@article {pmid38647894,
year = {2022},
author = {Li, N and Zeng, Y and Chen, Y and Shen, Y and Wang, W},
title = {Induction of cellulase production by Sr[2+] in Trichoderma reesei via calcium signaling transduction.},
journal = {Bioresources and bioprocessing},
volume = {9},
number = {1},
pages = {96},
pmid = {38647894},
issn = {2197-4365},
support = {2021-02-08-00-12-F00758//Shanghai Agriculture Applied Technology Development Program, China/ ; 22ZR1417600//Natural Science Foundation of Shanghai/ ; 32000050//National Natural Science Foundation of China/ ; },
abstract = {Trichoderma reesei RUT-C30 is a well-known high-yielding cellulase-producing fungal strain that converts lignocellulose into cellulosic sugar for resource regeneration. Calcium is a ubiquitous secondary messenger that regulates growth and cellulase production in T. reesei. We serendipitously found that adding Sr[2+] to the medium significantly increased cellulase activity in the T. reesei RUT-C30 strain and upregulated the expression of cellulase-related genes. Further studies showed that Sr[2+] supplementation increased the cytosolic calcium concentration and activated the calcium-responsive signal transduction pathway of Ca[2+]-calcineurin-responsive zinc finger transcription factor 1 (CRZ1). Using the plasma membrane Ca[2+] channel blocker, LaCl3, we demonstrated that Sr[2+] induces cellulase production via the calcium signaling pathway. Supplementation with the corresponding concentrations of Sr[2+] also inhibited colony growth. Sr[2+] supplementation led to an increase in intracellular reactive oxygen species (ROS) and upregulated the transcriptional levels of intracellular superoxide dismutase (sod1) and catalase (cat1). We further demonstrated that ROS content was detrimental to cellulase production, which was alleviated by the ROS scavenger N-acetyl cysteine (NAC). This study demonstrated for the first time that Sr[2+] supplementation stimulates cellulase production and upregulates cellulase genes via the calcium signaling transduction pathway. Sr[2+] leads to an increase in intracellular ROS, which is detrimental to cellulase production and can be alleviated by the ROS scavenger NAC. Our results provide insights into the mechanistic study of cellulase synthesis and the discovery of novel inducers of cellulase.},
}

@article {pmid38647195,
year = {2024},
author = {Picchi, SC and Rebelatto, D and Martins, PMM and Blumer, S and Mesquita, GL and Hippler, FWR and Mattos-Junior, D and Boaretto, RM and Machado, MA and Takita, MA and Coletta-Filho, HD and de Souza, AA},
title = {N-acetylcysteine absorption and its potential dual effect improve fitness and fruit yield in Xylella fastidiosa infected plants.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.8137},
pmid = {38647195},
issn = {1526-4998},
abstract = {BACKGROUND: Xylella fastidiosa is a multi-host bacterium that can be detected in hundreds of plant species including several crops. Diseases caused by X. fastidiosa are considered a threat to global food production. The primary method for managing diseases caused by X. fastidiosa involves using insecticides to control the vector. Hence, it is necessary to adopt new and sustainable disease management technologies to control not only the insect but also the bacteria and plant health. We demonstrated that N-Acetylcysteine (NAC), a low-cost cysteine analogue, is a sustainable molecule that can be used in agriculture to decrease the damage caused by X. fastidiosa and improve plant health.

RESULTS: Using [15]N-NAC we proved that it was absorbed by the roots and transported to different parts of the plant. Inside the plant, NAC reduced the bacterial population by 60-fold and the number of xylem vessels blocked by bacterial biofilms. This reflected in a recovery of 0.28-fold of the daily sap flow compared to health plants. In addition, NAC-treated CVC plants decreased the oxidative stress by improving the activity of detoxifying enzymes. Moreover, the use of NAC in field conditions positively contributed for the increase in fruit yield of CVC-diseased plants.

CONCLUSION: Our research not only advances the understanding of NAC absorption in plants but also indicates its dual effect as an antimicrobial and antioxidant molecule. This, in turn, negatively affects bacterial survival while improving plant health by decreasing oxidative stress. Overall, the positive field-based evidence supports the viability of NAC as a sustainable agricultural application. This article is protected by copyright. All rights reserved.},
}

@article {pmid38643270,
year = {2024},
author = {Bates, JN and Baby, SM and Getsy, PM and Coffee, GA and Hsieh, YH and Knauss, ZT and Dahan, A and Bubier, JA and MacFarlane, PM and Mueller, D and Lewis, SJ},
title = {L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {9091},
pmid = {38643270},
issn = {2045-2322},
support = {U01DA051373/DA/NIDA NIH HHS/United States ; },
mesh = {Rats ; Male ; Animals ; Fentanyl/pharmacology ; Acetylcysteine/*analogs & derivatives ; Rats, Sprague-Dawley ; *Substance Withdrawal Syndrome ; Naloxone/pharmacology ; Narcotic Antagonists/pharmacology ; *Morphine Dependence ; Lysine/*analogs & derivatives ; },
abstract = {N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 μmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 μmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 μg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 μg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.},
}

Rats
Male
Animals
Fentanyl/pharmacology
Acetylcysteine/*analogs & derivatives
Rats, Sprague-Dawley
*Substance Withdrawal Syndrome
Naloxone/pharmacology
Narcotic Antagonists/pharmacology
*Morphine Dependence
Lysine/*analogs & derivatives

@article {pmid38641841,
year = {2024},
author = {Sajedi, F and Abdi, A and Mehrpooya, M and Faramarzi, V and Mohammadi, Y and Sheida, F},
title = {Comparison of therapeutic effects of N-Acetylcysteine with pregabalin in improving the clinical symptoms of painful diabetic neuropathy: a randomized, double-blind clinical trial.},
journal = {Clinical diabetes and endocrinology},
volume = {10},
number = {1},
pages = {15},
pmid = {38641841},
issn = {2055-8260},
support = {IR.UMSHA.REC.1397.137//Hamadan University of Medical Sciences/ ; },
abstract = {OBJECTIVES: Painful diabetic neuropathy (PDN) is highly prevalent and annoyingly in patients with diabetes. The aim of this study was to investigate the effects of oral N-acetylcysteine (NAC) compared to pregabalin in PDN.

METHODS: One hundred two eligible patients with type 2 diabetes and PDN were randomly recievied pregabalin (150 mg/day) or N-Acetylcysteine (NAC) (600 mg/ twice a day) for 8 weeks. Mean pain score, Sleep interference score (SIS), Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and also, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study.

RESULTS: NAC was well tolerated in all patients. The decrease in mean pain scores and increase in SIS was similar between two groups. More improvement in PGIC and CGIC from the baseline was reported in NAC group. NAC, significantly, decreased serum levels of MDA, and NO, but increased TAC, TTG, and CAT. Pregabalin, significantly, decreased serum levels of MDA, and NO and increased TAC.

DISCUSSION: NAC is efficacious in alleviate symptoms of PDN which is probably related to its antioxidant effects.

TRIAL REGISTRATION: The research protocol received approval from the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.137). The trial registry URL and number in Iranian Registry of Clinical Trials (IRCT): https://www.irct.ir/trial/33313 , IRCT20180814040795N2 (Registration date: 2019-01-21, Retrospectively registered).},
}

@article {pmid38641701,
year = {2024},
author = {Hassan, YF and Shabaan, DA},
title = {Effect of N-acetylcysteine on hair follicle changes in mouse model of cyclophosphamide-induced alopecia: histological and biochemical study.},
journal = {Histochemistry and cell biology},
volume = {},
number = {},
pages = {},
pmid = {38641701},
issn = {1432-119X},
abstract = {Chemotherapy-induced alopecia (CIA) represents one of the most severe side effects of chemotherapy, which forces some patients to reject cancer treatment. The exact pathophysiological mechanisms of CIA are not clearly understood, which makes it difficult to discover efficient preventive or therapeutic procedures for this adverse effect. N-acetylcysteine (NAC) has a strong antioxidant activity as it stimulates glutathione synthesis and acts as an oxygen radical scavenger. The current study tried to investigate the efficacy of NAC in preserving biochemical parameters and hair follicle structure against cyclophosphamide (CYP) administration. In total, 40 adult female C57BL/6 mice were induced to enter anagen by depilation (day 0) and divided into four groups: group I (control), group II (CYP) received a single dose of CYP [150 mg/kg body weight (B.W.)/intraperitoneal injection (IP)] at day 9, group III (CYP & NAC) received a single dose of CYP at day 9 as well as NAC (500 mg/kg B.W./day/IP) from day 6-16, and group IV (NAC) received NAC from day 6-16. CYP administration in group II induced an increase in malondialdehyde (MDA), decrease in superoxide dismutase (SOD), histological hair follicle dystrophy, disruption of follicular melanogenesis, overexpression of p53, and loss of ki67 immunoreactivity. NAC coadministration in group III reversed CYP-induced alterations in the biochemical parameters and preserved hair follicle structure, typical follicular melanin distribution as well as normal pattern of p53 and ki67 expression. These findings indicated that NAC could be used as an efficient and safe therapeutic option for hair loss induced by chemotherapy.},
}

@article {pmid38636660,
year = {2024},
author = {Boeglin, WE and Stec, DF and Noguchi, S and Calcutt, MW and Brash, AR},
title = {The Michael addition of thiols to 13-oxo-octadecadienoate (13-oxo-ODE) with implications for LC-MS analysis of glutathione conjugation.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {107293},
doi = {10.1016/j.jbc.2024.107293},
pmid = {38636660},
issn = {1083-351X},
abstract = {Unsaturated fatty acid ketones with αβ,γδ conjugation are susceptible to Michael addition of thiols, with unresolved issues on the site of adduction and precise structures of the conjugates. Herein we reacted 13-keto-octadecadienoic acid (13-oxo-ODE or 13-KODE) with glutathione (GSH), N-acetyl-cysteine, and β-mercaptoethanol and identified the adducts. HPLC-UV analyses indicated none of the products exhibit a conjugated enone UV chromophore, a result that conflicts with the literature and relevant to mass spectral interpretation of 1,4 versus 1,6 thiol adduction. Aided by development of an HPLC solvent system that separates the GSH diastereomers and thus avoids overlap of signals in proton NMR experiments, we established the two major conjugates are formed by 1,6 addition of GSH at the 9-carbon of 13-oxo-ODE with the remaining double bond α to the thiol in the 10,11 position. N-acetyl cysteine reacts similarly, while β-mercaptoethanol gives equal amounts of 1,4 and 1,6 addition products. Equine glutathione transferase catalyzed 1,6 addition of GSH to the two major diastereomers in 44:56 proportions. LC-MS in positive ion mode gives a product ion interpreted before as evidence of 1,4-thiol adduction, whereas here we find this ion using the authentic 1,6 adduct. LC-MS with negative ion APCI gave a fragment selective for 1,4 adduction. These results clarify the structures of thiol conjugates of a prototypical unsaturated keto fatty acid and have relevance to the application of LC-MS for the structural analysis of keto-fatty acid glutathione conjugation.},
}

@article {pmid38634668,
year = {2024},
author = {Hakimi, F and Karimi Torshizi, MA and Hezavehei, M and Sharafi, M},
title = {Protective Effect of N-Acetylcysteine on Rooster Semen Cryopreservation.},
journal = {Biopreservation and biobanking},
volume = {},
number = {},
pages = {},
doi = {10.1089/bio.2023.0103},
pmid = {38634668},
issn = {1947-5543},
abstract = {Cryopreservation of avian semen is a useful reproductive technique in the poultry industry. However, during cooling, elevated reactive oxygen species (ROS) levels have destructive effects on both quality and function of thawed sperm. The aim of the current study is to investigate the antioxidant effects of N-acetylcysteine (NAC) during rooster semen cryopreservation. Semen samples were collected from ten Ross 308 broiler breeder roosters (32 weeks) and mixed. The mixed samples were divided into five equal parts and cryopreserved in Lake Buffer extender that contained different concentrations (0, 0.01, 0.1, 1, and 10 mM) of NAC. The optimum concentration of NAC was determined based on quality parameters of mobility, viability, membrane integrity, acrosome integrity, lipid peroxidation, and mitochondrial membrane potential after the freeze-thaw process. There was a higher percentage (p < 0.05) of total motility (TM) (60.9 ± 2.4%) and progressive motility (PM) (35.6 ± 1.9%) observed with the NAC-0.1 group compared to the other groups. Significantly higher percentages of viability (74.4 ± 2.3% and 71 ± 2.3%), membrane integrity (76.4 ± 1.5% and 74.7 ± 1.5%) and mitochondrial membrane potential (67.1 ± 1.6% and 66.3 ± 1.6%) were observed in the NAC-0.1 and NAC-1 groups compared to the other frozen groups (p < 0.05). The lowest percentage of lipid peroxidation and nonviable sperm was found in the NAC-0.1 and NAC-1 groups compared to the other groups (p < 0.05). The average path velocity (VAP), straight line velocity (VSL), curvilinear velocity (VCL), and acrosome integrity, were not affected by different concentrations of NAC in the thawed sperm (p > 0.05). Both NAC-0.1 and NAC-1 appear to be beneficial for maintaining the quality of rooster sperm after thawing.},
}

@article {pmid38633147,
year = {2024},
author = {Shams, G and Allah, SA and Ezzat, R and Said, MA},
title = {Ameliorative effects of berberine and selenium against paracetamol-induced hepatic toxicity in rats.},
journal = {Open veterinary journal},
volume = {14},
number = {1},
pages = {292-303},
pmid = {38633147},
issn = {2218-6050},
abstract = {BACKGROUND: Paracetamol (PCM) overdosing induces hepatotoxicity, which can result in death if the dose is high enough and the patients are not given N-acetyl cysteine. Berberine (BBR) has a variety of biological proprieties including anti-inflammatory and antioxidant activities.

AIM: Assessment of the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity in rats.

METHODS: This research involved 40 clinically healthy mature adult male albino rats, their weights ranged from 150 to 200 g and housed in standard conditions. Our study involved evaluating the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity via estimation of the liver function tests, determination of the antioxidant enzyme activities, lipid peroxidation markers, immune-modulatory effects, liver histopathological, and immunohistochemical studies.

RESULTS: Co-treatment of BBR (150 mg/kg BW) with selenium (5 mg/kg BW) showed significant improvement in the liver function parameters, the antioxidant enzyme activities, reduction in the nitric oxide (NO), lysozyme, malondialdehyde (MDA), TNF-α, and TGF-β1 levels, and marked elevation in the IgM levels.

CONCLUSION: Altogether, BBR, selenium, or both augment antioxidant activity and alleviate PCM-induced hepatic toxicity.},
}

@article {pmid38629620,
year = {2024},
author = {Kim, SH and Kang, DW and Kwon, D and Jung, YS},
title = {Critical role of endoplasmic reticulum stress on bisphenol A-induced cytotoxicity in human keratinocyte HaCaT cells.},
journal = {Environmental toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1002/tox.24290},
pmid = {38629620},
issn = {1522-7278},
support = {2022R1I1A1A01070024//National Research Foundation of Korea/ ; //Korean Government (MSIT)/ ; 20014436//Technology Innovation Program/ ; //Ministry of Trade, Industry & Energy (MOTIE, Korea)/ ; },
abstract = {Bisphenol A (BPA) is widely used in plastic and paper products, and its exposure can occur through skin contact or oral ingestion. The hazardous effects of BPA absorbed through the skin may be more severe; however, few studies have investigated the skin toxicity of BPA. This study investigated the effects of BPA on human epidermal keratinocyte cell lines, which is relevant for skin exposure. BPA treatment reduced cell viability in a time- and concentration-dependent manner and elevated oxidative and endoplasmic reticulum (ER) stress. N-acetylcysteine (NAC), an oxidative stress inhibitor, reduced BPA-induced reactive oxygen species (ROS) levels. However, only 10% of the decreased cell viability was restored at the highest NAC concentration. Treatment with tauroursodeoxycholic acid (TUDCA), which is an ER stress inhibitor, effectively countered the increase in ER stress-related proteins induced by BPA. Moreover, TUDCA treatment led to a reduction in oxidative stress, as demonstrated by the decrease in ROS levels, maintenance of mitochondrial membrane potential, and modulation of stress signaling proteins. Consequently, TUDCA significantly improved BPA-induced cytotoxicity in a concentration-dependent manner. Notably, combined treatment using TUDCA and NAC further reduced the BPA-induced ROS levels; however, no significant difference in cell viability was observed compared with that for TUDCA treatment alone. These findings indicated that the oxidative stress observed following BPA exposure was exacerbated by ER stress. Moreover, the principal factor driving BPA-induced cytotoxicity was indeed ER stress, which has potential implications for developing therapeutic strategies for diseases associated with similar stress responses.},
}

@article {pmid38622261,
year = {2024},
author = {Liu, C and Zha, J and Sun, T and Kong, L and Zhang, X and Wang, D and Ni, G},
title = {Cold atmospheric plasma attenuates skin cancer via ROS induced apoptosis.},
journal = {Molecular biology reports},
volume = {51},
number = {1},
pages = {518},
pmid = {38622261},
issn = {1573-4978},
mesh = {Animals ; *Skin Neoplasms/drug therapy/pathology ; *Carcinoma, Squamous Cell/drug therapy/pathology ; Reactive Oxygen Species/pharmacology ; Matrix Metalloproteinase 2/genetics ; Matrix Metalloproteinase 9/genetics ; *Plasma Gases/pharmacology ; Proliferating Cell Nuclear Antigen/genetics ; bcl-2-Associated X Protein ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; },
abstract = {BACKGROUND: Cold atmospheric plasma (CAP) has been widely used in biomedical research, especially in vitro cancer therapy. Cutaneous squamous cell carcinoma (CSCC) is a malignant tumor originating from epidermal keratinocytes. However, the mechanism of CAP therapy on CSCC remains unclear.

METHODS AND RESULTS: The animal models of CSCC induced by 7,12-dimethylbenz(a) anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) were constructed. For the CAP treatment group, after each TPA application, CAP was administered for 3 min twice weekly after drying. HE staining were used to detect the pathological status of tumor tissue in each group. The levels of PCNA, Bcl-2, Bax, MMP2 and MMP9 were evaluated by western blot and qPCR. TUNEL staining were used to detect apoptosis in tumor tissues. In vivo, serum samples were used for ELISA of total ROS. MTT assay was used to detect the viability of A431 cells. Western blot and qPCR were used to detect the levels of PCNA, Bcl-2, Bax, MMP2 and MMP9 in A431 cells. A431 cell proliferation was examined by colony formation assay. The proportions of apoptosis of A431 cells were detected by flow cytometry. Transwell assessed the ability of A431 cells migration and proliferation. We found that CAP could induce skin cancer cells apoptosis and inhibit the progress of skin cancer. Through experiments in vitro, reactive oxygen species (ROS) generated by N-acetylcysteine (NAC) and CAP inhibited the proliferation and migration of A431 skin cancer cells while promoting apoptosis.

CONCLUSIONS: These evidences suggest the protective effect of CAP in CSCC, and CAP has the potential clinical application of CSCC.},
}

Animals
*Skin Neoplasms/drug therapy/pathology
*Carcinoma, Squamous Cell/drug therapy/pathology
Reactive Oxygen Species/pharmacology
Matrix Metalloproteinase 2/genetics
Matrix Metalloproteinase 9/genetics
*Plasma Gases/pharmacology
Proliferating Cell Nuclear Antigen/genetics
bcl-2-Associated X Protein
Apoptosis
Cell Line, Tumor
Cell Proliferation

@article {pmid38618504,
year = {2024},
author = {Ameri, A and Rahmati, A and Soroushfar, S and Lalehzari, M and Dehghani, T and Haghi-Aminjan, H and Shamseddin, J and Omidi, M},
title = {The Protective Effect of N-acetylcysteine against Deltamethrin-Induced Hepatotoxicity in Mice.},
journal = {Avicenna journal of medical biotechnology},
volume = {16},
number = {2},
pages = {88-94},
pmid = {38618504},
issn = {2008-2835},
abstract = {BACKGROUND: Exposure to pesticides is of concern to public health officials worldwide. Deltamethrin is a synthetic pyrethroid pesticide which is widely used in agriculture and veterinary medicine. Deltamethrin poisoning is always one of the concerns in medical centers due to the deltamethrin induced hepatotoxicity. This study evaluated the hepato-protective effects of N-acetylcysteine (NAC) against deltamethrin induced hepatotoxicity in mice.

METHODS: A total of 40 BALB/c male mice were randomly divided into four groups; the first group was used as a control (0.5 ml normal saline); Groups 2-4 were treated with NAC [160 mg/kg Body Weight (BW)], deltamethrin (50 mg/kg BW), and NAC plus deltamethrin. At 1 and 24 hr after treatment, the animals were sacrificed and blood and liver samples were obtained for analysis and the liver/body ration, hepatic enzymes as Aspartate aminotransferase (AST), Alanine Transaminase (ALT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH), Glutathione (GSH) content and Reactive Oxygen Species (ROS) level were measured. For comparison between more than two experimental groups, one-way ANOVA following Tukey test was used by SPSS software.

RESULTS: The deltamethrin significantly increased AST, ALT, ALP, and the level of ROS level at the end of 1 and 24 hr after treatment; while the LDH level and GSH content were decreased. Mice in the deltamethrin treated group had a higher liver/body weight ratio than in other treated groups after 24 hr. On the other hand, NAC in combination with deltamethrin significantly reduced the activities of AST, ALT, ALP, and increased GSH levels.

CONCLUSION: This study demonstrated that NAC has a hepatoprotective role against deltamethrin-induced toxicity.},
}

@article {pmid38611747,
year = {2024},
author = {Abdelkader, I and Guisán, JM and Sayari, A and Fernández-Lorente, G},
title = {Various Strategies for the Immobilization of a Phospholipase C from Bacillus cereus for the Modulation of Its Biochemical Properties.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {7},
pages = {},
pmid = {38611747},
issn = {1420-3049},
mesh = {*Bacillus cereus ; Sepharose ; *Acetylcysteine ; Enzymes, Immobilized ; Type C Phospholipases ; *Glyoxylates ; },
abstract = {In this study, the effect of various immobilization methods on the biochemical properties of phospholipase C (PLC) from Bacillus cereus obtained from the oily soil located in Sfax, Tunisia, was described. Different supports were checked: octyl sepharose, glyoxyl agarose in the presence of N-acetyl cysteine, and Q-sepharose. In the immobilization by hydrophobic adsorption, a hyperactivation of the PLCBc was obtained with a fold of around 2 times. The recovery activity after immobilization on Q-sepharose and glyoxyl agarose in the presence of N-acetyl cysteine was 80% and 58%, respectively. Furthermore, the biochemical characterization showed an important improvement in the three immobilized enzymes. The performance of the various immobilized PLCBc was compared with the soluble enzyme. The derivatives acquired using Q-sepharose, octyl sepharose, and glyoxyl agarose were stable at 50 °C, 60 °C, and 70 °C. Nevertheless, the three derivatives were more stable in a large range of pH than the soluble enzyme. The three derivatives and the free enzyme were stable in 50% (v/v) ethanol, hexane, methanol, and acetone. The glyoxyl agarose derivative showed high long-term storage at 4 °C, with an activity of 60% after 19 days. These results suggest the sustainable biotechnological application of the developed immobilized enzyme.},
}

*Bacillus cereus
Sepharose
*Acetylcysteine
Enzymes, Immobilized
Type C Phospholipases
*Glyoxylates

@article {pmid38608750,
year = {2024},
author = {Salas, G and Litta, AA and Medeot, AC and Schuck, V and Andermatten, RB and Miszczuk, GS and Ciriaci, N and Razori, MV and Barosso, IR and Sánchez Pozzi, EJ and Roma, MG and Basiglio, CL and Crocenzi, FA},
title = {NADPH OXIDASE-GENERATED REACTIVE OXYGEN SPECIES ARE INVOLVED IN ESTRADIOL 17ß-d-GLUCURONIDE-INDUCED CHOLESTASIS.},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2024.04.002},
pmid = {38608750},
issn = {1638-6183},
abstract = {The endogenous metabolite of estradiol, estradiol 17β-D-glucuronide (E17G), is considered the main responsible of the intrahepatic cholestasis of pregnancy. E17G alters the activity of canalicular transporters through a signaling pathway-dependent cellular internalization, phenomenon that was attributed to oxidative stress in different cholestatic conditions. However, there are no reports involving oxidative stress in E17G-induced cholestasis, representing this the aim of our work. Using polarized hepatocyte cultures, we showed that antioxidant compounds prevented E17G-induced Mrp2 activity alteration, being this alteration equally prevented by the NADPH oxidase (NOX) inhibitor apocynin. The model antioxidant N-acetyl-cysteine prevented, in isolated and perfused rat livers, E17G-induced impairment of bile flow and Mrp2 activity, thus confirming the participation of reactive oxygen species (ROS) in this cholestasis. In primary cultured hepatocytes, pretreatment with specific inhibitors of ERK1/2 and p38MAPK impeded E17G-induced ROS production; contrarily, NOX inhibition did not affect ERK1/2 and p38MAPK phosphorylation. Both, knockdown of p47phox by siRNA and preincubation with apocynin in sandwich-cultured rat hepatocytes significantly prevented E17G-induced internalization of Mrp2, suggesting a crucial role for NOX in this phenomenon. Concluding, E17G-induced cholestasis is partially mediated by NOX-generated ROS through internalization of canalicular transporters like Mrp2, being ERK1/2 and p38MAPK necessary for NOX activation.},
}

@article {pmid38608558,
year = {2024},
author = {Madhu, M and Santhoshkumar, S and Tseng, WB and Kumar, ASK and Tseng, WL},
title = {Synthesis of rhenium disulfide nanodots exhibiting pH-dependent fluorescence and phosphorescence for anticounterfeiting and hazardous gas detection.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {315},
number = {},
pages = {124240},
doi = {10.1016/j.saa.2024.124240},
pmid = {38608558},
issn = {1873-3557},
abstract = {The synthesis and characterization of ReS2 nanodots (NDs) are detailed, by highlighting their structure, morphological, and optical properties. ReS2 NDs were synthesized using NH4ReO4 as a rhenium source, thiourea as a sulfur source, and N-acetyl cysteine as a capping agent. The synthesis involved the hydrothermal reaction of these precursors, leading to the nucleation and growth of ReS2 NDs. Characterization techniques including transmission electron microscopy, energy dispersive X-ray spectroscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy confirmed the formation of ReS2 NDs with a spherical morphology, crystalline structure, and rich sulfur sites. The fluorescence behavior of ReS2 NDs was found to be influenced by the solution pH, with fluorescence intensity increasing with rising pH values. This pH-dependent fluorescence response was attributed to the dissociation of functional groups and the subsequent impact on the excited-state proton transfer process. The fluorescence intensity of ReS2 NDs showed a correlation with solution pH, enabling pH detection from 3.0 to 12.5 with an interval of 0.5 pH unit. Additionally, the incorporation of ReS2 NDs into a polyvinyl alcohol (PVA) matrix resulted in pH-sensitive phosphorescence, offering a new avenue for pH sensing. The strong interaction between PVA and ReS2 NDs was proposed to enhance phosphorescence intensity and trigger a blue shift in the phosphorescent peak at high pH. The ReS2 NDs/PVA-deposited filter paper exhibited pH-sensitive fluorescence and phosphorescence, which could be utilized as unique identifiers or authentication markers. Moreover, the ReS2 NDs/PVA-deposited filter paper showed potential for discriminating between hydrogen chloride and ammonia, based on their distinct fluorescence and phosphorescence responses.},
}

@article {pmid38591866,
year = {2024},
author = {Monou, PK and Andriotis, E and Tzetzis, D and Tzimtzimis, E and Panteris, E and Andreadis, D and Demiri, E and Vizirianakis, IS and Fatouros, DG},
title = {Evaluation of 3D-Printed Solid Microneedles Coated with Electrosprayed Polymeric Nanoparticles for Simultaneous Delivery of Rivastigmine and N-Acetyl Cysteine.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.3c00750},
pmid = {38591866},
issn = {2576-6422},
abstract = {In the current study, coated microneedle arrays were fabricated by means of digital light processing (DLP) printing. Three different shapes were designed, printed, and coated with PLGA particles containing two different actives. Rivastigmine (RIV) and N-acetyl-cysteine (NAC) were coformulated via electrohydrodynamic atomization (EHDA), and they were incorporated into the PLGA particles. The two actives are administered as a combined therapy for Alzheimer's disease. The printed arrays were evaluated regarding their ability to penetrate skin and their mechanical properties. Optical microscopy and scanning electron microscopy (SEM) were employed to further characterize the microneedle structure. Confocal laser microscopy studies were conducted to construct 3D imaging of the coating and to simulate the diffusion of the particles through artificial skin samples. Permeation studies were performed to investigate the transport of the drugs across human skin ex vivo. Subsequently, a series of tape strippings were performed in an attempt to examine the deposition of the APIs on and within the skin. Light microscopy and histological studies revealed no drastic effects on the membrane integrity of the stratum corneum. Finally, the cytocompatibility of the microneedles and their precursors was evaluated by measuring cell viability (MTT assay and live/dead staining) and membrane damages followed by LDH release.},
}

@article {pmid38583854,
year = {2024},
author = {Kim, NY and Shivanne Gowda, SG and Lee, SG and Sethi, G and Ahn, KS},
title = {Cannabidiol induces ERK activation and ROS production to promote autophagy and ferroptosis in glioblastoma cells.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {110995},
doi = {10.1016/j.cbi.2024.110995},
pmid = {38583854},
issn = {1872-7786},
abstract = {Small molecule-driven ERK activation is known to induce autophagy and ferroptosis in cancer cells. Herein the effect of cannabidiol (CBD), a phytochemical derived from Cannabis sativa, on ERK-driven autophagy and ferroptosis has been demonstrated in glioblastoma (GBM) cells (U87 and U373 cells). CBD imparted significant cytotoxicity in GBM cells, induced activation of ERK (not JNK and p38), and increased intracellular reactive oxygen species (ROS) levels. It increased the autophagy-related proteins such as LC3 II, Atg7, and Beclin-1 and modulated the expression of ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4), SLC7A11, and TFRC. CBD significantly elevated the endoplasmic reticulum stress, ROS, and iron load, and decreased GSH levels. Inhibitors of autophagy (3-MA) and ferroptosis (Fer-1) had a marginal effect on CBD-induced autophagy/ferroptosis. Treatment with N-acetyl-cysteine (antioxidant) or PD98059 (ERK inhibitor) partly reverted the CBD-induced autophagy/ferroptosis by decreasing the activation of ERK and the production of ROS. Overall, CBD induced autophagy and ferroptosis through the activation of ERK and generation of ROS in GBM cells.},
}

@article {pmid38583502,
year = {2024},
author = {Kim, SG and Jeon, JH and Shin, SH and Varias, DC and Moon, SH and Ryu, BY},
title = {Inhibition of reactive oxygen species generation by N-Acetyl Cysteine can mitigate male germ cell toxicity induced by bisphenol analogs.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {114652},
doi = {10.1016/j.fct.2024.114652},
pmid = {38583502},
issn = {1873-6351},
abstract = {The estrogen-like effect of bisphenol A (BPA) disrupting the maintenance of functional male germ cells is associated with male sub-fertility. This study investigated toxicity of male germ cells induced by four bisphenol analogs: BPA, BPAF, BPF, and BPS. The investigation of bisphenol analogs' impact on male germ cells included assessing proliferation, apoptosis induction, and the capacity to generate reactive oxygen species (ROS) in GC-1 spermatogonia (spg) cells, specifically type B spermatogonia. Additionally, the therapeutic potential and protective effects of N-Acetyl Cysteine (NAC) and NF-κB inhibitor parthenolide was evaluated. In comparison to BPA, BPF and BPS, BPAF exhibited the most pronounced adverse effect in GC-1 spg cell proliferation. This effect was characterized by pronounced inhibition of phosphorylation of PI3K, AKT, and mTOR, along with increased release of cytochrome c and subsequent cleavages of caspase 3, caspase 7, and poly (ADP-ribose) polymerase. Both NAC and parthenolide were effective reducing cellular ROS induced by BPAF. However, only NAC demonstrated a substantial recovery in proliferation, accompanied by a significant reduction in cytochrome c release and cleaved PARP. These results suggest that NAC supplementation may play an effective therapeutic role in countering germ cell toxicity induced by environmental pollutants with robust oxidative stress-generating capacity.},
}

@article {pmid38576186,
year = {2024},
author = {Lopes, AR and Costa Silva, DG and Rodrigues, NR and Kemmerich Martins, I and Paganotto Leandro, L and Nunes, MEM and Posser, T and Franco, J},
title = {Investigating the impact of Psidium guajava leaf hydroalcoholic extract in improving glutamatergic toxicity-induced oxidative stress in Danio rerio larvae.},
journal = {Journal of toxicology and environmental health. Part A},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/15287394.2024.2337366},
pmid = {38576186},
issn = {1528-7394},
abstract = {Glutamate is one of the predominant excitatory neurotransmitters released from the central nervous system; however, at high concentrations, this substance may induce excitotoxicity. This phenomenon is involved in numerous neuropathologies. At present, clinically available pharmacotherapeutic agents to counteract glutamatergic excitotoxicity are not completely effective; therefore, research to develop novel compounds is necessary. In this study, the main objective was to determine the pharmacotherapeutic potential of the hydroalcoholic extract of Psidium guajava (PG) in a model of oxidative stress-induced by exposure to glutamate utilizing Danio rerio larvae (zebrafish) as a model. Data showed that treatment with glutamate produced a significant increase in oxidative stress, chromatin damage, apoptosis, and locomotor dysfunction. All these effects were attenuated by pre-treatment with the classical antioxidant N-acetylcysteine (NAC). Treatment with PG inhibited oxidative stress responsible for cellular damage induced by glutamate. However, exposure to PG failed to prevent glutamate-initiated locomotor damage. Our findings suggest that under conditions of oxidative stress, PG can be considered as a promising candidate for treatment of glutamatergic excitotoxicity and consequent neurodegenerative diseases.},
}

@article {pmid38565435,
year = {2024},
author = {Liu, JJ and Zhang, X and Cai, BL and Qi, MM and Chi, YB and Peng, B and Zhang, DH},
title = {Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells.},
journal = {Journal of integrative medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.joim.2024.03.007},
pmid = {38565435},
issn = {2095-4964},
abstract = {OBJECTIVE: Research has shown that celastrol can effectively treat a variety of diseases, yet when passing a certain dosage threshold, celastrol becomes toxic, causing complications such as liver and kidney damage and erythrocytopenia, among others. With this dichotomy in mind, it is extremely important to find ways to preserve celastrol's efficacy while reducing or preventing its toxicity.

METHODS: In this study, insulin-resistant HepG2 (IR-HepG2) cells were prepared using palmitic acid and used for in vitro experiments. IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine (NAC) or ferrostatin-1 (Fer-1) for 12, 24 or 48 h, at a range of doses. Cell counting kit-8 assay, Western blotting, quantitative reverse transcription-polymerase chain reaction, glucose consumption assessment, and flow cytometry were performed to measure celastrol's cytotoxicity and whether the cell death was linked to ferroptosis.

RESULTS: Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-HepG2 cells. Celastrol downregulated glutathione peroxidase 4 (GPX4) mRNA. Molecular docking models predicted that solute carrier family 7 member 11 (SLC7A11) and GPX4 were covalently bound by celastrol. Importantly, we found for the first time that the application of ferroptosis inhibitors (especially NAC) was able to reduce celastrol's toxicity while preserving its ability to improve insulin sensitivity in IR-HepG2 cells.

CONCLUSION: One potential mechanism of celastrol's cytotoxicity is the induction of ferroptosis, which can be alleviated by treatment with ferroptosis inhibitors. These findings provide a new strategy to block celastrol's toxicity while preserving its therapeutic effects. Please cite this article as: Liu JJ, Zhang X, Qi MM, Chi YB, Cai BL, Peng B, Zhang DH. Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells. J Integr Med. 2024; Epub ahead of print.},
}

@article {pmid38556154,
year = {2024},
author = {Teixeira-Fonseca, JL and Souza, DS and Conceição, MRL and Marques, LP and Durço, AO and Silva, PLD and Joviano-Santos, JV and Santos-Miranda, A and Roman-Campos, D},
title = {In vivo Tebuconazole administration impairs heart electrical function and facilitates the occurrence of dobutamine-induced arrhythmias: Involvement of reactive oxygen species.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {114596},
doi = {10.1016/j.fct.2024.114596},
pmid = {38556154},
issn = {1873-6351},
abstract = {Tebuconazole (TEB), a widely used pesticide in agriculture to combat fungal infections, is commonly detected in global food, potable water, groundwater, and human urine samples. Despite its known in vivo toxicity, its impact on heart function remains unclear. In a 28-day study on male Wistar rats (approximately 100 g), administering 10 mg/kg/day TEB or a control vehicle revealed no effect on body weight gain or heart weight, but an increase in the infarct area in TEB-treated animals. Notably, TEB induced time-dependent changes in in vivo electrocardiograms, particularly prolonging the QT interval after 28 days of administration. Isolated left ventricular cardiomyocytes exposed to TEB exhibited lengthened action potentials and reduced transient outward potassium current. TEB also increased reactive oxygen species (ROS) production in these cardiomyocytes, a phenomenon reversed by N-acetylcysteine (NAC). Furthermore, TEB-treated animals, when subjected to an in vivo dobutamine (Dob) and caffeine (Caf) challenge, displayed heightened susceptibility to severe arrhythmias, a phenotype prevented by NAC. In conclusion, TEB at the no observed adverse effect level (NOAEL) dose adversely affects heart electrical function, increases arrhythmic susceptibility, partially through ROS overproduction, and this phenotype is reversible by scavenging ROS with NAC.},
}

@article {pmid38555190,
year = {2024},
author = {Papi, A and Alfano, F and Bigoni, T and Mancini, L and Mawass, A and Baraldi, F and Aljama, C and Contoli, M and Miravitlles, M},
title = {N-acetylcysteine Treatment in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis/Pre-COPD: Distinct Meta-analyses.},
journal = {Archivos de bronconeumologia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.arbres.2024.03.010},
pmid = {38555190},
issn = {1579-2129},
abstract = {INTRODUCTION: N-acetylcysteine (NAC) is a mucolytic agent with antioxidant properties. Oxidative stress is a key pathogenic mechanism in chronic respiratory conditions such as COPD and chronic bronchitis (CB). In these meta-analyses we investigated the efficacy of NAC in subjects with COPD or CB, the latter being a potential pre-COPD condition (CB/pre-COPD).

METHODS: The meta-analyses were conducted according to PRISMA guidelines. Exacerbations were assessed using total number of exacerbations. Improvement in patients' respiratory symptoms and/or patients quality of life (QoL) were measured by validated tools or assessed at the end of the study.

RESULTS: Twenty studies were included, of which seven evaluated NAC in patients with symptoms of CB/pre-COPD as entry criterion. NAC treated patients showed a significant reduction of the incidence of exacerbations as compared to placebo both in COPD (IRR=0.76; 95% confidence interval (CI) 0.59-0.99) and CB/pre-COPD (IRR=0.81; 95% CI 0.69-0.95). Sensitivity analyses in studies with duration higher than 5 months, confirmed the overall results. CB/pre-COPD patients treated with NAC were significantly more likely to experience an improvement in symptoms and/or QoL compared to placebo (odds ratio (OR)=3.47; 95% CI 1.92-6.26). A similar trend was observed in the few COPD studies evaluable. Sensitivity analyses showed a significant association of NAC with improvement in symptoms and/or QoL both in CB/pre-COPD and COPD patients.

CONCLUSIONS: These findings provide novel data of NAC on the improvement in symptoms and QoL in addition to prevention of exacerbations in COPD and CB/pre-COPD. PROSPERO registry no. CRD42023468154.},
}

@article {pmid38554666,
year = {2024},
author = {Sriwastava, S and Elkhooly, M and Amatya, S and Shrestha, K and Kagzi, Y and Bhatia, D and Gupta, R and Jaiswal, S and Lisak, RP},
title = {Recent advances in the treatment of primary and secondary progressive Multiple Sclerosis.},
journal = {Journal of neuroimmunology},
volume = {390},
number = {},
pages = {578315},
doi = {10.1016/j.jneuroim.2024.578315},
pmid = {38554666},
issn = {1872-8421},
abstract = {BACKGROUND: The article highlights upcoming potential treatments, which target different phases of inflammation and offer remyelinating strategies as well as direct and indirect neuroprotective and oligodendrocyte protective effects, providing a hopeful outlook for patients with primary and secondary progressive multiple sclerosis (PPMS and SPMS).

OBJECTIVES: The review aims to identify potential treatments and ongoing clinical trials for PPMS and SPMS, and compare their mechanisms of action, efficacy, and side effects with current treatments.

METHODS: We reviewed ongoing clinical trials for PPMS and SPMS on the NIH website, as well as articles from PubMed, Embase, and clinicaltrails.gov since 2010.

RESULTS: BTKIs like, tolebrutinib, and fenebrutinib are being explored as potential PMS treatments. Vidofludimus calcium, an orally available treatment, has shown a reduction of active and new MRI lesions. Other treatments like simvastatin, N-acetylcysteine (NAC), and alpha-lipoic acid are being explored for their antioxidant properties. AHSCT and mesenchymal stem cell therapy are experimental options for younger patients with high inflammatory activity.

CONCLUSIONS: SPMS and PPMS are being studied for new treatments and future trials should consider combination therapies targeting inflammation, demyelination, and neuronal death, as the pathogenesis of PMS involves complex factors.},
}

@article {pmid38551724,
year = {2024},
author = {Adelusi, OB and Akakpo, JY and Eichenbaum, G and Sadaff, E and Ramachandran, A and Jaeschke, H},
title = {The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {38551724},
issn = {1432-0738},
support = {DK102142/DK/NIDDK NIH HHS/United States ; DK125465/DK/NIDDK NIH HHS/United States ; },
abstract = {Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO). Endogenous thrombopoietin is produced by hepatocytes and the TPO receptor is present on liver sinusoidal endothelial cells in addition to megakaryocytes and platelets, and we hypothesize that TPOm activity at the TPO receptor in the liver provides a beneficial effect following liver injury. Therefore, we evaluated the extent to which TPOm, NAC or 4-MP can provide a protective and regenerative effect in the liver when administered 2 h after an APAP overdose of 300 mg/kg in fasted male C57BL/6J mice. TPOm did not affect protein adducts, oxidant stress, DNA fragmentation and hepatic necrosis up to 12 h after APAP. In contrast, TPOm treatment was beneficial at 24 h, i.e., all injury parameters were reduced by 42-48%. Importantly, TPOm enhanced proliferation by 100% as indicated by PCNA-positive hepatocytes around the area of necrosis. When TPOm treatment was delayed by 6 h, there was no effect on the injury, but a proliferative effect was still evident. In contrast, 4MP and NAC treated at 2 h after APAP significantly attenuated all injury parameters at 24 h but failed to enhance hepatocyte proliferation. Thus, TPOm arrests the progression of liver injury by 24 h after APAP and accelerates the onset of the proliferative response which is essential for liver recovery.},
}

@article {pmid38547615,
year = {2024},
author = {Li, Z and Bao, Z and Tan, J and Chen, G and Ye, B and Zhao, J and Zhang, L and Xu, H},
title = {Neobractatin induces pyroptosis of esophageal cancer cells by TOM20/BAX signaling pathway.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {128},
number = {},
pages = {155547},
doi = {10.1016/j.phymed.2024.155547},
pmid = {38547615},
issn = {1618-095X},
abstract = {BACKGROUND: Emerging evidence suggests that pyroptosis, a form of programmed cell death, has been implicated in cancer progression. The involvement of specific proteins in pyroptosis is an area of growing interest. TOM20, an outer mitochondrial membrane protein, has recently garnered attention for its potential role in pyroptosis. Our previous study found that NBT could induce pyroptosis by ROS/JNK pathway in esophageal cancer cells.

PURPOSE: This study aims to investigate whether NBT induces pyroptosis and verify whether such effects are involved in up-regulation of TOM20 in esophageal cancer cells.

METHODS: The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) was used to analyze the clinical significance of GSDME in esophageal cancer. MTT assay, morphological observation and Western blot were performed to verify the roles of TOM20 and BAX in NBT-induced pyroptosis after CRISPR-Cas9-mediated knockout. Immunofluorescence was used to determine the subcellular locations of BAX and cytochrome c. MitoSOX Red was employed to assess the mitochondrial reactive oxygen species (ROS) level. KYSE450 and TOM20 knockout KYSE450-/- xenograft models were established to elucidate the mechanisms involved in NBT-induced cell death.

RESULTS: In this study, NBT effectively upregulated the expression of TOM20 and facilitated the translocation of BAX to mitochondria, which promoted the release of cytochrome c from mitochondria to the cytoplasm, leading to the activation of caspase-9 and caspase-3, and finally induced pyroptosis. Knocking out TOM20 by CRISPR-Cas9 significantly inhibited the expression of BAX and the downstream BAX/caspase-3/GSDME pathway, which attenuated NBT-induced pyroptosis. The elevated mitochondrial ROS level was observed after NBT treatment. Remarkably, the inhibition of ROS by N-acetylcysteine (NAC) effectively suppressed the activation of TOM20/BAX pathway. Moreover, in vivo experiments demonstrated that NBT exhibited potent antitumor effects in both KYSE450 and TOM20 knockout KYSE450-/- xenograft models. Notably, the attenuated antitumor effects and reduced cleavage of GSDME were observed in the TOM20 knockout model.

CONCLUSION: These findings reveal that NBT induces pyroptosis through ROS/TOM20/BAX/GSDME pathway, which highlight the therapeutic potential of targeting TOM20 and GSDME, providing promising prospects for the development of innovative and effective treatment approaches for esophageal cancer.},
}

@article {pmid38547333,
year = {2024},
author = {Smith, JE and Rockey, DC},
title = {Update on ischemic hepatitis.},
journal = {Current opinion in gastroenterology},
volume = {},
number = {},
pages = {},
pmid = {38547333},
issn = {1531-7056},
abstract = {PURPOSE OF REVIEW: Ischemic hepatitis (IH) refers to diffuse liver injury secondary to hypoperfusion. The condition is usually seen in the critical care setting and is associated with significant mortality. IH typically occurs in the setting of systemic hypotension superimposed on some form of underlying cardiac dysfunction. This review aims to report what is known and what is new about the etiology, pathophysiology, and clinical features associated with IH.

RECENT FINDINGS: In recent years, studies on IH have largely confirmed earlier reports regarding etiologies, comorbid conditions, and associated mortality. Recent study has also shed light on the potential treatment of IH with N-acetyl-cysteine (NAC).

SUMMARY: IH is typically associated with underlying cardiac disease, and patients with IH have a very high mortality rate. Treatment remains largely supportive, although the utility of agents such as NAC are being explored.},
}

@article {pmid38541080,
year = {2024},
author = {Russo, C and Rusciano, D and Santangelo, R and Malaguarnera, L},
title = {Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {60},
number = {3},
pages = {},
doi = {10.3390/medicina60030354},
pmid = {38541080},
issn = {1648-9144},
abstract = {Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.},
}

@article {pmid38539819,
year = {2024},
author = {Islam, A and Chang, YC and Tsao, NW and Wang, SY and Chueh, PJ},
title = {Calocedrus formosana Essential Oils Induce ROS-Mediated Autophagy and Apoptosis by Targeting SIRT1 in Colon Cancer Cells.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {3},
pages = {},
doi = {10.3390/antiox13030284},
pmid = {38539819},
issn = {2076-3921},
abstract = {Colorectal cancer is the most common cancer that affects both sexes and has a poor prognosis due to aggressiveness and chemoresistance. Essential oils isolated from Calocedrus formosana (CF-EOs) have been shown to demonstrate anti-termite, antifungal, anti-mosquito, and anti-microbial activities. However, the anticancer effects of CF-EOs are not yet fully understood. Therefore, the present study aimed to explore the molecular mechanism underlying CF-EOs-mediated anti-proliferative activity in colon cancer cells. Here, cell impedance measurements showed that CF-EOs inhibit proliferation in colon cancer cells with wild-type or mutant p53. Flow cytometry revealed that CF-EOs at 20, 50 µg/mL significantly induced ROS generation and autophagy in both HCT116 p53-wt and HCT116 p53-null cell lines, whereas pretreatment with the ROS scavenger N-acetyl cysteine (NAC) markedly attenuated these changes. CF-EOs also induced apoptosis at 50 µg/mL in both lines, as determined by flow cytometry. Protein analysis showed that CF-EOs markedly induced apoptosis markers, including Trail, cleaved caspase-3, cleaved caspase-9, and cleaved PARP, as well as autophagy markers, such as the levels of ULK1, Atg5, Atg6, Atg7, and the conversion of LC3-I to LC3-II. CF-EOs were further found to inhibit the activity and expression of the NAD[+]-dependent deacetylase SIRT1 to increase the levels of acetylated p53 (Ac-p53) in p53-wt cells and acetylated c-Myc (Ac-c-Myc) in p53-null cells, ultimately inducing apoptosis in both lines. Interestingly, suppression of SIRT1 by CF-EOs enhanced the acetylation of ULK1, which in turn prompted ROS-dependent autophagy in colon cancer cells. The induction of apoptosis and autophagy by CF-EOs suggests that they may have potential as a promising new approach for treating cancer. Collectively, our results suggest that essential oils isolated from Calocedrus formosana act as a promising anticancer agent against colon cancer cells by targeting SIRT1 to induce ROS-mediated autophagy and apoptosis.},
}

@article {pmid38537439,
year = {2023},
author = {Chen, X and Zhu, N and Wu, Y and Zhang, Y and Zhang, Y and Jin, K and Zhou, Z and Chen, G and Wang, J},
title = {Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {128},
number = {},
pages = {155317},
doi = {10.1016/j.phymed.2023.155317},
pmid = {38537439},
issn = {1618-095X},
abstract = {BACKGROUND: Sorafenib (Sora), a multi-target tyrosine kinase inhibitor, is widely recognized as a standard chemotherapy treatment for advanced hepatocellular carcinoma (HCC). However, drug resistance mechanisms hinder its anticancer efficacy. Derived from Withania somnifera, Withaferin A (WA) exhibits remarkable anti-tumor properties as a natural bioactive compound. This study aimed to examine the mechanisms that underlie the impacts of Sora and WA co-treatment on HCC.

METHODS: Cell proliferation was evaluated through colony formation and MTT assays. Flow cytometry was employed to determine cellular apoptosis and reactive oxygen species (ROS) levels. The evaluation of apoptosis-related protein levels, DNA damage, and endoplasmic reticulum stress was conducte utilizing IHC staining and western blotting. Moreover, the caspase inhibitor Z-VAD-FMK, ATF4 siRNA, ROS scavenger N-acetyl cysteine (NAC), and TrxR1 shRNA were used to elucidate the underlying signaling pathways. To validate the antitumor effects of Sora/WA co-treatment, in vivo experiments were ultimately executed using Huh7 xenografts.

RESULTS: Sora/WA co-treatment demonstrated significant synergistic antitumor impacts both in vivo and in vitro. Mechanistically, the enhanced antitumor impact of Sora by WA was achieved through the inhibition of TrxR1 activity, resulting in ROS accumulation. Moreover, ROS generation induced the activation of DNA damage and endoplasmic reticulum (ER) stress pathways, eventually triggering cellular apoptosis. Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment. Additionally, the inhibition of ATF4 by small interfering RNA (siRNA) attenuated Sora/WA co-treatment-induced apoptosis. In vivo, Sora/WA co-treatment significantly suppressed tumor growth in HCC xenograft models and decreased TrxR1 activity in tumor tissues.

CONCLUSION: Our study suggests that WA synergistically enhances the antitumor effect of Sora, offering promising implications for evolving treatment approaches for HCC.},
}

@article {pmid38536095,
year = {2024},
author = {Aragona, SE and Fabbri, C and Cammarota, G and Ciprandi, G and , },
title = {Probiotic mixture in patients after Helicobacter pylori eradication: a real-life experience.},
journal = {Minerva gastroenterology},
volume = {},
number = {},
pages = {},
doi = {10.23736/S2724-5985.24.03634-9},
pmid = {38536095},
issn = {2724-5365},
abstract = {BACKGROUND: Eradication for Helicobacter pylori usually induces digestive dysbiosis that, in turn, elicits symptoms. Consequently, probiotic supplementation may counterbalance the disturbed microbiota after this procedure. So, probiotics may restore microbiota homeostasis quickly relieve complaints.

METHODS: The current study evaluated the efficacy and safety of Abivisor[®], a food supplement containing Lacticaseibacillus rhamnosus LR06 (3 billion living cells), Lactiplantibacillus pentosus LPS01(100 million living cells), Lactiplantibacillus plantarum LP01 (1 billion living cells), and N-acetyl cysteine (60 mg). Patients were randomized into two groups (2:1). Group A took one stick/daily for 60 days after eradication. Group B was considered as control. Patients were evaluated at baseline (T0) and after 15 (T1), 30 (T2), and 60 (T3) days. The severity of digestive symptoms was measured by patients using a Visual Analog Scale. The percentage of patients with each symptom was also evaluated.

RESULTS: Abivisor[®] has significantly and progressively diminished intestinal symptoms' presence and severity at T1, T2, and even more at T3. Accordingly, the percentage of symptomatic patients diminished more rapidly and significantly in group A than in B. All patients well tolerated the food supplement.

CONCLUSIONS: The present study suggests that Abivisor[®] may be an effective and safe therapeutic option for managing patients undergoing H. pylori eradication.},
}

@article {pmid38535516,
year = {2024},
author = {Tamur, S and Alyahya, B and Alsani, F and Bahauddin, AA and Aljaid, M and Al-Malki, S and Alzahrani, A and Khayat, A and Shams, A and Chalut, DS},
title = {Two versus Three Infusion Regimens of N-Acetylcysteine for Acetaminophen Overdose.},
journal = {Pediatric reports},
volume = {16},
number = {1},
pages = {232-242},
doi = {10.3390/pediatric16010020},
pmid = {38535516},
issn = {2036-749X},
abstract = {BACKGROUND: Acetaminophen overdose is a common clinical condition, often leading to liver toxicity. Current treatments involve the three-infusion N-Acetylcysteine (NAC) regimen (FDA-labeled), which may be complex, time-consuming, and need to be changed. An alternative uses two infusions instead, which offers possible advantages regarding simplicity and administration errors. This study sought to compare the respective efficacies and safety outcomes when treating acute acetaminophen overdose among children and adolescents.

METHODS: At Montreal Children's Hospital, a retrospective study was conducted comparing pre-2003 FDA-labelled three-infusion NAC therapy with a two-infusion regimen. Information was collected regarding patient demographics, NAC administration details, errors, rates of hepatotoxicity, and adverse reactions, and the statistical test Chi-square test was employed to obtain the results.

RESULTS: A total of 126 patients met the inclusion criteria. Of these patients, 65 received a two-infusion regimen, and 61 patients received the FDA-labeled regimen. The two-infusion group experienced significantly fewer administration errors (4 errors vs. 23 errors; p < 0.001), while the rates of hepatotoxicity between them were similar. There were no instances of liver transplantation or mortality due to either regimen. Adverse reactions occurred equally frequently between both regimens with no discernible difference-the meantime to administer NAC was 9 h for the two-infusion regimen and 8.5 h for FDA-labeled regimen groups, respectively. Three cases of hepatitis were successfully treated with timely NAC therapy, and no liver transplantation or mortality occurred. Adverse reactions, including anaphylactoid reactions, were observed in both groups but were resolved when temporarily stopped and restarted at a slower infusion rate.

CONCLUSIONS: The two-infusion NAC regimen proved similar efficacy at protecting liver damage and improving patient outcomes compared to its FDA-labeled three-stage counterpart, with significantly fewer administration errors for this version of NAC treatment, suggesting potential advantages in terms of safety and simplicity. Future research should investigate larger cohorts and more variables to validate these results further and optimize the management of acetaminophen overdose cases; further investigation should focus on dosing strategies, personalized approaches, and long-term patient care in this context.},
}

@article {pmid38534586,
year = {2024},
author = {Domínguez-Martínez, J and López-Sánchez, J and García-Galván, F and Serrano, A and Barranco, V and Galván, JC and Rodríguez de la Fuente, Ó and Carmona, N},
title = {Eco-Friendly Sol-Gel Coatings with Organic Corrosion Inhibitors for Lightweight AZ61 Alloy.},
journal = {Gels (Basel, Switzerland)},
volume = {10},
number = {3},
pages = {},
doi = {10.3390/gels10030168},
pmid = {38534586},
issn = {2310-2861},
support = {PID2019-104717RB-I00//Spanish Ministry of Economics Affairs and Digital Transformation/ ; PID2021-122980OB-C51//Spanish Ministry of Economic Affairs and Digital Transformation (MINECO)/ ; RYC2022-035912-I and RYC2021-031236-I//MCIN "Ramón y Cajal" Program/ ; },
abstract = {The latest advances in technology and materials science have catalyzed a transformative shift towards the adoption of environmentally conscious and lightweight materials across key sectors such as aeronautics, biomedical, and automotive industries. Noteworthy among these innovations are the magnesium-aluminum (Mg-Al) alloys employed in aeronautical applications, contributing to the overall reduction in aircraft weight and subsequently diminishing fuel consumption and mitigating atmospheric emissions. The present work delves into a study of the anti-corrosive properties inherent in various sol-gel coatings, leveraging a range of environmentally friendly corrosion inhibitors, specifically tailored for samples of the AZ61 alloy. Methodologically, the work involves the synthesis and application of sol-gel coatings on AZ61 alloy containing eco-friendly inhibitors: L-cysteine, N-acetyl-cysteine, curcumin and methylene blue. Subsequently, an accelerated corrosion test in a simulated saline environment is performed. Through microstructural and compositional analyses, the best inhibitors responses are achieved with inhibitors containing S, N heteroatoms and conjugated double bonds in their structure, probably due to the creation of a continuous MgCl2 layer. This research contributes to the ongoing discourse on protective eco-coatings, aligning with the broader paradigm shift towards sustainable and lightweight materials in key industries.},
}

@article {pmid38525131,
year = {2024},
author = {Dong, G and Li, Q and Yu, C and Wang, Q and Zuo, D and Li, X},
title = {n-Acetylcysteine protects against diazinon-induced histopathological damage and apoptosis in renal tissue of rats.},
journal = {Toxicological research},
volume = {40},
number = {2},
pages = {285-295},
pmid = {38525131},
issn = {1976-8257},
abstract = {Diazinon (DZN) is a member of organophosphorus insecticides that has cytotoxic effects on different organs. n-Acetyl cysteine (NAC) is a widely used antioxidant in clinical, in vivo and in vitro studies. We evaluated the protective role of NAC against DZN-induced toxicity in kidney tissue of Wistar rats. 30 male Wistar rats were divided into 5 groups of control, single dose of DZN, continuous dose of DZN, single doses of DZN + NAC and continuous doses of DZN + NAC. Kidney function test (blood urea nitrogen, creatinine and uric acid) was provided. Levels of malondialdehyde (MDA), total antioxidant capacity (TAC) and total sulfhydryl (T-SH) were determined in renal tissues. Renal cells apoptosis was detected using TUNEL assay. The mRNA expressions of apoptosis, oxidative stress and inflammatory mediators, including B-cell lymphoma-2 (Bcl2), Bcl-2-associated X protein (Bax), superoxide dismutase (SOD), catalase (CAT), Interleukin 10 (IL-10), Tumor necrosis factor-α (TNF-α), Caspase-3 and Caspase-8 were analyzed in kidney tissues using Real Time PCR method. Chronic exposure to DZN was associated with severe morphological changes in the kidney, as well as impairment of its function and decreased kidney weights. Continues treatment with DZN significantly decreased the percentage of renal apoptotic cells as compared to rats treated with continuous dose of DZN alone (17.69 ± 3.67% vs. 39.46% ± 2.44%; p < 0.001). Continuous exposure to DZN significantly decreased TAC and T-SH contents, as well as SOD and CAT expression, but increased MDA contents in the kidney tissues (p < 0.001). A significant increase was observed in mRNA expression of Bax, Caspase-3, Caspase-8, as well as TNF-α following exposure to DZN, but the expression of IL-10 and Bcl2 was significantly decreased. NAC can protect kidney tissue against DZN-induced toxicity by elevating antioxidants capacity, mitigating oxidative stress, inflammation and apoptosis.},
}

@article {pmid38524728,
year = {2024},
author = {Khasnavis, S and Belliveau, T and Arnsten, A and Fesharaki-Zadeh, A},
title = {Combined Use of Guanfacine and N-Acetylcysteine for the Treatment of Cognitive Deficits After Traumatic Brain Injury.},
journal = {Neurotrauma reports},
volume = {5},
number = {1},
pages = {226-231},
pmid = {38524728},
issn = {2689-288X},
abstract = {Traumatic Brain Injury (TBI) is a significant contributor to disability across the world. TBIs vary in severity, and most cases are designated mild TBI (mTBI), involving only brief loss of consciousness and no intracranial findings on imaging. Despite this categorization, many persons continue to report persistent cognitive changes in the months to years after injury, with particular impairment in the cognitive and executive functions of the pre-frontal cortex. For these persons, there are no currently approved medications, and treatment is limited to symptom management and cognitive or behavioral therapy. The current case studies explored the use of the alpha-2A adrenoreceptor agonist, guanfacine, combined with the antioxidant, N-acetylcysteine (NAC), in the treatment of post-TBI cognitive symptoms, based on guanfacine's ability to strengthen pre-frontal cortical function, and the open-label use of NAC in treating TBI. Two persons from our TBI clinic were treated with this combined regimen, with neuropsychological testing performed pre- and post-treatment. Guanfacine + NAC improved attention, processing speed, memory, and executive functioning with minimal side effects in both persons. These results encourage future placebo-controlled trials to more firmly establish the efficacy of guanfacine and NAC for the treatment of cognitive deficits caused by TBI.},
}

@article {pmid38522494,
year = {2024},
author = {Mabrouk, NEL and Mastouri, M and Lizard, G and Aouni, M and Harizi, H},
title = {In vitro immunotoxicity effects of carbendazim were inhibited by n-acetylcysteine in microglial BV-2 cells.},
journal = {Toxicology in vitro : an international journal published in association with BIBRA},
volume = {},
number = {},
pages = {105812},
doi = {10.1016/j.tiv.2024.105812},
pmid = {38522494},
issn = {1879-3177},
abstract = {Carbendazim (CBZ) is a benzimidazole fungicide widely used worldwide in industrial, agricultural, and veterinary practices. Although, CBZ was found in all brain tissues causing serious neurotoxicity, its impact on brain immune cells remain scarcely understood. Our study investigated the in vitro effects of CBZ on activated microglial BV-2 cells. Lipopolysaccharide (LPS)-stimulated BV-2 cells were exposed to increasing concentrations of CBZ and cytokine release was measured by ELISA, and Cytometric Bead Array (CBA) assays. Mitochondrial superoxide anion (O2[·-]) generation was evaluated by Dihydroethidium (DHE) and nitric oxide (NO) was assessed by Griess reagent. Lipid peroxidation was evaluated by measuring the malonaldehyde (MDA) levels. The transmembrane mitochondrial potential (ΔΨm) was detected by cytometry analysis with dihexyloxacarbocyanine iodide (DiOC6(3)) assay. CBZ concentration-dependently increased IL-1β, IL-6, TNF-α and MCP-1 by LPS-activated BV-2 cells. CBZ significantly promoted oxidative stress by increasing NO, O2[·-] generation, and MDA levels. In contrast, CBZ significantly decreased ΔΨm. Pre-treatment of BV-2 cells with N-acetylcysteine (NAC) reversed all the above mentioned immunotoxic parameters, suggesting a potential protective role of NAC against CBZ-induced immunotoxicity via its antioxidant and anti-inflammatory effects on activated BV-2 cells. Therefore, microglial proinflammatory over-activation by CBZ may be a potential mechanism by which CBZ could induce neurotoxicity and neurodegenerative disorders.},
}

@article {pmid38520518,
year = {2024},
author = {Cao, W and Zhang, J and Yu, S and Gan, X and An, R},
title = {N-acetylcysteine regulates oxalate induced injury of renal tubular epithelial cells through CDKN2B/TGF-β/SMAD axis.},
journal = {Urolithiasis},
volume = {52},
number = {1},
pages = {46},
pmid = {38520518},
issn = {2194-7236},
support = {No.81370803//National Natural Science Foundation of China/ ; No.81370803//National Natural Science Foundation of China/ ; },
abstract = {This study was aimed to investigate the preventive effects of N-acetyl-L-cysteine (NAC) against renal tubular cell injury induced by oxalate and stone formation and further explore the related mechanism. Transcriptome sequencing combined with bioinformatics analysis were performed to identify differentially expressed gene (DEG) and related pathways. HK-2 cells were pretreated with or without antioxidant NAC/with or silencing DEG before exposed to sodium oxalate. Then, the cell viability, oxidative biomarkers of superoxidase dismutase (SOD) and malondialdehyde (MDA), apoptosis and cell cycle were measured through CCK8, ELISA and flow cytometry assay, respectively. Male SD rats were separated into control group, hyperoxaluria (HOx) group, NAC intervention group, and TGF-β/SMAD pathway inhibitor group. After treatment, the structure changes and oxidative stress and CaOx crystals deposition were evaluated in renal tissues by H&E staining, immunohistochemical and Pizzolato method. The expression of TGF-β/SMAD pathway related proteins (TGF-β1, SMAD3 and SMAD7) were determined by Western blot in vivo and in vitro. CDKN2B is a DEG screened by transcriptome sequencing combined with bioinformatics analysis, and verified by qRT-PCR. Sodium oxalate induced declined HK-2 cell viability, in parallel with inhibited cellular oxidative stress and apoptosis. The changes induced by oxalate in HK-2 cells were significantly reversed by NAC treatment or the silencing of CDKN2B. The cell structure damage and CaOx crystals deposition were observed in kidney tissues of HOx group. Meanwhile, the expression levels of SOD and 8-OHdG were detected in kidney tissues of HOx group. The changes induced by oxalate in kidney tissues were significantly reversed by NAC treatment. Besides, expression of SMAD7 was significantly down-regulated, while TGF-β1 and SMAD3 were accumulated induced by oxalate in vitro and in vivo. The expression levels of TGF-β/SMAD pathway related proteins induced by oxalate were reversed by NAC. In conclusion, we found that NAC could play an anti-calculus role by mediating CDKN2B/TGF-β/SMAD axis.},
}

@article {pmid38518686,
year = {2024},
author = {Kumar, S and Dhiman, M},
title = {Helicobacter pylori secretary Proteins-Induced oxidative stress and its role in NLRP3 inflammasome activation.},
journal = {Cellular immunology},
volume = {399-400},
number = {},
pages = {104811},
doi = {10.1016/j.cellimm.2024.104811},
pmid = {38518686},
issn = {1090-2163},
abstract = {Helicobacter pylori-associated stomach infection is a leading cause of gastric ulcer and related cancer. H. pylori modulates the functions of infiltrated immune cells to survive the killing by reactive oxygen and nitrogen species (ROS and RNS) produced by these cells. Uncontrolled immune responses further produce excess ROS and RNS which lead to mucosal damage. The persistent oxidative stress is a major cause of gastric cancer. H. pylori regulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), nitric oxide synthase 2 (NOS2), and polyamines to control ROS and RNS release through lesser-known mechanisms. ROS and RNS produced by these pathways differentiate macrophages and T cells from protective to inflammatory phenotype. Pathogens-associated molecular patterns (PAMPs) induced ROS activates nuclear oligomerization domain (NOD), leucine rich repeats (LRR) and pyrin domain-containing protein 3 (NLRP3) inflammasome for the release of pro-inflammatory cytokines. This study evaluates the role of H. pylori secreted concentrated proteins (HPSCP) related oxidative stress role in NLRP3 inflammasome activation and macrophage differentiation. To perceive the role of ROS/RNS, THP-1 and AGS cells were treated with 10 μM diphenyleneiodonium (DPI), 50 μM salicyl hydroxamic acid (SHX), 5 μM Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), which are specific inhibitors of NADPH oxidase (NOX), Myeloperoxidase (MPO), and mitochondrial oxidative phosphorylation respectively. Cells were also treated with 10 μM of NOS2 inhibitor l-NMMA and 10 μM of N-acetyl cysteine (NAC), a free radical scavenger·H2O2 (100 μM) treated and untreated cells were used as positive controls and negative control respectively. The expression of gp91[phox] (NOX2), NOS2, NLRP3, CD86 and CD163 was analyzed through fluorescent microscopy. THP-1 macrophages growth was unaffected whereas the gastric epithelial AGS cells proliferated in response to higher concentration of HPSCP. ROS and myeloperoxidase (MPO) level increased in THP-1 cells and nitric oxide (NO) and lipid peroxidation significantly decreased in AGS cells. gp91[phox] expression was unchanged, whereas NOS2 and NLRP3 downregulated in response to HPSCP, but increased after inhibition of NO, ROS and MPO in THP-1 cells. HPSCP upregulated the expression of M1 and M2 macrophage markers, CD86 and CD163 respectively, which was decreased after the inhibition of ROS. This study concludes that there are multiple pathways which are generating ROS during H. pylori infection which further regulates other cellular processes. NO is closely associated with MPO and inhibition of NLRP3 inflammasome. The low levels of NO and MPO regulates gastrointestinal tract homeostasis and overcomes the inflammatory response of NLRP3. The ROS also plays crucial role in macrophage polarization hence alter the immune responses duing H. pylori pathogenesis.},
}

@article {pmid38518383,
year = {2024},
author = {Sun, X and Qin, X and Liang, G and Chang, X and Zhu, H and Zhang, J and Zhang, D and Sun, Y and Feng, S},
title = {Manganese dioxide nanoparticles provoke inflammatory damage in BV2 microglial cells via increasing reactive oxygen species to activate the p38 MAPK pathway.},
journal = {Toxicology and industrial health},
volume = {},
number = {},
pages = {7482337241242508},
doi = {10.1177/07482337241242508},
pmid = {38518383},
issn = {1477-0393},
abstract = {With the widespread use of manganese dioxide nanoparticles (nano MnO2), health hazards have also emerged. The inflammatory damage of brain tissues could result from nano MnO2, in which the underlying mechanism is still unclear. During this study, we aimed to investigate the role of ROS-mediated p38 MAPK pathway in nano MnO2-induced inflammatory response in BV2 microglial cells. The inflammatory injury model was established by treating BV2 cells with 2.5, 5.0, and 10.0 μg/mL nano MnO2 suspensions for 12 h. Then, the reactive oxygen species (ROS) scavenger (20 nM N-acetylcysteine, NAC) and the p38 MAPK pathway inhibitor (10 μM SB203580) were used to clarify the role of ROS and the p38 MAPK pathway in nano MnO2-induced inflammatory lesions in BV2 cells. The results indicated that nano MnO2 enhanced the expression of pro-inflammatory cytokines IL-1β and TNF-α, elevated intracellular ROS levels and activated the p38 MAPK pathway in BV2 cells. Controlling intracellular ROS levels with NAC inhibited p38 MAPK pathway activation and attenuated the inflammatory response induced by nano MnO2. Furthermore, inhibition of the p38 MAPK pathway with SB203580 led to a decrease in the production of inflammatory factors (IL-1β and TNF-α) in BV2 cells. In summary, nano MnO2 can induce inflammatory damage by increasing intracellular ROS levels and further activating the p38 MAPK pathway in BV2 microglial cells.},
}

@article {pmid38513962,
year = {2024},
author = {Liang, Z and Sun, G and Zhang, J and Zhang, Q and Li, X and Qin, S and Lv, S and Ding, J and Zhang, Q and Xia, Y and Lu, D},
title = {Protein phosphatase 4 mediates palmitic acid-induced endothelial dysfunction by decreasing eNOS phosphorylation at serine 633 in HUVECs.},
journal = {Experimental cell research},
volume = {},
number = {},
pages = {113998},
doi = {10.1016/j.yexcr.2024.113998},
pmid = {38513962},
issn = {1090-2422},
abstract = {Plasma saturated free fatty acid (FFA)-induced endothelial dysfunction (ED) contributes to the pathogenesis of atherosclerosis and cardiovascular diseases. However, the mechanism underlying saturated FFA-induced ED remains unclear. This study demonstrated that palmitic acid (PA) induced ED by activating the NADPH oxidase (NOX)/ROS signaling pathway to activate protein phosphatase 4 (PP4) and protein phosphatase 2A (PP2A), thereby reducing endothelial nitric oxide synthase (eNOS) phosphorylation at Ser633 and Ser1177, respectively. Okadaic acid (OA) and fostriecin (FST), which are inhibitors of PP2A, inhibited the PA-induced decreases in eNOS phosphorylation at Ser633 and Ser1177. The antioxidants N-acetylcysteine (NAC) and apocynin (APO) or knockdown of gp91phox or p67phox (NOX subunits) restored PA-mediated downregulation of PP4R2 protein expression and eNOS Ser633 phosphorylation. Knockdown of the PP4 catalytic subunit (PP4c) specifically increased eNOS Ser633 phosphorylation, while silencing the PP2A catalytic subunit (PP2Ac) restored only eNOS Ser1177 phosphorylation. Furthermore, PA dramatically decreased the protein expression of the PP4 regulatory subunit R2 (PP4R2) but not the other regulatory subunits. PP4R2 overexpression increased eNOS Ser633 phosphorylation, nitric oxide (NO) production, cell migration and tube formation but did not change eNOS Ser1177 phosphorylation levels. Coimmunoprecipitation (Co-IP) suggested that PP4R2 and PP4c interacted with the PP4R3α and eNOS proteins. In summary, PA decreases PP4R2 protein expression through the Nox/ROS pathway to activate PP4, which contributes to ED by dephosphorylating eNOS at Ser633. The results of this study suggest that PP4 is a novel therapeutic target for ED and ED-associated vascular diseases.},
}

@article {pmid38513858,
year = {2024},
author = {Li, S and Gu, X and Zhang, M and Jiang, Q and Xu, T},
title = {Di (2-ethylhexyl) phthalate and polystyrene microplastics co-exposure caused oxidative stress to activate NF-κB/NLRP3 pathway aggravated pyroptosis and inflammation in mouse kidney.},
journal = {The Science of the total environment},
volume = {},
number = {},
pages = {171817},
doi = {10.1016/j.scitotenv.2024.171817},
pmid = {38513858},
issn = {1879-1026},
abstract = {Polystyrene microplastic (PS-MPs) contamination has become a worldwide hotspot of concern, and its entry into organisms can cause oxidative stress resulting in multi-organ damage. The plasticizer di (2-ethylhexyl) phthalate (DEHP) is a common endocrine disruptor, these two environmental toxins often occur together, but their combined toxicity to the kidney and its mechanism of toxicity are unknown. Therefore, in this study, we established PS-MPS and/or DEHP-exposed mouse models. The results showed that alone exposure to both PS-MPs and DEHP caused inflammatory cell infiltration, cell membrane rupture, and content spillage in kidney tissues. There were also down-regulation of antioxidant enzyme levels, increased ROS content, activated of the NF-κB pathway, stimulated the levels of heat shock proteins (HSPs), pyroptosis, and inflammatory associated factors. Notably, the co-exposure group showed greater toxicity to kidney tissues, the cellular assay further validated these results. The introduction of the antioxidant n-acetylcysteine (NAC) and the NLRP3 inhibitor (MCC950) could mitigate the changes in the above measures. In summary, co-exposure of PS-MPs and DEHP induced oxidative stress that activated the NF-κB/NLRP3 pathway and aggravated kidney pyroptosis and inflammation, as well as that HSPs are also involved in this pathologic injury process. This study not only enriched the nephrotoxicity of plasticizers and microplastics, but also provided new insights into the toxicity mechanisms of multicomponent co-pollution in environmental.},
}

@article {pmid38513841,
year = {2024},
author = {Malaviya, R and Meshanni, J and Sunil, VR and Venosa, A and Guo, C and Abramova, EV and Vayas, KN and Jiang, C and Cervelli, JA and Gow, AJ and Laskin, JD and Laskin, DL},
title = {Role of macrophage bioenergetics in N-acetylcysteine-mediated mitigation of lung injury and oxidative stress induced by nitrogen mustard.},
journal = {Toxicology and applied pharmacology},
volume = {},
number = {},
pages = {116908},
doi = {10.1016/j.taap.2024.116908},
pmid = {38513841},
issn = {1096-0333},
abstract = {Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, IL-6 and IL-12; macrophages expressing inducible nitric oxide synthase, cyclooxygenase-2 and tumor necrosis factor-α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury.},
}

@article {pmid38508437,
year = {2024},
author = {Liu, H and Wang, X and He, K and Chen, Z and Li, X and Ren, J and Zhao, X and Liu, S and Zhou, T and Chen, H},
title = {Oxidized DJ-1 activates the p-IKK/NF-κB/Beclin1 pathway by binding PTEN to induce autophagy and exacerbate myocardial ischemia-reperfusion injury.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {176496},
doi = {10.1016/j.ejphar.2024.176496},
pmid = {38508437},
issn = {1879-0712},
abstract = {Patients with myocardial infarction have a much worse prognosis when they have myocardial ischemia-reperfusion (I/R) injury. Further research into the molecular basis of myocardial I/R injury is therefore urgently needed, as well as the identification of novel therapeutic targets and linkages to interventions. Three cysteine residues are present in DJ-1 at amino acids 46, 53, and 106 sites, with the cysteine at position 106 being the most oxidation-prone. This study sought to understand how oxidized DJ-1(C106) contributes to myocardial I/R damage. Rats' left anterior descending branches were tied off to establish a myocardial I/R model in vivo. A myocardial I/R model in vitro was established via anoxia/reoxygenation (A/R) of H9c2 cells. The results showed that autophagy increased after I/R, accompanied by the increased expression of oxidized DJ-1 (ox-DJ-1). In contrast, after pretreatment with NAC (N-acetylcysteine, a ROS scavenger) or Comp-23 (Compound-23, a specific antioxidant binding to the C106 site of DJ-1), the levels of ox-DJ-1, autophagy and LDH release decreased, and cell survival rate increased. Furthermore, the inhibition of interaction between ox-DJ-1 and PTEN could increase PTEN phosphatase activity, inhibit the p-IKK/NF-κB/Beclin1 pathway, reduce injurious autophagy, and alleviate A/R injury. However, BA (Betulinic acid, a NF-κB activator) was able to reverse the protective effects produced by Comp-23 pretreatment. In conclusion, ox-DJ-1 could activate detrimental autophagy through the PTEN/p-IKK/NF-κB/Beclin1 pathway and exacerbate myocardial I/R injury.},
}

@article {pmid38507470,
year = {2024},
author = {Yin, J and Ge, X and Ding, F and He, L and Song, K and Shi, Z and Ge, Z and Zhang, J and Ji, J and Wang, X and Zhao, N and Shu, C and Lin, F and Wang, Q and Zhou, Q and Cao, Y and Liu, W and Ye, D and Rich, JN and Wang, X and You, Y and Qian, X},
title = {Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly.},
journal = {Science translational medicine},
volume = {16},
number = {739},
pages = {eadg5553},
doi = {10.1126/scitranslmed.adg5553},
pmid = {38507470},
issn = {1946-6242},
abstract = {Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery in differentiated glioma cells. PTEN was specifically succinated at cysteine (C) 211 in GSCs compared with matched differentiated glioma cells. Isotope tracing coupled with mass spectrometry analysis confirmed that fumarate, generated by adenylosuccinate lyase (ADSL) in the de novo purine synthesis pathway that is highly activated in GSCs, promoted PTEN C211 succination. This modification abrogated the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. Functionally, inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration-approved prescription drug N-acetylcysteine (NAC) impaired GSC maintenance. Reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery-mediated DNA damage repair. These findings reveal an immediately practicable strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC.},
}

@article {pmid38505087,
year = {2024},
author = {Liang, Z and Chen, Q and Pan, L and She, X and Chen, T},
title = {Mebendazole induces apoptosis and inhibits migration via the reactive oxygen species-mediated STAT3 signaling downregulation in non-small cell lung cancer.},
journal = {Journal of thoracic disease},
volume = {16},
number = {2},
pages = {1412-1423},
pmid = {38505087},
issn = {2072-1439},
abstract = {BACKGROUND: The incidence and mortality of non-small cell lung cancer (NSCLC) are extremely high. Previous research has confirmed that the signal transducer and activator of the transcription 3 (STAT3) protein critically participate in the tumorigenesis of NSCLC. Mebendazole (MBZ) has exerts a larger number of pharmacological activities and has anticancer effects in lung cancer, but its mechanism of action remains unclear. This study thus aimed to clarify the impacts of MBZ on NSCLC cell.

METHODS: Cell proliferation, migration, and apoptosis were investigated via cell counting kit 8 (CCK-8) assay, Transwell assay, colony formation assay, wound-healing assay, and flow cytometry. Reactive oxygen species (ROS) were detected with a multifunctional microplate reader. Markers of cell migration and apoptosis were detected with Western blotting. The transcriptional activity of STAT3 was detected via luciferase assay. ROS scavenger N-acetylcysteine (NAC) was used to determine the effect of MBZ on NSCLC via ROS-regulated STAT3 inactivation and apoptosis. A xenograft model was constructed in vivo to investigate the role of MBZ in NSCLC tumor growth.

RESULTS: The findings demonstrated that MBZ inhibited NSCLC cell proliferation and migration while promoting apoptosis through triggering ROS generation. In addition, the Janus kinase 2 (JAK2)-STAT3 signaling pathway was abrogated with the treatment of MBZ. NAC could distinctly weaken MBZ-induced apoptosis and STAT3 inactivation. Moreover, MBZ inhibited the tumor growth of NSCLC in vivo.

CONCLUSIONS: In summary, MBZ inhibited NSCLC cell viability and migration by inducing cell apoptosis via the ROS-JAK2-STAT3 signaling pathway. These data provide a theoretical basis for the use of MBZ in treating NSCLC.},
}

@article {pmid38503729,
year = {2024},
author = {Rodrigues, ACBDC and Silva, SLR and Dias, IRSB and Costa, RGA and Oliveira, MS and Soares, MBP and Dias, RB and Valverde, LF and Rocha, CAG and Johnson, EM and Pina, C and Bezerra, DP},
title = {Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling.},
journal = {Cell death discovery},
volume = {10},
number = {1},
pages = {147},
pmid = {38503729},
issn = {2058-7716},
abstract = {Acute myeloid leukaemia (AML) is a haematological malignancy characterised by the accumulation of transformed myeloid progenitors in the bone marrow. Piplartine (PL), also known as piperlongumine, is a pro-oxidant small molecule extracted from peppers that has demonstrated antineoplastic potential in solid tumours and other haematological malignancies. In this work, we explored the potential of PL to treat AML through the use of a combination of cellular and molecular analyses of primary and cultured leukaemia cells in vitro and in vivo. We showed that PL exhibits in vitro cytotoxicity against AML cells, including CD34[+] leukaemia-propagating cells, but not healthy haematopoietic progenitors, suggesting anti-leukaemia selectivity. Mechanistically, PL treatment increased reactive oxygen species (ROS) levels and induced ROS-mediated apoptosis in AML cells, which could be prevented by treatment with the antioxidant scavenger N-acetyl-cysteine and the pancaspase inhibitor Z-VAD(OMe)-FMK. PL treatment reduced NFKB1 gene transcription and the level of NF-κB p65 (pS536), which was depleted from the nucleus of AML cells, indicating suppression of NF-κB p65 signalling. Significantly, PL suppressed AML development in a mouse xenograft model, and its combination with current AML treatments (cytarabine, daunorubicin and azacytidine) had synergistic effects, indicating translational therapeutic potential. Taken together, these data position PL as a novel anti-AML candidate drug that can target leukaemia stem/progenitors and is amenable to combinatorial therapeutic strategies.},
}

@article {pmid38503013,
year = {2024},
author = {Li, Y and Long, W and Zhang, H and Zhao, M and Gao, M and Guo, W and Yu, L},
title = {Irbesartan ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing NLRP3 inflammasomes in vivo and in vitro.},
journal = {International immunopharmacology},
volume = {131},
number = {},
pages = {111844},
doi = {10.1016/j.intimp.2024.111844},
pmid = {38503013},
issn = {1878-1705},
abstract = {OBJECTIVES: Diabetic nephropathy (DN) is characterized by albuminuria and renal dysfunction caused by diabetes. At present there is no specific treatment for DN. Irbesartan (IRB) is an angiotensin receptor inhibitor indicated for the treatment of hypertension and DN. However, the underlying molecular mechanisms of IRB on DN remains obscure.

METHODS: RAW264.7 macrophages were incubated in RPMI-1640, cell viability was evaluated by CCK-8 assays, transcriptional level of proinflammatory cytokines and was measured by ELISA and qPCR, NLRP3 inflammasome and Nrf2/Keap1 related proteins were measured by Western blotting and immunohistochemistry. Streptozotocin (STZ)-induced diabetic male C57BL/6 mice were used to evaluate the therapeutic effect of IRB on DN. Key findings First, we found that IRB improved high glucose-induced cell inflammation by inhibiting the transcription of IL-1β and IL-18. IRB activated the Nrf2/Keap1 pathway and decreased the release of reactive oxygen species (ROS). IRB also suppressed the expression of NLRP3 and caspase-1. IRB combined with the N-acetylcysteine (NAC) significantly inhibited the activation of NLRP3 inflammasomes. Conversely, IRB combined with the Nrf2-related inhibitor ML385 enhanced NLRP3 inflammasome activation, suggesting that IRB suppressed NLRP3 inflammasome via the Nrf2 pathway. In vivo study, HE staining and immunohistochemistry analysis further showed that IRB ameliorated high glucose-induced renal injury by elevating the expression of the Nrf2/Keap1 signaling pathway and suppressing the proinflammatory cytokine and NLRP3 inflammasome activation.

CONCLUSIONS: Our results suggested that IRB ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing the NLRP3 inflammasomes in vivo and in vitro. These findings provide new therapeutic strategies of diabetic nephropathy.},
}

@article {pmid38500894,
year = {2024},
author = {Harlivasari, AD and Susanto, AD and Taufik, FF and Ginting, TT},
title = {The Role of Twice-Daily N-acetylcysteine (NAC) 2400 mg in Smoking Cessation: A Randomized, Placebo-Controlled Trial in Indonesia.},
journal = {Cureus},
volume = {16},
number = {2},
pages = {e54322},
pmid = {38500894},
issn = {2168-8184},
abstract = {INTRODUCTION: Tobacco smoking remains a health concern, especially in developing countries. Nicotine is significantly linked to many cancers and even second-hand exposure. Hence, smoking can increase the risk of lung and heart disease. This makes quitting smoking important and challenging. Success tends to rise by achieving abstinence with assisted pharmacology. These treatments aim to reduce symptoms of nicotine withdrawal. This is a preclinical trial on glutamate modulator in N-acetylcysteine (NAC) as a new potential treatment for smoking cessation. It is based on the administration of NAC related to elevated levels of dopamine in the central nervous system to accomplish successful smoking cessation.

AIM: This study evaluated the efficacy and tolerability of NAC for smoking cessation. The primary outcome was abstinence rate and the secondary outcomes of the study were to assess carbon monoxide exhalation value (COexh), the withdrawal symptoms, craving score, safety, and tolerability associated with the administration of NAC.

METHODS: This is a randomized clinical trial. Eligible smokers were treated with NAC 2400 mg twice daily (BID) or placebo to obtain a potential effective abstinence rate. Subjects recruited from the smoking cessation clinic were screened for eligibility and were randomized to either the NAC or placebo group. The trial consisted of a four-week treatment phase and participants were evaluated each week with a brief counseling. Intention to treat data analysis was performed from 2018 to 2019. Smoking cessation status was verified by measuring the amount of carbon monoxide exhaled and by documenting their smoking habits. Adverse events (AEs) have also been observed on each visit.

RESULTS: A total of 90 male smokers with a mean (SD) age of 38.7 (11) years were randomized into two groups to receive NAC (n=45) and placebo (n=45). The primary outcome revealed that the abstinence rate was significantly higher for the NAC group than the placebo group (37.7% vs 6.6%; p=0.02). These findings were supported by data comparison between the NAC group and placebo group of COexh (ppm) (9.59 ±7.4 vs 13,4 ±6.1; p=0.04) and cigarette consumption/week (10 vs 46; p <0.001), which were statistically significant. Comparison of withdrawal with the Minnesota Nicotine Withdrawal Score between the NAC group and the placebo group showed lower values (8 (1-31) vs 11 (0-43); p=0.178), respectively, even though not statistically significant. Compared to the placebo group, the craving score (6 (2-29) vs 12 (6-31); p=0.04) in the NAC group was significantly lower. The most common adverse event was mild gastrointestinal effects (28.9%) and arthralgia (2.2%). No serious adverse events were detected.

CONCLUSIONS:  Despite a small sample size, the data demonstrate the potential benefits of NAC that may help elevate abstinence rates and promote successful smoking cessation pharmacotherapy. Comprehensive treatment combining pharmacologic therapy and counseling increases smoking cessation success rates. It is essential to conduct a randomized multicenter study with a large population to support a sustained abstinence rate using NAC.},
}

@article {pmid38500550,
year = {2024},
author = {Takasaki, T and Hamabe, Y and Touchi, K and Khandakar, GI and Ueda, T and Okada, H and Sakai, K and Nishio, K and Tanabe, G and Sugiura, R},
title = {ACA-28, an ERK MAPK Signaling Modulator, Exerts Anticancer Activity through ROS Induction in Melanoma and Pancreatic Cancer Cells.},
journal = {Oxidative medicine and cellular longevity},
volume = {2024},
number = {},
pages = {7683793},
pmid = {38500550},
issn = {1942-0994},
abstract = {The extracellular signal-regulated kinase (ERK) MAPK pathway is dysregulated in various human cancers and is considered an attractive therapeutic target for cancer. Therefore, several inhibitors of this pathway are being developed, and some are already used in the clinic. We have previously identified an anticancer compound, ACA-28, with a unique property to preferentially induce ERK-dependent apoptosis in melanoma cells. To comprehensively understand the biological cellular impact induced by ACA-28, we performed a global gene expression analysis of human melanoma SK-MEL-28 cells exposed to ACA-28 using a DNA microarray. The transcriptome analysis identified nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor that combats oxidative stress, as the most upregulated genetic pathway after ACA-28 treatment. Consistently, ACA-28 showed properties to increase the levels of reactive oxygen species (ROS) as well as Nrf2 protein, which is normally repressed by proteasomal degradation and activated in response to oxidative stresses. Furthermore, the ROS scavenger N-acetyl cysteine significantly attenuated the anticancer activity of ACA-28. Thus, ACA-28 activates Nrf2 signaling and exerts anticancer activity partly via its ROS-stimulating property. Interestingly, human A549 cancer cells with constitutively high levels of Nrf2 protein showed resistance to ACA-28, as compared with SK-MEL-28. Transient overexpression of Nrf2 also increased the resistance of cells to ACA-28, while knockdown of Nrf2 exerted the opposite effect. Thus, upregulation of Nrf2 signaling protects cancer cells from ACA-28-mediated cell death. Notably, the Nrf2 inhibitor ML385 substantially enhanced the cell death-inducing property of ACA-28 in pancreatic cancer cells, T3M4 and PANC-1. Our data suggest that Nrf2 plays a key role in determining cancer cell susceptibility to ACA-28 and provides a novel strategy for cancer therapy to combine the Nrf2 inhibitor and ACA-28.},
}

@article {pmid38498979,
year = {2024},
author = {El-Habta, R and Af Bjerkén, S and Virel, A},
title = {N-acetylcysteine increases dopamine release and prevents the deleterious effects of 6-OHDA on the expression of VMAT2, α-synuclein, and tyrosine hydroxylase.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/01616412.2024.2325312},
pmid = {38498979},
issn = {1743-1328},
abstract = {OBJECTIVES: Current treatments for Parkinson's disease using pharmacological approaches alleviate motor symptoms but do not prevent neuronal loss or dysregulation of dopamine neurotransmission. In this article, we have explored the molecular mechanisms underlying the neuroprotective effect of the antioxidant N-acetylcysteine (NAC) on the damaged dopamine system.

METHODS: SH-SY5Y cells were differentiated towards a dopaminergic phenotype and exposed to 6-hydroxydopamine (6-OHDA) to establish an in vitro model of Parkinson's disease. We examined the potential of NAC to restore the pathological effects of 6-OHDA on cell survival, dopamine synthesis as well as on key proteins regulating dopamine metabolism. Specifically, we evaluated gene- and protein expression of tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and α-synuclein, by using qPCR and Western blot techniques. Moreover, we quantified the effect of NAC on total dopamine levels using a dopamine ELISA assay.

RESULTS: Our results indicate that NAC has a neuroprotective role in SH-SY5Y cells exposed to 6-OHDA by maintaining cell proliferation and decreasing apoptosis. Additionally, we demonstrated that NAC treatment increases dopamine release and protects SH-SY5Y cells against 6-OHDA dysregulations on the proteins TH, VMAT2, and α-synuclein.

CONCLUSIONS: Our findings contribute to the validation of compounds capable to restore dopamine homeostasis and shed light on the metabolic pathways that could be targeted to normalize dopamine turnover. Furthermore, our results highlight the effectiveness of the antioxidant NAC in the prevention of dopaminergic neurodegeneration in the present model.

ABBREVIATIONS: DAT, dopamine transporter; 6-OHDA, 6-hydroxydopamine; NAC, N-acetylcysteine; PARP, poly (ADP-ribose) polymerase; RA; retinoic acid; ROS, reactive oxygen species; TH, tyrosine hydroxylase; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; VMAT2, vesicle monoamine transporter 2.},
}

@article {pmid38497734,
year = {2024},
author = {Li, X and Zou, J and Lin, A and Chi, J and Hao, H and Chen, H and Liu, Z},
title = {Oxidative stress, endothelial dysfunction, and N-acetylcysteine in type-2 diabetes mellitus.},
journal = {Antioxidants & redox signaling},
volume = {},
number = {},
pages = {},
doi = {10.1089/ars.2023.0524},
pmid = {38497734},
issn = {1557-7716},
abstract = {Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally. Endothelial dysfunction is closely associated with the development and progression of CVDs. Patients with diabetes mellitus (DM) especially type-2 DM exhibit a significant endothelial cell dysfunction with substantially increased risk for CVDs. Excessive reactive oxygen species (ROS) and oxidative stress are important contributing factors to endothelial cell dysfunction and subsequent CVDs. ROS production is significantly increased in DM and is critically involved in the development of endothelial dysfunction in diabetic patients. In the present review, efforts are made to discuss the role of excessive ROS and oxidative stress in the pathogenesis of endothelial dysfunction and the mechanisms for excessive ROS production and oxidative stress in type-2 DM. Although studies with diabetic animal models have shown that targeting ROS with traditional antioxidant vitamins C and E or other antioxidant supplements provides promising beneficial effects on endothelial function, the cardiovascular outcomes of clinical studies with these antioxidant supplements have been inconsistent in diabetic patients. Preclinical and limited clinical data suggest that N-acetylcysteine (NAC) treatment may improve endothelial function in diabetic patients. However, well designed clinical studies are needed to determine if NAC supplementation would effectively preserve endothelial function and improve the clinical outcomes of diabetic patients with reduced cardiovascular morbidity and mortality. With better understanding on the mechanisms of ROS generation and ROS-mediated endothelial damages/dysfunction, it is anticipated that new selective ROS-modulating agents, and effective personalized strategies will be developed for the management of endothelial dysfunction in DM.},
}

@article {pmid38496055,
year = {2024},
author = {R, R and Routray, M},
title = {Management of Yellow Phosphorus-Induced Acute Liver Failure: A Case Report and Review of Literature.},
journal = {Cureus},
volume = {16},
number = {2},
pages = {e54223},
pmid = {38496055},
issn = {2168-8184},
abstract = {Three percent (3%) of yellow phosphorus is the active component of the rodenticide Ratol[®]. It is a potent hepatotoxin that leads to acute liver failure (ALF) with high mortality. There is no antidote available; the only definitive management is liver transplantation. Therapeutic plasma exchange, or plasmapheresis, appears to help these patients by removing the toxin, its metabolite, or the inflammatory mediators released in the body in response to the toxin. Here, we report a case of a 19-year-old male with an alleged history of Ratol[®] ingestion and ALF with acute kidney injury. He had a complete reversal of his condition with timely intervention in the form of plasmapheresis.},
}

@article {pmid38495889,
year = {2024},
author = {Gupta, A and Song, MH and Youn, DH and Ku, D and Sasidharan Nair, V and Oh, K},
title = {Prolyl hydroxylase inhibition protects against murine MC903-induced skin inflammation by downregulating TSLP.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1330011},
pmid = {38495889},
issn = {1664-3224},
abstract = {Previously, we reported an anti-inflammatory effect of mTORC1 in a mouse model of type 2 skin inflammation. TSLP, one of the epithelial cell-derived cytokines, was upregulated by Raptor deficiency or rapamycin treatment, which was inhibited by dimethyloxalylglycine (DMOG). However, it remains unclear how DMOG regulates TSLP expression and type 2 skin inflammation. In this study, we investigated the protective effect of DMOG on MC903 (calcipotriol)-induced type 2 skin inflammation. Morphological and immunological changes were assessed by H-E staining, flow cytometry and RT-qPCR. DMOG treatment attenuated MC903-induced skin inflammation in a T cell-independent manner. The anti-inflammatory effect of DMOG was accompanied by downregulation of TSLP and IL-33, and supplementation with recombinant TSLP and IL-33 abolished the effect of DMOG. MC903 increased ROS levels in skin tissue, which was prevented by DMOG. Furthermore, the ROS scavenger N-acetylcysteine (NAC) downregulated TSLP and ameliorated MC903-induced skin inflammation, as did DMOG. Finally, the effect of DMOG on ROS and TSLP was reduced by HIF knockdown. These results suggest that DMOG downregulates TSLP and ROS through the HIF pathway, which reduces MC903-induced skin inflammation.},
}

@article {pmid38494703,
year = {2024},
author = {Miyake, K and Mikami, Y and Asayama, T and Toriumi, T and Shinozuka, K and Tonogi, M and Yonehara, Y and Tsuda, H},
title = {Reactive oxygen species generation required for autophagy induction during butyrate- or propionate-induced release of damage-associated molecular patterns from dying gingival epithelial Ca9-22 cells.},
journal = {Journal of oral science},
volume = {},
number = {},
pages = {},
doi = {10.2334/josnusd.23-0421},
pmid = {38494703},
issn = {1880-4926},
abstract = {PURPOSE: Bacterial cells in mature dental plaque produce a high concentration of short-chain fatty acids (SCFAs) such as butyrate and propionate. SCFA-treatment on human gingival epithelial Ca9-22 cells induced cell death. However, the exact mechanism underlying cell death remains unclear. In this study, the relationship between reactive oxygen species (ROS) and autophagy induction during SCFA-induced cell death was examined.

METHODS: Human gingival epithelial Ca9-22 cells were treated with butyrate or propionate to induce cell death and the number of dead cells were measured using SYTOX-green dye. A siRNA for ATG5 and N-acetylcysteine (NAC) were used for autophagy reduction and ROS-scavenging, respectively. Release of damage-associated molecular patterns (DAMPs) such as Sin3A-associated protein 130 (SAP130) and high-mobility group box 1 (HMGB1) were detected using western blot.

RESULTS: Reducing autophagy significantly suppressed SCFA-induced Ca9-22 cell death. ROS generation was observed upon SCFA treatment, and scavenging ROS with NAC decreased cell death. NAC also reduced the SCFA-induced increase in microtubule-associated protein 1 light chain 3B (LC3B)-I and LC3B-II, and mitigated the release of DAMPs.

CONCLUSION: The findings suggest that ROS generation is necessary for autophagy, which is required for SCFA-induced cell death and accompanying DAMP release.},
}

@article {pmid38488660,
year = {2024},
author = {Cao, S and Yin, H and Li, X and Zeng, X and Liu, J},
title = {Nickel induces epithelial-mesenchymal transition in pulmonary fibrosis in mice via activation of the oxidative stress-mediated TGF-β1/Smad signaling pathway.},
journal = {Environmental toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1002/tox.24229},
pmid = {38488660},
issn = {1522-7278},
support = {22zx7153//Natural Science Foundation of Southwest University of Science and Technology/ ; },
abstract = {Nickel (Ni) is recognized as a carcinogenic metal, and its widespread use has led to severe environmental and health problems. Although the lung is among the main organs affected by Ni, the precise mechanisms behind this effect remain poorly understood. This study aimed to elucidate the physiological mechanisms underlying Ni-induced pulmonary fibrosis (PF), using various techniques including histopathological detection, biochemical analysis, immunohistochemistry, western blotting, and quantitative real-time PCR. Mice were treated with nickel chloride (NiCl2), which induced PF (detected by Masson staining), up-regulation of α-smooth muscle actin (α-SMA), and collagen-1 mRNA and protein expression. NiCl2 was found to induce PF by: activation of the epithelial-mesenchymal transition (EMT) and the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway; up-regulation of protein and mRNA expression of TGF-β1, p-Smad2, p-Smad3, vimentin, and N-cadherin; and down-regulation of protein and mRNA expression of E-cadherin. In addition, NiCl2 treatment increased malondialdehyde content while inhibiting antioxidant activity, as indicated by decreased catalase, total antioxidant capacity, and superoxide dismutase activities, and glutathione content. Co-treatment with the effective antioxidant and free radical scavenger N-acetyl cysteine (NAC) plus NiCl2 was used to study the effects of oxidative stress in NiCl2 -induced PF. The addition of NAC significantly mitigated NiCl2 -induced PF, and reversed activation of the TGF-β1/Smad signaling pathway and EMT. NiCl2 -induced PF was therefore shown to be due to EMT activation via the TGF-β1/Smad signaling pathway, mediated by oxidative stress.},
}

@article {pmid38480798,
year = {2024},
author = {Zhu, C and Lu, Y and Wang, S and Song, J and Ding, Y and Wang, Y and Dong, C and Liu, J and Qiu, W and Qi, W},
title = {Nortriptyline hydrochloride, a potential candidate for drug repurposing, inhibits gastric cancer by inducing oxidative stress by triggering the Keap1-Nrf2 pathway.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {6050},
pmid = {38480798},
issn = {2045-2322},
support = {No. 202003030451//Science and Technology Development Plan of Shandong Province/ ; No. KC2021-JX-0186-145//Beijing Science and Technology Innovation Medical Development Foundation/ ; No.202103030554//Health Science and Technology Development Plan Project/ ; },
abstract = {Effective drugs for the treatment of gastric cancer (GC) are still lacking. Nortriptyline Hydrochloride (NTP), a commonly used antidepressant medication, has been demonstrated by numerous studies to have antitumor effects. This study first validated the ability of NTP to inhibit GC and preliminarily explored its underlying mechanism. To begin with, NTP inhibits the activity of AGS and HGC27 cells (Human-derived GC cells) in a dose-dependent manner, as well as proliferation, cell cycle, and migration. Moreover, NTP induces cell apoptosis by upregulating BAX, BAD, and c-PARP and downregulating PARP and Bcl-2 expression. Furthermore, the mechanism of cell death caused by NTP is closely related to oxidative stress. NTP increases intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, decreasing the mitochondrial membrane potential (MMP) and inducing glucose (GSH) consumption. While the death of GC cells can be partially rescued by ROS inhibitor N-acetylcysteine (NAC). Mechanistically, NTP activates the Kelch-like ECH-associated protein (Keap1)-NF-E2-related factor 2 (Nrf2) pathway, which is an important pathway involved in oxidative stress. RNA sequencing and proteomics analysis further revealed molecular changes at the mRNA and protein levels and provided potential targets and pathways through differential gene expression analysis. In addition, NTP can inhibited tumor growth in nude mouse subcutaneous tumor models constructed respectively using AGS and MFC (mouse-derived GC cells), providing preliminary evidence of its effectiveness in vivo. In conclusion, our study demonstrated that NTP exhibits significant anti-GC activity and is anticipated to be a candidate for drug repurposing.},
}

@article {pmid38474543,
year = {2024},
author = {Beloglazkina, EK and Moiseeva, AA and Tsymbal, SA and Guk, DA and Kuzmin, MA and Krasnovskaya, OO and Borisov, RS and Barskaya, ES and Tafeenko, VA and Alpatova, VM and Zaitsev, AV and Finko, AV and Ol'shevskaya, VA and Shtil, AA},
title = {The Copper Reduction Potential Determines the Reductive Cytotoxicity: Relevance to the Design of Metal-Organic Antitumor Drugs.},
journal = {Molecules (Basel, Switzerland)},
volume = {29},
number = {5},
pages = {},
doi = {10.3390/molecules29051032},
pmid = {38474543},
issn = {1420-3049},
support = {19-29-08007//Russian Foundation for Basic Research/ ; },
abstract = {Copper-organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu[2+] to Cu[1+] triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)-organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with N-acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins. We demonstrate that the ability of the complexes to kill cells in combination with NAC is determined by the potential of the Cu[+2] → Cu[+1] redox transition rather than by the spatial structure of the organic ligand. For cell sensitization to the copper-organic complex, the electrochemical potential of the metal reduction should be lower than the oxidation potential of the reducing agent. Generally, the structural optimization of copper-organic complexes for combinations with the reducing agents should include uncharged organic ligands that carry hard electronegative inorganic moieties.},
}

@article {pmid38472735,
year = {2024},
author = {Farouk, F and Shebl, RI},
title = {LC-MS/MS determination of pyocyanin-N-acetyl cysteine adduct: application for understanding Pseudomonas aeruginosa virulence factor neutralization.},
journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry},
volume = {},
number = {},
pages = {},
pmid = {38472735},
issn = {1348-2246},
abstract = {Combating Pseudomonas aeruginosa infection is challenging. It secretes pyocyanin (PCN) pigment that contributes to its virulence. Neutralizing PCN via reaction with thiol-containing compounds may represent a potential therapeutic option. This study investigates the neutralization reaction between PCN and N-acetyl cysteine (NAC) for bacterial inhibition and explores its mechanism of action. The neutralization adduct (PCN-NAC) was synthesized by reacting the purified PCN and NAC. The adduct was analyzed and its structure was elucidated. LC-MS/MS method was developed for the determination of PCN-NAC in P. aeruginosa cultures post-treatment with NAC (0-5 mg/mL). The corresponding anti-bacterial potential was estimated and compared to nanoparticles (NPs) alone and under stress conditions. In silico studies were performed to support explaining the mechanism of action. Results revealed that PCN-NAC was exclusively detected in NAC-treated cultures in a concentration-dependent manner. PCN-NAC concentration (230-915 µg/mL) was directly proportional to the reduction in the bacterial viable count (28.3% ± 7.1-87.5% ± 5.9) and outperformed all tested NPs, where chitosan NPs induced 56.9% ± 7.9 inhibition, followed by zinc NPs (49.4% ± 0.9) and gold NPs (17.8% ± 7.5) even post-exposure to different stress conditions. A concomitant reduction in PCN concentration was detected. In silico studies revealed possible interactions between key bacterial proteins and PCN-NAC rather than the NAC itself. These results pose NAC as a potential choice for the management of P. aeruginosa infection, where it neutralizes PCN via the formation of PCN-NAC adduct.},
}

@article {pmid38470079,
year = {2024},
author = {Atefi, N and Ziaeifar, E and Seirafianpour, F and Sadeghzadeh-Bazargan, A and Amin, NG and Mozafarpoor, S and Abouie, A and Jafari, MA and Goodarzi, A},
title = {Evaluation of efficacy and safety of vitiligo treatment with micro-needling combined with N-Acetylcysteine and micro-needling alone: A double-blinded randomized controlled clinical trial.},
journal = {Journal of cosmetic dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jocd.16274},
pmid = {38470079},
issn = {1473-2165},
abstract = {INTRODUCTION: Vitiligo is a skin pigmentation disorder caused by the selective degradation of melanocytes. This study investigates the therapeutic effects of microneedling with and without N-acetylcysteine (NAC) in patients with persistent and limited vitiligo.

METHOD: This research employed a clinical trial design with double-blind randomization. Individuals affected by vitiligo and seeking treatment at Rasool Akram Medical Complex were divided into two separate treatment groups. In the intervention group, 24 affected areas underwent meso-microneedling using 5% NAC ampoules over six sessions, in addition to the application of 4.7% NAC cream once daily on the specified area. Conversely, the control group, consisting of 22 lesions, underwent microneedling using distilled water during six sessions. The severity of lesions and the extent of repigmentation were gauged using the Modified VETI Score. Assessment of treatment efficacy was determined through both physician evaluations and patient feedback.

RESULTS: Twenty patients with a mean age of 36.4 years were recruited. The mean percentage of lesions and their intensity were significantly improved 2 weeks after the third session and 1 month after the end of the treatment (p < 0.01). There was no statistically significant difference between the intervention and control groups. Gender, age, family history, duration of disease, duration of disease stability, and history of hypothyroidism had no statistically significant relationship with patients' treatment outcomes (p > 0.05).

CONCLUSION: Microneedling with or without the application of NAC appears to be an effective treatment option for persistent vitiligo lesions. However, despite the higher improvement rate with the application of NAC, the difference was not significant.},
}

@article {pmid38469128,
year = {2024},
author = {Gautam, N and Shrestha, N and Bhandari, S and Thapaliya, S},
title = {Severe dengue infection unmasking drug-induced liver injury: Successful management with N-acetylcysteine.},
journal = {Clinical case reports},
volume = {12},
number = {3},
pages = {e8578},
pmid = {38469128},
issn = {2050-0904},
abstract = {KEY CLINICAL MESSAGE: Clinicians in tuberculosis and dengue endemic regions should have heightened vigilance for drug-induced liver injury (DILI) overlapping with active infections, enabling prompt recognition and life-saving conservative management.

ABSTRACT: Severe dengue and drug-induced liver injury (DILI) are significant independent risk factors for acute liver failure. The co-occurrence of these conditions significantly complicates clinical management. Here, we describe the case of a 21-year-old Nepali female who developed acute liver failure during antitubercular therapy (ATT). The patient, presenting with fever and nausea after 3 weeks of ATT, subsequently received a diagnosis of severe dengue. Laboratory evidence indicated markedly elevated transaminases (AST 4335 U/L, ALT 1958 U/L), total bilirubin (72 μmol/L), and INR (>5). Prompt discontinuation of first-line ATT, initiation of a modified ATT regimen, and N-acetylcysteine (NAC) infusion facilitated the patient's recovery after a week of intensive care. This case underscores the potential for synergistic hepatotoxicity in regions where multiple endemic illnesses coincide. Early recognition of DILI, cessation of offending agents, and comprehensive intensive care are crucial interventions. While the definitive efficacy of NAC remains under investigation, its timely administration in these complex cases warrants exploration for its potential lifesaving benefits.},
}

@article {pmid38467612,
year = {2024},
author = {Zhang, L and Shi, X and Zhang, L and Mi, Y and Zuo, L and Gao, S},
title = {A first-in-class TIMM44 blocker inhibits bladder cancer cell growth.},
journal = {Cell death & disease},
volume = {15},
number = {3},
pages = {204},
pmid = {38467612},
issn = {2041-4889},
support = {81902565//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Mitochondria play a multifaceted role in supporting bladder cancer progression. Translocase of inner mitochondrial membrane 44 (TIMM44) is essential for maintaining function and integrity of mitochondria. We here tested the potential effect of MB-10 (MitoBloCK-10), a first-in-class TIMM44 blocker, against bladder cancer cells. TIMM44 mRNA and protein expression is significantly elevated in both human bladder cancer tissues and cells. In both patient-derived primary bladder cancer cells and immortalized (T24) cell line, MB-10 exerted potent anti-cancer activity and inhibited cell viability, proliferation and motility. The TIMM44 blocker induced apoptosis and cell cycle arrest in bladder cancer cells, but failed to provoke cytotoxicity in primary bladder epithelial cells. MB-10 disrupted mitochondrial functions in bladder cancer cells, causing mitochondrial depolarization, oxidative stress and ATP reduction. Whereas exogenously-added ATP and the antioxidant N-Acetyl Cysteine mitigated MB-10-induced cytotoxicity of bladder cancer cells. Genetic depletion of TIMM44 through CRISPR-Cas9 method also induced robust anti-bladder cancer cell activity and MB-10 had no effect in TIMM44-depleted cancer cells. Contrarily, ectopic overexpression of TIMM44 using a lentiviral construct augmented proliferation and motility of primary bladder cancer cells. TIMM44 is important for Akt-mammalian target of rapamycin (mTOR) activation. In primary bladder cancer cells, Akt-S6K1 phosphorylation was decreased by MB-10 treatment or TIMM44 depletion, but enhanced after ectopic TIMM44 overexpression. In vivo, intraperitoneal injection of MB-10 impeded bladder cancer xenograft growth in nude mice. Oxidative stress, ATP reduction, Akt-S6K1 inhibition and apoptosis were detected in MB-10-treated xenograft tissues. Moreover, genetic depletion of TIMM44 also arrested bladder cancer xenograft growth in nude mice, leading to oxidative stress, ATP reduction and Akt-S6K1 inhibition in xenograft tissues. Together, targeting overexpressed TIMM44 by MB-10 significantly inhibits bladder cancer cell growth in vitro and in vivo.},
}

@article {pmid38467037,
year = {2024},
author = {Gakuba, C and Dumitrascu, AD and Marson, PE and Legallois, D and Hanouz, JL and Vivien, D and Martinez De Lizarrondo, S and Gauberti, M and Cerasuolo, D},
title = {N-Acetylcysteine To Reduce Mortality For Patients Requiring Cardiac Catheterization or Cardiac Surgery: A Systematic Review And Meta-Analysis.},
journal = {Journal of cardiovascular pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1097/FJC.0000000000001551},
pmid = {38467037},
issn = {1533-4023},
abstract = {Multimers of von Willebrand factor (VWF) play a critical role in various processes inducing morbidity and mortality in cardiovascular risk patients. With the ability to reduce VWF multimers, N-acetylcysteine (NAC) could reduce mortality in patients undergoing coronary catheterization or cardiac surgery. However, its impact in perioperative period has never been studied so far in regard of its potential cardiovascular benefits. Then, four databases were searched for randomized controlled trials that compared in-hospital mortality between an experimental group, with NAC, and a control group without NAC, in patients undergoing coronary catheterization or cardiac surgery. The primary efficacy outcome was in-hospital mortality. Secondary outcomes were the occurrence of thrombotic events, major cardiovascular events, myocardial infarction, and contrast induced nephropathy. The safety outcome was occurrence of hemorrhagic events. Nineteen studies totaling 3718 patients were included. Pooled analysis demonstrated a reduction of in-hospital mortality associated with NAC: Odds Ratio (OR), 0.60; 95% CI, 0.39-0.92; P=0.02. The occurrence of secondary outcomes was not significantly reduced with NAC except for contrast-induced nephropathy. No difference was reported for hemorrhagic events. Subgroup analyses revealed a life-saving effect of NAC in a dose-dependent manner with reduction of in-hospital mortality for the NAC high-dose group, but not for the NAC standard-dose (<3500 mg) group. In conclusion, without being able to conclude on the nature of the mechanism involved, our review suggests a benefit of NAC in cardiovascular risk patients in perioperative period in terms of mortality and supports prospective confirmatory studies.},
}

@article {pmid38465147,
year = {2024},
author = {Martinez-Ortega, JI and Perez Hernandez, FJ and Ortegon Blanco, AE},
title = {Acro-Ischemia Associated With SARS-CoV-2: A Case Report.},
journal = {Cureus},
volume = {16},
number = {2},
pages = {e53798},
pmid = {38465147},
issn = {2168-8184},
abstract = {COVID-19 is known to cause various cutaneous lesions, including acro-ischemic lesions (AIL), which are associated with poor prognosis. Anticoagulant therapy has shown positive responses in AIL patients. However, in this case study, we present a fatal AIL case despite anticoagulant therapy. We propose different treatment approaches based on the limited current data on acro-ischemia pathogenesis related to SARS-CoV-2. The clinical case involved a 59-year-old male with severe COVID-19 symptoms, including acrocyanosis and right hemiparesis. Despite receiving anticoagulant therapy, the patient's condition worsened, leading to necrosis in the left foot. The discussion focuses on the high-risk nature of AIL, the potential link between angiotensin-converting enzyme 2 (ACE2) receptors and vasculitis or thromboembolic manifestations, and the role of immune clots in AIL pathogenesis. Behçet syndrome is referenced as a model of inflammation-induced thrombosis, guiding the suggestion for immunosuppressant-based treatment in addition to anticoagulants. Additionally, three substances, N-acetyl cysteine, sulodexide, and hydroxychloroquine, are proposed.},
}

@article {pmid38460408,
year = {2024},
author = {Liu, YL and Liu, JY and Zhu, XX and Wei, JH and Mi, SL and Liu, SY and Li, XL and Zhang, WW and Zhao, LL and Wang, H and Xu, DX and Gao, L},
title = {Pubertal exposure to Microcystin-LR arrests spermatogonia proliferation by inducing DSB and inhibiting SIRT6 dependent DNA repair in vivo and in vitro.},
journal = {Ecotoxicology and environmental safety},
volume = {274},
number = {},
pages = {116191},
doi = {10.1016/j.ecoenv.2024.116191},
pmid = {38460408},
issn = {1090-2414},
abstract = {The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2 μg/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.},
}

@article {pmid38460098,
year = {2024},
author = {Nam, Y and Na, J and Ma, SX and Park, H and Park, H and Lee, E and Kim, H and Jang, SM and Ko, HS and Kim, S},
title = {DJ-1 protects cell death from a mitochondrial oxidative stress due to GBA1 deficiency.},
journal = {Genes & genomics},
volume = {},
number = {},
pages = {},
pmid = {38460098},
issn = {2092-9293},
support = {2022R1C1C1009937//National Research foundation of korea/ ; },
abstract = {BACKGROUND: GBA1 mutations are the most common genetic risk factor for development of Parkinson's disease (PD). The loss of catalytic activity in GBA1, as well as the reduction of the GBA1 protein in certain cellular compartment, may increase disease progression. However, the mechanisms underlying cellular dysfunction caused by GBA1 deficiency are still mostly unknown.

OBJECTIVE: In this study, we focus on the genetic interaction between GBA1 deficiency and PD-causing genes, such as DJ-1, in mitochondrial dysfunction.

METHODS: GBA1 knockout (KO) SH-SY5Y cells were used to assess DJ-1 functions against oxidative stress in vitro. The levels of cellular reactive oxygen species were monitored with MitoSOX reagent. The expression of the PARK7 gene was analyzed using the quantitative real-time PCR (qRT-PCR). To understand the mechanism underlying DJ-1 upregulation in GBA1 KO cells, we assess ROS levels, antioxidant protein, and cell viability in GBA1 KO cells with treatment of ROS inhibitor N-acetyl-cysteine or miglustat, which is an inhibitor of glucosylceramide synthase. Dopaminergic degeneration was assessed from Gba1 L444P heterozygous mice mated with Park7 knockout mice.

RESULTS: We find that DJ-1 is significantly upregulated in GBA1 KO cells. Elevated levels of DJ-1 are attributed to the transcriptional expression of PARK7 mRNA, but not the inhibition of DJ-1 protein degradation. Because DJ-1 expression is highly linked to oxidative stress, we observe cellular reactive oxygen species (ROS) in GBA1 KO cells. Moreover, several antioxidant gene expressions and protein levels are increased in GBA1 KO cells. To this end, GBA1 KO cells are more susceptible to H2O2-induced cell death. Importantly, there is a significant reduction in dopaminergic neurons in the midbrain from Gba1 L444P heterozygous mice mated with Park7 knockout mice, followed by mild motor dysfunction.

CONCLUSION: Taken together, our results suggest that DJ-1 upregulation due to GBA1 deficiency has a protective role against oxidative stress. It may be supposed that mutations or malfunctions in the DJ-1 protein may have disadvantages in the survival of dopaminergic neurons in the brains of patients harboring GBA1 mutations.},
}

@article {pmid38455771,
year = {2024},
author = {Aulakh, G and Singh, A},
title = {A Case Report Demonstrating the Favorable Outcomes of Using N-acetylcysteine (NAC) in Managing Hepatic Injury Induced by Amphetamine-Related Drug Toxicity: Do We Underestimate Its Potential?.},
journal = {Cureus},
volume = {16},
number = {2},
pages = {e53697},
doi = {10.7759/cureus.53697},
pmid = {38455771},
issn = {2168-8184},
abstract = {A 59-year-old male with a history of alcohol abuse presented with altered mental status. Upon examination, he was hypertensive and lethargic, and laboratory results revealed severe transaminitis, coagulopathy, and lactic acidosis, despite having normal serum alcohol levels. Additionally, his urine drug screen tested positive for methamphetamine. Following the exclusion of infectious, autoimmune, and other common causes of acute hepatitis, a diagnosis of methamphetamine-induced acute hepatitis was established. A non-acetaminophen toxicity N-acetylcysteine (NAC) protocol was initiated, resulting in a positive response with improvement in mentation and a decrease in liver enzyme levels. This case emphasizes the potential effectiveness of NAC in treating amphetamine-induced liver injury, supported by the limited available literature on the subject.},
}

@article {pmid38455596,
year = {2024},
author = {Alkhattabi, NA and Khalifa, FK and Doghaither, HAA and Al-Ghafari, AB and Tarbiah, NI and Sabban, A},
title = {Protective effects of N-acetylcysteine and S-adenosyl-Lmethionine against nephrotoxicity and immunotoxicity induced by ochratoxin A in rats.},
journal = {International journal of health sciences},
volume = {18},
number = {2},
pages = {17-24},
pmid = {38455596},
issn = {1658-3639},
abstract = {OBJECTIVE: The present study was designed to investigate the nephroprotective and immunoprotective effects of S-adenosyl-L-methionine (SAMe) in comparison to N-acetylcysteine (NAC) against ochratoxin A (OTA) - intoxication.

METHODS: Forty-eight adult male Sprague-Dawley rats were categorized into four groups: Control; OTA intoxication (5 mg OTA/kg diet); OTA + NAC, rats received 200 mg NAC/day before feeding balanced diet contaminated with OTA; and (OTA + SAMe). Rats received 200 mg SAMe/day dissolved in distilled water orally just before feeding a balanced diet contaminated with OTA.

RESULTS: OTA administration altered serum kidney function biomarkers. These effects were pronouncedly alleviated by treatment with NAC. Results revealed a correlation between OTA-induced immunotoxicity and the reduced white blood cell (WBC) count. Treatments with SAMe significantly improved the WBCs count and hemoglobin concentration.

CONCLUSION: NAC and SAMe have a protective role against nephrotoxicity and immunotoxicity induced by continuous administration of OTA. NAC was more effective in reducing OTA nephrotoxicity, whereas SAMe was more potent than NAC in reducing OTA immunotoxicity.},
}

@article {pmid38451349,
year = {2024},
author = {Revand, R and Dontham, A and Sarkar, S and Patil, A},
title = {Subacute Exposure to Gaseous Pollutants from Diesel Engine Exhaust Attenuates Capsaicin-Induced Cardio-Pulmonary Reflex Responses Involving Oxidant Stress Mechanisms in Adult Wistar Rats.},
journal = {Cardiovascular toxicology},
volume = {},
number = {},
pages = {},
pmid = {38451349},
issn = {1559-0259},
abstract = {Intravenous injection of capsaicin produces vagal-mediated protective cardio-pulmonary (CP) reflexes manifesting as tachypnea, bradycardia, and triphasic blood pressure (BP) response in anesthetized rats. Particulate matter from diesel engine exhaust has been reported to attenuate these reflexes. However, the effects of gaseous constituents of diesel exhaust are not known. Therefore, the present study was designed to investigate the effects of gaseous pollutants in diesel exhaust, on capsaicin-induced CP reflexes in rat model. Adult male rats were randomly assigned to three groups: Non-exposed (NE) group, filtered diesel exhaust-exposed (FDE) group and N-acetyl cysteine (NAC)-treated FDE group. FDE group of rats (n = 6) were exposed to filtered diesel exhaust for 5 h a day for 5 days (D1-D5), and were taken for dissection on day 6 (D6), while NE group of rats (n = 6) remained unexposed. On D6, rats were anesthetized, following which jugular vein was cannulated for injection of chemicals, and femoral artery was cannulated to record the BP. Lead II electrocardiogram and respiratory movements were also recorded. Results show that intravenous injection of capsaicin (0.1 ml; 10 µg/kg) produced immediate tachypneic, hyperventilatory, hypotensive, and bradycardiac responses in both NE and FDE groups of rats. However, these capsaicin-induced CP responses were significantly attenuated in FDE group as compared to the NE group of rats. Further, FDE-induced attenuation of capsaicin-evoked CP responses were diminished in the N-acetyl cysteine-treated FDE rats. These findings demonstrate that oxidant stress mechanisms could possibly be involved in inhibition of CP reflexes by gaseous pollutants in diesel engine exhaust.},
}

@article {pmid38450909,
year = {2024},
author = {Yan, H and Ding, J and Li, X and Li, S and Zhang, D},
title = {Arecoline induces neurotoxicity in HT22 cells via the promotion of endoplasmic reticulum stress and downregulation of the Nrf2/HO-1 pathway.},
journal = {Environmental toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1002/tox.24194},
pmid = {38450909},
issn = {1522-7278},
support = {202301AY070001-262//Science and Technology Foundation of Yunnan Provincial/ ; 2023Y0617//Scientific Research Foundation of the Education Department of Yunnan Province/ ; },
abstract = {Arecoline, the predominant bioactive substance extracted from areca nut (AN), is the world's fourth most frequently used psychoactive material. Research has revealed that chewing AN can affect the central nervous system (CNS) and may lead to neurocognitive deficits that are possibly linked to the action of arecoline. However, the mechanism behind the neurotoxicity caused by arecoline remains unclear. This study aimed to investigate the neurotoxic effects of arecoline and its underlying mechanism. The results showed that arecoline caused cytotoxicity against HT22 cells in a dose-dependent manner and induced apoptosis by upregulating the expression of pro-apoptotic caspase and Bcl-2 family proteins. Furthermore, arecoline escalated intracellular reactive oxygen species (ROS) levels and Ca[2+] concentration with increasing doses, thereby motivating endoplasmic reticulum stress (ERS) and ERS-associated apoptotic protein expression. Additionally, the study found that arecoline attenuates intracellular antioxidant defense by inhibiting the translocation of NF-E2-related factor-2 (Nrf2) into the nucleus and decreasing downstream Heme oxygenase-1 (HO-1) levels. The specific inhibitor Sodium 4-phenylbutyrate (4-PBA) can dramatically attenuate arecoline-mediated cell apoptosis and ERS-associated apoptotic pathway expression by blocking ERS. The antioxidant N-Acetylcysteine (NAC) also effectively reverses the arecoline-mediated increase of ERS-related apoptotic pathway protein levels by scavenging intracellular ROS accumulation. In conclusion, this study suggests that arecoline induces neurotoxicity in HT22 cells via ERS mediated by oxidative stress- and Ca[2+] disturbance, as well as by downregulation of the Nrf2/HO-1 pathway.},
}

@article {pmid38446318,
year = {2024},
author = {Yang, R and Yan, F and Shen, J and Wang, T and Li, M and Ni, H},
title = {Geraniol attenuates oxygen-glucose deprivation/reoxygenation-induced ROS-dependent apoptosis and permeability of human brain microvascular endothelial cells by activating the Nrf-2/HO-1 pathway.},
journal = {Journal of bioenergetics and biomembranes},
volume = {},
number = {},
pages = {},
pmid = {38446318},
issn = {1573-6881},
abstract = {Blood-brain barrier breakdown and ROS overproduction are important events during the progression of ischemic stroke aggravating brain damage. Geraniol, a natural monoterpenoid, possesses anti-apoptotic, cytoprotective, anti-oxidant, and anti-inflammatory activities. Our study aimed to investigate the effect and underlying mechanisms of geraniol in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced human brain microvascular endothelial cells (HBMECs). Apoptosis, caspase-3 activity, and cytotoxicity of HBMECs were evaluated using TUNEL, caspase-3 activity, and CCK-8 assays, respectively. The permeability of HBMECs was examined using FITC-dextran assay. Reactive oxygen species (ROS) production was measured using the fluorescent probe DCFH-DA. The protein levels of zonula occludens-1 (ZO-1), occludin, claudin-5, β-catenin, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were determined by western blotting. Geraniol showed no cytotoxicity in HBMECs. Geraniol and ROS scavenger N-acetylcysteine (NAC) both attenuated OGD/R-induced apoptosis and increase of caspase-3 activity and the permeability to FITC-dextran in HBMECs. Geraniol relieved OGD/R-induced ROS accumulation and decrease of expression of ZO-1, occludin, claudin-5, and β-catenin in HBMECs. Furthermore, we found that geraniol activated Nrf2/HO-1 pathway to inhibit ROS in HBMECs. In conclusion, geraniol attenuated OGD/R-induced ROS-dependent apoptosis and permeability in HBMECs through activating the Nrf2/HO-1 pathway.},
}

@article {pmid38445814,
year = {2024},
author = {Iepsen, UW and Hjortdal, AR and Thuesen, AD and Finsen, SH and Hansen, PBL and Mortensen, SP},
title = {The role of T-type calcium channels in elderly human vascular function: A pilot randomized controlled trial.},
journal = {Experimental physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/EP091645},
pmid = {38445814},
issn = {1469-445X},
support = {ID 101390//TrygFonden (Tryg Foundation)/ ; ID 20045//TrygFonden (Tryg Foundation)/ ; //The Capital Region of Denmark/ ; //The Beckett Foundation/ ; //The Ehrenreich Foundation/ ; //Dansk Selskab for Anaestesiologi og Intensiv Medicin (DASAIM)/ ; //The Region of Southern Denmark/ ; //The Danish Medical Research Council/ ; },
abstract = {Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.},
}

@article {pmid38444903,
year = {2024},
author = {Williams, EE and Quach, D and Daigh, A},
title = {Massive acetaminophen ingestion managed successfully with N-acetylcysteine, fomepizole, and renal replacement therapy.},
journal = {Clinical nephrology. Case studies},
volume = {12},
number = {},
pages = {22-25},
pmid = {38444903},
issn = {2196-5293},
abstract = {Acetaminophen ingestion is routinely managed with the antidote, N-acetylcysteine (NAC). Massive acetaminophen poisoning has been treated successfully with adjunctive therapies such as fomepizole and hemodialysis. Fomepizole functions by inhibiting cytochrome p560, which prevents tylenol from forming its toxic metabolite, NAPQI. Prior cases have demonstrated favorable outcomes and a significant drop in acetaminophen levels after a single session of intermittent hemodialysis and continuous veno-venous hemofiltration (CVVH). However, the recommended dosage adjustments of NAC and fomepizole while a patient is undergoing CVVH has not been well reported. We present a case of an 18-year-old male who presented after ingesting 125 g of tylenol. His 4-hour acetaminophen level was 738.6 µg/mL. He was treated with NAC, fomepizole, and a single 4-hour session of hemodialysis. His acetaminophen level remained elevated at 730 µg/mL despite the hemodialysis session. CVVH was initiated, and he was given intravenous NAC at 12.5 mg/kg/h, oral NAC at 70 mg/kg every 4 hours, and intravenous fomepizole at 10 mg/kg every 6 hours. His tylenol levels became undetectable 57 hours after ingestion, and he did not develop permanent liver toxicity. This case encourages the use of CVVH for massive tylenol ingestion when a single run of intermittent hemodialysis is not effective in lowering the tylenol level. NAC, fomepizole, and CVVH can prevent unfavorable outcomes in massive acetaminophen ingestion when provided at an appropriate dose and frequency.},
}

@article {pmid38444704,
year = {2023},
author = {Rostamabadi, H and Samandari Bahraseman, MR and Esmaeilzadeh-Salestani, K},
title = {Froriepia subpinnata Leaf Extract-Induced Apoptosis in the MCF-7 Breast Cancer Cell Line by Increasing Intracellular Oxidative Stress.},
journal = {Iranian journal of pharmaceutical research : IJPR},
volume = {22},
number = {1},
pages = {e136643},
pmid = {38444704},
issn = {1726-6890},
abstract = {BACKGROUND: Froriepia subpinnata is one of the plants used in the diet of Iranian people. Previous studies have investigated the antioxidant and antibacterial effects of this plant extract, but no study has been conducted on its anticancer properties.

OBJECTIVES: In this study, we investigated the effect of F. subpinnata extract on MCF-7 breast cancer cells.

METHODS: The inhibitory effect of F. subpinnata leaf extract was determined on the growth of cancer cells by the MTT test. The ROS (reactive oxygen species) test was used to investigate the impact of the extract on intracellular oxidative stress. Flow cytometry and real-time PCR tests were used to investigate the apoptosis-related molecular processes. The GC-MS analysis was performed to determine the most abundant components.

RESULTS: The GC-MS analysis showed that phytol, mono-ethylhexyl phthalate (MEHP), cinnamaldehyde, and neophytadiene constituted 60% of the extracted content. The MTT assay demonstrated that F. subpinnata leaf extract caused 50% lethality at a 400 μg/mL dose in MCF7 cells. The F. subpinnata extract at low doses decreased the ROS level for 24 hours in MCF-7, but by increasing the concentration, the ROS levels increased. At the IC50 dose (inhibitory concentration (IC) associated with 50% impact), the ROS level increased 3.5 times compared to the control group. Examining the effect of N-acetyl cysteine (NAC) showed that this antioxidant agent could prevent the lethal impact of the extract and eliminate the ROS increase in MCF7 cells. Flow cytometry and real-time PCR results showed that the extract specifically induced apoptosis through the internal apoptosis pathway in this cancer cell line.

CONCLUSIONS: The F. subpinnata extract induced apoptosis by increasing ROS in MCF-7 cancer cells and can be considered for further studies.},
}

@article {pmid38438412,
year = {2024},
author = {Park, WH},
title = {Propyl gallate induces cell death in human pulmonary fibroblast through increasing reactive oxygen species levels and depleting glutathione.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {5375},
pmid = {38438412},
issn = {2045-2322},
abstract = {Propyl gallate (PG) exhibits an anti-growth effect on various cell types. The present study investigated the impact of PG on the levels of reactive oxygen species (ROS) and glutathione (GSH) in primary human pulmonary fibroblast (HPF) cells. Moreover, the effects of N-acetyl cysteine (NAC, an antioxidant), L-buthionine sulfoximine (BSO, a GSH synthesis inhibitor), and small interfering RNA (siRNAs) against various antioxidant genes on ROS and GSH levels and cell death were examined in PG-treated HPF cells. PG (100-800 μM) increased the levels of total ROS and O2[·-] at early time points of 30-180 min and 24 h, whereas PG (800-1600 μM) increased GSH-depleted cell number at 24 h and reduced GSH levels at 30-180 min. PG downregulated the activity of superoxide dismutase (SOD) and upregulated the activity of catalase in HPF cells. Treatment with 800 μM PG increased the number of apoptotic cells and cells that lost mitochondrial membrane potential (MMP; ΔΨm). NAC treatment attenuated HPF cell death and MMP (ΔΨm) loss induced by PG, accompanied by a decrease in GSH depletion, whereas BSO exacerbated the cell death and MMP (ΔΨm) loss without altering ROS and GSH depletion levels. Furthermore, siRNA against SOD1, SOD2, or catalase attenuated cell death in PG-treated HPF cells, whereas siRNA against GSH peroxidase enhanced cell death. In conclusion, PG induced cell death in HPF cells by increasing ROS levels and depleting GSH. NAC was found to decrease HPF cell death induced by PG, while BSO enhanced cell death. The findings shed light on how manipulating the antioxidant system influence the cytotoxic effects of PG in HPF cells.},
}

@article {pmid38435146,
year = {2024},
author = {Khan, S and Hughes, S and Hill, O},
title = {N-acetyl Cysteine Supplementation to Alleviate Skin Picking Disorder: A Case Report.},
journal = {Cureus},
volume = {16},
number = {2},
pages = {e53440},
pmid = {38435146},
issn = {2168-8184},
abstract = {There are body-focused repetitive behaviors, such as skin picking, trichotillomania, or nail biting, for which therapeutic interventions are available and can be tried, but unfortunately, there are no FDA-approved medications specifically for them. These disorders can cause functional impairment, disrupt activities of daily living, and be burdensome for both the patients and their loved ones. This case report will discuss an over-the-counter vitamin supplement, N-acetyl cysteine (NAC), that can be used safely but is often overlooked.},
}

@article {pmid38434559,
year = {2024},
author = {Zeng, H and Zou, P and Chen, Y and Zhang, P and Shao, L},
title = {NOX4 aggravates doxorubicin-induced cardiomyocyte pyroptosis by increasing reactive oxygen species content and activating the NLRP3 inflammasome.},
journal = {Cardiovascular diagnosis and therapy},
volume = {14},
number = {1},
pages = {84-100},
pmid = {38434559},
issn = {2223-3652},
abstract = {BACKGROUND: Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4)-mediated reactive oxygen species (ROS) has been reported to induce cardiomyocyte apoptosis, but its effect on pyroptosis of cardiomyocytes has been rarely reported. This paper aimed to explore the effects of NOX4-mediated ROS production on doxorubicin (DOX)-induced myocardial injury and pyroptosis through nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome.

METHODS: HL-1 cells were treated with DOX or mice (30 mice were divided into five groups with six mice/group) underwent intraperitoneal injection with DOX (5 mg/kg, once a week, five times) to induce myocardial injury, followed by assessment of NOX4 and NLRP3 expression in cell supernatant and myocardial tissues. In cardiomyocyte HL-1 cells, cell proliferation was tested by MTT assay and the activity of ROS by probes. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and glutathione (GSH) activity were evaluated by kits. The expression of pyroptosis proteins was assessed by western blotting. Subsequently, the expression of NOX4 or NLRP3 was altered to determine the effect of NOX4 or NLRP3 expression on cardiomyocyte injury and pyroptosis. The animal models were utilized to evaluate the changes in the cardiac function of mice using an echocardiographic system, with these parameters measured including left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and left ventricular end-diastolic diameter (LVEDD). Furthermore, the content of myocardial injury markers and the protein expression of pyroptosis proteins were determined to evaluate myocardial injury in the mice.

RESULTS: DOX treatment led to cardiomyocyte injury and pyroptosis, as evidenced by weakened LVEF, LVFS, and cell proliferation (P<0.05), elevated LVEDD, ROS, and MDA (P<0.05), increased expression of pyroptosis proteins (P<0.05), and decreased SOD and GSH (P<0.05). Additionally, NOX4 and NLRP3 were highly-expressed (P<0.05) in cell supernatant and myocardial tissues. In DOX-induced HL-1 cells, the overexpression of NOX4 intensified ROS levels to aggravate cardiomyocyte injury and pyroptosis, which was reversed by treatment of the ROS scavenger N-acetyl-cysteine. Furthermore, it was revealed that the combination of short hairpin RNA (sh)-NOX4 and overexpressed (oe)-NLRP3 reversed the cardioprotective effects of sh-NOX4 and increased myocardial tissue or cell injury and pyroptosis in vitro and in vivo. No mice died during the animal experiments, and only two were ruled out due to a weight loss greater than 20%.

CONCLUSIONS: NOX4-mediated ROS production activated NLRP3 inflammasome, thereby aggravating DOX-induced myocardial injury in vitro and in vivo.},
}

@article {pmid38431210,
year = {2024},
author = {Stewart, GW},
title = {Pyroglutamate Acidosis 2023. A Review of 100 Cases.},
journal = {Clinical medicine (London, England)},
volume = {},
number = {},
pages = {100030},
doi = {10.1016/j.clinme.2024.100030},
pmid = {38431210},
issn = {1473-4893},
abstract = {This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with under-nourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal.},
}

@article {pmid38420829,
year = {2024},
author = {Liao, L and Tao, P and Xu, Q and Chen, W and Chen, J and Liu, W and Liu, W and Hu, J and Lu, J},
title = {TRIM6 Promotes ROS-Mediated Inflammasome Activation and Pyroptosis in Renal Tubular Epithelial Cells via Ubiquitination and Degradation of GPX3 Protein.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {29},
number = {2},
pages = {58},
doi = {10.31083/j.fbl2902058},
pmid = {38420829},
issn = {2768-6698},
support = {NSFC-82074261//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Interleukin-18/metabolism/pharmacology ; Pyroptosis ; Interleukin-6/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Signal Transduction ; Inflammation ; Acetylcysteine/metabolism/pharmacology ; Superoxide Dismutase/metabolism ; Epithelial Cells/metabolism ; Glutathione Peroxidase/metabolism/pharmacology ; Ubiquitination ; Malondialdehyde/metabolism ; RNA, Messenger/metabolism ; *Tripartite Motif Proteins ; *Ubiquitin-Protein Ligases ; },
abstract = {BACKGROUND: Pyroptosis is a critical form of cell death during the development of chronic kidney disease (CKD). Tripartite motif 6 (TRIM6) is an E3-ubiquitin ligase that participates in the progression renal fibrosis (RF). The aim of this study was to investigate the roles of TRIM6 and Glutathione peroxidase 3 (GPX3) in oxidative stress-induced inflammasome activation and pyroptosis in Ang-II treated renal tubular epithelial cells.

METHODS: To study its role in RF, TRIM6 expression was either reduced or increased in human kidney-2 (HK2) cells using lentivirus, and Ang-II, NAC and BMS-986299 were served as reactive oxygen species (ROS) inducer, ROS scavenger and NLRP3 agonist respectively. Pyroptosis and mitochondrial ROS were measured by flow cytometry. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were determined using commercial kits, while the levels of IL-1β, IL-18, IL-6, and tumor necrosis factor-α (TNF-α) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). Co-immunoprecipitation (Co-IP) assay was used to evaluate the interaction between TRIM6 and GPX3. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to measure mRNA and protein expression, respectively.

RESULTS: Treatment with Angiotensin II (Ang II) increased the protein and mRNA levels of TRIM6 in HK2 cells. Ang II also increased mitochondrial ROS production and the malondialdehyde (MDA) level, but decreased the levels of GSH and SOD. In addition, Ang II enhanced HK2 cell pyroptosis, increased the levels of IL-1β, IL-18, IL-6, and TNF-α, and promoted the expression of active IL-1β, NLRP3, caspase-1, and GSDMD-N proteins. These effects were reversed by knockdown of TRIM6 and by treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. BMS-986299, an NLRP3 agonist treatment, did not affect ROS production in HK2 cells exposed to Ang II combined with NAC, but cell pyroptosis and inflammation were aggravated. Moreover, the overexpression of TRIM6 in HK2 cells resulted in similar effects to Ang II. NAC and GPX3 overexpression in HK2 cells could reverse ROS production, inflammation, and pyroptosis induced by TRIM6 overexpression. TRIM6 overexpression decreased the GPX3 protein level by promoting its ubiquitination, without affecting the GPX3 mRNA level. Thus, TRIM6 facilitates GPX3 ubiquitination, contributing to increased ROS levels and pyroptosis in HK2 cells.

CONCLUSIONS: TRIM6 increases oxidative stress and promotes the pyroptosis of HK2 cells by regulating GPX3 ubiquitination. These findings could contribute to the development of novel drugs for the treatment of RF.},
}

Humans
*Inflammasomes/metabolism
*NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism
Reactive Oxygen Species/metabolism
Interleukin-18/metabolism/pharmacology
Pyroptosis
Interleukin-6/metabolism
Tumor Necrosis Factor-alpha/metabolism
Signal Transduction
Inflammation
Acetylcysteine/metabolism/pharmacology
Superoxide Dismutase/metabolism
Epithelial Cells/metabolism
Glutathione Peroxidase/metabolism/pharmacology
Ubiquitination
Malondialdehyde/metabolism
RNA, Messenger/metabolism
*Tripartite Motif Proteins
*Ubiquitin-Protein Ligases

@article {pmid38422239,
year = {2024},
author = {Tuncer, G and Aktas, Z and Basaran, S and Cagatay, A and Eraksoy, H},
title = {Effect of N-acetyl cysteine, rifampicin, and ozone on biofilm formation in pan-resistant Klebsiella pneumoniae: an experimental study.},
journal = {Sao Paulo medical journal = Revista paulista de medicina},
volume = {142},
number = {4},
pages = {e2023113},
doi = {10.1590/1516-3180.2023.0113.R1.29112023},
pmid = {38422239},
issn = {1806-9460},
abstract = {BACKGROUND: To the best of our knowledge, this is the first study to evaluate the effectiveness of specific concentrations of antibiofilm agents, such as N-acetyl cysteine (NAC), rifampicin, and ozone, for the treatment of pan-resistant Klebsiella pneumoniae (PRKp).

OBJECTIVES: We evaluated the effectiveness of antibiofilm agents, such as NAC, rifampicin, and ozone, on biofilm formation in PRKp at 2, 6, 24, and 72 h.

DESIGN AND SETTING: This single-center experimental study was conducted on June 15, 2017, and July 15, 2018, at Istanbul Faculty of Medicine, Istanbul University, Turkey.

METHODS: Biofilm formation and the efficacy of these agents on the biofilm layer were demonstrated using colony counting and laser-screened confocal microscopy.

RESULTS: NAC at a final concentration of 2 μg/mL was administered to bacteria that formed biofilms (24 h), and no significant decrease was detected in the bacterial counts of all isolates (all P > 0.05). Rifampicin with a final concentration of 0.1 μg/mL was administered to bacteria that formed biofilm (24 h), and no significant decrease was detected in bacterial count (all P > 0.05). Notably, ozonated water of even 4.78 mg/L concentration for 72 h decreased the bacterial count by ≥ 2 log10.

CONCLUSION: Different approaches are needed for treating PRKp isolates. We demonstrate that PRKp isolates can be successfully treated with higher concentrations of ozone.},
}

@article {pmid38420067,
year = {2024},
author = {Ahmed Attari, MB and Zaman, T and Amjad, A and Khan, MH and Waqar, Z and Jabeen, S},
title = {Comparative Analysis of Outcomes in Acute Organophosphate Poisoning With and Without N-acetyl Cysteine Intervention.},
journal = {Cureus},
volume = {16},
number = {1},
pages = {e53155},
pmid = {38420067},
issn = {2168-8184},
abstract = {INTRODUCTION: Organophosphorus poisoning (OPP) stands as a significant health concern in numerous regions, especially in developing nations. Despite the rising complexities and case fatalities associated with exposure, the treatment approach has remained unchanged for many years. Based on clinical insights, certain pharmacologic agents have demonstrated utility in enhancing outcomes and reducing complications arising from this type of exposure.

OBJECTIVES: The objective of this study is to compare the outcome of N-acetyl cysteine in the treatment of acute organophosphate poisoning cases. In terms of a) its impact on the requirement of atropine, b) Length of hospital stay, and mortality.

METHODS: The study was conducted in the intensive care unit (ICU) of the General Hospital Lahore. Thirty patients with a history and clinical presentation indicative of acute organophosphorus poisoning were randomly divided into two groups in a 1:1 ratio. The treatment group received parenteral administration of atropine, pralidoxime, and N-acetylcysteine (NAC) as an adjuvant, and the control group received standard treatment for acute organophosphate (OP) toxicity.

RESULT: Throughout the study duration, 30 patients suffering acute organophosphate (OP) toxicity (14 men, 16 women) were examined, with an age mean of (25.83±11.59) years. In the interventional group, only four patients required ICU admission, but in the control group, eight patients were admitted to ICU. The correlation result between the dose of atropine and length of hospital stays was not statistically significant between both study groups (<0.005). Plasma Cholinesterase (PChE) level (KU L-1) and total dose of Pralidoxime (g) were statistically significant in the length of hospital stay. The data was not normally distributed, so the non-parametric tests were applied. The Wilcoxon ranked test showed significant improvement in both the controlled and interventional groups because the p-value was (<0.005). Intergroup comparison analyzed by using the Mann-Whitney U test showed a significant reduction in the severity and other associated symptoms in the interventional group because the p-value was (0.001).

CONCLUSION: The outcome demonstrated that the NAC group had a decreased demand for atropine rather than Pralidoxime. In the NAC group, the length of hospital stay and mortality was decreased. The administration of NAC to the present study procedure for acute organophosphate (OP) poisoning is suggested.},
}

@article {pmid38417537,
year = {2024},
author = {Yang, Y and Zhou, M and Huang, Y and Ye, X and Mo, Y and Huang, Y and Wang, S},
title = {LCP1-mediated cytoskeleton alterations involve in arsenite-triggered malignant phenotype of human immortalized prostate stromal cells.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {114548},
doi = {10.1016/j.fct.2024.114548},
pmid = {38417537},
issn = {1873-6351},
abstract = {The connection between continuous arsenic exposure and prostate cancer is already established. However, the exact mechanisms of arsenic tumorigenesis are far from clear. Here, we employed human prostate stromal immortalized cells (WPMY-1) continuous exposure to 1 and 2 μM arsenite for 29 weeks to identify the malignant phenotype and explore the underlying molecular mechanism. As expected, continuous low-dose arsenite exposure led to the malignant phenotype of WPMY-1 cells. Quantitative proteomics identified 517 differentially expressed proteins (DEPs), of which the most remarkably changed proteins (such as LCP1 and DDX58, etc.) and the bioinformatic analysis were focused on the regulation of cytoskeleton, cell adhesion, and migration. Further, cell experiments showed that continuous arsenite exposure altered cytoskeleton structure, enhanced cell adhesive capability, and raised the levels of reactive oxygen species (ROS), ATM, p-ATM, p-ERK1/2, and LCP1 proteins. N-acetylcysteine (NAC) treatment antagonized the increase of LCP1 proteins, and LCP1 knockdown partially restored F-actin organization caused by arsenic. Overall, the results demonstrated that ROS-ATM-ERK1/2 signaling pathway was involved in the activation of LCP1, leading to cytoskeleton alterations. These alterations are believed to play a significant role in arsenite-triggered tumor microenvironment cell-acquired malignant phenotype, which could provide potential biomarkers with therapeutic implications for prostate cancer.},
}

@article {pmid38414064,
year = {2024},
author = {Smabers, LP and Wensink, E and Verissimo, CS and Koedoot, E and Pitsa, KC and Huismans, MA and Higuera Barón, C and Doorn, M and Valkenburg-van Iersel, LB and Cirkel, GA and Brousali, A and Overmeer, R and Koopman, M and Braat, MN and Penning de Vries, B and Elias, SG and Vries, RG and Kranenburg, O and Boj, SF and Roodhart, JM},
title = {Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response.},
journal = {Journal of experimental & clinical cancer research : CR},
volume = {43},
number = {1},
pages = {61},
pmid = {38414064},
issn = {1756-9966},
abstract = {BACKGROUND: The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies.

METHODS: We optimized drug screen methods on 5-11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness.

RESULTS: Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003).

CONCLUSIONS: Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens.},
}

@article {pmid38363806,
year = {2024},
author = {Wu, T and Zhang, H and Zhang, P and James, TD and Sun, X},
title = {A Rationally Designed Prodrug for the Fluorogenic Labeling of Albumin and Theranostic Effects on Drug-Induced Liver Injury.},
journal = {Analytical chemistry},
volume = {96},
number = {8},
pages = {3498-3507},
doi = {10.1021/acs.analchem.3c05272},
pmid = {38363806},
issn = {1520-6882},
mesh = {Humans ; Antioxidants/pharmacology ; *Prodrugs/pharmacology/chemistry ; Precision Medicine ; Serum Albumin/chemistry ; Acetylcysteine ; Serum Albumin, Human ; *Chemical and Drug Induced Liver Injury ; },
abstract = {The development of small-molecular fluorogenic tools for the chemo-selective labeling of proteins in live cells is important for the evaluation of intracellular redox homeostasis. Dynamic imaging of human serum albumin (HSA), an antioxidant protein under oxidative stress with concomitant release of antioxidant drugs to maintain redox homeostasis, affords potential opportunities for disease diagnosis and treatment. In this work, we developed a nonfluorogenic prodrug named TPA-NAC, by introducing N-acetyl-l-cysteine (NAC) into a conjugated acceptor skeleton. Through combined thiol and amino addition, coupling with HSA results in fluorescence turn-on and drug release. It was reasoned that the restricted intramolecular motion of the probe under an HSA microenvironment after covalent bonding inhibited the nonradiative transitions. Furthermore, the biocompatibility and photochemical properties of TPA-NAC enabled it to image exogenous and endogenous HSA in living cells in a wash-free manner. Additionally, the released drug evoked upregulation of superoxide dismutase (SOD), which synergistically eliminated reactive oxygen species in a drug-induced liver injury model. This study provides insights into the design of new theranostic fluorescent prodrugs for chemo-selective protein labeling and disease treatments.},
}

Humans
Antioxidants/pharmacology
*Prodrugs/pharmacology/chemistry
Precision Medicine
Serum Albumin/chemistry
Acetylcysteine
Serum Albumin, Human
*Chemical and Drug Induced Liver Injury

@article {pmid38408632,
year = {2024},
author = {Guan, S and Qu, X and Wang, J and Zhang, D and Lu, J},
title = {3-Monochloropropane-1,2-diol esters induce HepG2 cells necroptosis via CTSB/TFAM/ROS pathway.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {114525},
doi = {10.1016/j.fct.2024.114525},
pmid = {38408632},
issn = {1873-6351},
abstract = {3-monochloropropane-1,2-diol esters (3-MCPDE) are toxic substances that form in food thermal processing and have a diverse range of toxicities. In this study, we found that 3-MCPDE triggered necroptosis by RIPK1/RIPK3/MLKL pathway in HepG2 cells. Previous studies have shown that ROS is an important activator of RIPK1 and RIPK3. The data showed that 3-MCPDE induced excessive ROS production through mitochondrial damage. After treatment with ROS inhibitor N-acetylcysteine (NAC), 3-MCPDE-induced necroptosis was relieved. Further, we explored how 3-MCPDE destroys mitochondria. The data suggested that 3-MCPDE induced mitochondrial dysfunction through the CTSB/TFAM pathway. Overall, the results indicated that 3-MCPDE induced necroptosis through CTSB/TFAM/ROS pathway in HepG2 cells. Our study provided a new mechanism for 3-MCPDE hepatotoxicity.},
}

@article {pmid38408264,
year = {2024},
author = {Doumi, I and Lang, L and Vileno, B and Deponte, M and Faller, P},
title = {Glutathione Protects other Cellular Thiols against Oxidation by Cu[II] -Dp44mT.},
journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e202304212},
doi = {10.1002/chem.202304212},
pmid = {38408264},
issn = {1521-3765},
support = {ANR-10-IDEX-0002//Agence Nationale de la Recherche/ ; ITI-CSC-PFA-22//ITI LabEx Chimie des Systèmes Complexes/ ; DE 1431/20-1//Deutsche Forschungsgemeinschaft/ ; },
abstract = {Cu-thiosemicarbazones have been intensively investigated for their application in cancer therapy or as antimicrobials. Copper(II)-di-2-pyridylketone-4,4-dimethyl-thiosemicarbazone (Cu[II] -Dp44mT) showed anticancer activity in the submicromolar concentration range in cell culture. The interaction of Cu[II] -Dp44mT with thiols leading to their depletion or inhibition was proposed to be involved in this activity. Indeed, Cu[II] -Dp44mT can catalyze the oxidation of thiols although with slow kinetics. The present work aims to obtain insights into the catalytic activity and selectivity of Cu[II] -Dp44mT toward the oxidation of different biologically relevant thiols. Reduced glutathione (GSH), L-cysteine (Cys), N-acetylcysteine (NAC), D-penicillamine (D-Pen), and the two model proteins glutaredoxin (Grx) and thioredoxin (Trx) were investigated. Cu[II] -Dp44mT catalyzed the oxidation of these thiols with different kinetics, with rates in the following order D-Pen>Cys≫NAC>GSH and Trx>Grx. Cu[II] -Dp44mT was more efficient than Cu[II] chloride for the oxidation of NAC and GSH, but not D-Pen and Cys. In mixtures of biologically relevant concentrations of GSH and either Cys, Trx, or Grx, the oxidation kinetics and spectral properties were similar to that of GSH alone, indicating that the interaction of these thiols with Cu[II] -Dp44mT is dominated by GSH. Hence GSH could protect other thiols against potential deleterious oxidation by Cu[II] -Dp44mT.},
}

@article {pmid38407768,
year = {2024},
author = {Jimenez-Chavez, A and Pedroza-Herrera, G and Betancourt-Reyes, I and De Vizcaya Ruiz, A and Masuoka-Ito, D and Zapien, JA and Medina-Ramirez, IE},
title = {Aluminum enhances the oxidative damage of ZnO NMs in the human neuroblastoma SH-SY5Y cell line.},
journal = {Discover nano},
volume = {19},
number = {1},
pages = {36},
pmid = {38407768},
issn = {2731-9229},
support = {Fordecyt-Pronaces/568494/2020 and C-104/2021//CONAHCYT/ ; },
abstract = {Bare and doped zinc oxide nanomaterials (ZnO NMs) are of great interest as multifunctional platforms for biomedical applications. In this study, we systematically investigate the physicochemical properties of Aluminum doped ZnO (AZO) and its bio-interactions with neuroblastoma (SH-SY5Y) and red blood (RBCs) cells. We provide a comprehensive chemical and structural characterization of the NMs. We also evaluated the biocompatibility of AZO NMs using traditional toxicity assays and advanced microscopy techniques. The toxicity of AZO NMs towards SH-SY5Y cells, decreases as a function of Al doping but is higher than the toxicity of ZnO NMs. Our results show that N-acetyl cysteine protects SH-SY5Y cells against reactive oxygen species toxicity induced by AZO NMs. ZnO and AZO NMs do not exert hemolysis in human RBCs at the doses that cause toxicity (IC50) in neuroblastoma cells. The Atomic force microscopy qualitative analysis of the interaction of SH-SY5Y cells with AZO NMs shows evidence that the affinity of the materials with the cells results in morphology changes and diminished interactions between neighboring cells. The holotomographic microscopy analysis demonstrates NMs' internalization in SH-SY5Y cells, changes in their chemical composition, and the role of lipid droplets in the clearance of toxicants.},
}

@article {pmid38405665,
year = {2024},
author = {Abdallah, R and Shaito, AA and Badran, A and Baydoun, S and Sobeh, M and Ouchari, W and Sahri, N and Eid, AH and Mesmar, JE and Baydoun, E},
title = {Fractionation and phytochemical composition of an ethanolic extract of Ziziphus nummularia leaves: antioxidant and anticancerous properties in human triple negative breast cancer cells.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1331843},
pmid = {38405665},
issn = {1663-9812},
abstract = {Natural products have long been utilized in traditional medicine as remedies to improve health and treat illnesses, and have had a key role in modern drug discovery. Recently, there has been a revived interest in the search for bioactives from natural sources as alternative or complementary modalities to synthetic medicines; especially for cancer treatment, which incidence and mortality rates are on the rise worldwide. Ziziphus nummularia has been widely used in traditional medicine for the treatment of various diseases. Its traditional uses and numerous ethnopharmacological properties may be attributed to its richness in bioactive metabolites. However, its phytochemical composition or chemopreventive effects against the aggressive triple-negative breast cancer (TNBC) are still poorly explored. Here, phytochemical composition of an ethanolic extract of Z. nummularia leaves (ZNE) and its chromatographically isolated fractions was identified both qualitatively by spectrophotometric assays and analytically by HPLC-PDA-MS/MS. The anti-proliferative effects of ZNE were tested in several cancer cell lines, but we focused on its anti-TNBC effects since they were not explored yet. The anti-cancerous potential of ZNE and its fractions was tested in vitro in MDA-MB-231, a TNBC cell line. Results showed that ZNE and its Fraction 6 (F6) reduced the viability of MDA-MB-231 cells. F6 decreased MDA-MB-231 viability more than crude ZNE or its other fractions. ZNE and F6 are rich in phytochemicals and HPLC-PDA-MS/MS analysis identified several metabolites that were previously reported to have anti-cancerous effects. Both ZNE and F6 showed potent antioxidant capacity in the DPPH assay, but promoted reactive oxygen species (ROS) production in MDA-MB-231 cells; an effect which was blunted by the antioxidant N-acetyl cysteine (NAC). NAC also blunted ZNE- and F6-induced reduction in TNBC cell viability. We also demonstrated that ZNE and F6 induced an arrest of the cell cycle, and triggered apoptosis- and autophagy-mediated cell death. ZNE and F6 inhibited metastasis-related cellular processes by modifying cell migration, invasion, and adhesion. Taken together, our findings reveal that Z. nummularia is rich in phytochemicals that can attenuate the malignant phenotype of TNBC and may offer innovative avenues for the discovery of new drug leads for treatment of TNBC and other cancers.},
}

@article {pmid38399445,
year = {2024},
author = {Lu, HI and Chen, KL and Yen, CY and Chen, CY and Chien, TM and Shu, CW and Chen, YH and Jeng, JH and Chen, BH and Chang, HW},
title = {Michelia compressa-Derived Santamarine Inhibits Oral Cancer Cell Proliferation via Oxidative Stress-Mediated Apoptosis and DNA Damage.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {17},
number = {2},
pages = {},
doi = {10.3390/ph17020230},
pmid = {38399445},
issn = {1424-8247},
support = {MOST 111-2320-B-037-015-MY3//Ministry of Science and Technology/ ; #NSYSUKMU 112-P06//National Sun Yat-sen University-KMU Joint Research Project/ ; 111CM-KMU-05, 112CM-KMU-05//Chimei-KMU jointed project/ ; KMU-DK(A)112008//Kaohsiung Medical University/ ; KMU-TC112A04//Kaohsiung Medical University Research Center/ ; },
abstract = {The anti-oral cancer effects of santamarine (SAMA), a Michelia compressa var. compressa-derived natural product, remain unclear. This study investigates the anticancer effects and acting mechanism of SAMA against oral cancer (OC-2 and HSC-3) in parallel with normal (Smulow-Glickman; S-G) cells. SAMA selectively inhibits oral cancer cell viability more than normal cells, reverted by the oxidative stress remover N-acetylcysteine (NAC). The evidence of oxidative stress generation, such as the induction of reactive oxygen species (ROS) and mitochondrial superoxide and the depletion of mitochondrial membrane potential and glutathione, further supports this ROS-dependent selective antiproliferation. SAMA arrests oral cancer cells at the G2/M phase. SAMA triggers apoptosis (annexin V) in oral cancer cells and activates caspases 3, 8, and 9. SAMA enhances two types of DNA damage in oral cancer cells, such as γH2AX and 8-hydroxy-2-deoxyguanosine. Moreover, all of these anticancer mechanisms of SAMA are more highly expressed in oral cancer cells than in normal cells in concentration and time course experiments. These above changes are attenuated by NAC, suggesting that SAMA exerts mechanisms of selective antiproliferation that depend on oxidative stress while maintaining minimal cytotoxicity to normal cells.},
}

@article {pmid38397782,
year = {2024},
author = {Tuell, D and Ford, G and Los, E and Stone, W},
title = {The Role of Glutathione and Its Precursors in Type 2 Diabetes.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {2},
pages = {},
doi = {10.3390/antiox13020184},
pmid = {38397782},
issn = {2076-3921},
support = {C06RR0306551/NH/NIH HHS/United States ; },
abstract = {Type 2 diabetes (T2D) is a major worldwide health crisis affecting about 6.2% of the world's population. Alarmingly, about one in five children in the USA have prediabetes. Glutathione (GSH) and its precursors play a promising role in the prevention and management of type T2D. Oxidative stress (OxS) is a probable factor in both T2D initiation and progression. GSH is the major cytosolic water-soluble chemical antioxidant and emerging evidence supports its role in improving T2D outcomes. Dietary supplementation with N-acetyl-cysteine (NAC) and/or glycine (GLY), which are GSH precursors, has also been studied for possible beneficial effects on T2D. This review will focus on the underlying pathophysiological and molecular mechanisms linking GSH and its precursors with T2D and OxS. In addition to their traditional antioxidant roles, the in vivo effects of GSH/NAC/GLY supplements will be evaluated for their potential abilities to modulate the complex pro-oxidant pathophysiological factors (e.g., hyperglycemia) driving T2D progression. Positive feedback loops that amplify OxS over long time intervals are likely to result in irreversible T2D micro- and macro-vascular damage. Most clinical studies with GSH/NAC/GLY have focused on adults or the elderly. Future research with pediatric populations should be a high priority since early intervention is critical.},
}

@article {pmid38397769,
year = {2024},
author = {Khan, S and Wang, T and Cobo, ER and Liang, B and Khan, MA and Xu, M and Qu, W and Gao, J and Barkema, HW and Kastelic, JP and Liu, G and Han, B},
title = {Antioxidative Sirt1 and the Keap1-Nrf2 Signaling Pathway Impair Inflammation and Positively Regulate Autophagy in Murine Mammary Epithelial Cells or Mammary Glands Infected with Streptococcus uberis.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {2},
pages = {},
doi = {10.3390/antiox13020171},
pmid = {38397769},
issn = {2076-3921},
support = {32172928//National Natural Science Foundation of China/ ; 31772813//National Natural Science Foundation of China/ ; G2022108009L//High-end Foreign Experts Recruitment Program/ ; 2019BBF02027//Ningxia Key Development Programs/ ; 6222031//Beijing Natural Science Foundation/ ; },
abstract = {Streptococcus uberis mastitis in cattle infects mammary epithelial cells. Although oxidative responses often remove intracellular microbes, S. uberis survives, but the mechanisms are not well understood. Herein, we aimed to elucidate antioxidative mechanisms during pathogenesis of S. uberis after isolation from clinical bovine mastitis milk samples. S. uberis's in vitro pathomorphology, oxidative stress biological activities, transcription of antioxidative factors, inflammatory response cytokines, autophagosome and autophagy functions were evaluated, and in vivo S. uberis was injected into the fourth mammary gland nipple of each mouse to assess the infectiousness of S. uberis potential molecular mechanisms. The results showed that infection with S. uberis induced early oxidative stress and increased reactive oxygen species (ROS). However, over time, ROS concentrations decreased due to increased antioxidative activity, including total superoxide dismutase (T-SOD) and malondialdehyde (MDA) enzymes, plus transcription of antioxidative factors (Sirt1, Keap1, Nrf2, HO-1). Treatment with a ROS scavenger (N-acetyl cysteine, NAC) before infection with S. uberis reduced antioxidative responses and the inflammatory response, including the cytokines IL-6 and TNF-α, and the formation of the Atg5-LC3II/LC3I autophagosome. Synthesis of antioxidants determined autophagy functions, with Sirt1/Nrf2 activating autophagy in the presence of S. uberis. This study demonstrated the evasive mechanisms of S. uberis in mastitis, including suppressing inflammatory and ROS defenses by stimulating antioxidative pathways.},
}

@article {pmid38396357,
year = {2024},
author = {Kamel, AA and Nassar, AY and Meligy, FY and Omar, YA and Nassar, GAY and Ezzat, GM},
title = {Acetylated oligopeptide and N-acetylcysteine protect against iron overload-induced dentate gyrus hippocampal degeneration through upregulation of Nestin and Nrf2/HO-1 and downregulation of MMP-9/TIMP-1 and GFAP.},
journal = {Cell biochemistry and function},
volume = {42},
number = {2},
pages = {e3958},
doi = {10.1002/cbf.3958},
pmid = {38396357},
issn = {1099-0844},
abstract = {Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.},
}

@article {pmid38392216,
year = {2024},
author = {Shih, LJ and Hsu, PC and Chuu, CP and Shui, HA and Yeh, CC and Chen, YC and Kao, YH},
title = {Epigallocatechin-3-gallate Synergistically Enhanced Arecoline-Induced Cytotoxicity by Redirecting Cycle Arrest to Apoptosis.},
journal = {Current issues in molecular biology},
volume = {46},
number = {2},
pages = {1516-1529},
doi = {10.3390/cimb46020098},
pmid = {38392216},
issn = {1467-3045},
support = {MOST106-2320-B-008-008-MY3, MOST109-2320-B-008-001-MY3//National Science and Technology Council/ ; 11001-62-021, TPCH-110-05//Taipei City Hospital; Department of Health, Taipei City Government/ ; TYAFGH-E-111053, TYAFGH-E-112050//Taoyuan Armed Forces General Hospital/ ; MND-MAB-110-025, MND-MAB-C-11107-111026//National Defense Medical Center/ ; },
abstract = {Carcinogens, such as arecoline, play a crucial role in cancer progression and continuous gene mutations by generating reactive oxygen species (ROS). Antioxidants can reduce ROS levels and potentially prevent cancer progression but may paradoxically enhance the survival of cancer cells. This study investigated whether epigallocatechin-3-gallate (EGCG), an antioxidant from green tea, could resolve this paradox. Prostate cancer cells (PC-3 cell line) were cultured and treated with arecoline combined with NAC (N-acetylcysteine) or EGCG; the combined effects on intracellular ROS levels and cell viability were examined using the MTT and DCFDA assays, respectively. In addition, apoptosis, cell cycle, and protein expression were investigated using flow cytometry and western blot analysis. Our results showed that EGCG, similar to NAC (N-acetylcysteine), reduced the intracellular ROS levels, which were elevated by arecoline. Moreover, EGCG not only caused cell cycle arrest but also facilitated cell apoptosis in arecoline-treated cells in a synergistic manner. These were evidenced by elevated levels of cyclin B1 and p27, and increased fragmentation of procaspase-3, PARP, and DNA. Our findings highlight the potential use of EGCG for cancer prevention and therapy.},
}

@article {pmid38390944,
year = {2024},
author = {Alvarez, IA and Lee, M and Eshaq, RS and Leskova, W and Harris, NR},
title = {High Glucose Induces Oxidative Stress That Alters Glycocalyx Proteoglycan Levels in Primary Rat Retinal Microvascular Endothelial Cells and in Isolated Ophthalmic Arteries.},
journal = {Pathophysiology : the official journal of the International Society for Pathophysiology},
volume = {31},
number = {1},
pages = {89-99},
doi = {10.3390/pathophysiology31010007},
pmid = {38390944},
issn = {1873-149X},
support = {NEI EY025632/NH/NIH HHS/United States ; },
abstract = {Our purpose in this study was to identify the role played by oxidative stress in the changes to proteoglycans that occur under hyperglycemic conditions, using primary rat retinal microvascular endothelial cells (RRMEC) and cultured ophthalmic arteries. The cells and blood vessels obtained from rats were cultured in normal glucose (5.6 mM) and high glucose (25 mM) with or without N-acetylcysteine (NAC), an antioxidant. Intracellular oxidative stress was determined by measuring dihydroethidium (DHE) fluorescence and malondialdehyde (MDA)-modified protein levels. mRNA and protein levels were evaluated using quantitative real-time polymerase chain reaction and immunoblot, respectively. High glucose increased levels of glypican-1 mRNA and protein. The level of syndecan-1 mRNA also was increased, but its protein level was decreased, by high glucose. Evaluation of DHE and MDA showed that high glucose increased oxidative stress. These changes caused by high glucose were significantly reversed by NAC treatment. Matrix metalloproteinase-9 (MMP-9) levels, which increased under high glucose conditions, were suppressed by NAC treatment. Oxidative stress caused by hyperglycemia may be responsible for significant changes to the ocular endothelial glycocalyx.},
}

@article {pmid38385491,
year = {2024},
author = {Zhao, X and Shan, G and Xing, D and Gao, H and Xiong, Z and Hui, W and Gong, M},
title = {UBE2L3 Promotes Oxidative Stress-regulated Necroptosis to Accelerate Osteosarcoma Progression.},
journal = {Recent patents on anti-cancer drug discovery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115748928297557240212112531},
pmid = {38385491},
issn = {2212-3970},
abstract = {BACKGROUND: Osteosarcoma is a highly invasive bone marrow stromal tumor with limited treatment options. Oxidative stress plays a crucial role in the development and progression of tumors, but the underlying regulatory mechanisms are not fully understood. Recent studies have revealed the significant involvement of UBE2L3 in oxidative stress, but its specific role in osteosarcoma remains poorly investigated.

OBJECTIVE: This study aimed to explore the molecular mechanisms by which UBE2L3 promotes oxidative stress-regulated necroptosis to accelerate the progression of osteosarcoma using in vitro cell experiments.

METHODS: Human osteoblast hFOB1.19 cells and various human osteosarcoma cell lines (MG-63, U2OS, SJSA-1, HOS, and 143B) were cultured in vitro. Plasmids silencing UBE2L3 and negative control plasmids were transfected into U2OS and HOS cells. The cells were divided into the following groups: U2OS cell group, HOS cell group, si-NC-U2OS cell group, si-UBE2L3-U2OS cell group, si-NC-HOS cell group, and si-UBE2L3-HOS cell group. Cell viability and proliferation capacity were measured using the Tunnel method and clonogenic assay. Cell migration and invasion abilities were assessed by Transwell and scratch assays. Cell apoptosis was analyzed by flow cytometry, and ROS levels were detected using immunofluorescence. The oxidative stress levels in various cell groups and the expression changes of necroptosis-related proteins were assessed by PCR and WB. Through these experiments, we aim to evaluate the impact of oxidative stress on necroptosis and uncover the specific mechanisms by which targeted regulation of oxidative stress promotes tumor cell necroptosis as a potential therapeutic strategy for osteosarcoma.

RESULTS: The mRNA expression levels of UBE2L3 in human osteosarcoma cell lines were significantly higher than those in human osteoblast hFOB1.19 cells (p <0.01). UBE2L3 expression was significantly decreased in U2OS and HOS cells transfected with si-UBE2L3, indicating the successful construction of stable cell lines with depleted UBE2L3. Tunnel assay results showed a significant increase in the number of red fluorescent-labeled cells in si-UBE2L3 groups compared to si-NC groups in both cell lines, suggesting a pronounced inhibition of cell viability. Transwell assay demonstrated a significant reduction in invasion and migration capabilities of si-UBE2L3 groups in osteosarcoma cells. The clonogenic assay revealed significant suppression of proliferation and clonogenic ability in both U2OS and HOS cells upon UBE2L3 knockdown. Flow cytometry confirmed that UBE2L3 knockdown significantly enhanced apoptosis in U2OS and HOS cells. Immunofluorescence results showed that UBE2L3 silencing promoted oxidative stress levels in osteosarcoma cells and facilitated tumor cell death. WB analysis indicated a significant increase in phosphorylation levels of necroptosis-related proteins, RIP1, RIP3, and MLKL, in both osteosarcoma cell lines after UBE2L3 knockdown. In addition, the expression of necrosis-associated proteins was inhibited by the addition of the antioxidant N-acetylcysteine (NAC).

CONCLUSION: UBE2L3 is upregulated in osteosarcoma cells, and silencing of UBE2L3 promotes oxidative stress in these cells, leading to enhanced necroptosis and delayed progression of osteosarcoma.},
}

@article {pmid38381146,
year = {2024},
author = {Rasouli, H and Razavi, BM and Ghasemzadeh Rahbardar, M and Sadeghian, H and Tabatabaee Yazdi, SA and Hosseinzadeh, H},
title = {Hepatoprotective effect of amifostine and WR-1065 on acetaminophen-induced liver toxicity on Wistar rats.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {38381146},
issn = {1432-1912},
support = {910351//Pharmaceutical Research Center and the Vice-Chancellor of Research, Mashhad University of Medical Sciences/ ; },
abstract = {PURPOSE: The most important problem with acetaminophen is its hepatotoxicity. N-acetylcysteine (NAC) is used to treat the hepatotoxicity of acetaminophen. Due to the structural similarities of this compound with amifostine, we decided to test the effect of this substance and its metabolite, WR-1065, on the hepatotoxicity of acetaminophen.

METHODS: The single-dose method contained 1. Control; 2. Acetaminophen (1 g/kg, gavage); 3-5. Acetaminophen + amifostine (100, 200, 400 mg/kg, i.p.); 6-8. Acetaminophen + WR-1065 (50, 100, 200 mg/kg, i.p.); and 9. Acetaminophen + NAC (100, 200 mg/kg, i.p.). The multiple-dose method included the same groups: amifostine (50, 100, 200 mg/kg), WR-1065 (25, 50, 100 mg/kg), and NAC (100 mg/kg). Then, animals were sacrificed, and blood samples were collected for measuring ALT, AST, ALP, and T-Bil, liver tissue for histopathological examination, MDA, and GSH amounts.

RESULTS: Acetaminophen increased the levels of MDA, T-Bil, ALT, AST, and ALP, decreased GSH levels, and augmented necrosis, neutrophils, lymphocytes, and macrophages in the port space in single-dose and multiple-dose studies. Amifostine and WR-1065 significantly reduced the levels of MDA, T-Bil, ALT, AST, ALP, increased GSH content, and ameliorated histopathological alterations in a single-dose and multiple-dose method compared to the acetaminophen group. Moreover, NAC caused a significant decrease in the levels of MDA, T-Bil, ALT, AST, and ALP, and reduced GSH amounts in single-dose and multiple-dose studies.

CONCLUSION: Amifostine and WR-1065 as antioxidant and hepatoprotective compounds are effective in reducing acetaminophen-induced hepatotoxicity with a similar effect to NAC and can be administered as an adjunct in the treatment of acetaminophen overdose.},
}

@article {pmid38379848,
year = {2024},
author = {Lee, KI and Fang, KM and Kuo, CY and Huang, CF and Liu, SH and Liu, JM and Lai, WC and Chang, KC and Su, CC and Chen, YW},
title = {Roles of oxidative stress/JNK/ERK signals in paraquat-triggered hepatic apoptosis.},
journal = {Current research in toxicology},
volume = {6},
number = {},
pages = {100155},
pmid = {38379848},
issn = {2666-027X},
abstract = {Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the liver is an important target organ for PQ poisoning in humans. However, the mechanism of PQ in hepatotoxicity remains unclear. In this study, we found that exposure of rat hepatic H4IIE cells to PQ (0.1-2 mM) induced significant cytotoxicity and apoptosis, which was accompanied by mitochondria-dependent apoptotic signals, including loss of mitochondrial membrane potential (MMP), cytosolic cytochrome c release, and changes in the Bcl-2/Bax mRNA ratio. Moreover, PQ (0.5 mM) exposure markedly induced JNK and ERK1/2 activation, but not p38-MAPK. Blockade of JNK and ERK1/2 signaling by pretreatment with the specific pharmacological inhibitors SP600125 and PD98059, respectively, effectively prevented PQ-induced cytotoxicity, mitochondrial dysfunction, and apoptotic events. Additionally, PQ exposure stimulated significant oxidative stress-related signals, including reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion, which could be reversed by the antioxidant N-Acetylcysteine (NAC). Buffering the oxidative stress response with NAC also effectively abrogated PQ-induced hepatotoxicity, MMP loss, apoptosis, and phosphorylation of JNK and ERK1/2 protein, however, the JNK or ERK inhibitors did not suppress ROS generation in PQ-treated cells. Collectively, these results demonstrate that PQ exposure induces hepatic cell toxicity and death via an oxidative stress-dependent JNK/ERK activation-mediated downstream mitochondria-regulated apoptotic pathway.},
}

@article {pmid38378126,
year = {2024},
author = {Ramos-León, J and Valencia, C and Gutiérrez-Mariscal, M and Rivera-Miranda, DA and García-Meléndrez, C and Covarrubias, L},
title = {The loss of antioxidant activities impairs intestinal epithelium homeostasis by altering lipid metabolism.},
journal = {Experimental cell research},
volume = {},
number = {},
pages = {113965},
doi = {10.1016/j.yexcr.2024.113965},
pmid = {38378126},
issn = {1090-2422},
abstract = {Reactive oxygens species (ROS) are common byproducts of metabolic reactions and could be at the origin of many diseases of the elderly. Here we investigated the role of ROS in the renewal of the intestinal epithelium in mice lacking catalase (CAT) and/or nicotinamide nucleotide transhydrogenase (NNT) activities. Cat[-/-] mice have delayed intestinal epithelium renewal and were prone to develop necrotizing enterocolitis upon starvation. Interestingly, crypts lacking CAT showed fewer intestinal stem cells (ISC) and lower stem cell activity than wild-type. In contrast, crypts lacking NNT showed a similar number of ISCs as wild-type but increased stem cell activity, which was also impaired by the loss of CAT. No alteration in the number of Paneth cells (PCs) was observed in crypts of either Cat[-/-] or Nnt[-/-] mice, but they showed an evident decline in the amount of lysozyme. Cat deficiency caused fat accumulation in crypts, and a fall in the remarkable high amount of adipose triglyceride lipase (ATGL) in PCs. Notably, the low levels of ATGL in the intestine of Cat [-/-] mice increased after a treatment with the antioxidant N-acetyl cysteine. Supporting a role of ATGL in the regulation of ISC activity, its inhibition halt intestinal organoid development. These data suggest that the reduction of the intestine renewal capacity originates from fatty acid metabolic alterations caused by peroxisomal ROS.},
}

@article {pmid38376812,
year = {2024},
author = {Radan, M and Abol Nejadian, F and Bayati, V and Hemmati, AA and Hoseinynejad, K and Mard, SA},
title = {N-Acetyl Cysteine Augments Adipose Tissue-Derived Stem Cell Efficacy on Inflammatory Markers and Regulatory T Cell System Balance in an Allergic Asthma Model.},
journal = {The Journal of asthma : official journal of the Association for the Care of Asthma},
volume = {},
number = {},
pages = {1-27},
doi = {10.1080/02770903.2024.2321296},
pmid = {38376812},
issn = {1532-4303},
abstract = {Background Allergic asthma is a destructive inflammatory process in the respiratory system. The anti-inflammatory and antioxidant effects of N-acetylcysteine (NAC) have been reported in patients with obstructive pulmonary disease. On the other hand, several studies have shown the modulatory effects of mesenchymal stem cells on the immune system and inflammatory responses. Accordingly, the purpose of the current study was to evaluate the effect of administration of adipose tissue-derived stem cells (ADSCs) plus NAC on regulatory T cell system balance in an allergic asthma model. Methods: Eighty Sprague- Dawley rats were randomly divided into the following groups: Control, Plasmalite, Allergic asthma, Allergic asthma + ADSCs, NAC, Allergic asthma + NAC, Allergic asthma + ADSCs + NAC and Allergic asthma + Prednisolone. at the end of the experiment, arterial blood gas analysis, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), inflammatory cytokine concentration, total IgE and specific OVA-IgE levels, gene expression levels of CD4+-T cell subsets, pulmonary indicators, edema, and lung histopathology were evaluated in all groups. Results: Administration of NAC plus ADSCs demonstrated a significant decrease in total WBC and eosinophil counts, which was in line with remarkable decrease in IL-17 and TNF-α concentrations and increases in IL-10 level compared with other treated groups. NAC plus ADSC treatment showed significant increases in Treg gene expression, although Th17 and Th2 expression significantly decreased compared with that in prednisolone- treated rats. Conclusion: The results of the present study documented that the administration of ADSCs plus NAC has an inhibitory effect on the inflammation caused by allergic asthma in a rat model. The improvement of inflammatory indexes was significantly higher than that with prednisolone treatment.},
}

@article {pmid38373369,
year = {2024},
author = {Yuce, M and Yildirim, E and Ekinci, M and Turan, M and Ilhan, E and Aydin, M and Agar, G and Ucar, S},
title = {N-acetyl-cysteine mitigates arsenic stress in lettuce: Molecular, biochemical, and physiological perspective.},
journal = {Plant physiology and biochemistry : PPB},
volume = {207},
number = {},
pages = {108390},
doi = {10.1016/j.plaphy.2024.108390},
pmid = {38373369},
issn = {1873-2690},
abstract = {Agricultural land contaminated with heavy metals such as non-biodegradable arsenic (As) has become a serious global problem as it adversely affects agricultural productivity, food security and human health. Therefore, in this study, we investigated how the administration of N-acetyl-cysteine (NAC), regulates the physio-biochemical and gene expression level to reduce As toxicity in lettuce. According to our results, different NAC levels (125, 250 and 500 μM) significantly alleviated the growth inhibition and toxicity induced by As stress (20 mg/L). Shoot fresh weight, root fresh weight, shoot dry weight and root dry weight (33.05%, 55.34%, 17.97% and 46.20%, respectively) were decreased in plants grown in As-contaminated soils compared to lettuce plants grown in soils without the addition of As. However, NAC applications together with As stress increased these growth parameters. While the highest increase in shoot fresh and dry weight (58.31% and 37.85%, respectively) was observed in 250 μM NAC application, the highest increase in root fresh and dry weight (75.97% and 63.07%, respectively) was observed in 125 μM NAC application in plants grown in As-polluted soils. NAC application decreased the amount of ROS, MDA and H2O2 that increased with As stress, and decreased oxidative damage by regulating hormone levels, antioxidant and enzymes involved in nitrogen metabolism. According to gene expression profiles, LsHIPP28 and LsABC3 genes have shown important roles in reducing As toxicity in leaves. This study will provide insight for future studies on how NAC applications develop resistance to As stress in lettuce.},
}

@article {pmid38104651,
year = {2024},
author = {Wen, T and Xie, J and Ma, L and Hao, Z and Zhang, W and Wu, T and Li, L},
title = {Vitamin D Receptor Activation Reduces Hepatic Inflammation via Enhancing Macrophage Autophagy in Cholestatic Mice.},
journal = {The American journal of pathology},
volume = {194},
number = {3},
pages = {369-383},
doi = {10.1016/j.ajpath.2023.11.016},
pmid = {38104651},
issn = {1525-2191},
mesh = {Animals ; Mice ; *Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Calcitriol/metabolism ; Macrophages/metabolism ; *Cholestasis/metabolism ; Inflammation/metabolism ; Autophagy/physiology ; Acetylcysteine ; p38 Mitogen-Activated Protein Kinases/metabolism ; Interleukin-1beta/metabolism ; },
abstract = {Macrophage autophagy dysfunction aggravates liver injury by activating inflammasomes, which can cleave pro-IL-1β to its active, secreted form. We investigated whether the vitamin D/vitamin D receptor (VDR) axis could up-regulate macrophage autophagy function to inhibit the activation of inflammasome-dependent IL-1β during cholestasis. Paricalcitol (PAL; VDR agonist) was intraperitoneally injected into bile duct-ligated mice for 5 days. Up-regulation of VDR expression by PAL reduced liver injury by reducing the oxidative stress-induced inflammatory reaction in macrophages. Moreover, PAL inhibited inflammasome-dependent IL-1β generation. Mechanistically, the knockdown of VDR increased IL-1β generation, whereas VDR overexpression exerted the opposite effect following tert-butyl hydroperoxide treatment. The inflammasome antagonist glyburide, the caspase-1-specific inhibitor YVAD, and the reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) blocked the increase in Vdr shRNA-induced IL-1β production. Interestingly, up-regulation of VDR also enhanced macrophage autophagy. Autophagy reduction impaired the up-regulation of VDR-inhibited macrophage inflammasome-generated IL-1β, whereas autophagy induction showed a synergistic effect with VDR overexpression through ROS-p38 mitogen-activated protein kinase (MAPK) pathway. This result was confirmed by p38 MAPK inhibitor, MAPK activator, and ROS inhibitor NAC. Collectively, PAL triggered macrophage autophagy by suppressing activation of the ROS-p38 MAPK pathway, which, in turn, suppressed inflammasome-generated cleaved, active forms of IL-1β, eventually leading to reduced inflammation. Thus, triggering the VDR may be a potential target for the anti-inflammatory treatment of cholestatic liver disease.},
}

Animals
Mice
*Inflammasomes/metabolism
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Reactive Oxygen Species/metabolism
Receptors, Calcitriol/metabolism
Macrophages/metabolism
*Cholestasis/metabolism
Inflammation/metabolism
Autophagy/physiology
Acetylcysteine
p38 Mitogen-Activated Protein Kinases/metabolism
Interleukin-1beta/metabolism

@article {pmid38369618,
year = {2024},
author = {Sun, C and Zhang, M and Guan, C and Li, W and Peng, Y and Zheng, J},
title = {In vitro and in vivo metabolic activation and hepatotoxicity of chlorzoxazone mediated by CYP3A.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {38369618},
issn = {1432-0738},
abstract = {Chlorzoxazone (CZX), a benzoxazolone derivative, has been approved for the treatment of musculoskeletal disorders to relieve localized muscle spasm. However, its idiosyncratic toxicity reported in patients brought attention, particularly for hepatotoxicity. The present study for the first time aimed at the relationship between CZX-induced hepatotoxicity and identification of oxirane intermediate resulting from metabolic activation of CZX. Two N-acetylcysteine (NAC) conjugates (namely M1 and M2) and two glutathione (GSH) conjugates (namely M3 and M4) were detected in rat & human microsomal incubations with CZX (200 μM) fortified with NAC or GSH, respectively. The formation of M1-M4 was NADPH-dependent and these metabolites were also observed in urine or bile of SD rats given CZX intragastrically at 10 mg/kg or 25 mg/kg. NAC was found to attach at C-6' of the benzo group of M1 by sufficient NMR data. CYPs3A4 and 3A5 dominated the metabolic activation of CZX. The two GSH conjugates were also observed in cultured rat primary hepatocytes after exposure to CZX. Inhibition of CYP3A attenuated the susceptibility of hepatocytes to the cytotoxicity of CZX (10-400 μM). The in vitro and in vivo studies provided solid evidence for the formation of oxirane intermediate of CZX. This would facilitate the understanding of the underlying mechanisms of toxic action of CZX.},
}

@article {pmid38369538,
year = {2024},
author = {Wu, T and Liu, W and Chen, H and Hou, L and Ren, W and Zhang, L and Hu, J and Chen, H and Chen, C},
title = {Toxoflavin analog D43 exerts antiproliferative effects on breast cancer by inducing ROS-mediated apoptosis and DNA damage.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {4008},
pmid = {38369538},
issn = {2045-2322},
support = {2023M731448//China Postdoctoral Science Foundation/ ; 2023M731011//China Postdoctoral Science Foundation/ ; 82203878//National Science Foundation of China/ ; U2102203//National Science Foundation of China/ ; 2023J01385//the Natural Science Foundation of Fujian Province/ ; 2020YFA0112300//National Key R&D Program of China/ ; 202302AA310046//Biomedical Projects of Yunnan Key Science and Technology Program/ ; 202101AS070050//Yunnan Fundamental Research Projects/ ; YSZJGZZ-2020025//Yunnan (Kunming) Academician Expert Workstation/ ; },
abstract = {Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.},
}