N and Séchet, N and Topp, A and Bilyard, M and Malnight-Alvarez, A and Plitzko, I and Hilbert, M and Kalayil, S and Burger, D and Bonardi, C and Saal, W and Haider, A and Wittwer, MB and Brigo, A and Benz, J and Keaney, J},
title = {Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy.},
journal = {Journal of medicinal chemistry},
volume = {68},
number = {6},
pages = {6558-6575},
doi = {10.1021/acs.jmedchem.4c03127},
pmid = {40100796},
issn = {1520-4804},
mesh = {Animals ; *Armadillo Domain Proteins/antagonists & inhibitors/metabolism ; Mice ; *Cytoskeletal Proteins/antagonists & inhibitors/metabolism ; Humans ; Structure-Activity Relationship ; Drug Discovery ; Male ; },
abstract = {Sterile alpha and TIR Motif Containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD[+]) hydrolase that plays a central role in programmed axonal degeneration. Axonal degeneration has been linked to neurodegenerative and neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and peripheral neuropathies. Therefore, developing potent and selective SARM1 inhibitors could be an effective strategy to treat these disorders. We present herein the structure-guided discovery of two novel SARM1 inhibitors, 7 and 35. Compounds 7 and 35 are potent inhibitors across assays and possess favorable ADMET properties. When tested in vivo, compound 7 showed efficacy after oral dosing in a mouse model of peripheral nerve injury by decreasing plasma neurofilament light (NfL) levels at 50 mg/kg compared with vehicle-treated control mice, holding promise for the treatment of neurodegenerative and neurological disorders.},
}

Animals
*Armadillo Domain Proteins/antagonists & inhibitors/metabolism
Mice
*Cytoskeletal Proteins/antagonists & inhibitors/metabolism
Humans
Structure-Activity Relationship
Drug Discovery
Male

@article {pmid40099804,
year = {2025},
author = {Zheng, W and Zhang, X and Chen, J and Luan, X and Wang, J and Zhang, L and Liu, K and Zhao, Y and Xu, Z},
title = {The Effect of Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex on the Amyotrophic Lateral Sclerosis Patients With Cognitive Impairment: A Double-Blinded, Randomized, and Sham Control Trial.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {3},
pages = {e70316},
pmid = {40099804},
issn = {1755-5949},
support = {20YF1436400//Shanghai Sailing program/ ; 23DZ2291500//Shanghai Science and Technology Innovation Action Plan/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications/psychology ; *Transcranial Magnetic Stimulation/methods ; Double-Blind Method ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/therapy/etiology/psychology ; *Dorsolateral Prefrontal Cortex/physiology ; Treatment Outcome ; Prefrontal Cortex ; Adult ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. A large number of ALS patients have cognitive impairment. In this double-blinded, randomized, and sham-controlled study, we aimed to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on ALS patients with cognitive impairment.

METHODS: A total of 90 ALS patients with cognitive impairment were recruited from two cohorts; 80 participants were randomly assigned in a 1:1 ratio to receive 10 Hz rTMS or sham treatment on the bilateral dorsolateral prefrontal cortices (DLPFC) for 4 consecutive weeks. The patients were assessed by ECAS and ALSFRS-R scales. The Zarit care burden scale was administered to caregivers of ALS patients. The primary outcome measured was the rate of decline in the total ECAS score between pretreatment, 6 months post-treatment, and 12 months post-treatment. Secondary outcomes included the group difference in the slope of the Zarit score, ALSFRS-R total score, and the neurofilament light chain plasma levels.

RESULTS: The ECAS total score in the intention-to-treat population significantly changed from 79.74 ± 6.39 to 81.98 ± 6.51 and 79.22 ± 6.50 with rTMS intervention at the 6-month and 12-month follow-ups, respectively (p = 0.031, p = 0.042). The Zarit score also significantly decreased from 57.65 ± 3.42 to 52.24 ± 3.34 and 56.42 ± 3.41 at the 3-month and 6-month post-treatment time points, respectively (p = 0.003, p = 0.014). No significant differences were observed between the groups for other secondary endpoints. However, there was a trend of decreasing NF-L level rates in the treatment group over the first 6 months' follow-up.

CONCLUSIONS: rTMS could yield short-term positive effects on the ALS patients subgroup with cognitive impairment and alleviate caregivers' burden. No improvement was observed in the severity of ALS and ALS plasma biomarkers.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/complications/psychology
*Transcranial Magnetic Stimulation/methods
Double-Blind Method
Male
Female
Middle Aged
Aged
*Cognitive Dysfunction/therapy/etiology/psychology
*Dorsolateral Prefrontal Cortex/physiology
Treatment Outcome
Prefrontal Cortex
Adult

@article {pmid40099353,
year = {2025},
author = {Giorgio, CM and Tancredi, V and Licata, G and Moscarella, E and Argenziano, G and Fulgione, E and Babino, G and Franzese, P and Di Brizzi, EV},
title = {Cutting-edge insights: LC-OCT and 5% cyclosporine for early lichen sclerosus treatment.},
journal = {Dermatology reports},
volume = {},
number = {},
pages = {},
doi = {10.4081/dr.2025.10279},
pmid = {40099353},
issn = {2036-7392},
abstract = {Dear Editor, Atrophic lichen sclerosus (ALS) is a chronic inflammatory dermatosis with significant morbidity, primarily affecting genital areas. The disease is often misdiagnosed or underdiagnosed, resulting in delayed treatment and progression to atrophic stages and permanent scars. While corticosteroids remain the first-line treatment, their long-term use may lead to adverse effects such as skin atrophy, prompting the need for alternative therapies. Cyclosporine, a calcineurin inhibitor, has shown efficacy in managing immune-mediated skin diseases and is delivered effectively through the Pentravan® vehicle. [...].},
}

@article {pmid40097762,
year = {2025},
author = {Nabakhteh, S and Lotfi, A and Afsartaha, A and Khodadadi, ES and Abdolghaderi, S and Mohammadpour, M and Shokri, Y and Kiani, P and Ehtiati, S and Khakshournia, S and Khatami, SH},
title = {Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40097762},
issn = {1559-1182},
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.},
}

@article {pmid40097075,
year = {2025},
author = {Cuevas, EP and Madruga, E and Valenzuela-Martínez, I and Ramírez, D and Gil, C and Nagaraj, S and Martin-Requero, A and Martinez, A},
title = {MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers.},
journal = {Neurobiology of disease},
volume = {208},
number = {},
pages = {106871},
doi = {10.1016/j.nbd.2025.106871},
pmid = {40097075},
issn = {1095-953X},
abstract = {MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fatal disease that lacks of not only effective treatments, but also presents delays in its diagnosis, since reliable clinical biomarkers are unavailable. In recent years, advancements in high-throughput sequencing strategies have led to the identification of novel ALS biomarkers, facilitating earlier diagnosis and assessment of treatment efficacy. Since immortalized lymphocytes obtained from peripheral blood are a suitable model to study pathological features of ALS, we employed these samples with the aim of characterize the dysregulated miRNAs in ALS patients. Next-generation sequencing (NGS) was utilized in order to analyze the expression profiles of miRNAs in immortalized lymphocytes from healthy controls, sporadic ALS (sALS), and familial ALS with mutations in superoxide dismutase 1 (SOD1-ALS). The screening analysis of the NGS data identified a set of dysregulated miRNAs, of which nine candidates were selected for qRT-PCR validation, identifying for the first time the possible importance of hsa-miR-6821-5p as a potential ALS biomarker. Furthermore, the up-regulated miRNAs identified are predicted to have direct or indirect interactions with genes closely related to ALS, such as SIGMAR1, HNRNPA1 and TARDBP. Additionally, by Metascape enrichment analysis, we found the VEGFA/VEGFR2 signaling pathway, previously implicated in neuroprotective effects in ALS, as a candidate pathway for further analyses.},
}

@article {pmid40095345,
year = {2025},
author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A},
title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40095345},
issn = {1559-1182},
abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.},
}

@article {pmid40092960,
year = {2025},
author = {Liu, Y and Li, XF},
title = {Characteristics and therapeutic strategies for familial gastrointestinal stromal tumors.},
journal = {World journal of gastrointestinal oncology},
volume = {17},
number = {3},
pages = {100463},
pmid = {40092960},
issn = {1948-5204},
abstract = {This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.},
}

@article {pmid40091916,
year = {2025},
author = {Ansari, U and Wen, J and Karabala, M and Syed, B and Abed, I and Razick, DI and Lui, F},
title = {Analysis of Respiratory Muscle Strength Training in Amyotrophic Lateral Sclerosis (ALS) Patients: A Systematic Review.},
journal = {Cureus},
volume = {17},
number = {2},
pages = {e78903},
pmid = {40091916},
issn = {2168-8184},
abstract = {Respiratory muscle weakness is a significant contributor to morbidity and mortality in amyotrophic lateral sclerosis (ALS) patients. Respiratory muscle strength training (RMST) has emerged as a potential therapeutic approach to mitigate respiratory muscle weakness in ALS. Still, its efficacy and safety remain unclear due to conflicting evidence and methodological heterogeneity in existing studies. A systematic review was conducted across three databases (PubMed (United States National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, Netherlands), and Cochrane Library (Cochrane, Alberta, Canada)) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess the effectiveness of RMST in ALS patients. Eligible studies included comparative studies for RMST, focusing on outcomes such as maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and ALS Functional Rating Scale (ALSFRS-R). Quality assessment was performed using the Cochrane Risk of Bias tool. This study included six studies, including 183 patients with a mean age of 58.0 years (49.6 to 63.2) and a mean follow-up time of 21.2 weeks (eight to 52). The average mean difference for ALSFRS-R (three studies), MIP (three studies), MEP (three studies), and FVC (two studies) were 2.062 (0.04 to 5.3), 2.285 (-8.145 to 10.8), 19.435 (10.86 to 21.7), and 7.23 (3.6 to 10.86), respectively. Complications related to RMST were poorly reported across studies. Secondary outcomes, such as depression scores, blood oxygen levels, and heart rate variability, showed promising trends but lacked consistency. Despite positive findings on respiratory muscle strength, RMST's efficacy in ALS management remains inconclusive. Challenges include methodological heterogeneity, limited sample sizes, and inadequate reporting of complications. Future research should focus on standardized protocols, larger sample sizes, longer follow-ups, and comprehensive assessment of adverse effects to clarify the role of RMST in ALS treatment.},
}

@article {pmid40090808,
year = {2025},
author = {Rosina, M and Scaricamazza, S and Fenili, G and Nesci, V and Valle, C and Ferri, A and Paronetto, MP},
title = {Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis.},
journal = {Trends in endocrinology and metabolism: TEM},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tem.2025.02.004},
pmid = {40090808},
issn = {1879-3061},
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.},
}

@article {pmid40089090,
year = {2025},
author = {Men, J and Wang, X and Zhou, Y and Huang, Y and Zheng, Y and Wang, Y and Yang, S and Chen, N and Yan, N and Duan, X},
title = {Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential.},
journal = {Cellular signalling},
volume = {131},
number = {},
pages = {111715},
doi = {10.1016/j.cellsig.2025.111715},
pmid = {40089090},
issn = {1873-3913},
abstract = {Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.},
}

@article {pmid40076771,
year = {2025},
author = {Aguiar, B and Alfenim, AR and Machado, CS and Moreira, J and Pinto, M and Otero-Espinar, FJ and Borges, F and Fernandes, C},
title = {Exploring Nano-Delivery Systems to Enhance the Edaravone Performance in Amyotrophic Lateral Sclerosis Treatment.},
journal = {International journal of molecular sciences},
volume = {26},
number = {5},
pages = {},
pmid = {40076771},
issn = {1422-0067},
support = {2023.13291.PEX//Foundation for Science and tecnhology/ ; UIDB/00081/2020 (CIQUP)//Foundation for Science and Technology/ ; LA/P/0056/2020(IMS)//Foundation for Science and Technology/ ; 2021.04016.CEECIND/CP1655/CT0004//Foundation for Science and Technology/ ; IMPULSE: IMproving User experience, Long-term sustainability, and Services//EU-OPENSCREEN HORIZON-INFRA-2023-DEV-0/ ; 2020.08731.BD//Foundation for Science and Technology/ ; 2023.01250.BD//Foundation for Science and Technology/ ; 2024.00809.BD//Foundation for Science and Technology/ ; SFRH/BD/145637/2019//Foundation for Science and Technology/ ; },
mesh = {*Edaravone/pharmacology/chemistry/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Nanoparticles/chemistry ; Drug Delivery Systems/methods ; Free Radical Scavengers/chemistry/pharmacology ; Drug Carriers/chemistry ; Nanoparticle Drug Delivery System/chemistry ; Polyethylene Glycols/chemistry ; },
abstract = {Edaravone is one of the treatment options for Amyotrophic Lateral Sclerosis, but its therapeutic efficacy is limited due to the incapacity to cross the blood-brain barrier, as well as its short life span and poor stability, which is ultimately caused by its tautomerism in physiological condions. This work presents an overview about the use of several nanoformulations based on polymeric, protein, lipidic, or hybrid structure as suitable and stable drug delivery systems for encapsulating edaravone. We also evaluated the functionalization of nanoparticles with pegylated chains using the polyethylene glycol or tocopherol polyethylene glycol succinate and the possibility of preparing polymeric nanoparticles at different pH (7.4, 9, and 11). Edaravone was sucessfully encapsulated in polymeric, lipid-polymer hybrid, and lipidic nanoparticles. The use of higher pH values in the synthesis of polymeric nanoparticles has led to a decrease in nanoparticle size and an increase in the percentage of encapsulation efficiency. However, the resulting nanoformulations are not stable. Only polymeric and hybrid nanoparticles showed good stability over 80 days of storage, mainly at 4 °C. Overall, the nanoformulations tested did not show cytotoxicity in the SH-SY5Y cell line except the nanostructured lipid carrier formulations that showed some cytotoxicity possibly due to lipidic peroxidation. In conclusion, this work shows that edaravone can be encapsulated in different nanocarriers that could act as an interesting alternative for the treatment of Amyotrophic Lateral Sclerosis.},
}

*Edaravone/pharmacology/chemistry/administration & dosage
*Amyotrophic Lateral Sclerosis/drug therapy
Humans
*Nanoparticles/chemistry
Drug Delivery Systems/methods
Free Radical Scavengers/chemistry/pharmacology
Drug Carriers/chemistry
Nanoparticle Drug Delivery System/chemistry
Polyethylene Glycols/chemistry

@article {pmid40069959,
year = {2025},
author = {Chiò, A and Foucher, J and Gwathmey, KG and Ingre, C},
title = {Minimum clinically important difference for drug effectiveness in an area of patient-oriented therapeutic goals in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2475893},
pmid = {40069959},
issn = {2167-9223},
abstract = {Objective: In this review, we will examine the more common endpoints incorporated in randomized controlled trials (RCTs) and their strength of evidence, focusing on the definition of what constitutes a clinically meaningful change. We will also reflect on the perspective of patients and their families regarding the design of RCTs in amyotrophic lateral sclerosis (ALS). Methods: Authors performed a scoping review of the literature around clinical meaningfulness in the ALS field and the minimum clinically important difference to deem a treatment effective. Results: The use of survival as an RCT endpoint, as well as the ALS functional rating scale-revised slope, has been criticized, and their relevance for patients remains debated. Biomarkers are promising alternatives as surrogate endpoints, but currently, only cerebrospinal fluid and plasma neurofilaments have emerged as reliable and sensitive biomarkers of disease progression. Incorporating patients' preferences and priorities for their care when treatments are selected is important to minimize the burden of care and limit the potential harms of overtreatment. Patients' interest in and acceptance of a new therapy is also determined by its impact on their quality of life. Discussion and conclusion: While scientifically sound trials must be conducted, this must be balanced with patient expectations of limiting trial burden, duration and placebo usage. An important approach in uniting these diverging needs is the inclusion of people with ALS and their organizations to advise in the design and execution of clinical trials, facilitating the design of RCTs more focused on patients' expectations while retaining a high scientific rigor.},
}

@article {pmid40067821,
year = {2025},
author = {, and Berry, JD and Maragakis, NJ and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Stommel, EW and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, KJ and Simmons, Z and Miller, T and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, L and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, C and Ladha, S and Heiman-Patterson, T and Caress, J and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, CE and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Rynders, A and Evan, J and Evan, J and Hartford, A and Sepassi, M and Ho, KS and Glanzman, R and Greenberg, B and Hotchkin, MT and Paganoni, S and Cudkowicz, ME and , },
title = {CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.},
journal = {JAMA},
volume = {333},
number = {13},
pages = {1138-1149},
pmid = {40067821},
issn = {1538-3598},
abstract = {IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.

OBJECTIVE: To determine the effects of CNM-Au8 on ALS disease progression.

CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses.

INTERVENTIONS: Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation.

RESULTS: Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]).

CONCLUSIONS AND RELEVANCE: No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345.},
}

@article {pmid40067755,
year = {2025},
author = {, and Shefner, JM and Oskarsson, B and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Heiman-Patterson, T and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Caress, JB and Swenson, A and Peltier, A and Lewis, RA and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Leitner, ML and Chen, K and Goldberg, YP and Cohen, Y and Geva, M and Hayden, MR and Paganoni, S and Cudkowicz, ME and , },
title = {Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.},
journal = {JAMA},
volume = {333},
number = {13},
pages = {1128-1137},
pmid = {40067755},
issn = {1538-3598},
abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.

OBJECTIVE: To determine the effects of pridopidine, a σ1-receptor agonist, in ALS.

Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.

INTERVENTIONS: Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.

RESULTS: Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).

CONCLUSIONS AND RELEVANCE: In this 24-week study, pridopidine did not impact the progression of ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.},
}

@article {pmid40067754,
year = {2025},
author = {, and Andrews, J and Paganoni, S and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Young, E and Chase, M and Pothier, L and Harkey, B and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Connolly, MR and Berry, JD and D'Agostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Heitzman, D and Ajroud-Driss, S and Appel, SH and Shroff, S and Katz, J and Felice, K and Maragakis, NJ and Simmons, Z and Goutman, SA and Olney, N and Miller, T and Fernandes, JA and Ilieva, H and Jawdat, O and Weiss, MD and Foster, L and Vu, T and Ladha, S and Owegi, MA and Newman, DS and Arcila-Londono, X and Jackson, CE and Swenson, A and Heiman-Patterson, T and Caress, J and Fee, D and Peltier, A and Lewis, R and Rosenfeld, J and Walk, D and Johnson, K and Elliott, M and Kasarskis, EJ and Rutkove, S and McIlduff, CE and Bedlack, R and Elman, L and Goyal, NA and Rezania, K and Twydell, P and Benatar, M and Glass, J and Cohen, JA and Jones, V and Zilliox, L and Wymer, JP and Beydoun, SR and Shah, J and Pattee, GL and Martinez-Thompson, J and Nayar, S and Granit, V and Donohue, M and Grossman, K and Campbell, DJ and Qureshi, IA and Cudkowicz, ME and Babu, S and , },
title = {Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
pmid = {40067754},
issn = {2168-6157},
abstract = {IMPORTANCE: Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.

OBJECTIVE: To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.

Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.

INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.

RESULTS: A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.

CONCLUSIONS AND RELEVANCE: Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.

TRIAL REGISTRATION: Clinical Trial Identifiers: NCT04297683 and NCT04436510.},
}

@article {pmid40064496,
year = {2025},
author = {Su, Y and Yang, F and Xie, JC and Zhang, C and Luo, RX and Li, WS and Liu, BL and Su, MZ},
title = {Electroacupuncture Neural Stimulation Mitigates Bladder Dysfunction and Mechanical Allodynia in Cyclophosphamide Induced Cystitis through Downregulation of the BDNF-TrkB Signaling Pathway.},
journal = {eNeuro},
volume = {12},
number = {3},
pages = {},
pmid = {40064496},
issn = {2373-2822},
abstract = {Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is effective in mitigating pain-sensitive symptoms of BPS/IC and the mechanisms involved. This study aims to investigate the analgesic effect and mechanism of EA therapy. To achieve this goal, we employed several techniques: mechanical pain threshold tests to assess pain sensitivity, urodynamic studies to evaluate bladder function, Western blotting (WB) for protein analysis, immunofluorescence for visualizing, and transcriptomics. A rat cystitis model was established through a systemic intraperitoneal injection with cyclophosphamide (CYP). EA therapy was executed by stimulating the deep part of the hypochondriac point, where the 2nd-4th sacral nerves traverse. EA treatment was observed to effectively reduce mechanical allodynia, enhance urinary function, suppress the activation of microglial cells, and alleviate neuroinflammation. Additionally, EA demonstrated the capability to downregulate BDNF-TrkB signal transduction in the spinal dorsal horn. Transcriptome sequencing has indicated that EA therapy potentially inhibits excitatory neural transmission and modulates several pathways related to longevity. Furthermore, EA therapy has shown efficacy in treating conditions such as Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. In conclusion, by regulating the BDNF-TrkB signaling, EA nerve stimulation can effectively alleviate bladder dysfunction and mechanical allodynia in cyclophosphamide-induced cystitis model. Our research elucidates the underlying mechanisms of EA therapy in treating bladder dysfunction and offers new theoretical insights for addressing painful sensitization in BPS.Significance Statement Central sensitization is a major factor in bladder pain syndrome/interstitial cystitis (BPS/IC), making effective pain management crucial. This study explores the potential of electroacupuncture (EA) as a therapeutic approach to alleviate pain and improve bladder function in a rat model of BPS/IC induced by cyclophosphamide. Our findings demonstrate that EA therapy significantly reduces mechanical allodynia, enhances urinary function, and decreases neuroinflammation by modulating BDNF-TrkB signaling in the spinal dorsal horn. The research highlights EA's capability to inhibit excitatory neural transmission and provide relief in chronic pain conditions. These results offer new insights into the mechanisms of EA therapy, potentially improving treatment strategies for BPS/IC and similar pain syndromes.},
}

@article {pmid40064491,
year = {2025},
author = {Izumi, Y and Nakayama, Y},
title = {[Communicating the Diagnosis of Amyotrophic Lateral Sclerosis].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {3},
pages = {259-263},
doi = {10.11477/mf.188160960770030259},
pmid = {40064491},
issn = {1881-6096},
mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Communication ; Patient Care Team ; },
abstract = {When explaining amyotrophic lateral sclerosis, family members, caregivers, and other professionals are encouraged to be present with the patient's consent. Patients' perceptions vary considerably depending on their condition, personality, and home environment; therefore, the content of the explanation should be carefully considered. If the patient did not fully understand or provide consent to participate, the explanation was repeated. Depending on the patient's level of understanding and acceptance, we provided step-by-step explanations. The patients were informed that the decision could change later, even after the treatment plan had been decided. In explanations involving a multidisciplinary team, each professional explains; however, it is also important for the team leader to understand the patient's perceptions.},
}

*Amyotrophic Lateral Sclerosis/diagnosis
Humans
*Communication
Patient Care Team

@article {pmid40061972,
year = {2025},
author = {Yi, XM and Cai, HQ and Jiao, Y},
title = {Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer.},
journal = {World journal of gastrointestinal surgery},
volume = {17},
number = {2},
pages = {100257},
pmid = {40061972},
issn = {1948-9366},
abstract = {This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.},
}

@article {pmid40030015,
year = {2025},
author = {Johnson, EA and Nowar, R and Viola, KL and Huang, W and Zhou, S and Bicca, MA and Zhu, W and Kranz, DL and Klein, WL and Silverman, RB},
title = {Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {10},
pages = {e2402117122},
pmid = {40030015},
issn = {1091-6490},
support = {R01 AG061708/AG/NIA NIH HHS/United States ; R56 AG050492/AG/NIA NIH HHS/United States ; AG061708//HHS | National Institutes of Health (NIH)/ ; AG050492//HHS | National Institutes of Health (NIH)/ ; },
mesh = {*Amyloid beta-Peptides/metabolism ; Animals ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; Neurons/metabolism/drug effects ; Mice ; Hippocampus/metabolism/pathology ; Alzheimer Disease/metabolism/drug therapy/pathology ; Lysosomes/metabolism ; Protein Aggregation, Pathological/metabolism/drug therapy ; Autophagy/drug effects ; },
abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.},
}

*Amyloid beta-Peptides/metabolism
Animals
Humans
*Neurodegenerative Diseases/metabolism/drug therapy
Neurons/metabolism/drug effects
Mice
Hippocampus/metabolism/pathology
Alzheimer Disease/metabolism/drug therapy/pathology
Lysosomes/metabolism
Protein Aggregation, Pathological/metabolism/drug therapy
Autophagy/drug effects

@article {pmid40057669,
year = {2025},
author = {Hatcher, H and Stankeviciute, S and Learn, C and Qu, AX},
title = {Regulatory, Translational, and Operational Considerations for the Incorporation of Biomarkers in Drug Development.},
journal = {Therapeutic innovation & regulatory science},
volume = {},
number = {},
pages = {},
pmid = {40057669},
issn = {2168-4804},
abstract = {BACKGROUND: Biomarkers are an integral component in the drug development paradigm. According to the US Food and Drug Administration (FDA), a biomarker is "a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic intervention" (FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Glossary. 2016 [Updated 2021 Nov 29, cited 2024 Apr 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK338448/ Co-published by National Institutes of Health (US), Bethesda (MD)). The European Medicines Agency (EMA) defines a biomarker as "an objective and quantifiable measure of a physiological process, pathological process or response to a treatment (excluding measurements of how an individual feels or functions" European Medicines Agency (EMA). Biomaker. 2020a. Available from: https://www.ema.europa.eu/en/glossary-terms/biomarker#:~:text=Biomarker-,Biomarker,an%20individual%20feels%20or%20functions . Several clinical biomarkers are well-documented and have been used routinely for decades in health care settings and have long been accepted as valid endpoints for drug approval (for example, blood pressure measurement as a biomarker for cardiovascular health) (European Medicines Agency (EMA). Assessment report, TAGRISSO. 2016. Available from: https://www.ema.europa.eu/en/documents/assessment-report/tagrisso-epar-public-assessment-report_en.pdf . Accessed 15 Apr 2024). Recently, novel biomarkers have been identified and validated to accelerate developing innovative therapies indicated for serious human diseases, for example targeted/immune therapies of cancer (Chen in Med Drug Discov 21:100174, 2024). As indicators of the efficacy of new pharmacological treatments or therapeutic interventions, biomarkers can improve clinical trial efficacy and reduce uncertainty in regulatory decision making (Bakker et al. in Clin Pharmacol Ther 112:69-80, 2022; Califf in Exp Biol Med 243:213-221, 2018; Parker et al. in Cancer Med 10:1955-1963, 2021).

METHODOLOGY: This article describes case studies of recent drug approvals that successfully leveraged validated and non-validated biomarkers (i.e., tofersen for the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in adults; and osimertinib for treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC)).

CONCLUSIONS: Best practices for biomarker selection and strategies for health authority biomarker qualification programs are presented along with an overview of current limitations and challenges to optimizing biomarker applications along the drug development continuum from regulatory, translational, and operational perspectives.},
}

@article {pmid40056503,
year = {2025},
author = {Zhan, A and Zhong, K and Zhang, K},
title = {Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.},
journal = {Biochemical and biophysical research communications},
volume = {756},
number = {},
pages = {151582},
doi = {10.1016/j.bbrc.2025.151582},
pmid = {40056503},
issn = {1090-2104},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Proteostasis ; Animals ; Mitochondria/metabolism ; Protein Aggregates ; Homeostasis ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.},
}

*Amyotrophic Lateral Sclerosis/metabolism/pathology
Humans
*Proteostasis
Animals
Mitochondria/metabolism
Protein Aggregates
Homeostasis

@article {pmid40044193,
year = {2025},
author = {Ross, WT and Buday, S and Yakel, E and Khabele, D and Balls-Berry, J and As-Sanie, S and Colditz, G and Baumann, AA},
title = {Does interdisciplinary group care for the treatment of endometriosis improve pain interference: protocol for a pilot randomised controlled trial at an urban academic medical centre.},
journal = {BMJ open},
volume = {15},
number = {3},
pages = {e097372},
pmid = {40044193},
issn = {2044-6055},
support = {K23 HD110710/HD/NICHD NIH HHS/United States ; KL2 TR002346/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; Female ; Pilot Projects ; *Endometriosis/complications/therapy ; *Quality of Life ; *Pelvic Pain/therapy/etiology ; Academic Medical Centers ; Pain Management/methods ; Adult ; Randomized Controlled Trials as Topic ; Patient Care Team/organization & administration ; Pain Measurement ; },
abstract = {INTRODUCTION: Endometriosis affects 10-15% of people assigned female at birth and can cause chronic pelvic pain and impair many domains of quality of life, such as fertility, mood and bladder, bowel and sexual function. Current treatments often fail, leading to recurrent pain and the need for reintervention. As endometriosis negatively affects many domains of life, a variety of non-pharmacological treatments modestly improve symptoms. To bundle these interventions into accessible packaging, our interdisciplinary team developed a novel endometriosis intervention titled 'Peer-Empowered Endometriosis Pain Support (PEEPS)', an 8-week integrative group care intervention. Here, we present the protocol for a pilot randomised controlled trial (RCT) to evaluate the effectiveness and implementation of PEEPS for people with endometriosis-associated pain refractory to surgical management. We hypothesise that patients who complete the PEEPS programme will show a greater decrease in pain interference in daily activities at intervention completion as compared with baseline than those in the education arm.

METHODS AND ANALYSIS: This is a hybrid type 1 effectiveness-implementation mixed-methods RCT in which 60 participants will be randomised using computer-generated random numbers stratified by group in the ratio 1:1 to PEEPS plus usual versus educational handout plus usual care. The primary outcome is change in pain interference from baseline to intervention completion. Secondary outcomes include change in pain interference from baseline to 6 months and 12 months postintervention, as well as change in other quality-of-life measures as measured by nine validated questionnaires from baseline to completion, 6 months and 12 months. Proctor et al's Implementation Outcomes Framework will be used to evaluate acceptability, appropriateness and feasibility of PEEPS implementation, and the Consolidated Framework for Implementation Research will be used to guide the evaluation of barriers and facilitators of PEEPS at the patient and provider levels. Primary data analyses will follow the intention-to-treat principle. Descriptive statistics and two-sample t-tests for normally distributed values and Wilcoxon Rank-Sum test were performed for non-normally distributed values. Frequency analysis and Fisher's exact or χ[2] tests will be used for categoric variables as appropriate. Longitudinal analysis of the primary and secondary outcomes will be conducted with a mixed-effects model to investigate the effect of PEEPS compared with education. Least square means (LSMs) and the corresponding 95% CIs at each timepoint, as well as LSM differences and 95% CIs between any post-baseline and baseline will be provided for the outcomes. ORs and 95% CIs will be calculated for categorical outcomes. Qualitative data will be collected in the form of open-ended feedback, focus groups with programme completers and semistructured interviews with participants who complete two or fewer sessions. The analysis will use an embedded design-experimental model in which quantitative and qualitative outcomes will occur concurrently with weight priority given to quantitative data.

ETHICS AND DISSEMINATION: This trial was approved by the Washington University in St. Louis Institutional Review Board (protocol 202402082) on 27 March 2024 and has low risk of harm to participants. All deidentified data from this project will be shared via Digital Commons@Becker. The findings of this study will be disseminated via scientific meetings and peer-reviewed journals. The results and conclusions will be summarised for patients and the public in common language using infographics to make the findings accessible. This pilot RCT will yield the effect size for PEEPS and generate implementation context and outcomes data to guide PEEPS application to real-world practice. If PEEPS proves to be effective, this study will inform adaptation and scaling to improve the lives of people with endometriosis through a non-hormonal, fertility-preserving approach.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; NCT06549985.},
}

Humans
Female
Pilot Projects
*Endometriosis/complications/therapy
*Quality of Life
*Pelvic Pain/therapy/etiology
Academic Medical Centers
Pain Management/methods
Adult
Randomized Controlled Trials as Topic
Patient Care Team/organization & administration
Pain Measurement

@article {pmid40041912,
year = {2025},
author = {Dash, UC and Bhol, NK and Swain, SK and Samal, RR and Nayak, PK and Raina, V and Panda, SK and Kerry, RG and Duttaroy, AK and Jena, AB},
title = {Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {1},
pages = {15-34},
pmid = {40041912},
issn = {2211-3835},
abstract = {Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards.},
}

@article {pmid40038221,
year = {2025},
author = {Mustafa, F and Mittal, S and Garg, D and Agarwal, A and Garg, A and Gupta, BK and Soneja, M and Srivastava, AK},
title = {HIV associated motor neuron disease (MND): A case series with systematic review of literature.},
journal = {Journal of neurovirology},
volume = {31},
number = {1},
pages = {1-15},
pmid = {40038221},
issn = {1538-2443},
mesh = {Humans ; *HIV Infections/drug therapy/complications/virology ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/virology/drug therapy/diagnostic imaging/pathology ; Female ; Adult ; *Motor Neuron Disease/virology/drug therapy ; Viral Load ; CD4 Lymphocyte Count ; Anti-HIV Agents/therapeutic use ; },
abstract = {Human immunodeficiency virus (HIV) associated motor neuron disease (MND) is very rare. HIV infection can cause an MND-like syndrome due to central nervous system (CNS) involvement de novo or during antiretroviral therapy (ART) due to CNS escape. We present two cases: one with a classic amyotrophic lateral sclerosis (ALS) phenotype, which was the manifestation of symptomatic CNS escape from ART, and the second with a primary lateral sclerosis (PLS) phenotype associated with underlying HIV infection. A systematic review of published literature of people living with HIV (PLHIV) who developed ALS/ MND was conducted using the PubMed, Embase, and Lilacs databases. A total of 91 cases were found, 89 of which were obtained from 37 articles, and two were included from our own case series. In patients with HIV-associated MND, 63 patients reviewed had a classic ALS phenotype followed by progressive muscular atrophy variant (12), progressive bulbar palsy (8), PLS (7) and bulbar onset ALS (1). Neuroimaging, electrophysiology, cerebrospinal fluid (CSF) analysis, CSF and serum HIV viral load, and CD4 count investigations were used for diagnosis. Following the initiation or modification of antiretroviral therapy (ART), approximately 70% exhibited an improvement or a stable disease course. HIV-associated MND is a rare condition that can occur in both ART-naive individuals and those on treatment. A proportion of cases (~ 70%) show improvement with ART. Accurate diagnosis requires the exclusion of opportunistic infections, which remains a critical yet challenging aspect of managing this condition.},
}

Humans
*HIV Infections/drug therapy/complications/virology
Male
Middle Aged
*Amyotrophic Lateral Sclerosis/virology/drug therapy/diagnostic imaging/pathology
Female
Adult
*Motor Neuron Disease/virology/drug therapy
Viral Load
CD4 Lymphocyte Count
Anti-HIV Agents/therapeutic use

@article {pmid40033250,
year = {2025},
author = {Lu, C and Huang, XX and Huang, M and Liu, C and Xu, J},
title = {Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {82},
pmid = {40033250},
issn = {1471-2377},
mesh = {Humans ; *Mendelian Randomization Analysis/methods ; *Amyotrophic Lateral Sclerosis/genetics/blood ; *Proteomics/methods ; *Genome-Wide Association Study/methods ; *Biomarkers/blood ; Blood Proteins/genetics/analysis/metabolism ; Quantitative Trait Loci ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder with an increasing incidence rate. Despite advances in ALS research over the years, the precise etiology and pathogenic mechanisms remain largely elusive.

OBJECTIVE: To identify novel plasma proteins associated with ALS through Mendelian randomization methods in large-scale plasma proteomics and to provide potential biomarkers and therapeutic targets for ALS treatment.

METHODS: This study employed a large-scale plasma proteomic Mendelian randomization approach using genetic data from 80,610 individuals of European ancestry (including 20,806 ALS patients and 59,804 controls) derived from a genome-wide association study (GWAS). Protein quantitative trait loci (pQTLs) data were obtained from Ferkingstad et al. (2021), which measured 4,907 proteins in 35,559 Icelandic individuals. Multiple Mendelian randomization (MR) techniques were utilized, including weighted median, MR-Egger, Wald ratio, inverse-variance weighting (IVW), basic model, and weighted model. Heterogeneity was evaluated using Cochran's Q test. Horizontal pleiotropy was assessed through the MR-Egger intercept test and MR-PRESSO outlier detection. Sensitivity analysis was performed via leave-one-out analysis.

RESULTS: MR analysis revealed potential causal associations between 491 plasma proteins and ALS, identifying 19 novel plasma proteins significantly linked to the disease. Proteins such as C1QC, UMOD, SLITRK5, ASAP2, TREML2, DAPK2, ARHGEF10, POLM, SST, and SIGLEC1 showed positive correlations with ALS risk, whereas ADPGK, BTNL9, COLEC12, ADGRF5, FAIM, CRTAM, PRSS3, BAG5, and PSMD11 exhibited negative correlations. Reverse MR analyses confirmed that ALS negatively correlates with ADPGK and ADGRF5 expression. Enrichment analyses, including Gene Ontology (GO) functional analysis, indicated involvement in critical biological processes such as external encapsulating structure organization, extracellular matrix organization, chemotaxis, and taxis. KEGG pathway analysis highlighted significant enrichment in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and axon guidance.

CONCLUSION: This study enhances the understanding of ALS pathophysiology and proposes potential biomarkers and mechanistic insights for therapeutic development. Future research should explore the clinical translation of these findings to improve ALS patient outcomes and quality of life.},
}

Humans
*Mendelian Randomization Analysis/methods
*Amyotrophic Lateral Sclerosis/genetics/blood
*Proteomics/methods
*Genome-Wide Association Study/methods
*Biomarkers/blood
Blood Proteins/genetics/analysis/metabolism
Quantitative Trait Loci

@article {pmid40030850,
year = {2025},
author = {Hong, Z and Yi, S and Deng, M and Zhong, Y and Zhao, Y and Li, L and Zhou, H and Xiao, Y and Hu, X and Niu, L},
title = {Transcranial Focused Ultrasound Modifies Disease Progression in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.},
journal = {IEEE transactions on ultrasonics, ferroelectrics, and frequency control},
volume = {72},
number = {2},
pages = {191-201},
doi = {10.1109/TUFFC.2024.3525143},
pmid = {40030850},
issn = {1525-8955},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnostic imaging/genetics ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Ultrasonic Therapy/methods ; Superoxide Dismutase-1/genetics ; Disease Progression ; Muscle, Skeletal/physiopathology ; Male ; Motor Cortex ; Humans ; Elasticity Imaging Techniques ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressively worsening neurodegenerative condition with very few treatment options available. Ultrasound neuromodulation offers promising benefits for treating neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. However, the effects and underlying mechanisms of ultrasound neuromodulation on ALS remain unclear. A head-mounted ultrasound neuromodulation system was developed to noninvasively stimulate the motor cortex of symptomatic mice carrying the G93A human SOD1 mutation (SOD $1^{\text {G93A}}
$) for four weeks. Motor performance was assessed through the rotarod locomotor test, grip strength test, and open field test. In addition, the effect of ultrasound stimulation on the elastic modulus of gastrocnemius muscle atrophy was measured using real-time shear wave elastography (SWE). Subsequently, the brain tissues of the mice were harvested. Gastrocnemius morphology was examined using hematoxylin-eosin and Gomori aldehyde-fuchsin (GAF) staining. The number of neurons and the phenotype of microglia in the motor cortex were observed by immunohistochemical analysis. Ultrasound therapy delayed disease onset by 10.7% and increased the lifespan by 6.7% in SOD $1^{\text {G93A}}
$ mice by reduction of neuronal loss and enhancement of M2 microglia in the motor cortex. Furthermore, we found significant improvements in motor function for ultrasound-treated mice. More importantly, ultrasound stimulation ameliorated gastrocnemius muscle atrophy in the SOD $1^{\text {G93A}}
$ mice. These results revealed the neuroprotective effects of ultrasound against the disease pathogenesis of SOD $1^{\text {G93A}}
$ mice. Transcranial ultrasound neuromodulation provides an innovative tool for the intervention and treatment of neurodegenerative diseases.},
}

Animals
*Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnostic imaging/genetics
Mice
Disease Models, Animal
Mice, Transgenic
*Ultrasonic Therapy/methods
Superoxide Dismutase-1/genetics
Disease Progression
Muscle, Skeletal/physiopathology
Male
Motor Cortex
Humans
Elasticity Imaging Techniques

@article {pmid40029136,
year = {2025},
author = {Revi, N and Nandeshwar, M and Harijan, D and Sankaranarayanan, SA and Joshi, M and Prabusankar, G and Rengan, AK},
title = {Acridine Benzimidazolium Derivatives Induced Protective Microglia Polarization and In Silico TDP-43 Interaction─Potential Implications for Amyotrophic Lateral Sclerosis.},
journal = {ACS chemical neuroscience},
volume = {16},
number = {6},
pages = {1103-1116},
doi = {10.1021/acschemneuro.4c00791},
pmid = {40029136},
issn = {1948-7193},
mesh = {*Microglia/drug effects/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Animals ; *DNA-Binding Proteins/metabolism ; Benzimidazoles/pharmacology ; Neuroprotective Agents/pharmacology ; Mice ; Acridines/pharmacology ; Humans ; Molecular Docking Simulation ; },
abstract = {Abnormal protein aggregation and associated neuronal-glial cell cytotoxicity lead to a plethora of neurodegenerative disorders. Most of the earlier investigations on understanding neurodegenerative disease progression and cure focused on neuronal damage and restoration potential. With increased evidence on the role of glial cells like microglia and astrocytes in mediating these disorders, more studies are dedicated to understanding the role of inflammatory responses mediated by glial cells and how they lead to neuroinflammation. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder caused by TDP-43 aggregation that affects motor neurons. Pro-inflammatory microglia are considered to aggravate the disorder condition. In the current study, a previously reported molecule with TDP-43 inhibition, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)imidazol-3-ium) dibromide salt (AIM4), is analyzed for its microglia polarization properties along with two other derivatives, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)benzoimidazol-3-ium) dibromide salt (ABA). The 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl) benzimidazol-3-ium) dibromide salt (ABA) display the increased ability to maintain microglial cells to anti-inflammatory state and TDP-43 binding as compared to 3,3'-(acridine-4,5-diylbis(methylene)) bis(carboxymethyl)imidazolium dibromide salt (AIM4). This was confirmed from total nitrite levels, mitochondria membrane potential analysis, and molecular docking studies. The selected pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) displayed decreased levels, and anti-inflammatory cytokines IL-4 and IL-10 displayed increased levels, however not very significantly, upon treatment with all acridine derivatives. The compounds were investigated on lipopolysaccharides (LPS)-triggered mouse microglial cells and Danio rerio embryos displaying no significant cytotoxicity and physiological changes (cardiac rhythm), respectively. In molecular docking studies, alanine at 315 mutated to glutamate of TDP-43 directly interacts with AIM4. However, π-σ interactions of the aromatic backbone of acridine in ABE and ABA with 313 phenylalanine of TDP-43 along with hydrogen bonds formed between 309, 310 glycine amino acids and imidazolium bromide side chains rendered a stronger binding of these acridine derivatives with the protein potentially inhibiting fibrillation. Conclusion: ABA, ABE, and AIM4 maintain microglia in an anti-inflammatory state. However, more studies are required to understand its interaction with TDP-43 and the mechanism of its anti-inflammatory nature.},
}

*Microglia/drug effects/metabolism
*Amyotrophic Lateral Sclerosis/metabolism/drug therapy
Animals
*DNA-Binding Proteins/metabolism
Benzimidazoles/pharmacology
Neuroprotective Agents/pharmacology
Mice
Acridines/pharmacology
Humans
Molecular Docking Simulation

@article {pmid40027570,
year = {2025},
author = {Giorgio, A and Ciracì, E and De Luca, M and Stella, G and Giorgio, V},
title = {Hepatic abscess and hydatid liver cyst: European infectious disease point of view.},
journal = {World journal of hepatology},
volume = {17},
number = {2},
pages = {103325},
pmid = {40027570},
issn = {1948-5182},
abstract = {This manuscript is based on a recent study by Pillay et al that was published in recently. Liver abscesses can be caused by rare potentially life-threatening infections of either bacterial or parasitic origin. The incidence rate in Europe is lower than in developing countries, but it is a major complication with high morbidity, particularly in immunocompromised patients. They are most frequently caused by Enterobacterales infections, but hypervirulent Klebsiella strains are an emerging problem in Western countries. Amoebiasis has been a public health problem in Europe, primarily imported from other endemic foci. At the same time, this infection is becoming an emerging disease, as the number of infected patients who have not traveled to endemic areas is rising. Treatment options for hydatid liver cyst include chemotherapy, open or laparoscopic surgery, percutaneous treatment (percutaneous aspiration, re-aspiration and injection and its modification) and ''wait and watch'' strategy. Most hydatid liver cyst patients in Pillay et al's study received surgical treatment, but several studies have confirmed the safety and efficacy of percutaneous aspiration, re-aspiration and injection.},
}

@article {pmid40025240,
year = {2025},
author = {Maier, A and Kettemann, D and Weyen, U and Grehl, T and Schulte, PC and Steinbach, R and Rödiger, A and Weydt, P and Petri, S and Wolf, J and Grosskreutz, J and Koch, JC and Weishaupt, JH and Rosseau, S and Norden, J and Körtvélyessy, P and Koch, B and Holm, T and Hildebrandt, B and Schumann, P and Walter, B and Riitano, A and Münch, C and Meyer, T and Spittel, S},
title = {Provision, cough efficacy and treatment satisfaction of mechanical insufflation-exsufflation in a large multicenter cohort of patients with amyotrophic lateral sclerosis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {7360},
pmid = {40025240},
issn = {2045-2322},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Cough ; Male ; Female ; *Insufflation/methods ; Middle Aged ; Aged ; *Patient Satisfaction ; Longitudinal Studies ; Treatment Outcome ; Germany ; },
abstract = {In patients with amyotrophic lateral sclerosis (ALS), mechanical insufflation-exsufflation (MI-E) addresses cough deficiency to achieve major therapeutic goals: improving costal muscle and joint function, reducing atelectasis through insufflation, and clearing bronchial secretions via exsufflation. Despite its perceived benefits, there is limited systematic research on MI-E provision, symptom alleviation, or patient satisfaction. The research platform Ambulanzpartner coordinated this longitudinal observational study conducted in 12 German ALS centers from July 2018 to September 2023. Patients were enrolled based on ALS-related cough deficiency requiring MI-E therapy. The study recorded provision, reasons for withholding MI-E, clinical parameters, therapy frequency, subjective cough deficiency, and symptomatic relief. Satisfaction with MI-E therapy was determined by the likelihood of recommendation. Out of 694 ALS patients indicated for MI-E, 527 (75.9%) received the therapy. The primary reason for non-provision was that the patient had died before provision (n = 66 of 167; 39.5%). These patients were significantly more affected as represented by higher progression rates and lower cough peak flows (CPF) at the time of MI-E indication (p < 0.05). Most patients who received MI-E used it daily (n = 290 of 370; 78.4%). Self-assessed cough deficiency correlated with clinical measurements, especially for patients with higher deficits. At follow-up visits, patients reported reduced cough deficiency (p < 0.001). Frequent MI-E use was linked to greater symptom relief and higher likelihood of recommending the therapy. This study highlights the symptomatic and palliative potential of MI-E therapy for ALS patients.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/complications
*Cough
Male
Female
*Insufflation/methods
Middle Aged
Aged
*Patient Satisfaction
Longitudinal Studies
Treatment Outcome
Germany

@article {pmid40024955,
year = {2025},
author = {Masood, S and Almas, MS and Hassan, SSU and Tahira, S and Fiaz, MH and Minhas, UEA and Zafar, HMQ and Masood, M},
title = {Safety and efficacy of arimoclomol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40024955},
issn = {1590-3478},
abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) is a debilitating motor neuron disorder characterized by muscle weakness, atrophy, and spasticity. This meta-analysis aims to assess the safety and efficacy of Arimoclomol in patients with ALS.

METHOD: A comprehensive literature search was conducted on 3 databases to discover articles published up to August 2024. Included studies were randomized controlled trials (RCTs). Data was analysed using Review Manager (v5.4). Cochrane Risk of Bias-2 (RoB-2) was adopted to assess the quality of RCTs.

RESULTS: A total of 359 patients were analysed, with 239 individuals in the Arimoclomol group and 120 individuals in the placebo group. The pooled analysis of the primary outcome, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score from baseline, did not demonstrate a statistically significant difference favoring the Arimoclomol group (MD = 0.4495; 95% CI: -0.39, 1.27; p = 0.30). Similarly, secondary outcomes, including the Combined Assessment of Function and Survival (CAFS) rank score (MD = 1.00; 95% CI: -2.68, 4.67; p = 0.60), increase in transaminases (RR = 1.05; 95% CI: 0.19, 5.70; p = 0.95), mortality rate (RR = 0.86; 95% CI: 0.55, 1.34; p = 0.50), and adverse events (RR = 0.86; 95% CI: 0.55, 1.34; p = 0.50), showed no statistically significant differences between the groups.

CONCLUSION: This study does not conclusively demonstrate that Arimoclomol has beneficial effects on ALS patients' physical functionality but shows promise for safety. Further clinical trials are needed to explore the neuroprotective effects of Arimoclomol in the treatment of ALS.},
}

@article {pmid40019593,
year = {2025},
author = {Dobroniak, CC and Lesche, V and Olgemöller, U and Beck, P and Lehmann, W and Spering, C},
title = {Surgical strategy for chest wall reconstruction secondary to cardiopulmonary resuscitation versus post-traumatic.},
journal = {European journal of trauma and emergency surgery : official publication of the European Trauma Society},
volume = {51},
number = {1},
pages = {122},
pmid = {40019593},
issn = {1863-9941},
mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; Male ; Female ; Retrospective Studies ; Middle Aged ; *Thoracic Wall/injuries/surgery ; *Flail Chest/surgery/etiology ; *Rib Fractures/surgery ; *Sternum/injuries/surgery ; Germany ; Plastic Surgery Procedures/methods ; Aged ; Fracture Fixation, Internal/methods ; Adult ; Length of Stay/statistics & numerical data ; Bone Plates ; },
abstract = {PURPOSE: In mechanically cardiopulmonary resuscitated (CPR) patients, chest compressions at the level of the 3rd to 5th rib on the sternum result in reproducibly similar injury patterns: parasternal osteochondral dissociation (OCS) on both sides in combination with a sternal fracture with or without an additional serial rib fracture in the anterolateral column (ALS). This injury biomechanically impairs physiological breathing, resulting in an inverse breathing pattern. Trauma patients, on the other hand, often show a mixed pattern depending on the location of the main energy. The aim of the study was to evaluate the surgical technique of chest wall reconstruction (CWR) using transsternal refixation of the 5th rib on both sides in combination with plate osteosynthesis of the sternum and to analyze its success in comparison to the surgical strategy of CWR in the context of a traumatic genesis.

METHOD: Data acquisition was performed using medical records of a Level I Trauma Centre in Germany and compare patients with radiologically or clinically diagnosed flail chest as a result of cardiopulmonary mechanical resuscitation (CPR). The retrospective study included patients in the period 2018-2023 after surgical CWR. The patients were either post-CPR (n = 29; CPR) or trauma patients (n = 36; trauma). The collective was described and analyzed using the digital patient file, as well as data on ICU stay and duration of ventilation or conversion to assisted ventilation modes, reason for chest wall instability, time of surgery, length of stay and mortality. As a long-term follow-up, body plethysmography was analyzed comparatively. Primary endpoints were mean length of stay in ICU, time to surgery, ventilator dependency and mortality rate. Secondary endpoints were time to transfer to rehabilitation, ventilation disorders and long term outcome.

RESULTS: In the period 65 patients (48 m, 17w) were included, 29 of whom had been mechanically resuscitated (CPR), 36 formed to post-traumatic cohort (trauma). The CPR were significantly older (69 vs. 58 years; p-value 0.003). The duration from CPR to surgery was on average significantly longer than trauma to surgery (16.76 vs. 4.11 days). The mean length of stay in ICU were 30 days (trauma) and 45 days for CPR (significantly longer, p-value 0.0008). The mean duration of ventilation was 188 h for trauma and 593 h for CPR. Extubation or conversion to assisted, relevant de-escalating ventilation modes was possible in both groups after a mean of 38 h post-OP. Among the CPR patients, 4 died in hospital (hospital mortality: CPR 20.7% vs. trauma 5.6%), 7 (30%) were transferred to an early clinical rehabilitation and 10 were discharged to home or follow-up treatment. In the case of trauma, 5 (14.7%) were transferred to an early clinical rehabilitation and 20 were discharged to home or follow-up treatment. Bodyplethysmography 6 months after CPR / trauma showed no differences in both collectives with regard to ventilation disorders. Diffusion was prolonged in both groups, presumably due to the healing process of lungs contusion. Both showed no restriction disorders.

CONCLUSION: Chest wall reconstruction, including plate osteosynthesis of the sternum in combination with transsternal fixation of the 5th rib on both sides can largely restore physiological respiratory mechanics immediately after surgery and accelerate the weaning success. In the management of patients after CPR, the initial diagnosis which had indicated resuscitation, is the main focus and can often be an obstacle to extubation. Nevertheless, independent breathing can be accelerated by restoring the biomechanics through early surgical treatment using CWR and saves long-term ICU stays with the potential for further complication and resource consumption. CWR forms the essential basis for early rehabilitation of the underlying cause of resuscitation. Ventilation disorders do not occur after surgical CWR, even during the course of the procedure.},
}

Humans
*Cardiopulmonary Resuscitation/methods
Male
Female
Retrospective Studies
Middle Aged
*Thoracic Wall/injuries/surgery
*Flail Chest/surgery/etiology
*Rib Fractures/surgery
*Sternum/injuries/surgery
Germany
Plastic Surgery Procedures/methods
Aged
Fracture Fixation, Internal/methods
Adult
Length of Stay/statistics & numerical data
Bone Plates

@article {pmid40017137,
year = {2025},
author = {Lovett, A and Chary, S and Babu, S and Bruneteau, G and Glass, JD and Karlsborg, M and Ladha, S and Mayl, K and McDermott, C and Bucelli, RC and Chiò, A and Ferguson, TA and Cochrane, T and Fradette, S and Smirnakis, K and Inra, J and Malek, S and Fanning, L},
title = {Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28372},
pmid = {40017137},
issn = {1097-4598},
support = {//Biogen/ ; },
abstract = {INTRODUCTION/AIMS: Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1-ALS). Here we report serious neurologic adverse events (AEs) that occurred in the tofersen clinical trials in people with SOD1-ALS.

METHODS: Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described. Serious AEs were defined according to International Conference for Harmonization guidelines, and neurologic AEs in clinical trials were diagnosed by investigators based on symptoms, clinical examination findings, and diagnostic workup.

RESULTS: Ten participants (approximately 7% of tofersen 100-mg-treated trial participants) experienced a total of 12 serious neurologic AEs-4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis, and 4 of intracranial hypertension (ICH) and/or papilledema. All events but one resolved either spontaneously, with dosing interruption/modification, or with concomitant therapies. One event was ongoing but improved as of December 2022. While 3 events led to tofersen treatment discontinuation, all other participants were able to remain on treatment. No event was life-threatening or fatal.

DISCUSSION: Some antisense oligonucleotides (ASOs) have been described as having pro-inflammatory properties. Aseptic meningitis has been reported with nusinersen; however, myelitis, radiculitis, increased intracranial pressure, and papilledema have not been reported with ASO treatment. These neurologic AEs should be considered when assessing the overall benefit/risk of tofersen treatment for SOD1-ALS. Safety data from the open-label extension and expanded access program will continue to characterize these events and further inform the safety profile of tofersen in SOD1-ALS.},
}

@article {pmid40012174,
year = {2025},
author = {Rajamanickam, G and Hu, Z and Liao, P},
title = {Targeting the TRPM4 Channel for Neurologic Diseases: Opportunity and Challenge.},
journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry},
volume = {},
number = {},
pages = {10738584251318979},
doi = {10.1177/10738584251318979},
pmid = {40012174},
issn = {1089-4098},
abstract = {As a monovalent cation channel, the transient receptor potential melastatin 4 (TRPM4) channel is a unique member of the transient receptor potential family. Abnormal TRPM4 activity has been identified in various neurologic disorders, such as stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, pathologic pain, and epilepsy. Following brain hypoxia/ischemia and inflammation, TRPM4 up-regulation and enhanced activity contribute to the cell death of neurons, vascular endothelial cells, and astrocytes. Enhanced ionic influx via TRPM4 leads to cell volume increase and oncosis. Depolarization of membrane potential following TRPM4 activation and interaction between TRPM4 and N-methyl-d-aspartate receptors exacerbate excitotoxicity during hypoxia. Importantly, TRPM4 expression and activity remain low in healthy neurons, making it an ideal drug target. Current approaches to inhibit or modulate the TRPM4 channel have various limitations that hamper the interpretation of TRPM4 physiology in the nervous system and potentially hinder their translation into therapy. In this review, we discuss the pathophysiologic roles of TRPM4 and the different inhibitors that modulate TRPM4 activity for potential treatment of neurologic diseases.},
}

@article {pmid40011745,
year = {2025},
author = {Rödström, KEJ and Eymsh, B and Proks, P and Hayre, MS and Cordeiro, S and Mendez-Otalvaro, E and Madry, C and Rowland, A and Kopec, W and Newstead, S and Baukrowitz, T and Schewe, M and Tucker, SJ},
title = {Cryo-EM structure of the human THIK-1 K2P K[+] channel reveals a lower Y gate regulated by lipids and anesthetics.},
journal = {Nature structural & molecular biology},
volume = {},
number = {},
pages = {},
pmid = {40011745},
issn = {1545-9985},
abstract = {THIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K[+] channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer's disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-Å-resolution cryo-EM structure of human THIK-1 that reveals several distinct features, in particular, a tyrosine in M4 that contributes to a lower 'Y gate' that opens upon activation by physiologically relevant G-protein-coupled receptor and lipid signaling pathways. We demonstrate that linoleic acid bound within a modulatory pocket adjacent to the filter influences channel activity, and that halothane inhibition involves a binding site within the inner cavity, both resulting in conformational changes to the Y gate. Finally, the extracellular cap domain contains positively charged residues that line the ion exit pathway and contribute to the distinct biophysical properties of this channel. Overall, our results provide structural insights into THIK-1 function and identify distinct regulatory sites that expand its potential as a drug target for the modulation of microglial function.},
}

@article {pmid40011434,
year = {2025},
author = {Gao, G and Shi, Y and Deng, HX and Krainc, D},
title = {Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {1982},
pmid = {40011434},
issn = {2041-1723},
support = {R21 NS114765/NS/NINDS NIH HHS/United States ; NS114765//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS099623/NS/NINDS NIH HHS/United States ; R35 NS122257/NS/NINDS NIH HHS/United States ; NS122257//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS099623//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Animals ; *Lipid Peroxidation ; *Ketoglutarate Dehydrogenase Complex/metabolism/genetics ; Humans ; *Mitochondria/metabolism ; *Parkinson Disease/metabolism/genetics ; Male ; Mice ; *alpha-Synuclein/metabolism/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; *Dopaminergic Neurons/metabolism/pathology ; Thioctic Acid/metabolism ; Transcription Factors/metabolism/genetics ; Mitochondrial Proteins/metabolism/genetics ; Mice, Knockout ; Ketoglutaric Acids/metabolism ; Brain/metabolism ; },
abstract = {Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.},
}

Animals
*Lipid Peroxidation
*Ketoglutarate Dehydrogenase Complex/metabolism/genetics
Humans
*Mitochondria/metabolism
*Parkinson Disease/metabolism/genetics
Male
Mice
*alpha-Synuclein/metabolism/genetics
*Disease Models, Animal
*DNA-Binding Proteins/metabolism/genetics
*Dopaminergic Neurons/metabolism/pathology
Thioctic Acid/metabolism
Transcription Factors/metabolism/genetics
Mitochondrial Proteins/metabolism/genetics
Mice, Knockout
Ketoglutaric Acids/metabolism
Brain/metabolism