picture
RJR-logo

About | BLOGS | Portfolio | Misc | Recommended | What's New | What's Hot

About | BLOGS | Portfolio | Misc | Recommended | What's New | What's Hot

icon

Bibliography Options Menu

icon
QUERY RUN:
19 Feb 2025 at 01:56
HITS:
12812
PAGE OPTIONS:
Hide Abstracts   |   Hide Additional Links
NOTE:
Long bibliographies are displayed in blocks of 100 citations at a time. At the end of each block there is an option to load the next block.

Bibliography on: N-Acetyl-Cysteine: Wonder Drug?

RJR-3x

Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 19 Feb 2025 at 01:56 Created: 

N-Acetyl-Cysteine: Wonder Drug?

Wikipedia: Acetylcysteine, also known as N-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. It has been used to treat lactobezoar in infants. It can be taken intravenously, by mouth, or inhaled as a mist. Some people use it as a dietary supplement. Common side effects include nausea and vomiting when taken by mouth. The skin may occasionally become red and itchy with any route of administration. A non-immune type of anaphylaxis may also occur. It appears to be safe in pregnancy. For paracetamol overdose, it works by increasing the level of glutathione, an antioxidant that can neutralise the toxic breakdown products of paracetamol. When inhaled, it acts as a mucolytic by decreasing the thickness of mucus.

NAC, as a commercially available dietary supplement, is touted as A potent antioxidant that supports comprehensive wellness, including lung, liver, kidney and immune function.

Is NAC a life-extending wonder drug? What does the scientific literature say?

Created with PubMed® Query: nac acetylcysteine OR "acetyl-cysteine" NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

-->

RevDate: 2025-02-17
CmpDate: 2025-02-17

Chaves AS, Ventura RD, Pacini MF, et al (2025)

Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands.

Frontiers in endocrinology, 16:1500630.

We previously showed that antioxidants induced an impairment of negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in rats, in parallel to a down-regulation of the glucocorticoid receptor (GR) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the pituitary gland. This study evaluated the role of the Nrf2-heme-oxygenase-1 (HO-1) pathway on the impairment of the negative feedback of the HPA axis induced by N-acetylcysteine (NAC). Male Swiss-Webster mice were orally supplemented with NAC for 5 consecutive days. The Nrf2-HO-1 pathway activator cobalt protoporphyrin IX (CoPPIX) was injected intraperitoneally on days 2 and 5 after the starting of NAC supplementation. NAC reduced the expression of Nrf2 in the pituitary of mice. Furthermore, NAC induced adrenal enlargement and hypercorticoidism, along with a decrease in the GRα expression and an increase of GRβ expression in the pituitary gland. Treatment with CoPPIX reduced adrenal enlargement, systemic corticosterone levels, and GRβ expression in the pituitary gland of mice supplemented with NAC, besides increasing the expression of GRα. CoPPIX treatment also restored the failure in the negative feedback of the HPA axis induced by NAC. In conclusion, these findings showed that NAC reduced the Nrf2-HO-1 pathway activation in the pituitary gland, in a mechanism probably related to a local downregulation of GRα and an up-regulation of GRβ, leading to a failure of negative feedback of the HPA axis and consequently to the hyperactivity of this neuroendocrine axis.

RevDate: 2025-02-17

Subiksha K, Jena A, Sarangi P, et al (2024)

Comparative evaluation of antibacterial efficacy of N-acetylcysteine, Aegle marmelos, and chitosan as intracanal medicaments against Enterococcus faecalis biofilm - An in vitro study.

Journal of conservative dentistry and endodontics, 27(12):1246-1250.

CONTEXT: The main objective of root canal treatment is the removal of bacteria. Established medicaments and their combinations have been compromised in efficacy against Enterococcus faecalis, causing the need to explore novel intracanal medicaments.

AIM: The aim of the study was to evaluate the antibacterial efficacy of chitosan, N-acetylcysteine (NAC), and Aegle marmelos as intracanal medicaments against E. faecalis biofilm.

MATERIALS AND METHODOLOGY: Minimum inhibitory concentration and susceptibility of medicaments determined. Two hundred and forty dentin disc specimens were prepared and inoculated with E. faecalis for 21 days. Samples were divided into four groups (A - N-acetylcysteine; B - Aegle marmelos; C - Chitosan; D -Control) (n = 60), and two subgroups (n = 30) based on the duration of medicament placed (subgroup 1: 24 h, subgroup 2: 7 days). Thereafter, dentinal shavings were retrieved, incubated in agar plate, visible colonies counted, and statistically analyzed.

RESULTS: At 24 h Group C1 exhibited the lowest CFUs, followed by Group A1, Group B, and Group D1. On the 7[th] day, Group B2 showed the lowest CFUs, followed by Group A2, Group C2, and Group D2.

CONCLUSIONS: Against E. faecalis, NAC has the highest antimicrobial properties closely followed by Aegle marmelos and both provide promising novel possibilities for use as intracanal medicaments.

RevDate: 2025-02-15

Wang J, Zhao R, Ma J, et al (2025)

Biallelic FDXR mutations induce ferroptosis in a rare mitochondrial disease with ataxia.

Free radical biology & medicine pii:S0891-5849(25)00087-5 [Epub ahead of print].

Biallelic mutations in the FDXR are known to cause rare mitochondrial diseases. However, the underlying pathogenic mechanisms remain elusive. This study investigated a patient affected by optic atrophy, ataxia, and peripheral neuropathy resulting from compound heterozygous mutations in FDXR. Structural abnormalities in mitochondria were observed in muscle and nerve tissues. Lymphoblastic cell lines (LCLs) and muscle samples from the patient exhibited signs of mitochondrial dysfunction, iron overload, oxidative stress, and lipid peroxidation. Dysregulation of the glutathione peroxidase-4 was noted in the LCLs. Furthermore, treatment with deferoxamine, N-acetyl-cysteine, and ferrostatin-1 effectively alleviated oxidative stress and cell death. Cortical neurons demonstrate that FDXR deficiency impacts the morphogenesis of neurites. Collectively, these findings suggest that ferroptosis plays a significant role in the pathogenesis of FDXR-associated diseases. Additionally, idebenone appeared to have protective effects against various cellular injuries induced by FDXR mutations, providing novel insights and therapeutic approaches for the treatment of FDXR-associated diseases.

RevDate: 2025-02-15

Kumar S, D'Souza LC, Shaikh FH, et al (2025)

Multigenerational immunotoxicity assessment: A three-generation study in Drosophila melanogaster upon developmental exposure to triclosan.

Environmental pollution (Barking, Essex : 1987) pii:S0269-7491(25)00233-7 [Epub ahead of print].

Triclosan (TCS) is widely used as an antibacterial agent, nevertheless, its presence in different environmental matrices and its persistent environmental nature pose a significant threat to the organism, including humans. Numerous studies showed that TCS exposure could lead to multiple toxicities, including immune dysfunction. However, whether parental TCS exposure could impair the offspring's immune response remains limited. Maintaining the immune homeostasis is imperative to neutralize the pathogen and crucial for tissue repair and the organism's survival. Thus, this study aimed to assess the multigenerational immune response of TCS using Drosophila melanogaster. TCS was administered to organisms (1.0, 10, and 100.0 μg/mL) over three generations during their developing phases, and its effect on the immunological response of the unexposed progeny was evaluated. Total circulatory hemocyte (immune cells) count, crystal cell count, phagocytic activity, clotting time, gene expression related to immune response and epigenetics, ROS generation, and cell death were assessed in the offspring. A concentration-dependent decline in total hemocytes, crystal cells, phagocytic activity, and increased clotting time in the subsequent generations was observed. Furthermore, parental TCS exposure enhanced the ROS levels, induced cell death, and altered the expression of antimicrobial peptides drosomycin, diptericin, and inflammatory genes upd1, upd2, and upd3, in the offspring's hemocytes across successive generations. The upregulation of reaper hid, and grim suggests that TCS promotes apoptotic death in the offspring's hemocytes. Notably, the increased mRNA expression of epigenetic regulators dnmt2 and g9a in the hemocytes of the offspring indicates epigenetic modifications. Further, we also observed that the antioxidant N-acetylcysteine (NAC) supplementation to the parents alleviated TCS toxicity and improved immunological functions in the progeny, indicating the role of ROS in the TCS-induced multigenerational immune toxicity. This finding provides valuable insights into the potential immune risk of prenatal TCS exposure to their offspring in the higher organism.

RevDate: 2025-02-15
CmpDate: 2025-02-15

Zhou Y, Yuan X, M Guo (2025)

Unlocking NAC's potential ATF4 and m6A dynamics in rescuing cognitive impairments in PTSD.

Metabolic brain disease, 40(2):129.

In this study, we investigated the therapeutic potential of N-acetylcysteine (NAC) in a mouse model of post-traumatic stress disorder (PTSD) induced by a single prolonged stress (SPS) protocol. Our findings demonstrate that NAC treatment significantly improved cognitive function and mitigated hippocampal neuronal apoptosis in PTSD model mice. These positive effects were accompanied by a reduction in m6A methylation levels and activating transcription factor 4 (ATF4) expression. Silencing ATF4 further attenuated hippocampal neuronal apoptosis and cognitive dysfunction, while ATF4 overexpression partially reversed the beneficial effects of NAC. It suggests that NAC's efficacy in PTSD may be mediated by its regulation of ATF4 expression and m6A methylation levels. Overall, our study provides valuable insights into the potential mechanism of action for NAC in PTSD treatment, offering promising avenues for future therapeutic strategies.

RevDate: 2025-02-15

Zhu X, Yuan F, Sun Q, et al (2025)

N-acetylcysteine remodels the tumor microenvironment of primary and recurrent mouse glioblastoma.

Journal of neuro-oncology [Epub ahead of print].

PURPOSE: Glioblastoma (GBM) exhibits a high ROS character, giving rise to an immunosuppressive microenvironment and tumor vascular abnormality. This study investigated the potential effect of N-acetylcysteine (NAC), an antioxidant, on primary and recurrent mouse brain tumors.

METHODS: We measured reactive oxygen species (ROS)/ glutathione (GSH) levels in human GBM. Additionally, we conducted NAC trials on primary mouse brain tumor models (GL261-Luc, CT2A-Luc) and a recurrent mouse GBM model (GL261-iCasp9-Luc). After brain tumor inoculation, mice received a daily 100 mg/kg NAC treatment, and the tumor volume was monitored via IVIS imaging. The efficacy of NAC was evaluated through survival time, tumor volume, ROS/GSH levels, M1/M2 macrophages, immune cells infiltration, and tumor vascularization.

RESULTS: Human GBM suffered from significant oxidative stress. With NAC treatment, mouse brain tumors exhibited a lower ROS level, more M1-like tumor-associated macrophages/microglia (TAMs), more CD8 + T cell infiltration, and a normalized vascular character. NAC inhibited tumor growth and suppressed recurrence in mouse brain tumor models.

CONCLUSION: NAC is a promising adjunctive drug to remodel the brain tumors microenvironment.

RevDate: 2025-02-14

Liu X, Zhong D, Tang CZ, et al (2025)

In vitro and In vivo Drug Metabolism Analysis of BPI-460372 - A Covalent TEAD1/3/4 Inhibitor.

Current drug metabolism pii:CDM-EPUB-146595 [Epub ahead of print].

BACKGROUND: BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the transcriptional enhanced associate domain (TEAD) 1/3/4, which is currently in clinical development for the treatment of cancers with Hippo pathway alterations.

OBJECTIVE: This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and in vitro and in vivo metabolic profile of BPI-460372.

METHODS: The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes and rat and dog plasma was analyzed using ultra-high-performance liquid chromatography combined with Orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).

RESULTS: BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human-unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic site was 2-fluoro-acrylamide, and major metabolic pathways in hepatocytes, and rat and dog plasma involved oxidative defluorination, hydration, glutathione (GSH) conjugation, hydrolysis, cysteine conjugation, and N-acetyl cysteine conjugation. β-lyase pathway contributed to the metabolism of BPI-460372 in rats to a certain degree.

CONCLUSION: This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, and assessment of clinical co-administration limitations and possible metabolic pathways in humans.

RevDate: 2025-02-15

Qian X, Liu Y, Chen W, et al (2025)

Paris saponin VII induces Caspase-3/GSDME-dependent pyroptosis in pancreatic ductal adenocarcinoma cells by activating ROS/Bax signaling.

Chinese herbal medicines, 17(1):94-107.

OBJECTIVE: Paridis Rhizoma (Chonglou in Chinese), a traditional Chinese herbal medicine, has been shown have strong anti-tumor effects. Paris saponin VII (PSVII), an active constituent isolated from Paridis Rhizoma, was demonstrated to significantly suppress the proliferation of BxPC-3 cells in our previous study. Here, we aimed to elucidate the anti-pancreatic ductal adenocarcinoma (PDAC) effect of PSVII and the underlying mechanism.

METHODS: Cell viability was determined by CCK-8, colony formation, and cell migration assays. Cell apoptosis and reactive oxygen species (ROS) production were measured by flow cytometry with annexin V/propidine iodide (Annexin V/PI) and 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), respectively. Pyroptosis was evaluated by morphological features, Hoechst 33342/PI staining assay, and release of lactate dehydrogenase (LDH). JC-1 fluorescent dye was employed to measure mitochondrial membrane potential. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to determine the levels of proteins or mRNAs. The effect in vivo was assessed by a xenograft tumor model.

RESULTS: PSVII inhibited the viability of PDAC cells (BxPC-3, PANC-1, and Capan-2 cells) and induced gasdermin E (GSDME) cleavage, as well as the simultaneous cleavage of Caspase-3 and poly (ADP-ribose) polymerase 1 (PARP). Knockdown of GSDME shifted PSVII-induced pyroptosis to apoptosis. Additionally, the effect of PSVII was significantly attenuated by Z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone (Z-DEVD-FMK), on the induction of GSDME-dependent pyroptosis. PSVII also elevated intracellular ROS accumulation and stimulated Bax and Caspase-3/GSDME to conduct pyroptosis in PDAC cells. The ROS scavenger N-acetyl cysteine (NAC) suppressed the release of LDH and inhibited Caspase-9, Caspase-3, and GSDME cleavage in PDAC cells, ultimately reversing PSVII-induced pyroptosis. Furthermore, in a xenograft tumor model, PSVII markedly suppressed the growth of PDAC tumors and induced pyroptosis.

CONCLUSION: These results demonstrated that PSVII exerts therapeutic effects through Caspase-3/GSDME-dependent pyroptosis and may constitute a novel strategy for preventing chemotherapeutic resistance in patients with PDAC in the future.

RevDate: 2025-02-13
CmpDate: 2025-02-13

Lee SO, Joo SH, Park J, et al (2025)

Deoxybouvardin Glucoside Induces Apoptosis in Oxaliplatin-Sensitive and -Resistant Colorectal Cancer Cells via Reactive Oxygen Species-Mediated Activation of JNK and p38 MAPK.

Journal of microbiology and biotechnology, 35:e2410008 pii:jmb.2410.10008.

The roots of Rubia spp. (Rubiaceae) have been employed to treat hematemesis, inflammatory disease, and tumor. Cyclohexapeptides derived from Rubia spp. have been reported to have antitumor potential; however, the mechanism of action for their antitumor activity remains unclear. We aimed to examine the antitumor effect of deoxybouvardin glucoside (DBG), a cyclohexapeptide from Rubia spp. on oxaliplatin (Ox)-resistant human HCT116 colorectal cancer (CRC) cells. Cell viability in the presence of DBG was monitored using an MTT viability assay, and flow cytometry was used to analyze changes in apoptosis, cell cycle, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) activity. The antiproliferative activity involved apoptosis and phosphorylation of JNK and p38 MAPK. Inhibition of JNK and p38 MAPK by specific inhibitors prevented DBG-induced apoptosis, underscoring the close involvement of these kinases. Further, DBG induced cell cycle arrest in CRC cells at the G2/M phase by regulating the p21, p27, cyclin B1, and cdc2 proteins. DBG-induced apoptosis was accompanied mitochondrial membrane depolarization, resulting in cytochrome c release into the cytoplasm and caspase activation. Remarkably, DBG induced apoptosis by generating high ROS levels. The mediation of apoptosis by increased ROS generation was confirmed by pretreatment with the ROS scavenger N-acetyl cysteine (NAC). Collectively, DBG exhibited anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting JNK and p38 MAPK, inducing cell cycle arrest, elevating cellular ROS levels, and disrupting MMP. This study suggests that DBG has the potential to be utilized as a therapeutic agent for treating Ox-resistant CRC.

RevDate: 2025-02-14

Bellone S, Siegel ER, AD Santin (2025)

N-acetylcysteine (NAC) supplementation improves dyspnea and may normalize von Willebrand plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID.

Gynecologic oncology reports, 57:101682.

OBJECTIVES: A subset of COVID-infected cancer patients may develop post-acute sequelae of COVID-19 (PASC), also known as Long COVID (LC). While LC is considered multifactorial in its pathogenesis, growing evidence suggests that persistent microvascular inflammation (ie, spike-induced endotheliosis) causing chronically elevated levels of clotting factors including von Willebrand factor (vWF), clumping/clotting of red blood cells and platelets, and thrombotic complications may be at the root of PASC/LC symptoms. N-Acetylcysteine (NAC), a precursor of glutathione, is an inexpensive FDA-approved drug/supplement endowed with mucolytic, antioxidant, anti-inflammatory and thrombolytic properties. Multiple reports have recently demonstrated the potential clinical activity of NAC in COVID-19 patients. We retrospectively evaluated responses to NAC supplementation in a total of 9 PASC/LC patients, 3 of which reporting regular use of NAC, followed in our Gynecologic Oncology clinic.

METHODS: Gynecologic patients using NAC supplement (3 patients) vs controls (6 patients) with persistent LC/PASC symptoms and with elevated plasmatic vWF levels were identified in our Gynecologic Oncology clinic database and evaluated for improvement/normalization in LC/PASC symptoms and vWF levels.

RESULTS: Subjective improvement in shortness of breath, brain fog and fatigue with normalization of vWF levels were noted in 3 out of 3 PASC/LC patients using oral NAC (600-1200 mg BID) vs none of the randomly selected cancer control patients with PASC/LC (Fisher's exact P = 0.0119).

CONCLUSIONS: These preliminary results suggest that NAC may represent an inexpensive, safe and potentially effective supplement to improve many PASC/LC-related symptoms. Prospective randomized studies with NAC in PASC/LC patients are needed to confirm these findings.

RevDate: 2025-02-13
CmpDate: 2025-02-13

Iciek M, Bilska-Wilkosz A, Górny M, et al (2025)

The Effect of Disulfiram and N-Acetylcysteine, Potential Compensators for Sulfur Disorders, on Lipopolysaccharide-Induced Neuroinflammation Leading to Memory Impairment and the Metabolism of L-Cysteine Disturbance.

Molecules (Basel, Switzerland), 30(3): pii:molecules30030578.

BACKGROUND: The role of sulfur-containing drugs, disulfiram (DSF) and N-acetylcysteine (NAC), in alleviating neuroinflammation is poorly understood. The objective of this study was to examine the effect of DSF and NAC on memory and on the metabolism of L-cysteine and inflammation-related parameters in the cerebral cortex of rats in a model of neuroinflammation induced by the administration of lipopolysaccharide (LPS).

METHODS: All the treatments were administered intraperitoneally for 10 days (LPS at a dose of 0.5 mg/kg b.w., DSF at a dose of 100 mg/kg b.w, and NAC at a dose of 100 mg/kg b.w.). Behavior was evaluated by the novel object recognition (NOR) test and object location (OL) test, and the level of brain-derived neurotrophic factor (BDNF) was assayed to evaluate neuronal functioning. Cerebral cortex homogenates were tested for hydrogen sulfide (H2S), sulfane sulfur, sulfates, non-protein sulfhydryl groups (NPSH), nitric oxide (NO), and reactive oxygen species (ROS) by biochemical analysis.

RESULTS: Neither DSF nor NAC alleviated LPS-induced memory disorders estimated by the NOR test and OL test. The studied compounds also did not affect significantly the levels of BDNF, ROS, NO, H2S, and sulfane sulfur in the cerebral cortex. However, we observed an increase in sulfate concentration in brain tissues after LPS treatment, while DSF and NAC caused an additional increase in sulfate concentration. On the other hand, our study showed that the administration of DSF or NAC together with LPS significantly enhanced the cortical level of NPSH, of which glutathione is the main component.

CONCLUSIONS: Our study did not confirm the suggested potential of DSF and NAC to correct memory disorders; however, it corroborated the notion that they reduced oxidative stress induced by LPS by increasing the NPSH level. Additionally, our study showed an increase in sulfate concentration in the brain tissues after LPS treatment, which means the upregulation of sulfite and sulfate production in inflammatory conditions.

RevDate: 2025-02-13

Lee SH, Park GS, Lee R, et al (2025)

Gintonin-Enriched Panax ginseng Extract Induces Apoptosis in Human Melanoma Cells by Causing Cell Cycle Arrest and Activating Caspases.

Foods (Basel, Switzerland), 14(3): pii:foods14030381.

Gintonin, a non-saponin glycolipoprotein from Panax ginseng, acts as a lysophosphatidic acid ligand. However, its anticancer effects, especially in melanoma, remain unclear. This study investigated the anti-proliferative effects and intracellular signaling mechanisms of a gintonin-enriched fraction (GEF) from Panax ginseng in human melanoma cell lines. In vitro, GEF treatment significantly inhibited cell proliferation, reduced clonogenic potential, and delayed wound healing in melanoma cells. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining showed that GEF induced apoptosis, as evidenced by increased apoptotic cell populations and nuclear changes. GEF also caused cell cycle arrest in the G1 phase for A375 cells and the G2/M phase for A2058 cells. It triggered apoptotic signaling via activation of caspase-3, -9, poly (ADP-ribose) polymerase cleavage, and downregulation of B cell lymphoma-2 (Bcl-2). GEF treatment also raised intracellular reactive oxygen species (ROS) levels and mitochondrial stress, which were mitigated by N-acetyl cysteine (NAC), an ROS inhibitor. In vivo, GEF suppressed tumor growth in A375- and A2058-xenografted mice without toxicity. These findings suggest that GEF from Panax ginseng has potential antitumor effects in melanoma by inducing apoptosis and cell cycle arrest, presenting a promising therapeutic avenue.

RevDate: 2025-02-11

Mishra AK, Hossain MM, Sata TN, et al (2025)

ALR inhibits HBV replication and autophagosome formation by ameliorating HBV-induced ROS production in hepatic cells.

Virus genes [Epub ahead of print].

HBV has a small genome and thrives in the infected hepatocytes by hijacking the cellular machinery and cellular pathways. HBV induces incomplete autophagy for its replication and survival. This study showed that HBV replication induces Reactive oxygen species (ROS) production, which in turn augments the formation of autophagosomes. Augmenter of liver regeneration (ALR) is a sufhydryl oxidase and has an anti-oxidative property. We sought to determine the interplay between HBV and antioxidant protein ALR. We showed that HBV downregulated ALR expression in hepatic cells. There was increased ROS production in HBV-infected cells while ALR downregulated ROS levels and expression of NADPH oxidase NOX4. N-acetyl cysteine, a ROS scavenger, downregulated ROS level and autophagosome formation in HBV-expressing cells. ALR overexpression in HBV-expressing cells downregulated the expression of autophagy marker proteins while upregulated the expression of p-MTOR. ALR overexpression decreased the expression of HBx, HBsAg, and total HBV load. This study showed that HBx relieved ALR-mediated inhibition by upregulating the miR-181a expression in HBV-infected cells, which in turn downregulated ALR expression.

RevDate: 2025-02-11

Kwon MJ, Raut PK, Jang JH, et al (2025)

Isoliquiritigenin Induces Apoptosis via ROS-Mediated Inhibition of p38/mTOR/STAT3 Pathway in Human Melanoma Cells.

Biomolecules & therapeutics pii:biomolther.2024.118 [Epub ahead of print].

Isoliquiritigenin (ISL), a phenolic compound derived from licorice, exhibits various biological activities, including anti-inflammatory, anti-viral, anti-tumor, and antioxidant effects. However, the molecular mechanisms underlying its anti-cancer effects are not well understood in SK-MEL-28 melanoma cells. Melanoma, a highly aggressive and treatment-resistant cancer, remains a significant health challenge. This study investigates the anti-cancer effects of ISL, focusing on identifying reactive oxygen species (ROS)-mediated apoptosis mechanisms on SK-MEL-28 melanoma cells. Our results show that ISL treatment induces apoptosis in SK-MEL-28 cells, as evidenced by the cleavage of caspase-9, -7, -3, and PARP. ISL increased Bax expression, decreased Bcl-2 expression, and promoted cytochrome C release into the cytosol. ISL also reduced the expression of cell cycle markers, including cyclin D1, D3, and survivin. Notably, ISL treatment markedly increased intracellular ROS levels and pretreatment with N-acetyl cysteine, a ROS scavenger, abrogated the ISL-induced inhibition of the p38/mTOR/STAT3 pathway and prevented apoptosis. Moreover, ISL significantly diminished the constitutive phosphorylation of mTOR and STAT3 in SK-MEL-28 cells by blocking the phosphorylation of p38 MAPK, an upstream kinase of mTOR. Pharmacological inhibition of mTOR attenuated the STAT3 signaling, indicating that mTOR acts as an upstream kinase of STAT3 in these cells. Collectively, these findings demonstrate that ISL inhibits SK-MEL-28 cell growth by downregulating cell survival proteins and inducing apoptosis through ROS generation.

RevDate: 2025-02-11

Lee SO, Joo SH, Cho SS, et al (2025)

Licochalcone D Exerts Antitumor Activity in Human Colorectal Cancer Cells by Inducing ROS Generation and Phosphorylating JNK and p38 MAPK.

Biomolecules & therapeutics pii:biomolther.2024.123 [Epub ahead of print].

Anticancer activities of Licochalcone D (LCD) in human colorectal cancer (CRC) cells HCT116 and oxaliplatin-resistant HCT116 (HCT116-OxR) were determined. Cell viability assay and soft agar assay were used to analyze antiproliferative activity of LCD. Flow cytometry was performed to determine effects of LCD on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. Western blot analysis was used to monitor levels of proteins involved in cell cycle and apoptosis signaling pathways. LCD suppressed the growth and anchorageindependent colony formation of both HCT116 and HCT116-OxR cells. Cell cycle analysis by flow cytometry indicated that LCD induced cell cycle arrest and increased cells in sub-G1 phase. In parallel with the antiproliferative effect of LCD, LCD up-regulated levels of p21 and p27 while downregulating cyclin B1 and cdc2. In addition, phosphorylation levels of JNK and p38 mitogen-activated protein kinase (MAPK) were increased by LCD. Inhibition of these kinases somehow prevented the antiproliferative effect of LCD. Moreover, LCD increased ROS and deregulated mitochondrial membrane potential, leading to the activation of multiple caspases. An ROS scavenger N-acetyl-cysteine (NAC) or pan-caspase inhibitor Z-VAD-FMK prevented the antiproliferative effect of LCD, supporting that ROS generation and caspase activation mediated LCD-induced apoptosis in CRC cells. In conclusion, LCD exerted antitumor activity in CRC cells by inducing ROS generation and phosphorylation of JNK and p38 MAPK. These results support that LCD could be further developed as a chemotherapeutic agent for treating CRC.

RevDate: 2025-02-09

Kim YH, Kim JB, Bae JE, et al (2025)

ZLDI-8 facilitates pexophagy by ROS-mediated activation of TFEB and ATM in HeLa cells.

Bioorganic & medicinal chemistry letters pii:S0960-894X(25)00039-3 [Epub ahead of print].

Autophagy-mediated organelle quality control is vital for cellular homeostasis. However, the mechanisms underlying selective autophagy of peroxisomes, known as pexophagy, are less well understood than those of other organelles, such as mitochondria. In this study, we screened a phosphatase inhibitor library using a cell-based system and identified several potent pexophagy inducers, including ZLDI-8, a known inhibitor of lymphoid-specific tyrosine phosphatase. Notably, treatment with ZLDI-8 selectively induces the loss of peroxisomes without affecting other organelles, such as mitochondria, the endoplasmic reticulum, or the Golgi apparatus. The peroxisome loss induced by ZLDI-8 was significantly blocked in ATG5-knockout HeLa cells, confirming its dependence on autophagy. We further found that ZLDI-8 treatment increases both cellular and peroxisomal reactive oxygen species (ROS), which were effectively scavenged by N-acetylcysteine (NAC). The increase in peroxisomal ROS leads to the activation of ATM kinase and the dephosphorylation of TFEB. Moreover, ROS scavenging prevents all of these processes. Taken together, these findings demonstrate that ZLDI-8 induces pexophagy through a mechanism involving peroxisomal ROS-mediated activation of TFEB and ATM. This study provides valuable insights into the molecular mechanisms regulating selective peroxisome degradation and potential therapeutic strategies for targeting pexophagy.

RevDate: 2025-02-09

Lin KA, Su CC, Lee KI, et al (2025)

The herbicide 2,4-dichlorophenoxyacetic acid induces pancreatic β-cell death via oxidative stress-activated AMPKα signal downstream-regulated apoptotic pathway.

Toxicology letters, 405:16-29 pii:S0378-4274(25)00015-3 [Epub ahead of print].

2,4-Dichlorophenoxyacetic acid (2,4-D) is one of commonly and widely used organic herbicides in agriculture. It has been reported that 2,4-D can induce adverse effects in mammalian cells. Epidemiological and animal studies have indicated that exposure to 2,4-D is associated with poorer glycemic control and impaired pancreatic β-cell function. However, limited information is available on 2,4-D-induced toxicological effects in β-cells, with the underlying toxicological mechanisms remains unclear. Herein, our results showed that 2,4-D exposure (30-500 μg/mL) significantly reduced cell viability, induced mitochondria dysfunction (including the mitochondrial membrane potential (MMP) loss, the increase in cytosolic cytochrome c release, and the change in Bcl-2 and Bax protein expression), and triggered apoptotic events (including the increased population of apoptotic cells, caspase-3 activity, and caspase-3/-7 and PAPR activation) in RIN-m5F β-cells, accompanied with insulin secretion inhibition. Exposure of cells to 2,4-D could also evoke JNK, ERK1/2, p38, and AMP-activated protein kinase (AMPK)α activation as well as reactive oxygen species (ROS) generation. Pretreatment of cells with compound C (an AMPK inhibitor) and the antioxidantN-acetylcysteine (NAC), but not that SP600125/PD98059/SB203580 (the inhibitors of JNK/ERK/p38, respectively), obviously attenuated the 2,4-D-triggered AMPKα phosphorylation, MMP loss, apoptotic events, and insulin secretion dysfunction,as similar effects with the transfection with AMPKα1-specific siRNA. Of note, buffering the ROS production with NAC obviously prevented the 2,4-D-induced ROS generation as well as AMPKα activation, but the either compound C and AMPKα1-specific siRNA transfection could not effectively reduce 2,4-D-induced ROS generation. Collectively, these findings indicate that the induction of oxidative stress-activated AMPKα signaling is a crucial mechanism underlying 2,4-D-triggered mitochondria-dependent apoptosis, ultimately leading to β-cell death.

RevDate: 2025-02-07
CmpDate: 2025-02-08

Roe T, Talbot T, Terrington I, et al (2025)

Physiology and pathophysiology of mucus and mucolytic use in critically ill patients.

Critical care (London, England), 29(1):68.

Airway mucus is a highly specialised secretory fluid which functions as a physical and immunological barrier to pathogens whilst lubricating the airways and humifying atmospheric air. Dysfunction is common during critical illness and is characterised by changes in production rate, chemical composition, physical properties, and inflammatory phenotype. Mucociliary clearance, which is determined in part by mucus characteristics and in part by ciliary function, is also dysfunctional in critical illness via disease related and iatrogenic mechanisms. The consequences of mucus dysfunction are potentially devastating, contributing to prolonged ventilator dependency, increased risk of secondary pneumonia, and worsened lung injury. Mucolytic therapies are designed to decrease viscosity, improve expectoration/suctioning, and thereby promote mucus removal. Mucolytics, including hypertonic saline, dornase alfa/rhDNase, nebulised heparin, carbocisteine/N-Acetyl cysteine, are commonly used in critically ill patients. This review summarises the physiology and pathophysiology of mucus and the existing evidence for the use of mucolytics in critically ill patients and speculates on journey to individualised mucolytic therapy.

RevDate: 2025-02-07

Henaidy MF, Ghanem M, Shehata SF, et al (2025)

Therapeutic effects of NAC and CoQ10 on aluminium phosphide poisoning as an adjuvant therapy: A Pilot study.

Toxicology reports, 14:101907.

UNLABELLED: In aluminium phosphide (AlP) poisoning, death is mainly due to acute heart failure. There is some evidence showing that N-acetylcysteine (NAC) and coenzyme Q10 have antioxidant and cardioprotective effects. This study investigated a new approach for treating acute AlP poisoning by using NAC and Co-Q10 as adjuvant therapy.

SUBJECTS AND METHODS: The study design was a retrospective-prospective study. It was conducted in the poisoning unit of Kafer Eldwar General Hospital. Sixty patients with acute aluminium phosphide poisoning were included. The patients were divided into two groups. The first group (standard protocol) considered the control group received the standard supportive care, and their data were collected from the medical records. The second group (new protocol) in addition to the standard supportive care received the NAC and CoQ10 regimen, and all data were collected in a specially designed sheet.

RESULTS: The results showed that the highest percentage of patients in both groups were aged 18-25, followed by those under 18, and females outnumbered the males. The systolic (SBP) and diastolic (DBP) blood pressure showed significant improvement in the new protocol group. A significant statistical difference was found between the two groups regarding mechanical ventilation (p = 0.015), where mechanical ventilation was used in 20 % of patients in the new protocol group and 50 % in the standard group. Regarding the outcome of patients, the survival rate reached 73.3 % upon using the new protocol, compared to 50 % who received the standard protocol.

CONCLUSION: The data imply that further investigation in using the NAC and CoQ10 regimen is warranted. It gave an improvement of the survival rate and decrease the need for mechanical ventilation in AlP.

RevDate: 2025-02-06

Li M, Hu Y, Wu X, et al (2025)

Placental Ferroptosis May Be Involved in Prenatal Arsenic Exposure Induced Cognitive Impairment in Offspring.

Biological trace element research [Epub ahead of print].

The association between prenatal arsenic (As) exposure and offspring's cognition is still unclear, and the underlying etiology has also not been elucidated. Based on the Ma'anshan Birth Cohort (MABC) study in China, 1814 mother-child pairs were included in this study, and the association of As levels in cord serum with preschoolers' intelligence scores was explored. To validate the results from population study, in vivo models were adopted to observe the association between prenatal As exposure and spatial learning and memory abilities of mice offsprings. The As-exposure induced ferroptosis in the placenta of human beings as well as C57BL/6 J mice and HTR-8/SVneo cells was explored in order to clarify the potential cause of impairment of offspring's cognition related to As exposure, respectively. In the population study, we observed a significant inverse association between natural logarithm transformed (ln) As levels and preschoolers' intelligence scores, especially for the fluid reasoning index (FRI) [(β (95%CI): - 1.07 (- 1.98, - 0.16)] and working memory index (WMI) [β (95%CI): - 1.51 (- 2.76, - 0.25)]. Meanwhile, the data from in vivo models revealed that the learning and memory abilities of offspring mice decreased after prenatal As exposure. The occurrence of ferroptosis-like characteristics in the placenta and HTR-8/SVneo cells after As exposure was observed, accompanying with evident oxidative stress, iron accumulation, mitochondrial damage, and decreased protein levels of GPX4, xCT, and FTH1 (or FPN1). Notably, the ferroptosis-like alterations induced by NaAsO2 can be effectively alleviated by N-acetylcysteine (NAC) and ferrostatin-1 (Fer-1) treatment in HTR-8/SVneo cells, respectively. In conclusion, prenatal As exposure associates with impairment of offspring's cognition, and placental ferroptosis may be involved in the association. Further studies are needed to confirm the findings.

RevDate: 2025-02-07
CmpDate: 2025-02-07

Wang Y, Wang Q, Ji Q, et al (2025)

Supplementation with N-Acetyl-L-cysteine during in vitro maturation improves goat oocyte developmental competence by regulating oxidative stress.

Theriogenology, 235:221-230.

Oocyte quality can affect mammal fertilization rate, early embryonic development, pregnancy maintenance, and fetal development. Oxidative stress induced by reactive oxygen species (ROS) is one of the most important causes of poor oocyte maturation in vitro. To reduce the degree of cellular damage caused by ROS, supplementation with the antioxidant N-Acetyl-L-cysteine (NAC) serves as an effective pathway to alleviate glutathione (GSH) depletion during oxidative stress. This study investigated the effects of NAC supplementation during in vitro maturation of goat oocytes and explored the molecular mechanisms of maturation by transcriptome sequencing of MⅡ oocytes. The results showed that 1.5 mM NAC significantly increased the rates of oocyte maturation and cumulus cell expansion and improved the subsequent development of embryos. During the subsequent culture of parthenogenetically activated embryos, 1.5 mM NAC significantly increased the division rate of oocytes and blastocyst rate. It also reduced the accumulation of ROS, increased the level of GSH, alleviated oxidative stress, and enhanced the antioxidant capacity and cell metabolic activity. Transcriptome sequencing results revealed that NAC treatment significantly increased the expression of SIRT1, GGCT, and MITF genes related to the cellular antioxidant system, as well as the IDH3G gene related to energy metabolism, and decreased the expression of CASP8, FOS, and MMP1 genes related to apoptosis and cell invasion, as well as the CCL2. and CXCL8 genes related to the inflammatory response. In conclusion, the findings suggest that NAC supplementation significantly reduces oxidative stress, improves antioxidant capacity and metabolic activity, promotes oocyte maturation, and improves oocyte quality.

RevDate: 2025-02-06

Sui B, Li X, Li N, et al (2025)

Synergistic action of mucoactive drugs and phages against Pseudomonas aeruginosa and Klebsiella pneumoniae.

Microbiology spectrum [Epub ahead of print].

N-acetylcysteine (NAC) and ambroxol hydrochloride (AMB) are commonly prescribed alongside antibiotics to alleviate sputum retention in lower respiratory tract infections, which are often caused by bacterial pathogens. With the rising threat of antibiotic resistance, phage therapy has emerged as a promising alternative alongside. However, no studies have explored the potential interactions between phages and these mucoactive agents despite their frequent concurrent use during phage therapy. Therefore, investigating the potential synergy and its subsequent impact on phage infection dynamics could enhance clinical strategies for treating bacterial infections with phages. Our study utilized Pseudomonas aeruginosa strain ZS-PA-35 and Klebsiella pneumoniae strain Kp36, alongside their respective phages, to investigate their interactions in the presence of NAC or AMB. Our findings indicate that, under specific conditions, these mucoactive agents can function as adjuvants to lytic phages, enhancing bacterial susceptibility to phage infection and facilitating subsequent phage proliferation. Our study revealed that these synergistic interactions are strongly influenced by the physiological characteristics of the phages, the surrounding microenvironments, and the physiology of host tissues, as varying outcomes of phage-host interactions were observed among different phages and across distinct media. Taken together, our results emphasize the complexity of interactions between phages and NAC or AMB, underscoring the need for caution when using combination treatments.IMPORTANCEN-acetylcysteine (NAC) and ambroxol hydrochloride (AMB) are used in medical treatment of patients with acute and chronic bronchitis. Often, the choice of NAC or AMB is empirically determined by physicians. However, the potential impact of combining NAC or AMB with phage therapy remains unclear. To address this gap, a comprehensive understanding of their interplay is crucial to determine any potential synergistic effects. This study aims to elucidate how NAC or AMB influence phages targeting different receptors, thereby affecting their antibacterial activity against Pseudomonas aeruginosa and Klebsiella pneumoniae. Our results suggest that, under certain conditions, NAC or AMB provides an adjuvant effect by rendering the cells more susceptible to phage infection. These results contribute to advancing our understanding of the clinical combination of mucoactive agents and phage therapy, offering insights for optimizing treatment efficacy.

RevDate: 2025-02-05
CmpDate: 2025-02-05

Tawalbeh M, Ibrahim RM, Al-Saraireh T, et al (2025)

Intratympanic N-acetylcysteine in the prevention of cisplatin-induced ototoxicity: a systematic review and meta-analysis of randomized controlled trials.

BMC pharmacology & toxicology, 26(1):26.

OBJECTIVE: To evaluate the efficacy of the otoprotective transtympanic application of N-acetylcysteine in preventing chemotherapy-induced ototoxicity in patients subjected to platinum-based chemotherapy.

DATA SOURCES: PubMed, Scopus, Web of Science, Cochrane Central, and ClinicalTrials.gov were searched for the following concepts: (("Acetylcysteine" [Mesh]) AND ("Ototoxicity" [Mesh]) AND ("Cisplatin" [Objective: To evaluate the efficacy of otoprotective transtympanic application of N-acetylcysteine in the prevention of chemotherapy-induced ototoxicity in patients subjected to platinum-based chemotherapy. [Mesh]).

STUDY SELECTION: Inclusion: randomized controlled trials, Exclusion: (1) case reports or case series; (2) thesis; (3) review articles; (4) conference abstracts; (5) animal studies; (6) non-english studies; (7) studies whose population was other than patients on platinum-based chemotherapy.

DATA EXTRACTION: changes in hearing thresholds measured by pure tone tympanometry, covering high and low frequencies: 250, 500, 1000, 2000, 4000, and 8000 Hz. We used RevMan (Review Manager) version 5.3 to conduct the meta-analysis and GRADE to assess the quality of the evidence.

DATA SYNTHESIS: The literature search yielded 277 unique articles. After reviewing six full-text articles, three RCTs provided data available for meta-analysis. A total of 88 cisplatin-based chemotherapy candidates were included for final analysis. Hearing thresholds showed a significant threshold difference between the ear treated with N-acetylcysteine and the control ear (ear not treated with N-acetylcysteine), especially at high frequencies as high as 8000 Hz (pooled effect size - 10.67, 95% CI [-12.33, -9.02], P < 0.00001). The data favored the Nac group in all frequencies as well, at 4000 Hz (pooled effect size - 2.13, 95% CI [-3.49, -0.77], P = 0.002), at 2000 Hz (pooled effect size - 1.38, 95% CI [-2.69, -0.06], P = 0.04), at 1000 Hz (pooled effect size - 1.58, 95% CI [-2.63, -0.53], P = 0.003), at 500 Hz (pooled effect size - 1.58, 95% CI [-2.62, -0.54], P = 0.003), and at the low frequency of 250 after solving the heterogeneity (pooled effect size - 0.96, 95% CI [-2.88, 0.95], P = 0.32).

CONCLUSIONS: Current data justifies the transtympanic administration of N-acetylcysteine for otoprotection in chemotherapy patients, minimizing the enduring consequences of cisplatin-induced ototoxicity and auditory impairment. Given the results' emphasis on the Sarafraz et al. (2018) study, more randomized controlled trials are necessary with an expanded sample size and standardization of N-acetylcysteine concentration, study population, and assessed outcomes.

RevDate: 2025-02-04

Sun M, Lu Z, Chen WM, et al (2025)

N-acetylcysteine therapy reduces major adverse cardiovascular events in patients with type 2 diabetes mellitus.

Atherosclerosis, 402:119117 pii:S0021-9150(25)00014-0 [Epub ahead of print].

BACKGROUND: Effective preventive strategies for major adverse cardiovascular events (MACE) in T2DM patients are limited. Recent studies have explored the cardiovascular benefits of N-Acetylcysteine (NAC), an antioxidant with endothelial protective properties. This study investigates the long-term effects of NAC on MACE risk in T2DM patients, focusing on its potential as an adjunctive therapy.

METHODS: This population-based cohort study used data from Taiwan's National Health Insurance Research Database (NHIRD) and included 46,718 T2DM patients diagnosed between 2008 and 2018, with follow-up until December 31, 2021. Propensity score matching (PSM) ensured balanced comparisons between NAC users and non-users. Cox regression and time-dependent Cox hazards models assessed MACE risk, adjusting for multiple covariates.

RESULTS: In the matched cohort of 23,359 NAC users and 23,359 non-users, NAC users had a significantly lower incidence of MACE (41.74 % vs. 46.87 %, P < .0001). Adjusted Hazard Ratios (aHRs) indicated a consistent protective effect of NAC against overall MACE (aHR: 0.84; 95 % CI: 0.81-0.86, P < .0001). Higher cumulative defined daily doses (cDDD) of NAC correlated with reduced MACE risk, with the highest quartile (Q4) showing an aHR of 0.61 (95 % CI: 0.58-0.64, P < .0001).

CONCLUSION: This study underscores the significant reduction in MACE risk among T2DM patients with long-term NAC therapy. Notably, the findings emphasize NAC's dose-dependent effectiveness in diminishing MACE incidence, indicating its potential as a valuable adjunctive therapy for managing cardiovascular risk in T2DM patients.

RevDate: 2025-02-05
CmpDate: 2025-02-05

Ge S, Sun A, Zhou X, et al (2025)

Functionalized Nanozyme Microcapsules Targeting Deafness Prevention via Mitochondrial Homeostasis Remodeling.

Advanced materials (Deerfield Beach, Fla.), 37(5):e2413371.

Mitochondrial dysfunction, which is the primary mechanism underlying cisplatin-induced hearing loss, can potentially be mitigated by modulating the redox balance and reprogramming the energy metabolism to remodel mitochondrial homeostasis. Herein, N-acetyl-l-cysteine-derived carbonized polymer dots (NAC CPDs) are embedded into manganese porphyrin-doped metal-organic frameworks and encapsulated using a polydopamine (PDA) coating and gelatin methacryloyl (GelMA) hydrogel to afford functionalized nanozyme microcapsules. Owing to their injectability and adhesion properties, these microcapsules exhibit the advantages of prolonged retention in the middle ear and sustained release in the inner ear. The synergy between the manganese porphyrin and polymer dots results in excellent antioxidant properties. The developed nanozymes activate the PI3K-AKT pathway, reprogramming the energy supply mechanism, and inhibiting the oligomerization of BAX in mitochondria to prevent the leakage of mitochondrial DNA and cytochrome c. Therapeutic efficacy and related mechanisms are validated in vivo. Thus, this study on mitochondrial homeostasis remodeling by nanozyme microcapsules opens a new chapter in the treatment of hearing loss.

RevDate: 2025-02-04

Chamberlain SR, Ioannidis K, JE Grant (2025)

Trait Impulsivity Predicts Treatment Response in Gambling Disorder.

Clinical neuropharmacology pii:00002826-990000000-00105 [Epub ahead of print].

OBJECTIVES: Impulsivity is thought to be a core feature of gambling disorder, yet little is known as to whether trait impulsivity predicts treatment response.

METHODS: Data were pooled from 2 previous randomized controlled pharmacological trials using naltrexone and N-acetyl cysteine.

RESULTS: Trait impulsivity statistically explained variation in medication treatment response (P = 0.0260, R2 = 0.26). Higher baseline motor impulsiveness was associated with greater treatment response (P = 0.009).

CONCLUSIONS: Measures of impulsivity may thus be important to include in future large-scale datasets, in trial settings but also routine clinical gambling clinic practice, toward building predictive algorithms that may ultimately help to inform optimal treatment choices and improve outcomes.

RevDate: 2025-02-04
CmpDate: 2025-02-04

Lu YT, Chen TY, Lin HH, et al (2025)

Small Extracellular Vesicles Engineered Using Click Chemistry to Express Chimeric Antigen Receptors Show Enhanced Efficacy in Acute Liver Failure.

Journal of extracellular vesicles, 14(2):e70044.

Acetaminophen (APAP) overdose can cause severe liver injury and life-threatening conditions that may lead to multiple organ failure without proper treatment. N-acetylcysteine (NAC) is the accepted and prescribed treatment for detoxification in cases of APAP overdose. Nonetheless, in acute liver failure (ALF), particularly when the ingestion is substantial, NAC may not fully restore liver function. NAC administration in ALF has limitations and potential adverse effects, including nausea, vomiting, diarrhoea, flatus, gastroesophageal reflux, and anaphylactoid reactions. Mesenchymal stromal cell (MSC)-based therapies using paracrine activity show promise for treating ALF, with preclinical studies demonstrating improvement. Recently, MSC-derived extracellular vesicles (EVs) have emerged as a new therapeutic option for liver injury. MSC-derived EVs can contain various therapeutic cargos depending on the cell of origin, participate in physiological processes, and respond to abnormalities. However, most therapeutic EVs lack a distinct orientation upon entering the body, resulting in a lack of targeting specificity. Therefore, enhancing the precision of natural EV delivery systems is urgently needed. Thus, we developed an advanced targeting technique to deliver modified EVs within the body. Our strategy aims to employ bioorthogonal click chemistry to attach a targeting molecule to the surface of small extracellular vesicles (sEVs), creating exogenous chimeric antigen receptor-modified sEVs (CAR-sEVs) for the treatment. First, we engineered azido-modified sEVs (N3-sEVs) through metabolic glycoengineering by treating MSCs with the azide-containing monosaccharide N-azidoacetyl-mannosamine (Ac4ManNAz). Next, we conjugated N3-sEVs with a dibenzocyclooctyne (DBCO)-tagged single-chain variable fragment (DBCO-scFv) that targets the asialoglycoprotein receptor (ASGR1), thus producing CAR-sEVs for precise liver targeting. The efficacy of CAR-sEV therapy in ALF models by targeting ASGR1 was validated. MSC-derived CAR-sEVs reduced serum liver enzymes, mitigated liver damage, and promoted hepatocyte proliferation in APAP-induced injury. Overall, CAR-sEVs exhibited enhanced hepatocyte specificity and efficacy in ameliorating liver injury, highlighting the significant advancements achievable with cell-free targeted therapy.

RevDate: 2025-02-03
CmpDate: 2025-02-04

El-Abassy OM, Fawzy MG, EB Kamel (2025)

Two chromatographic methods for analyzing paracetamol in spiked human plasma with its toxic metabolite, N-acetyl parabenzoquinone imine and its antidote, N-acetyl-L-cysteine.

Scientific reports, 15(1):4119.

Acetaminophen, also known as paracetamol (APAP), is a highly utilized pharmaceutical agent on a global scale, particularly in the field of pediatrics. Regrettably, an overdose of APAP, resulting from the predominant oxidation, has the potential to trigger acute liver injury. The study's goal was to find an easy, accurate, and selective way to measure APAP, N-acetyl para benzoquinone imine (NAPQI) (an APAP metabolite that is harmful), and N-acetyl-L-cysteine (NAC) (an antidote). Two different chromatographic methods were used. The HPTLC method, which used silica gel 60 F254 as a stationary phase and a developing liquid made up of methanol, ethyl acetate, and glacial acetic acid (8:2:0.2, v/v/v) and a UV detection at 254 nm. The HPLC method was developed using a mobile phase consisting of water, methanol, and formic acid in a proportion of (70:30:0.15, v/v/v). The stationary phase used in the approach was a C18 column. Analytes quantification was established utilizing a UV detector operating at a wavelength of 254 nm. The present methods make it possible to measure the amount of APAP in plasma samples. When it comes to pharmacokinetics or medication levels in children's plasma, for example, this may be also very helpful. The current methods can quantify NAPQI, which is helpful in figuring out drug concentrations in individuals with APAP intoxication diagnoses. Additionally, the current approaches can estimate NAC as an antidote; as a result, this study is a complete study because it can analyse drug, toxic metabolite, and antidote in one analytical run. Using the innovative blue applicability grade index software, which measures the practicality of procedures, both methodologies were compared with a reported methods. Additionally, the achievement of the eco-friendliness profile of the designed procedures was assessed. Both techniques passed the ICH validation tests.

RevDate: 2025-02-03
CmpDate: 2025-02-03

Supervía A, Gispert MªÀ, Puiguriguer J, et al (2025)

Paracetamol poisoning: a prospective comparison of 2 protocols for N-acetylcysteine treatment.

Emergencias : revista de la Sociedad Espanola de Medicina de Emergencias, 37(1):39-43.

OBJECTIVE: Paracetamol poisoning can be serious and require treatment with N-acetylcysteine (NAC). A dose of 300 mg/kg is usually given in 3 fractions over 21 hours. An alternative regimen, the Scottish and Newcastle Acetylcysteine Protocol (SNAP), specifies the same total dose given in 2 intravenous injections over 12 hours. This study aimed to compare the 2 regimens in terms of effectiveness, adverse events, and lengths of emergency department (ED) and hospital stays.

METHODS: Prospective multicenter study to compare outcomes associated with the traditional NAC regimen vs SNAP. We enrolled all patients with paracetamol poisoning requiring NAC treatment in the participating hospital EDs from 2021 through 2023. Data related to referrals, poisoning episodes, and discharge destinations were collected. Patients were studied in 2 groups according to the protocol assigned in the EDs.

RESULTS: A total of 165 patients were treated (SNAP, 103; traditional protocol, 62). The mean (SD) age was 28.1 (19.7) years, and most were female (70.5%). No differences in peak transaminase levels were observed. SNAP-treated patients had significantly fewer adverse effects as well as shorter stays both in the ED (17.8 [15.2] hours vs 25.9 [17.1] hours; P = .001) and on the ward (2.6 [2.3] days vs 4.4 [3.6] days; P = .019).

CONCLUSIONS: Fewer adverse events occurred with the SNAP approach. The 2 protocols were similarly effective. The SNAP-treated patients spent less time in the ED, and those who were admitted to hospital had shorter stays.

RevDate: 2025-02-02

Amini H, Shirpoor A, R Naderi (2025)

Nandrolone decanoate induces heart injury via oxidative damage and mitochondrial apoptotic pathway by regulation of TLR4/NF-κB/NLRP3 axis in male rats: The rescue effect of N-acetylcysteine.

Steroids pii:S0039-128X(25)00004-2 [Epub ahead of print].

Myocardial apoptosis is a leading cause of damage in cardiac tissues of nandrolone (ND) treatment. However, its molecular mechanism is not fully understood. This study aims to investigate the effect of ND with or without N -acetylcysteine (NAC) treatment on oxidative damage and TLR4/NF-κB /NLRP3 signaling pathway in the heart of male rats. Eighteen male Wistar rats with a weight range of 220 ± 10 g were selected. They were divided into three groups (n = 6): control (C) group, ND group, NAC + ND group. After six weeks of treatment, the TUNEL staining indicated that ND increased the number of apoptotic cells in the hearts of male rats. The molecular analysis demonstrated that ND exposure resulted in increased protein levels of cytochrome c, c-Caspase-3/p-Caspase-3 ratio, p53, TLR4, NF-κB, NLRP3, and 8-OHdG with a concomitant up-regulation of LDH and CK-MB enzymes activity in the heart tissue compared to the C group. Our findings suggested that ND can cause damage to heart tissue via induction of DNA damage, apoptosis, and probably TLR4/NF-κB/NLRP3 signaling pathway plays a crucial role in this process. It also demonstrates that these negative effects of ND can be reduced by using NAC treatment as an antioxidant and anti-inflammatory agent.

RevDate: 2025-02-02

Abu Hasna A, Khoury RD, Mendes GV, et al (2025)

N-acetylcysteine antimicrobial action against endodontic pathogens-systematic review and meta-analysis.

Odontology [Epub ahead of print].

Effective root canal disinfection is crucial for the success of endodontic treatment. N-acetylcysteine (NAC), known for its antimicrobial properties, has recently been investigated as a potential endodontic irrigant or intracanal medication. This systematic review aims to assess the antimicrobial efficacy of NAC in comparison to sodium hypochlorite, chlorhexidine, and calcium hydroxide against endodontic pathogens. A comprehensive search was conducted in PubMed, Scopus, Web of Science, Cochrane Library, and LILACS databases up to April 2024, without language or date restrictions. The PICO strategy for this review were as follows: population-teeth requiring endodontic treatment; intervention-NAC used as an endodontic irrigant or intracanal medication; comparison-sodium hypochlorite, chlorhexidine, and calcium hydroxide; Outcomes: reduction in microbial load, encompassing clinical and in vitro studies. Risks of bias assessment and data extraction were conducted with two reviewers independently selecting studies, extracting data, and assessing risk of bias. A general meta-analysis was performed across all included studies, with additional meta-analyses evaluating different exposure times, NAC concentrations, control groups and evaluation methods. After removing duplicates, 9170 studies were initially identified, and seven in vitro studies were included in the systematic review, of which five were included in the meta-analysis. Data were compared using standardized mean differences within a random-effects model. No clinical studies using NAC as an antimicrobial agent were identified. The overall meta-analysis demonstrated that NAC effectively reduced Enterococcus faecalis. Further meta-analyses revealed that exposure time, NAC concentration and choice of control group significantly influenced NAC's effectiveness. NAC effectively reduced Enterococcus faecalis, showing comparable antimicrobial activity to CHX and NaOCl, especially at concentrations of 25-50 mg/mL over a 7-day exposure. Despite significant heterogeneity across studies, NAC demonstrated satisfactory antimicrobial effects in vitro. This suggests that NAC merits reconsideration as an effective intracanal medication for clinical use.

RevDate: 2025-02-01

Gong L, Chang L, Chen S, et al (2025)

Multifunctional injectable hydrogel with self-supplied H2S release and bacterial inhibition for the wound healing with enhanced macrophages polarization via interfering with PI3K/Akt pathway.

Biomaterials, 318:123144 pii:S0142-9612(25)00063-8 [Epub ahead of print].

Hydrogen sulfide (H2S) gas therapy is beneficial for accelerating wound healing and alleviating the inflammatory process, but is seriously hindered by insufficient delivery and unsustainable release in vivo. This study presents a multifunctional injectable hydrogel, OC@ε-PL-SATO, composed of oxidized hyaluronic acid and N-acetylcysteine (NAC) as an initiator, carboxymethyl chitosan and S-aroylthiooxime modified ε-Poly-(l-lysine) (ε-PL-SATO). ε-PL-SATO is a NAC-responsive H2S donor. OC@ε-PL-SATO hydrogel is designed for the desired wound healing process, with rapid gelation (<30 s) and a sustained H2S release. After mixing and gelling, H2S could be long-term released from the hydrogel and effectively drives macrophages toward M2 polarization, thereby ameliorating the inflammatory response. Revealed by transcriptome analysis, the underlying mechanism is that OC@ε-PL-SATO hydrogel releasing H2S inhibits LPS-mediated inflammatory responses in RAW264.7 cells by interfering with phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling and NF-κB activation. Furthermore, the OC@ε-PL-SATO hydrogel effectively eliminates the bacterial burden and alleviates the accompanying inflammation in a rat model of cutaneous wound infection. Importantly, the sustained generation of H2S gas significantly promotes angiogenesis and collagen deposition, ultimately accelerating the wound repair. In conclusion, this study provides a multifunctional injectable hydrogel with rapid gelatinization and continuous H2S release for accelerating the infected wound healing.

RevDate: 2025-01-31

Sharma P, Kumar R, Bari A, et al (2025)

N-Acetyl Cysteine and Vitamin C Modulate the Antibiotic Efficacy Against Escherichia coli Cells.

Microbial drug resistance (Larchmont, N.Y.) [Epub ahead of print].

Supplements with their own beneficial effect on hosts are consumed by us. N-acetyl cysteine (NAC) and Vitamin C (Vit C) are antioxidants and supplements, consumed for their beneficial properties. The present investigation evaluates the effect of their antioxidant property on antibiotic efficacy against Escherichia coli cells from different physiological states, including exponential and stationary-phase, cell aggregates, and in-vitro stress-induced persister cells. Survival was measured in cfu/mL by cfu (colony-forming unit) counting, with efficacy determined by log-fold change in survival by comparing CFUs in antibiotics alone and antibiotic + antioxidant combinations. Fluoroquinolones in the presence of NAC reduced ∼1 log CFUs of log-phase and persister cells, while Vit C reduced CFUs (∼1-3-log increase) of cells from all physiological states. Aminoglycosides results were inconclusive; streptomycin's activity declined (∼1-3-log increase in survival), whereas amikacin's activity potentiated (∼1-log reduction in cfu/mL). Rifampicin's showed reduced activity (∼2-3 log increase in survival) with Vit C in all the states and a ∼1-2 log increase with NAC, especially in cell aggregates and persisters. Beta-lactams activity showed variability, with amoxicillin and ampicillin not being influenced, but ceftriaxone showed significant reduction of efficacy (∼2-3-log increase in survival) in all the treatments. The findings suggest that the overall impact of antioxidants on antibiotic efficacy varies depending on the antibiotic class.

RevDate: 2025-01-31

Brites GS, Ferreira I, Sebastião AI, et al (2025)

Blocking the adverse outcome pathway of skin sensitization through a N-acetyl cysteine and lysine-loaded hydrogel.

Journal of pharmaceutical analysis, 15(1):101071.

Image 1.

RevDate: 2025-01-30

Chen K, Li J, Chen Z, et al (2025)

Notoginsenoside R1 alleviates blue light-induced corneal injury and wound healing delay by binding to and inhibiting TRIB1.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 138:156399 pii:S0944-7113(25)00038-8 [Epub ahead of print].

BACKGROUND: With the escalating use of digital devices, blue light (BL) exposure has emerged as a critical concern due to its potential to cause ocular damage. This study explores the protective effects of notoginsenoside R1 (NR1), a bioactive compound from Panax notoginseng (Burkill) F.H. Chen (Sanqi), against BL-induced corneal epithelial injury.

PURPOSE: This research aims to investigate the protective effects of NR1 on BL-induced corneal injury and wound healing delay.

METHODS: Human corneal epithelial cells (hCECs) were pretreated with NR1 (0-50 μM) or N-acetylcysteine (NAC, 10 mM), then exposed to BL (570 μW/cm²) for 24 h. Cell viability, proliferation, migration, and ROS levels were assessed using various techniques. In mice, NR1 (25 μM and 50 μM) and NAC (0.3 %) eye drops were administered during BL exposure. Corneal injury, healing rates, cell proliferation, migration, ROS, and inflammation were evaluated. RNA-sequencing, bioinformatics, and molecular binding validation identified tribbles homolog 1 (TRIB1) as a key molecule mitigating BL damage with NR1. Functional studies via gene silencing, overexpression, and pharmacological modulation further explored TRIB1's role in BL exposure.

RESULTS: NR1 significantly reduced BL-induced inflammation, ROS production, and inhibited migration and proliferation in hCECs and murine corneas. It also alleviated BL-induced corneal injury and delayed healing in mice. NR1 inhibited TRIB1 upregulation, a marker of BL-induced injury and healing delay. Overexpression of TRIB1 negated NR1's therapeutic effects on hCECs, while TRIB1 silencing mitigated functional impairment. In mice, increased Trib1 expression caused corneal injury and delayed healing, reversed by NR1 treatment.

CONCLUSION: NR1 shows potential as a therapeutic agent by inhibiting TRIB1 elevation in response to BL exposure, providing a novel promising target for corneal injury and wound healing delay induced by BL, and offering a comprehensive strategy for clinical pharmacological intervention.

RevDate: 2025-01-30

Biering V, Bellouard R, Martin M, et al (2024)

N-acetylcysteine use in a cocaine-induced liver failure: a case report.

Frontiers in toxicology, 6:1502716.

BACKGROUND: Cocaine intoxication and abuse is a worldwide problem that can be the cause of numerous acute medical complications, including severe acute hepatitis. Although these cases are scarce, they are extremely serious and may lead to liver transplantation or death. Management of toxic hepatitis, once the causative agent has been discontinued, is essentially symptomatic, based on clinical and biological monitoring and prevention of complications related to acute hepatitis.

CASE DETAILS: We present a case of a 28-year-old woman admitted to the emergency department for acute hepatitis due to cocaine intoxication. In addition to a sharp rise in her liver enzymes, the patient also presented metabolic acidosis, renal failure, and rhabdomyolysis. Treatment consisted of administering N-acetylcysteine (NAC), dialysis, and additional supportive measures. An improvement in the liver function with a decrease in transaminases occurred after the NAC administration. The toxicokinetics of major cocaine metabolites and clinical chemistry concentrations were monitored.

CONCLUSION: In addition to the usual management measures for acute hepatitis, the administration of N-acetylcysteine should be investigated further, although it is currently used only in cases of acetaminophen acute toxic hepatitis.

RevDate: 2025-01-30
CmpDate: 2025-01-29

Ruths L, Hengge J, Teixeira GQ, et al (2024)

Terminal complement complex deposition on chondrocytes promotes premature senescence in age- and trauma-related osteoarthritis.

Frontiers in immunology, 15:1470907.

BACKGROUND: The complement system is locally activated after joint injuries and leads to the deposition of the terminal complement complex (TCC). Sublytic TCC deposition is associated with phenotypical alterations of human articular chondrocytes (hAC) and enhanced release of inflammatory cytokines. Chronic inflammation is a known driver of chondrosenescence in osteoarthritis (OA). Therefore, we investigated whether TCC deposition contributes to stress-induced premature senescence (SIPS) during aging in vivo and after ex vivo cartilage injury.

METHODS: Femoral condyles of male 13-week-old and 72-week-old CD59-ko (higher TCC deposition), C6-deficient (insufficient TCC formation), and C57BL/6 (WT) mice were collected to assess age-related OA. Furthermore, macroscopically intact human and porcine cartilage explants were traumatized and cultured with/without 30% human serum (HS) to activate the complement system. Explants were additionally treated with clusterin (CLU, TCC inhibitor), N-acetylcysteine (NAC, antioxidant), Sarilumab (IL-6 receptor inhibitor), STAT3-IN-1 (STAT3 inhibitor), or IL-1 receptor antagonist (IL-1RA) in order to investigate the consequences of TCC deposition. Gene and protein expression of senescence-associated markers such as CDKN1A and CDKN2A was determined.

RESULTS: In the murine aging model, CD59-ko mice developed after 72 weeks more severe OA compared to C6-deficient and WT mice. mRNA analysis revealed that the expression of Cdkn1a, Cdkn2a, Tp53, Il1b, and Il6 was significantly increased in the cartilage of CD59-ko mice. In human cartilage, trauma and subsequent stimulation with HS increased mRNA levels of CDKN1A, CDKN2A, and IL6, while inhibition of TCC formation by CLU reduced the expression. Antioxidative therapy with NAC had no anti-senescent effect. In porcine tissue, HS exposure and trauma had additive effects on the number of CDKN2A-positive cells, while Sarilumab, STAT-IN-1, and IL-1RA reduced CDKN2A expression by trend.

CONCLUSION: Our results demonstrate that complement activation and consequent TCC deposition is associated with chondrosenescence in age-related and trauma-induced OA. We provided evidence that the SIPS-like phenotype is more likely induced by TCC-mediated cytokine release rather than oxidative stress. Overall, targeting TCC formation could be a future approach to attenuate OA progression.

RevDate: 2025-01-29
CmpDate: 2025-01-29

Song M, Han M, Zhang H, et al (2025)

The Effective Compound Combination of Bufei Yishen Formula III Improves the Mitochondrial Dysfunction via Inhibiting JNK/Sab Pathway in COPD Mice.

Drug design, development and therapy, 19:525-538.

PURPOSE: The effective compound combination of Bufei Yishen formula III (ECC-BYF III) has shown protective effects against chronic obstructive pulmonary disease (COPD). However, its effect on mitochondrial dysfunction remains unclear. The current study aimed to investigate the effect of ECC-BYF III on mitochondrial dysfunction in COPD mice and elucidate its potential mechanisms.

METHODS: Twenty-eight BALB/c mice were randomized into four groups: control, model, ECC-BYF III, and NAC (N-acetylcysteine) groups. A COPD model was established using cigarette smoke and Klebsiella pneumoniae for 8 weeks. The mice in the ECC-BYF III group were treated with ECC-BYF III (7.7 mg/kg/d), and the NAC group was treated with NAC (78 mg/kg/d) for eight weeks. Mice in the control and model groups were administered with 0.5% sodium carboxymethyl cellulose (25 mL/kg/d) for eight weeks. Then pulmonary function, histopathology, inflammatory factor levels, mitochondrial ultrastructure and function, and immunoblotting analyses were evaluated.

RESULTS: Compared with the model, ECC-BYF III significantly improved the decline in pulmonary function and histopathological changes. Furthermore, ECC-BYF III ameliorated mitochondrial dysfunction by restoring the mitochondrial membrane potential, increasing mitochondrial complex I activity, and decreasing tumor necrosis factor-α (TNF-α) level and protein expressions of SH3BP5 (Sab), Phospho-JNK (P-JNK), and cleaved CASP3.

CONCLUSION: The results suggest that the potential therapeutic benefit of ECC-BYF III against mitochondrial dysfunction in COPD is due to the inhibition of the JNK/Sab pathway, which will help to further understand the potential mechanisms of ECC-BYF III in the treatment of COPD.

RevDate: 2025-01-29

Komatsu K, Chao D, Matsuura T, et al (2025)

Advancing osseointegration research: A dynamic three-dimensional (3D) in vitro culture model for dental implants.

Journal of dental sciences, 20(1):350-360.

BACKGROUND/PURPOSE: In-vitro studies are essential for understanding cellular responses, but traditional culture systems often neglect the three-dimensional (3D) structure of real implants, leading to limitations in cellular recruitment and behavior largely governed by gravity. The objective of this study was to pioneer a novel 3D dynamic osteoblastic culture system for assessing the biological capabilities of dental implants in a more clinically and physiologically relevant manner.

MATERIALS AND METHODS: Rat bone marrow-derived osteoblasts were cultured in a 24-well dish with a vertically positioned dental implant. Controlled rotation using a 3D rotator with 3° tilts was applied. Cell attachment, proliferation, and differentiation on implant surfaces were evaluated in response to different surface topographies, physicochemical properties, and local environments.

RESULTS: Among the tested rotational speeds (0, 10, 30, 50 rpm), optimal osteoblast attachment and proliferation were observed at 30 rpm. A linear correlation was found between cell attachment and rotation speed up to 30 rpm, declining at 50 rpm. Alkaline phosphatase (ALP) activity and mineralized matrix formation were elevated on newly acid-etched, hydrophilic surfaces compared to their 4-week-old hydrophobic surfaces. Sandblasted implants showed higher ALP activity and matrix mineralization. Adding N-acetyl cysteine to the culture medium increased ALP activity and mineralization.

CONCLUSION: Osteoblasts successfully attached, proliferated, and mineralized on dental implants in vitro under optimized dynamic conditions. This system differentiated the biological capabilities of implants with varying surface topographies, wettability, and biochemically modulated environments. These findings support developing a 3D dynamic dental implant culture model, advancing osseointegration research and innovating dental implant designs.

RevDate: 2025-01-28

Li F, Deng L, Xu T, et al (2024)

Getah virus triggers ROS-mediated autophagy in mouse Leydig cells.

Frontiers in microbiology, 15:1519694.

INTRODUCTION: Getah virus (GETV) is a zoonotic virus transmitted via a mosquito-vertebrate cycle. While previous studies have explored the epidemiology and pathogenicity of GETV in various species, its molecular mechanisms remain largely unexplored.

METHODS: This study investigated the impact of GETV infection and associated molecular mechanisms on reactive oxygen species (ROS) and autophagy levels in mouse Leydig cells both in vivo and in vitro. The male mice and TM3 cells were treatment with N-acetylcysteine (NAC) to reduce cellular ROS levels. Rapamycin (Rapa) and 3-Methyladenine (3- MA) were used to change autophagy in both infected and uninfected TM3 cells.

RESULTS AND DISCUSSION: The findings revealed that GETV infection in mouse testes speciffcally targeted Leydig cells and induced oxidative stress while enhancing autophagy in testicular tissue. Using TM3 cells as an in vitro model, the study confirmed GETV replication in this cell line, triggering increased ROS and autophagy levels. Treatment with N-acetylcysteine (NAC) to reduce cellular ROS levels markedly reduced autophagy in testicular tissue and TM3 cells infected with GETV. Interestingly, the use of rapamycin (Rapa) and 3-Methyladenine (3- MA) led to autophagy change in both infected and uninfected TM3 cells, with no signiffcant alterations in cellular ROS levels. These results indicate that GETV infection elevates ROS levels, subsequently inducing autophagy in mouse Leydig cells. We also found that autophagy plays an important role in GETV replication. When autophagy levels were reduced using NAC and 3-MA, a corresponding decrease in TCID50 was observed. Conversely, upregulation of autophagy using Rapa resulted in an increase in TCID50 of GETV. Therefore, we speculate that GETV may exploit the autophagy pathway to facilitate its replication. These ffndings illuminate the interplay between GETV and host cells, providing valuable insights for therapeutic strategies targeting autophagy in GETV infections.

RevDate: 2025-01-26

Pfau K, Callizo J, Rossouw P, et al (2025)

[Not Available].

Klinische Monatsblatter fur Augenheilkunde [Epub ahead of print].

RevDate: 2025-01-28

McLaughlin RM, Top I, Laguna A, et al (2023)

Cortical Spheroid Model for Studying the Effects of Ischemic Brain Injury.

In vitro models, 2(1-2):25-41.

PURPOSE: Ischemic brain injury occurs when there is reduced or complete disruption of blood flow to a brain region, such as in stroke or severe traumatic brain injury. Even short interruptions can lead to devastating effects including excitotoxicity and widespread cell death. Despite many decades of research, there are still very few therapeutic options for patients suffering from brain ischemia.

METHODS: We developed an in vitro brain ischemia model using our previously established 3D spheroids derived from primary postnatal rat cortex. These spheroids provide an in vivo-relevant model containing a similar cellular composition to the native cortex and a cell-synthesized extracellular matrix. This model is cost-effective, highly reproducible, and can be produced in a high-throughput manner, making it an ideal candidate for screening potential therapeutics. To study the cellular and molecular mechanisms of stroke in this model, spheroids were deprived of glucose, oxygen, or both oxygen and glucose for 24 h.

RESULTS: Both oxygen and oxygen-glucose deprived spheroids demonstrated many of the hallmarks of ischemic brain injury, including a decrease in metabolism, an increase in neural dysfunction, breakdown in the neurovascular unit, and an increase in reactive astrocytes. Pretreatment of spheroids with the antioxidant agent N-acetylcysteine (NAC) mitigated the decrease in ATP after oxygen-glucose deprivation, was partially neuroprotective, and enhanced the expression of laminin.

CONCLUSION: This 3D cortical spheroid model provides a platform for studying ischemic injury and has the potential for screening therapeutics.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s44164-023-00046-z.

RevDate: 2025-01-25
CmpDate: 2025-01-25

Nabipur L, Mouawad M, V Venketaraman (2025)

Additive Effects of Glutathione in Improving Antibiotic Efficacy in HIV-M.tb Co-Infection in the Central Nervous System: A Systematic Review.

Viruses, 17(1): pii:v17010127.

BACKGROUND: HIV and tuberculosis (TB) co-infection poses a significant health challenge, particularly when involving the central nervous system (CNS), where it leads to severe morbidity and mortality. Current treatments face challenges such as drug resistance, immune reconstitution inflammatory syndrome (IRIS), and persistent inflammation. Glutathione (GSH) has the therapeutic potential to enhance treatment outcomes by improving antibiotic efficacy, reducing inflammation, and mitigating immune dysfunction.

METHODS: Relevant studies were identified through systematic searches of PubMed, Elsevier, WHO, and related databases. Inclusion criteria focused on preclinical and clinical research examining GSH or its precursors in HIV, TB, or co-infection, with emphasis on microbial control, immune modulation, and CNS-related outcomes.

RESULTS: Preclinical studies showed that GSH improves macrophage antimicrobial function, reduces oxidative stress, and limits Mycobacterium tuberculosis (M.tb) growth. Animal models demonstrated reduced bacterial burden in the lungs, liver, and spleen with GSH supplementation, along with enhanced granuloma stability. Clinical studies highlighted increased TH1 cytokine production, reduced inflammatory markers, and improved CD4+ T cell counts in HIV-M.tb co-infected patients. N-acetylcysteine (NAC), a GSH precursor, was shown to significantly enhance the efficacy of first-line TB antibiotics and mitigate treatment-associated toxicity.

DISCUSSION: GSH shows promise as an adjunct therapy for HIV-M.tb co-infection, particularly for cases involving the CNS, where it may improve immune recovery and reduce inflammation. However, evidence is limited by small sample sizes and a lack of randomized trials. Future research should focus on developing CNS-directed GSH formulations and evaluating its integration into current treatment protocols to address the dual burden of HIV and TB, ultimately improving patient outcomes.

RevDate: 2025-01-25
CmpDate: 2025-01-25

Viña I, Viña JR, Carranza M, et al (2025)

Efficacy of N-Acetylcysteine in Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis.

Nutrients, 17(2): pii:nu17020284.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age and requires better treatment. N-acetylcysteine (NAC) is known to be beneficial under such conditions owing to its antioxidant potential and insulin-sensitizing properties. The effect of NAC on the reproductive outcomes of PCOS patients was examined in this meta-analysis.

METHODS: In accordance with PRISMA standards, this meta-analysis included studies that compared N-acetylcysteine, metformin, clomiphene citrate, and a placebo in patients with POCS. The main indicators were follicular growth, endometrial thickness, and hormone level. The risk of bias was evaluated using the Cochrane ROB2 tool.

RESULTS: Twenty-two studies (n = 2515) were included. NAC was associated with a statistically significant increase in progesterone (SMD 0.95, 95% CI: 0.13-1.77, p = 0.02) and endometrial thickness (SMD 0.58, 95% CI: 0.10-1.06, p = 0.02) compared to the placebo and other drugs (SMD 0.71, 95% CI: 0.48-0.94, p < 0.0001). LH levels were significantly increased by NAC compared to metformin (SMD 0.67, 95% CI: 0.23-1.12, p = 0.003). However, no significant differences were observed in the estradiol, SHBG, or FSH levels.

CONCLUSIONS: NAC had a major effect on progesterone, endometrial thickness, and LH levels in women with PCOS. Therefore, it may be a potential treatment option.

RevDate: 2025-01-25

Sanduzzi Zamparelli S, Sanduzzi Zamparelli A, M Bocchino (2025)

Immune-Boosting and Antiviral Effects of Antioxidants in COVID-19 Pneumonia: A Therapeutic Perspective.

Life (Basel, Switzerland), 15(1): pii:life15010113.

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has profoundly impacted global health, with pneumonia emerging as a major complication in severe cases. The pathogenesis of COVID-19 is marked by the overproduction of reactive oxygen species (ROS) and an excessive inflammatory response, resulting in oxidative stress and significant tissue damage, particularly in the respiratory system. Antioxidants have garnered considerable attention for their potential role in managing COVID-19 pneumonia by mitigating oxidative stress and modulating immune responses. This review provides a comprehensive overview of the literature on the use of antioxidants in hospitalized patients with mild-to-moderate COVID-19. Studies exploring antioxidants, including vitamins, trace elements, nitric oxide (NO), ozone (O3), glutathione (GSH), L-carnitine, melatonin, bromelain, N-acetylcysteine (NAC), and numerous polyphenols, have yielded promising outcomes. Through their ROS-scavenging properties, these molecules support endothelial function, reduce the thrombosis risk, and may help mitigate the effects of the cytokine storm, a key contributor to COVID-19 morbidity and mortality. Clinical evidence suggests that antioxidant supplementation may improve patient outcomes by decreasing inflammation, supporting immune cell function, and potentially shortening recovery times. Furthermore, these molecules may mitigate the symptoms of COVID-19 by exerting direct antiviral effects that inhibit the infection process and genomic replication of SARS-CoV-2 in host cells. Moreover, antioxidants may work synergistically with standard antiviral treatments to reduce viral-induced oxidative damage. By integrating findings from the literature with real-world data from our clinical experience, we gain a more profound understanding of the role of antioxidants in managing COVID-19 pneumonia. Further research combining comprehensive literature reviews with real-world data analysis is crucial to validate the efficacy of antioxidants and establish evidence-based guidelines for their use in clinical practice.

RevDate: 2025-01-25

Vorwerk J, Liu L, Stadler TH, et al (2025)

Germline Single-Nucleotide Polymorphism GFI1-36N Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia.

Biomedicines, 13(1): pii:biomedicines13010107.

Background/Objectives: GFI1-36N represents a single-nucleotide polymorphism (SNP) of the zinc finger protein Growth Factor Independence 1 (GFI1), in which the amino acid serine (S) is replaced by asparagine (N). The presence of the GFI1-36N gene variant is associated with a reduced DNA repair capacity favoring myeloid leukemogenesis and leads to an inferior prognosis of acute myeloid leukemia (AML) patients. However, the underlying reasons for the reduced DNA repair capacity in GFI1-36N leukemic cells are largely unknown. Since we have demonstrated that GFI1 plays an active role in metabolism, in this study, we investigated whether increased levels of reactive oxygen species (ROS) could contribute to the accumulation of genetic damage in GFI1-36N leukemic cells. Methods: We pursued this question in a murine model of human AML by knocking in human GFI1-36S or GFI1-36N variant constructs into the murine Gfi1 gene locus and retrovirally expressing MLL-AF9 to induce AML. Results: Following the isolation of leukemic bone marrow cells, we were able to show that the GFI1-36N SNP in our model is associated with enhanced oxidative phosphorylation (OXPHOS), increased ROS levels, and results in elevated γ-H2AX levels as a marker of DNA double-strand breaks (DSBs). The use of free radical scavengers such as N-acetylcysteine (NAC) and α-tocopherol (αT) reduced ROS-induced DNA damage, particularly in GFI1-36N leukemic cells. Conclusions: We demonstrated that the GFI1-36N variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage.

RevDate: 2025-01-25

Cusato J, Mulasso A, Ferrara M, et al (2025)

How Antiretroviral Drug Concentrations Could Be Affected by Oxidative Stress, Physical Capacities and Genetics: A Focus on Dolutegravir Treated Male PLWH.

Antioxidants (Basel, Switzerland), 14(1): pii:antiox14010082.

High levels of reactive oxygen species (ROS) are present in people living with HIV (PLWH), produced by intense physical activity; in response, our body produces antioxidant molecules. ROS influence the expression of gene-encoding enzymes and transporters involved in drug biotransformation. In addition, pharmacogenetics can influence transporter activity, and thus drug exposure. Currently, no studies concerning this topic are present in the literature. The aim of this study was to investigate whether some antioxidant molecules, physical exercise, and genetic variants could affect dolutegravir (DTG) concentrations in PLWH, switching from triple to dual therapy. Thirty PLWH were recruited and analyzed at baseline (triple therapy), and 6 months after (dual therapy). Physical capacities were investigated using validated tools. Drug concentrations and oxidative stress biomarkers levels were evaluated through liquid chromatography coupled with tandem mass spectrometry, while genetic variants through real-time PCR. No statistical differences were suggested for drug concentrations, with the exception of intracellular DTG (p = 0.047). Statistically significant correlations between DTG plasma concentrations and white blood cells (p = 0.011; S = 0.480) and cytoplasmic N-acetyl-cysteine (p = 0.033; S = -0.419) were observed. Finally, white blood cells and BMI remained in the final multivariate regression model as predictors of DTG concentrations. This is the first study showing possible factors related to oxidative stress impacting DTG exposure.

RevDate: 2025-01-24

Cimmino A, Gioia M, Clementi ME, et al (2024)

Polydatin-Induced Shift of Redox Balance and Its Anti-Cancer Impact on Human Osteosarcoma Cells.

Current issues in molecular biology, 47(1): pii:cimb47010021.

Cancer cells demonstrate remarkable resilience by adapting to oxidative stress and undergoing metabolic reprogramming, making oxidative stress a critical target for cancer therapy. This study explores, for the first time, the redox-dependent anticancer effects of Polydatin (PD), a glucoside derivative of resveratrol, on the human Osteosarcoma (OS) cells SAOS-2 and U2OS. Using cell-based biochemical assays, we found that cytotoxic doses of PD (100-200 µM) promote ROS production, deplete glutathione (GSH), and elevate levels of both total iron and intracellular malondialdehyde (MDA), which are key markers of ferroptosis. Notably, the ROS scavenger N-acetylcysteine (NAC) and the ferroptosis inhibitor ferrostatin-1 (Fer-1) partially reverse PD's cytotoxic effects. Interestingly, PD's ability to hinder cell adhesion and migration appears independent of its pro-oxidant effect. Analysis of the oxidative stress regulators SIRT1 and Nrf2 at the gene and protein levels using real-time PCR and Western blot indicates an early oxidative response to PD treatment. PD remains effective under tumor-like conditions of hypoxia and serum starvation, and sensitizes OS cells to ROS-inducing chemotherapeutics like doxorubicin (DOX) and cisplatin (CIS). Importantly, PD exhibits minimal toxicity to non-tumorigenic cells (hFOB), suggesting a favorable therapeutic profile. Overall, our findings underscore that PD-induced redox imbalance plays a crucial role in its anti-OS effects, warranting further exploration into the molecular mechanisms behind its pro-oxidant activity.

RevDate: 2025-01-25
CmpDate: 2025-01-25

Farhadi M, Sohbatzadeh F, Moghaddam AH, et al (2025)

Enhancing the efficacy of low doses of N-acetyl-L-cysteine in mitigating CCl4-induced hepatotoxicity in animal model using physical cold plasma.

Ecotoxicology and environmental safety, 289:117642.

Liver diseases have become widespread especially due to various factors of modern life. Although the effect of N-acetyl-L-cysteine (NAC) is investigated in the recovery of liver damage, gas plasma therapy can be identified as a promising candidate. Our study aimed to enhance the effectiveness of ineffective doses of NAC in stopping CCl4-induced hepatotoxicity in rats by physical cold plasma. The plasma-treated NAC (PTN) structural changes were investigated through FTIR and LCMS/MS analysis. It was observed that the PTN consists of various chemical bioproducts with different molecular weights. We investigated an ineffective dose of NAC and its parallel effect through the administration of PTN on liver and kidney morphology and several biochemical factors including ALT, AST, and ALP. Additionally, we examined oxidative stress, antioxidant parameters, and glutathione (GSH) levels. Results showed that PTN exhibited greater antioxidant properties and increased GSH levels, contributing to its therapeutic effects. Also, the antioxidant enzymes and oxidative stress activities improved after receiving PTN. It also enhanced histological parameters, although various damages were detected in both liver and kidney tissues after CCl4 injection, PTN remarkably prevented the tissue changes caused by CCl4. PTN could protect against liver damage even at a very low dose of NAC, acting as a prophylactic drug with a high margin of safety for hepatotoxicity.

RevDate: 2025-01-23

Moka MK, George M, Rathakrishnan D, et al (2025)

Trends in drug repurposing: Advancing cardiovascular disease management in geriatric populations.

Current research in translational medicine, 73(2):103496 pii:S2452-3186(25)00005-4 [Epub ahead of print].

Drug repurposing is a promising strategy for managing cardiovascular disease (CVD) in geriatric populations, offering efficient and cost-effective solutions. CVDs are prevalent across all age groups, with a significant increase in prevalence among geriatric populations. The middle-age period (40-65 years) is critical due to factors like obesity, sedentary lifestyle, and psychosocial stress. In individuals aged 65 and older, the incidence of CVDs is highest due to age-related physiological changes and prolonged exposure to risk factors. In this review we find that certain drugs, such as non-cardiovascular drugs like anakinra, probenecid, N-acetyl cysteine, quercetin, resveratrol, rapamycin, colchicine, bisphosphonates, hydroxychloroquine, SGLT-2i drugs, GLP-1Ras drugs and sildenafil are recommended for drug repurposing to achieve cardiovascular benefits in geriatric patients. However, agents such as canakinumab, methotrexate, ivermectin, erythromycin, capecitabine, carglumic acid, chloroquine, and furosemide are constrained in their therapeutic use and warrant meticulous consideration, rendering them less favorable for this specific application. This review emphasizes the importance of exploring alternative therapeutic strategies to improve outcomes in geriatric populations and suggests drug repurposing as a promising avenue to enhance treatment efficacy.

RevDate: 2025-01-22

Candela ME, Addison M, Aird R, et al (2025)

Cryopreserved human alternatively activated macrophages promote resolution of acetaminophen-induced liver injury in mouse.

NPJ Regenerative medicine, 10(1):5.

Acute liver failure is a rapidly progressing, life-threatening condition most commonly caused by an overdose of acetaminophen (paracetamol). The antidote, N-acetylcysteine (NAC), has limited efficacy when liver injury is established. If acute liver damage is severe, liver failure can rapidly develop with associated high mortality rates. We have previously demonstrated that alternatively, activated macrophages are a potential therapeutic option to reverse acute liver injury in pre-clinical models. In this paper, we present data using cryopreserved human alternatively activated macrophages (hAAMs)-which represent a potential, rapidly available treatment suitable for use in the acute setting. In a mouse model of APAP-induced injury, peripherally injected cryopreserved hAAMs reduced liver necrosis, modulated inflammatory responses, and enhanced liver regeneration. hAAMs were effective even when administered after the therapeutic window for NAC. This cell therapy approach represents a potential treatment for APAP overdose when NAC is ineffective because liver injury is established.

RevDate: 2025-01-23
CmpDate: 2025-01-22

Kagemichi N, Umemura M, Ishikawa S, et al (2024)

Cytotoxic effects of the cigarette smoke extract of heated tobacco products on human oral squamous cell carcinoma: the role of reactive oxygen species and CaMKK2.

The journal of physiological sciences : JPS, 74(1):35.

BACKGROUND: The increasing prevalence of heated tobacco products (HTPs) has heightened concerns regarding their potential health risks. Previous studies have demonstrated the toxicity of cigarette smoke extract (CSE) from traditional tobacco's mainstream smoke, even after the removal of nicotine and tar. Our study aimed to investigate the cytotoxicity of CSE derived from HTPs and traditional tobacco, with a particular focus on the role of reactive oxygen species (ROS) and intracellular Ca[2+].

METHODS: A human oral squamous cell carcinoma (OSCC) cell line, HSC-3 was utilized. To prepare CSE, aerosols from HTPs (IQOS) and traditional tobacco products (1R6F reference cigarette) were collected into cell culture media. A cell viability assay, apoptosis assay, western blotting, and Fluo-4 assay were conducted. Changes in ROS levels were measured using electron spin resonance spectroscopy and the high-sensitivity 2',7'-dichlorofluorescein diacetate assay. We performed a knockdown of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) by shRNA lentivirus in OSCC cells.

RESULTS: CSE from both HTPs and traditional tobacco exhibited cytotoxic effects in OSCC cells. Exposure to CSE from both sources led to an increase in intracellular Ca[2+] concentration and induced p38 phosphorylation. Additionally, these extracts prompted cell apoptosis and heightened ROS levels. N-acetylcysteine (NAC) mitigated the cytotoxic effects and p38 phosphorylation. Furthermore, the knockdown of CaMKK2 in HSC-3 cells reduced cytotoxicity, ROS production, and p38 phosphorylation in response to CSE.

CONCLUSION: Our findings suggest that the CSE from both HTPs and traditional tobacco induce cytotoxicity. This toxicity is mediated by ROS, which are regulated through Ca[2+] signaling and CaMKK2 pathways. GRAPHICAL ABSTRACT.

RevDate: 2025-01-22

Gu D, Zhou L, Zhang Y, et al (2025)

N-acetylcysteine and chitosan conjugate modified dexamethasone nanostructured lipid carriers: Enhanced permeability, precorneal retention and lower inflammation for the treatment of dry eye syndrome.

International journal of biological macromolecules pii:S0141-8130(25)00672-5 [Epub ahead of print].

Dexamethasone (Dex) is a primary medication for treating dry eye syndrome, and tobramycin-dexamethasone eye drops are commercially available. However, the eye's complex physiological environment reduces its bioavailability, and repeated use can lead to significant systemic toxicity and side effects. This study introduces a novel conjugate of chitosan (CS) and N-acetylcysteine (NAC), a bioadhesive material, which was grafted onto the surface of a Dex-supported nanostructured lipid carrier (NLC) to develop an innovative nanoparticle lipid ocular drug delivery system (CS-NAC@Dex-NLC). The enhancements afforded by CS-NAC, such as adhesion, osmotic, and targeting properties, address the limitations of traditional eye drops. NMR characterization confirmed the successful synthesis of the copolymer (CS-NAC). Particle size (PS), zeta potential, and transmission electron microscopy (TEM) verified the proper formation of the CS-NAC@Dex-NLC system. Cytotoxicity tests confirmed its excellent biocompatibility and safety. Cellular uptake studies showed that CS-NAC@Dex-NLC achieved the highest efficiency. Pharmacokinetic assessments revealed a significant increase in Dex's bioavailability in tears and aqueous humor. In vitro corneal penetration and in vivo imaging experiments demonstrated effective corneal penetration and retention, enhancing the drug's duration on the ocular surface and overcoming the barrier effect. Pharmacodynamic studies in rabbits with dry eye syndrome indicated that CS-NAC@Dex-NLC effectively alleviates symptoms, repairs corneal damage, and stabilizes the tear film. ELISA results showed a reduction in inflammation caused by dry eye. These findings suggest that CS-NAC@Dex-NLC is a promising vector for dry eye treatment, offering significant clinical relevance.

RevDate: 2025-01-20

Mishra S, Botlagunta M, S Rajasekaran (2024)

Arsenic-Induced Inflammatory Response via ROS-Dependent Activation of ERK/NF-kB Signaling Pathways: Protective Role of Natural Polyphenol Tannic Acid.

Journal of applied toxicology : JAT [Epub ahead of print].

Arsenic (As), a highly toxic metalloid, is present throughout our environment as a result of both natural and human-related activities. Furthermore, As exposure could lead to a persistent inflammatory response, which may facilitate the pathogenesis of several diseases in various organs. This study was performed to investigate the As-induced inflammatory response and the underlying molecular mechanisms in vitro. Further, the anti-inflammatory effects of a natural dietary polyphenol tannic acid (TA) were also explored. In human normal bronchial (BEAS-2B), adenocarcinoma alveolar basal (A549), and murine macrophages (J774) cell lines, a trivalent form of As (as As[3+]) exposure markedly induced the expression of various pro-inflammatory mediators (cytokines and chemokines). Additionally, it was found that As[3+] exposure induced reactive oxygen species (ROS) generation and activation of the nuclear factor-kappa B (NF-kB) p65 and extracellular signal-regulated kinase (ERK)1/2 pathways in BEAS-2B cells. As expected, the blockade of either ERK1/2 (PD98059) or NF-kB p65 (IMD0354), or both pathways attenuated As[3+]-induced pro-inflammatory mediators release. Interestingly, pre-treatment with ROS inhibitor N-acetylcysteine (NAC) attenuated activation of ERK/NF-kB pathways, suggesting that ROS have a critical role in pathway's activation and subsequent inflammatory response. Further, TA pre-treatment effectively attenuated As[3+]-induced inflammatory response by suppressing ROS production and ERK/NF-kB signaling pathways activation. Therefore, this study provides scientific evidence for the anti-inflammatory activities of TA and the underlying molecular mechanisms.

RevDate: 2025-01-20

Shri P, Singh KP, Rani V, et al (2025)

N-acetylcysteine prevents cholinergic and non-cholinergic toxic effects induced by nerve agent poisoning in rats.

Toxicology research, 14(1):tfae223 pii:tfae223.

OBJECTIVE: Organophosphorus Nerve Agent, VX [(O-Ethyl S-diisopropylaminomethyl) methylphosphonothioate] compound interferes with acetylcholine signaling by targeting the AChE enzyme. Studies suggest that in nerve agents poisoning, non-cholinergic effects are also responsible for damage in peripheral tissues including long term damage in brain. Present study reports cholinergic and non-cholinergic effects of VX poisoning and their prevention by use of N-acetylcysteine (NAC) in addition to conventional antidotes atropine sulphate and 2-PAM chloride as an antioxidant. NAC was chosen being an approved drug for medical conditions including oxidative damage and as mucolytic.

RESULTS: Results of the study showed that after 1x LD 50 exposure to VX and standard atropine and oxime therapy resulted in recovery of cholinesterase activity up to 51%, while additional NAC administration resulted in increased recovery up to 89% in brain cholinesterase activity. NAC also helped in maintaining intracellular and tissue GSH level, reduced ROS generation and lipid peroxidation. NAC treatment could able to reduce the lipid peroxidation (MDA) levels in liver of NAC administered groups as compared to standard treatment of atropine sulphate and PAM chloride at 10 LD 50 VX. Likewise, a 20% higher level of GSH was found in NAC treated group at 1x LD 50 dose in brain. Cell cycle analysis and histopathological results showed that NAC prevents VX induced damage.

CONCLUSION: it was found that use of antioxidant agent NAC along with standard atropine-oxime treatment is helpful in reducing the cholinergic and oxidative stress mediated toxicity induced by VX.

RevDate: 2025-01-20

Abd El-Khalek SH, Amin SA, El-Ebiary AA, et al (2025)

The potential role of N-acetylcysteine as an adjuvant therapy in acute aluminum phosphide poisoning: a randomized clinical trial.

Toxicology research, 14(1):tfae210 pii:tfae210.

OBJECTIVE: Aluminum phosphide (AP) intoxication is a life-threatening emergency with no available effective antidote. This study evaluated the efficacy and safety of N-acetylcysteine (NAC) infusion in cases of acute AP poisoning.

METHODS: This randomized, single-blinded, parallel-group, controlled, clinical trial enrolled 96 patients with acute AP poisoning. The patients were allocated to two groups and received either conventional treatment (control group) or conventional treatment plus NAC infusion (NAC group). The patients were subjected to full clinical evaluation, routine laboratory investigations, silver nitrate test, and evaluation of the oxidative markers, malondialdehyde (MDA) and total antioxidant capacity (TAC), at admission and after 24 h treatment. The primary outcome was mortality, and the secondary outcomes were the arterial blood pressure, the length of hospital stay, and the need for intubation or mechanical ventilation.

RESULTS: Compared to the control group, the NAC group showed significantly lower MDA (median [interquartile range (IQR)]: 4.6 [1.9-10.6] vs. 6.8 [3.5-17.4] nmol/mL, P = 0.014) and higher TAC levels (median [IQR]: 0.7 [0.6-0.7] vs. 0.6 [0.6-06] mM/L, P < 0.001). The mortality rate and the need for mechanical ventilation were comparable in both groups (P = 0.601 and 0.505, respectively). However, the NAC group showed significant improvements of both systolic and diastolic blood pressure values (both P = 0.030). The duration of hospitalization was significantly shorter in the NAC group (P = 0.017). No adverse events were reported in patients who received NAC infusion.

CONCLUSION: In patients with acute AP poisoning, the use of NAC mitigates oxidative stress and partially enhances clinical manifestations without inducing noticeable adverse effects.

RevDate: 2025-01-18
CmpDate: 2025-01-18

Linares-Ramírez JD, Córdoba AC, Calderón-Franco CH, et al (2024)

Premedication in upper gastrointestinal endoscopy to improve mucosal visualization. A systematic review.

Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru, 44(4):346-353.

OBJECTIVE: This review aims to evaluate the efficacy and safety of premedication comprising mucolytics and/or defoaming agents to improve the quality of visualization during elective upper digestive endoscopy (elective upper GI endoscopy) procedure.

MATERIALS AND METHODS: A systematic review of the literature contained in electronic databases (Medline/Pubmed, Embase, and Lilacs) was performed to identify randomized controlled trials and systematic reviews that assessed patients undergoing upper gastrointestinal endoscopy (elective upper GI Endoscopy) under sedation, after being premedicated with mucolytics and/or defoaming agents for mucous clearance. A meta-analysis was conducted to determine the relative efficacy and safety profile of such premedication.

RESULTS: In patients undergoing an elective procedure, premedication with defoaming and/or mucolytic agents improved the visibility score of the gastric antrum during upper GI endoscopy. The use of combined agents such as simethicone vs. water and N-acetyl cysteine (NAC) vs. water showed significant differences in favor of the active substance; however, no significant differences were found between the use of simethicone alone vs. simethicone + NAC. The use of pronase and dimethylpolysiloxane, among others, produced no significant difference (additive effect) in the visualization score. This is associated with the limited number of studies that performed similar comparisons and the heterogeneity of the outcomes. No major adverse effects were reported in the studies that were included regarding safety outcomes (i.e., volume of fluids required for clearance, risk of bronchoaspiration, and disinfection of equipment).

CONCLUSIONS: The results of this review evidence that premedication with simethicone (a drug registered in Colombia for use against functional gastrointestinal disorders; ATC group A03A) is safe and effective for improving the quality of visualization during elective upper GI endoscopy procedures. However, no significant differences were observed in the visualization quality with the use or addition of other agents. The use simethicone should be set as off-label use and should be implemented at the prescriber's discretion. The use of simethicone as a premedication is recommended to improve the endoscopic visualization score in elective procedures.

RevDate: 2025-01-18
CmpDate: 2025-01-18

Wang J, Yang Y, Ma J, et al (2025)

Molecular Mechanism of N-Acetylcysteine Regulating Proliferation and Hormone Secretion of Granulosa Cells in Sheep.

Reproduction in domestic animals = Zuchthygiene, 60(1):e70006.

Granulosa cells (GCs) are pivotal in the development of ovarian follicles, serving not only as supportive cells but also as the primary producers of steroid hormones. The proliferation of these cells and the synthesis of steroid hormones are crucial for follicular development and atresia. In our study, GCs were isolated using follicular fluid aspiration and subsequently identified through immunofluorescence. We investigated the impact of varying concentrations of N-acetylcysteine (NAC) at 50, 100, 500, and 1000 μmol/L on sheep GCs, focusing on antioxidant levels, proliferation, apoptosis, and steroid hormone secretion. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) inhibitor LY294002 was used to explore the molecular mechanism of NAC on GCs proliferation and steroid hormone secretion in sheep. Our findings indicate that all concentrations of NAC tested promoted GC proliferation and suppressed apoptosis in sheep GCs. Notably, 100 μmol/L NAC exhibited the most pronounced effect on GC proliferation after 48 h. The expression levels of CCND1, CDK4, and Bcl-2 were significantly elevated in all NAC concentration groups, whereas Bax expression was notably reduced. Furthermore, all NAC concentrations led to a significant reduction in reactive oxygen species (ROS) levels and an increase in the expression of CAT and SOD1. NAC also significantly enhanced the expression of CYP19A1 and 3β-HSD, as well as the secretion of estradiol (E2) and progesterone (P4) by GCs. In summary, NAC activates the PI3K/AKT signalling pathway, thereby promoting the proliferation of GCs and the secretion of E2 and P4 by sheep GCs in vitro.

RevDate: 2025-01-17

Zarowin DH, Buros Stein A, Sheppard SE, et al (2025)

A Retrospective Review of Oral N-Acetylcysteine for Habit-Driven Cutaneous Disorders.

Pediatric dermatology [Epub ahead of print].

Oral N-acetylcysteine (NAC) has shown efficacy for debilitating habit-driven and neuropsychiatric disorders in small, mostly adult studies. We retrospectively evaluated the therapeutic use and safety of oral NAC in 93 children from the Children's Hospital of Philadelphia. This study supports the use of oral NAC for habit-driven skin, hair, and nail abnormalities in pediatric patients.

RevDate: 2025-01-16

Shishodia S, Rinnert H, Balan L, et al (2025)

Microwave-assisted synthesis of highly photoluminescent core/shell CuInZnSe/ZnS quantum dots as photovoltaic absorbers.

Nanoscale advances [Epub ahead of print].

Water-dispersible core/shell CuInZnSe/ZnS (CIZSe/ZnS) quantum dots (QDs) were efficiently synthesized under microwave irradiation using N-acetylcysteine (NAC) and sodium citrate as capping agents. The photoluminescence (PL) emission of CIZSe/ZnS QDs can be tuned from 593 to 733 nm with varying the Zn : Cu molar ratio in the CIZSe core. CIZSe/ZnS QDs prepared with a Zn : Cu ratio of 0.5 exhibit the highest PL quantum yield (54%) and the longest PL lifetime (515 ns) originating from the recombination of donor-acceptor pairs. The potential of CIZSe/ZnS QDs as photoabsorbers in QD-sensitized solar cells was also evaluated. An adequate type-II band alignment is observed between TiO2 and CIZSe/ZnS QDs, indicating that photogenerated electrons in CIZSe/ZnS QDs could efficiently be injected into TiO2.

RevDate: 2025-01-15
CmpDate: 2025-01-16

Jing Q, Wu Y, Li Y, et al (2025)

Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma.

Biology direct, 20(1):7.

Thioredoxin1 (TRX1) and telomerase are both attractive oncology targets that are tightly implicated in tumor initiation and development. Here, we reported that the 6-dithio-2-deoxyguanosine analog thiotert exhibits an effective cytotoxic effect on myelodysplastic syndromes (MDS) cell SKM-1 and lymphoma cell U-937. Further studies confirmed that thiotert effectively disrupts cellular redox homeostasis, as evidenced by elevated intracellular reactive oxygen species (ROS) levels, increased MnSOD, accelerated DNA impairment, and activated apoptosis signal. Mechanistically, our present study revealed that thiotert treatment effectively inhibited the function of the TRX1/TRXR1 system and telomerase reverse transcriptase (TERT), rendering oxidative damage and impairment of telomeres. Meanwhile, pharmacological administration of glutathione (GSH), N-acetylcysteine (NAC), and mitoquinone (MitoQ), or genetic overexpression of TRX1 or TERT in MDS and cells could dampen the toxicity caused by thiotert. Remarkably, the in vivo mouse model of MDS demonstrated that thiotert administration exhibited greater efficacy in tumor reduction compared to the conventional chemotherapy drug cytarabine. Collectively, these results provide experimental insights into the mechanism of thiotert-induced MDS and lymphoma cell death and unveil that thiotert may be an effective and promising new drug for future MDS and lymphoma treatment.

RevDate: 2025-01-15
CmpDate: 2025-01-15

Fatima S (2025)

N-acetyl-L-cysteine and lauric acid; effective antioxidant and antimicrobial feed additives for juvenile Pacific white shrimp (Litopenaeus vannamei) cultured at high stocking density.

PloS one, 20(1):e0315819 pii:PONE-D-24-08985.

Present study aimed at improving the immune and antioxidant response of Pacific white shrimp (Litopenaeus vannamei) cultured at high stocking density fed with 0.2% supplementation of lauric acid (LA) and N-acetyl-L-cysteine (NAC). Shrimp (initial average weight = 0.65 g; n = 270) were grown at low stocking density (LSD) (n = 10/0.80 ft3 per replicate) and high stocking density (HSD) (n = 20/0.80 ft3 per replicate). They were randomly distributed into five groups (T1: negative control at LSD, T2: positive control at HSD, T3: at HSD and fed with LA supplement diet, T4: at HSD and fed with NAC supplemented diet, T5: at HSD and fed with combination of LA and NAC). All these five treatments were studied in triplicates and study continued for eight weeks. Better growth and higher levels of glucose, total protein, total hemocyte count and phagocytic index were observed in shrimp fed with NAC and LA supplemented diets. Observed survival rate and feed conversion ratio in all treatments was 75-89% and < 0.82, respectively. All parameters indicating stress were observed to be higher in T1 as compared to T2. Improved expression of superoxide dismutase and glutathione peroxidase and lower levels of malondialdehyde genes in T3, T4 and T5 showed that supplementation with these nutraceuticals can improve antioxidant response at high stocking density. A parallel increase was observed in the profiles of prophenoloxidase and lysozyme, underscoring the immune-boosting effects of both NAC and LA. This finding was further supported by higher expression of innate immune signaling pathway-related gene, toll like receptor-2 in T3, T4 and T5. In conclusion, NAC and LA, can possibly improve the resistance of white pacific shrimp against oxidative stress and pathogens when cultured in intensive production system.

RevDate: 2025-01-15

Baraldi F, Bigoni T, Foschino Barbaro MP, et al (2025)

Mucus production and chronic obstructive pulmonary disease, a possible treatment target: zooming in on N-acetylcysteine.

Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace [Epub ahead of print].

Mucus hypersecretion is a trait of chronic obstructive pulmonary disease (COPD) associated with poorer outcomes. As it may be present before airway obstruction, its early treatment may have a preventive role. This narrative review of the literature presents the role of mucus dysfunction in COPD, its pathophysiology, and the rationale for the use of N-acetylcysteine (NAC). NAC can modify mucus rheology, improving clearance and reducing damage induced MUC5AC expression. It exerts a direct and indirect (glutathione replenishment) antioxidant mechanism; it interferes with inflammatory molecular pathways, including inhibition of nuclear factor-kB activation in epithelial airway cells and reduction in the expression of cytokine tumor necrosis factor α, interleukin (IL)-6, and IL-10. Some clinical experiences suggest that the adjunctive use of NAC may reduce symptoms and improve outcomes for patients with COPD. In conclusion, NAC may be a candidate drug for the early treatment of subjects at risk of COPD development.

RevDate: 2025-01-14

Finotti M, Zanetto A, Vitale A, et al (2025)

N-Acetylcysteine and Liver Transplant. Advantages of its Administration in Multi-Organ Donors Especially During World-Economical-Crisis. Long-Term Sub-Group Analysis in a Randomized Study.

Transplantation proceedings pii:S0041-1345(24)00676-6 [Epub ahead of print].

BACKGROUND: Liver transplantation (LT) is the main indication for the treatment of end-stage liver disease but have to face organ shortages. Using marginal donors is an option to increase the donor pool. Previous studies showed that the graft procured using N-acetylcysteine (NAC) provides a longer survival compared to perfusion with standard solutions, especially in marginal liver donors. We now evaluate the effect of NAC perfusion compared to control (no NAC protocol) at a 5-year follow-up, with a special focus on the overall survival (OS) and graft survival.

METHODS: Single-center, retrospective review of the OS and graft survival among NAC and control group, with a sub-stratification based on the LT indication.

RESULTS: 140 donors were enrolled: 69 in the NAC protocol and 71 in the control group. The 5-year OS was 84% in the NAC protocol compared to 63% in the control (P = .0045). In LT for HCC, the OS at 5 years was 80% and 55% in the study group and control group, respectively (P = .04), with no statistical difference in the RFS (P = .46). Furthermore, in cost analysis, the resources needed for the NAC protocol is negligible compared to the control group. Beneficial tendency of NAC protocol application has been seen in the other organs (lungs, hearts, pancreas, kidney and intestine) CONCLUSION: The application of NAC infusion in liver donors improves the overall survival of the recipient, especially in the HCC and HCV LT indications.

RevDate: 2025-01-14

Tanadi C, Pajala FB, Supranoto YTN, et al (2025)

Simethicone with or without N-acetylcysteine as premedication in esophagogastroduodenoscopy: a systematic review and meta-analysis.

Annals of gastroenterology, 38(1):28-40.

BACKGROUND: The impairment of gastrointestinal mucosa visibility during esophagogastroduodenoscopy (EGD), due to the presence of foam and bubbles, may lead to reduced quality in the EGD results. The combination of simethicone, a defoaming agent, along with N-acetylcysteine (NAC), which has mucolytic properties, has been proposed to improve the visibility of the mucosa. This study aimed to evaluate the effectiveness of pre-procedural administration of simethicone and N-acetylcysteine in improving mucosal visibility, procedure time and mucosal cleansing volume needed during EGD.

METHODS: We conducted a comprehensive literature search from inception to November 23, 2023, in PubMed, CENTRAL, ProQuest, SAGE, and JSTOR. We included randomized clinical trials that investigated the effects of simethicone with or without NAC as premedication in EGD. For the quantitative analysis, standardized mean difference (SMD) was used to assess continuous outcomes and risk ratio for dichotomous outcomes. The Cochrane risk of bias 2 tool was used to evaluate the risk of bias.

RESULTS: This meta-analysis comprised a total of 20 studies and found that simethicone with or without NAC improved mucosal visibility compared with control (SMD -1.27, 95% confidence interval [CI] -1.74 to -0.81, P<0.001). The combination of simethicone and NAC was significantly better than simethicone alone (SMD -0.68, 95%CI -1.08 to -0.28, P=0.001). Simethicone with or without NAC also shortened the procedure time compared to control (MD -1.40, 95%CI -2.67 to -0.12, P=0.03). The risk of bias was low with a moderate grade of certainty.

CONCLUSION: The administration of simethicone with or without NAC may improve EGD quality.

RevDate: 2025-01-13

Ford JW, VanNatta JM, Mondal D, et al (2025)

Drug-Linker Constructs Bearing Unique Dual-Mechanism Tubulin Binding Payloads Tethered through Cleavable and Non-Cleavable Linkers.

Tetrahedron, 171:.

Antibody-drug conjugates (ADCs) have advanced as a mainstay among the most promising cancer therapeutics, offering enhanced antigen targeting and encompassing wide diversity in their linker and payload components. Small-molecule inhibitors of tubulin polymerization have found success as payloads in FDA approved ADCs and represent further promise in next-generation, pre-clinical and developmental ADCs. Unique dual-mechanism payloads (previously designed and synthesized in our laboratories) function as both potent antiproliferative agents and promising vascular disrupting agents capable of imparting selective and effective damage to tumor-associated microvessels. These payloads have been incorporated into a variety of drug-linker constructs utilizing the clinically relevant cathepsin B cleavable Val-Cit dipeptide linker, employed within several FDA approved ADCs, along with other non-cleavable constructs. Various synthetic strategies were evaluated to prepare these drug-linker constructs. Aniline-based payloads were incorporated utilizing the Val-Cit dipeptide linker similar to FDA approved ADCs such as Adcetris[®] (brentuximab vedotin). An additional self-immolative group, previously described in the literature for related model systems, was employed to tether the phenolic payloads. A variety of drug-linker constructs (with each bearing a unique dual mechanism payload) were synthesized and evaluated biologically for their enzyme-mediated release of payload and inhibition of tubulin polymerization. Following deactivation of the highly electrophilic maleimido terminus as its corresponding N-acetyl cysteine (NAC) derivative, the most promising construct (NAC-4) demonstrated approximately 90% release of an aniline-functionalized payload (1) upon treatment with cathepsins B or L over 90 minutes. Building on these promising results, future studies will examine the conjugation of drug-linker construct 4 to selected antibodies and engineered proteins and evaluate the biological activity of the resultant antibody-drug conjugates (ADCs).

RevDate: 2025-01-11

Mohammed SS, Zaaqoq A, Talaat S, et al (2025)

A randomized, clinical trial of intravenous N-acetylcysteine as an antioxidant therapy in acute organophosphorus pesticide poisoning.

Toxicology research, 14(1):tfae234.

The incidence of acute organophosphate (OP) poisoning has steadily increased in developing countries. Many studies showed that oxidative stress could have a significant role in its mechanism. The current study aimed to evaluate the role of N acetylcysteine (NAC) as an antioxidant in acute OP poisoned. A randomized, controlled, parallel-group trial was conducted in the period from the beginning of January 2022 to the end of June 2022. The study included 56 acute OP poisoned patients admitted to the intensive care unit (ICU) at the Poison Control Center of Ain Shams University Hospitals within 6 h after the exposure. The patients were randomly allocated in two equal groups; group (A): received the standard treatment plus NAC in a total dose of 300 mg/kg administered intravenously (IV) while group (B) received the standard treatment. Then both groups were compared as regards clinical parameters, laboratory investigations, ECG, and outcomes. Baseline parameters were comparable between the groups. However, NAC treatment significantly elevated concentrations of both serum catalase and glutathione peroxidase levels at 24 h, it did not significantly affect the total dose of atropine required, duration of atropine and oximes treatment or need for mechanical ventilation, and length of hospital stay. Mortality was lower in the NAC group (2 out of 28) than the standard treatment-only group (5 out of 28) but the difference was not statistically significant. This trial found that NAC improved antioxidant enzyme levels including serum CAT and GPX but did not affect clinically relevant outcomes.

RevDate: 2025-01-09
CmpDate: 2025-01-09

Kang Y, Chen JJ, Mah E, et al (2024)

Developing Topics.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 20 Suppl 8:e095550.

BACKGROUND: Oxidative stress (OS) has been a target of interest for vascular dementia, given its implications in pathogenesis. OS may be important in prodromal stage, such as vascular mild cognitive impairment (vMCI), and examining OS markers in vMCI may help better understand biological processes in the onset of cognitive impairment. Our study compared OS levels in vMCI vs controls, and explored whether OS markers predicted the response to antioxidant treatments in vMCI.

METHOD: Cardiac rehabilitation patients with cardiovascular risk factors (CVRFs) were recruited as vMCI (1SD below norms in executive function (EF), memory, processing speed or working memory) or cognitively-healthy controls. vMCI patients were classified as probable vMCI if they had neuroimaging evidence of vascular pathology. vMCI patients were randomized to 2400mg N-acetylcysteine (NAC) or placebo in a 24-week, double-blind trial. Serum 8-isoprostane (8ISO), 4-hydroxynonenal (4HNE) and lipid hydroperoxides (LPH) collection and cognitive assessments were done at three time points. ANCOVA models adjusting for age, sex and CVRFs compared OS markers between groups at baseline. Linear mixed-effects models were used for longitudinal analyses.

RESULT: LPH levels were significantly lower in vMCI (n = 60) compared to controls (n = 16) (0.86±0.45 vs 1.18±0.31, F(1,62) = 7.0, p = 0.011). 4HNE were significantly higher in vMCI compared to controls (1.03±0.06 vs 0.99±0.04, F(1,70) = 6.6, p = 0.012). vMCI patients had significantly higher 4HNE/LPH (0.17±0.44 vs -0.18±0.29, F(1,62) = 9.3, p = 0.003) and (8ISO+4HNE)/LPH ratio (0.41±0.45 vs 0.13±0.38, F(1,62) = 5.9, p = 0.018) compared to controls. In probable vMCI group (n = 25), there was significant decreases in 4HNE/LPH (β = -0.68, SE = 0.27, p = 0.02) and (8ISO+4HNE)/LPH ratio (β = -0.65, SE = 0.28, p = 0.028) after NAC treatment. A significant time by baseline 8ISO effect on EF in the NAC group was observed (β = 0.78, SE = 0.26, p<0.01) after adjusting for age, sex and education.

CONCLUSION: This study showed that the ratios of late- to early-phase lipid peroxidation markers were significantly elevated in vMCI groups compared to controls. This aligns with existing literature that altered lipid peroxidation may be implicated in vMCI. Antioxidant treatments decreased OS in probable vMCI groups, and higher baseline 8ISO was associated with greater improvement in EF in the NAC group, suggesting that probable vMCI patients with high OS may be appropriately targeted for antioxidant treatments.

RevDate: 2025-01-09

Nemetova U, Önem AN, Er A, et al (2024)

A fast and responsive turn-on fluorescent probe based on a quinone conjugated alkoxy derivative for biothiols and a cellular imaging study.

Turkish journal of chemistry, 48(6):830-842.

The detection of intracellular biothiols (cysteine, N-acetyl cysteine, and glutathione) with high selectivity and sensitivity is important to reveal biological functions. In this study, a 2-(2-methoxy-4-methylphenoxy)-3-chloro-5,8-dihydroxynaphthalene-1,4-dione (DDN-O) compound (3) was newly synthesized and used as a fluorogenic probe (detector molecule) in the fluorometric method for the rapid, highly selective, and sensitive determination of biothiols. The intensity values (λex = 260 nm, λem = 620 nm) of the product were measured by adding biothiols to the reaction medium at varying concentrations and the glutathione equivalent thiol content values of each biothiol were calculated. Using compound 3, glutathione as the reference biothiol was detected in the linear concentration range of 10-70 μM and the LOD value was found to be 0.11 μM. Biothiol detection with structurally simple compound 3 was performed at the cellular level within 1 min and the probe was also successfully used in bioimaging with low cytotoxicity. It was concluded that this probe can serve as an alternative to existing fluorescence-based biothiol probes with applications in rapid biothiol detection at the cellular level for biological functions. To evaluate the molecular structure of 3, conformational analysis was performed using the PM3 semiempirical method. The most stable obtained molecular geometry was then optimized at the DFT/wb97xd/6-311++G(d,p) level of theory. Frontier molecular orbitals (HOMO and LUMO) and molecular electrostatic potential map analyses were performed for the optimized structure. Molecular docking studies demonstrated the interactions of 3 with HAS (1AO6) and FhGST (2FHE) target proteins.

RevDate: 2025-01-09
CmpDate: 2025-01-09

Poudel SB, Kim MH, Bhattarai G, et al (2025)

n-acetyl-l-cysteine stimulates bone healing by recovering the age-associated degenerative complications relative to osteoblastic Wntless ablation.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 182:117761.

Dysregulated Wnt signaling causes age-related characteristics such as oxidative stress, stem cell senescence, and abnormal bone homeostasis. Here we explored whether supplemental n-acetyl-l-cysteine (NAC) recovers the age-associated complications relative to osteoblastic Wntless (Wls) ablation and examined the possible mechanisms therein. For this work, we administered Col2.3-Cre;Wls[fl/fl] mutant and littermate control (Wls[fl/fl]) mice (14 weeks of age) with NAC (40 mM)-supplemented or NAC-free water for four weeks. A proportion of these mice received non-critical-sized femoral defects at 16 weeks of age. Blood, bone, and bone marrow (BM) samples were collected and adjusted for in vivo, ex vivo, and in vitro analyses. Osteoblastic Wls deletion delayed bone mass accrual and the healing of bone defects, stimulated osteoclastic activation and inflammatory factor expression, and decreased antioxidant enzyme activity in the BM. Osteoblastic Wls deletion also promoted oxidative stress, apoptosis, and senescence in BM stromal cells (BMSCs) and decreased BMSC' multipotencies. Supplementation of Wls[fl/fl] mice with NAC enhanced bone mass accrual and regenerative bone healing via a Wnt signal-associated osteogenic activation. However, supplemental NAC induced new bone formation in the mutant mice by inhibiting the age-related complications of BM/BMSCs, as well as by restoring endogenous antioxidant system without any alterations in Wnt ligand secretion, hematopoiesis, and expression of osteogenic and growth factors. This study indicates that supplemental NAC protects mice against Wnt deficiency-mediated and age-associated degenerative complications. Overall, this study highlights the therapeutic potency of NAC for restoring the antioxidant system, stem cell function, and regenerative bone homeostasis in osteoblastic Wls-dispensable manner.

RevDate: 2025-01-08

Li P, Tang W, Wen H, et al (2025)

Senkyunolide I prevent chondrocytes from oxidative stress through Nrf2/HO-1 signaling pathway.

Naunyn-Schmiedeberg's archives of pharmacology [Epub ahead of print].

Osteoarthritis (OA) is a degenerative musculoskeletal disease, featured by the destruction of articular cartilage. Oxidative stress, one of the drivers of the extracellular matrix degradation in cartilage, plays a vital role in OA pathogenesis. Senkyunolide I (SEI) is a natural compound with a prominent anti-oxidative stress property against multiple diseases. However, the protective effect of SEI on OA has not been explored. Here, we aimed to elucidate the effect of SEI on OA in vitro. Our results showed that SEI suppressed the expression of senescence-related markers such as P16 and P21 in IL-1β-induced chondrocytes. Besides, SEI alleviated IL-1β-induced the degradation of extracellular matrix (ECM) by suppressing the matrix proteinase like MMP13 and ATAMDS5 while promoting matrix synthesis regulated biomarkers like COL2A1 and ACAN in chondrocytes. Mechanically, the mitochondrial dysfunction and overproduction of intracellular reactive oxygen species (ROS) in chondrocytes induced by IL-1β were reversed by SEI. Additionally, the ROS inhibitor N-acetylcysteine (NAC) synergistically enhanced the biological effect of SEI in IL-1β-induced chondrocytes. Moreover, it was also found that the expression of Nrf2 and HO-1 was increased by the treatment of SEI in IL-1β-stimulated chondrocytes, while the Nrf2 inhibitor ML385 reversed the protective effect of SEI on OA chondrocytes. In conclusion, SEI could inhibit senescence, the degradation of ECM, and the production of ROS through activating Nrf2/ HO-1 signaling pathway, which provide a novel candidate for OA treatment.

RevDate: 2025-01-08
CmpDate: 2025-01-08

Hamed S, Emara M, Tohidifar P, et al (2025)

N-Acetyl cysteine exhibits antimicrobial and anti-virulence activity against Salmonella enterica.

PloS one, 20(1):e0313508 pii:PONE-D-24-31564.

Salmonella enterica is a common foodborne pathogen that causes intestinal illness varying from mild gastroenteritis to life-threatening systemic infections. The frequency of outbreaks due to multidrug-resistant Salmonella has been increased in the past few years with increasing numbers of annual deaths. Therefore, new strategies to control the spread of antimicrobial resistance are required. In this work, we found that N-acetyl cysteine (NAC) inhibits S. enterica at MIC of 3 mg ml-1 and synergistically activates the bactericidal activities of common antibiotics from three-fold for ampicillin and apramycin up to1000-fold for gentamycin. In addition, NAC inhibits the expression of virulence genes at sub-inhibitory concentrations in a dose-dependent manner. The whole-genome sequencing revealed that continuous exposure of S. enterica to NAC leads to the development of resistance; these resistant strains are attenuated for virulence. These results suggest that NAC may be a promising adjuvant to antibiotics for treating S. enterica in combination with other antibiotics.

RevDate: 2025-01-08
CmpDate: 2025-01-08

Wang K, Qu H, Hu R, et al (2025)

Polymerase delta-interacting protein 2 mediates brain vascular permeability by regulating ROS-mediated ZO-1 phosphorylation and localization at the interendothelial border.

Cell communication and signaling : CCS, 23(1):9.

BACKGROUND: Polymerase delta-interacting protein 2 (Poldip2) is a novel regulator of vascular permeability that has been shown to be involved in aggravating blood-brain barrier (BBB) disruption following stroke; however, the underlying mechanisms are unknown. While endothelial tight junctions (TJ) are critical mediators of BBB permeability, the effect of Poldip2 on TJ function has not been elucidated yet. Here, we aim to define the mechanism by which Poldip2 mediates BBB disruption, specifically focusing on phosphorylation and stabilization of the TJ integral protein ZO-1.

METHODS AND RESULTS: Cerebral ischemia was induced in endothelial-specific Poldip2 knockout mice and controls. Cerebral vascular permeability was assessed by Evans blue dye extravasation. Endothelial-specific Poldip2 deletion abolished Evans blue dye extravasation after ischemia induction. In vitro permeability assays demonstrated that Poldip2 knockdown suppressed TNF-α-induced endothelial cell (EC) permeability. Immunofluorescence staining showed that Poldip2 depletion prevented TNF-α-induced ZO-1 disruption at interendothelial junctions. Conversely, Poldip2 overexpression increased endothelial permeability, loss of ZO-1 localization at cell-cell junctions and enhanced reactive oxygen species (ROS) production. Treatment with the antioxidant N-acetyl cysteine (NAC) reduced Poldip2-induced ZO-1 disruption at inter interendothelial junctions. Immunoprecipitation studies demonstrated Poldip2 overexpression induced tyrosine phosphorylation of ZO-1, which was prevented by treatment with NAC or MitoTEMPO, a mitochondrial ROS scavenger.

CONCLUSIONS: These data reveal a novel mitochondrial ROS-driven mechanism by which Poldip2 induces ZO-1 tyrosine phosphorylation and promotes EC permeability following cerebral ischemia.

RevDate: 2025-01-08

La Mensa A, Buscetta M, Woldhuis RR, et al (2025)

Caspase Inhibition Restores Collagen I α1 and Fibronectin Release in Cigarette Smoke Extract-Exposed Human Lung Fibroblasts.

American journal of physiology. Lung cellular and molecular physiology [Epub ahead of print].

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by obstructed airflow, airway remodeling, and inflammation, with cigarette smoke (CS) exposure being the main risk factor. While CS extract (CSE) has been shown to activate caspases in various cell types, the role of caspases in human lung fibroblasts (hLFs), in COPD remains poorly understood. Recent studies have linked caspases to extracellular matrix (ECM) remodeling in skin and kidney fibrosis. Caspase activation can be triggered by oxidative stress, with active caspase-3 executing the pore-forming protein gasdermin E (GSDME) in the cleaved N-terminal form GSDME-NT. We investigated whether CSE activates caspases and GSDME in hLFs, and their role in ECM remodeling. MRC-5 lung fibroblasts were treated with CSE with or without the antioxidant N-acetyl cysteine (NAC), and the caspase-8 inhibitor z-IETD-fmk. We measured the effects on caspase-1-8-3/7 activation, GSDME cleavage, ECM remodeling (procollagen Iα1, COLIα1, and fibronectin, FN), and mitochondrial superoxide (mSOX) generation. Key findings were validated in patient-derived hLFs (phLFs). Our results showed that CSE induced caspase-1-8-3/7 activation, mSOX generation, and decreased COLIα1 and FN levels in MRC-5. CSE caused caspase-8-dependent activation of caspase-3, leading to the GSDME cleavage. Treatment with NAC inhibited mSOX and caspase activation. Inhibition of caspase-8 and mSOX restored FN and COLIα1 levels. In phLFs, we confirmed caspase-1 and -8 activation, mSOX increase, COLIα1/FN decrease, and the effects of NAC. Our findings highlight the role of the axis caspase-8-3/7-GSDME and mSOX in regulating ECM protein, suggesting that these pathways may contribute to remodeling in COPD.

RevDate: 2025-01-08
CmpDate: 2025-01-08

Kim TW, SG Ko (2024)

Anti-Inflammatory and Anticancer Effects of Kaurenoic Acid in Overcoming Radioresistance in Breast Cancer Radiotherapy.

Nutrients, 16(24): pii:nu16244320.

Background/Objectives: Peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in mediating anti-inflammatory and anticancer effects in the tumor microenvironment. Kaurenoic acid (KA), a diterpene compound isolated from Sphagneticola trilobata (L.) Pruski, has been demonstrated to exert anti-inflammatory, anticancer, and antihuman immunodeficiency virus effects. Methods: In this study, we identified KA as a novel activator of PPARγ with potent anti-inflammatory and antitumor effects both in vitro and in vivo. Given the potential of PPARγ regulators in overcoming radioresistance and chemoresistance in cancer therapies, we hypothesized that KA may enhance the efficacy of breast cancer radiotherapy. Results: In a lipopolysaccharide (LPS)-induced mouse inflammation model, KA treatment reduced the levels of pro-inflammatory cytokines, including COX-2, IL-6, IL-1β, and TNFα. In a xenograft mouse mode of breast cancer, KA treatment inhibited tumor growth. Specifically, KA treatment enhanced caspase-3 activity and cytotoxicity against MDA-MB-231 and MCF-7 breast cancer cells. When KA was co-treated with a caspase inhibitor, Z-VAD-FMK, caspase-dependent apoptosis was suppressed in these cells. KA was found to induce the generation of cytosolic calcium ions (Ca[2+]) and reactive oxygen species (ROS), triggering endoplasmic reticulum (ER) stress via the PERK-ATF4-CHOP axis. Hence, the ER stressor thapsigargin (TG) synergized with KA treatment to enhance apoptosis in these cells, while the loss of the PERK or CHOP function inhibited this phenomenon. KA treatment was shown to induce oxidative stress via the NADPH oxidase 4 (NOX4) and stimulate ROS production. Specifically, NOX4 knockdown (KD) and antioxidant treatment (N-acetyl cysteine or diphenyleneiodonium) suppressed such ER stress-mediated apoptosis by inhibiting KA-enhanced caspase-3 activity, cytotoxicity, and intracellular ROS production in the treated cells. In radioresistant MDA-MB-231R and MCF-7R cells, KA combined with 2 Gy radiation overcame radioresistance by upregulating PPARγ and modulating epithelial-mesenchymal transition (EMT) markers, such as E-cadherin, N-cadherin, and vimentin. In PPARγ KD MDA-MB-231R and MCF-7R cells, this phenomenon was inhibited due to reduced PPARγ and NOX4 expression. Conclusions: In conclusion, these findings demonstrated KA as a novel PPARγ regulator with promising potential to enhance the efficacy of breast cancer radiotherapy.

RevDate: 2025-01-08
CmpDate: 2025-01-08

Karwowski BT (2024)

A Comparison of the Electronic Properties of Selected Antioxidants Vitamin C, Uric Acid, NAC and Melatonin with Guanosine Derivatives: A Theoretical Study.

Molecules (Basel, Switzerland), 29(24): pii:molecules29245944.

Each cell in the human body is continually exposed to harmful external and internal factors. During evolution, cells have developed various defence systems, divided into enzymatic and non-enzymatic types, to which low-weight molecule antioxidants belong. In this article, the ionisation potential and electron affinity, as well as global reactivity descriptors of Vitamin C, Melatonin, Uric Acids, and N-acetyl-L-cysteine, were theoretically investigated at the MP-2/aug-cc-pVTZ level of theory in the condensed (aqueous) phase. The vertical ionisation potential and electron affinity are discussed in terms of non-equilibrated and equilibrated solvent-solute interactions. Additionally, at the same theoretical level, the electronic properties of canonical and oxidised derivatives of guanine were analysed. The presented results indicate that the selected antioxidants for this study (Vitamin C, Uric Acid, NAC, and Melatonin) exhibit the highest adiabatic electron affinity, while guanine derivatives (Gua, [OXO]Gua, Guo, dGuo, [OXO]Guo, [OXO]dGuo) are more prone to adiabatic radical cation formation. A red-ox balance (redox homeostasis) is crucial for intracellular signalling pathways that are reactive oxygen and nitrogen species (RO/NS)-dependent. Should this gentle balance be disrupted, either by an overload or deficit of species, physiological consequences may result, which in turn lead to pathological outcomes. On the other hand, maintaining the stability of the above balance of antioxidants/radicals may result in the improved effectiveness and safety of anticancer radiotherapy/chemotherapy or combined therapies with a subsequent increase in a patient's quality of life.

RevDate: 2025-01-08

Martin V, Trus M, D Atlas (2024)

Thiol-Based Redox Molecules: Potential Antidotes for Acrylamide Toxicity.

Antioxidants (Basel, Switzerland), 13(12): pii:antiox13121431.

Acrylamide (ACR) is a low-molecular weight, non-aromatic reagent, widely used in industry, such as in the manufacture of paper, textiles, plastics, cosmetics, and dyes. ACR is formed during the cooking of starchy food and its toxicity results mainly by conferring oxidative stress by elevating reactive oxygen species (ROS). To identify potential antidotes for ACR toxicity, we evaluated the efficacy of several thiol-based molecules known for ROS-scavenging, disulfide-reducing properties, and inhibition of oxidative stress-induced activation of the mitogen-activated protein kinases (MAPKs): the extracellular-signal-regulated-kinases (ERK1/2), p38-mitogen-activated-protein-kinases (p38[MAPK]), and c-Jun-N-terminal-kinases (JNKs). We established a reproducible assay testing N-acetylcysteine (NAC), AD4/NACA, and the N-and C-blocked tri- and tetra-thioredoxin-mimetic (TXM) peptides, in PC12 cells. Our results demonstrate that these compounds exhibited high efficacy in suppressing ACR-induced MAPK activation, either prior to or subsequent to ACR exposure. The inhibition by single cysteine (Cys) residue, NAC and AD4/NACA (NAC-amide), 2 Cys peptides TXM-CB30, AcDCys-Gly-DCysNH2, TXM-CB20, AcCys-Gly-CysNH2, SuperDopa (SD, Ac-CysL-Levodopa-CysNH2, TXM-CB13, AcCys-Met-Lys-CysNH2, and a 3-Cys peptide, TXM-CB16, AcCys-γGlu-Cys-CysNH2 was dose-dependent and potency displayed a direct correlation with the number of Cys residues. Cellular proteolysis of SD, which consists of levodopa flanked by two Cys, may suppress the manifestation of Parkinson's disease (PD)-like symptoms mediated by chronic ACR exposure not only through lowering oxidative stress but also by replenishing cellular levels of dopamine. Overall, these results could advance the clinical application of TXM peptides as potential treatments for acute and/or chronic exposure to ACR and show promise as antidotes for preventing ACR-triggered PD-like neurotoxic symptoms.

RevDate: 2025-01-06

Li X, Duan Z, Zhao Z, et al (2025)

Mercury(II)-Triggered Targeted and NIR-II Fluorescence/Photoacoustic Imaging Probe for High-Sensitivity Early Diagnosis and Evaluating Drug against Acute Liver and Kidney Injury.

Analytical chemistry [Epub ahead of print].

Mercury ions (Hg[2+]) have been found to disrupt the body's antioxidant defense mechanisms, leading to oxidative stress and physiological dysfunction. Early diagnosis and real-time monitoring of Hg[2+] fluctuations in organ damage are crucial but limited due to the lack of noninvasive and deep tissue imaging probes. Herein, a Hg[2+]-triggered targeted and NIR-II fluorescence/photoacoustic (PA) dual-mode molecular probe (NHG-2) was developed for real-time monitoring Hg[2+] fluctuations in Hg[2+]-induced acute liver and kidney injury mice. NHG-2 was designed through rational adjustment of the conjugated ring structure and further screening processes, enabling it to sensitively recognize Hg[2+] and subsequently open mitochondrial targeting, producing NIR-II fluorescence/PA signals. This probe allowed for noninvasive NIR-II fluorescence/PA imaging for real-time monitoring of Hg[2+]-induced acute liver and kidney injury, demonstrating excellent detection sensitivity. Furthermore, NHG-2 can be utilized to evaluate the efficacy of N-acetylcysteine (NAC) in Hg[2+]-induced liver and kidney injury through dual signal indication. Mechanism studies suggested that NAC activated the antioxidant Akt/Nrf2 signaling pathway, reversed the changes of related biomarkers, and restored mitochondrial membrane potential. Thus, this study not only presents the first specific NIR-II fluorescence/PA dual-mode probe for Hg[2+] but also provides a potential tool for early diagnosis and treatment evaluation and potential pathogenesis study.

RevDate: 2025-01-05

Mapamba DA, Sabi I, Lalashowi J, et al (2025)

N-acetylcysteine modulates markers of oxidation, inflammation and infection in tuberculosis.

The Journal of infection pii:S0163-4453(24)00314-1 [Epub ahead of print].

BACKGROUND: Half the global tuberculosis health burden is due to post-tuberculosis lung disease. Host-directed therapies have been proposed to reduce this burden. N-acetylcysteine (NAC) provides the conditionally essential amino acid cysteine required for synthesis of glutathione, an antioxidant thiol. We recently reported clinical outcomes of a trial of adjunctive NAC in patients with pulmonary tuberculosis, finding that NAC improved the secondary endpoint of recovery of lung function. Here we report the effects of NAC on biomarkers of oxidation, inflammation, and infection in that trial.

METHODS: 140 adults with moderate or far-advanced pulmonary tuberculosis were randomly assigned to standard tuberculosis treatment with or without NAC 1200mg twice daily for months 1-4. Sputum and blood samples were obtained at specified intervals to measure total glutathione, MTB-induced cytokines, haemoglobin, whole blood mycobactericidal activity (WBA), and sputum MTB burden.

RESULTS: NAC treatment rapidly increased total glutathione (P<.0001), but levels did not reach those of healthy volunteers (P<.001). NAC reduced MTB-induced TNF-α (P =.011) without affecting IL-10, and accelerated the recovery of hemoglobin in participants with low values on entry. NAC did not affect killing in ex vivo whole blood culture but did slow the clearance of MTB from sputum (P=0.003).

CONCLUSION: Adjunctive NAC showed antioxidant and anti-inflammatory effects consistent with the amelioration of immunopathology seen in preclinical models. Two biomarkers of antimicrobial activity showed discordant results; neither demonstrated the enhanced antimicrobial effects seen preclinically. The reduction of oxidative stress and inflammation by NAC may explain its effects on the recovery of lung function post-TB.

RevDate: 2025-01-03

Sun E, Torices S, Osborne OM, et al (2025)

Microvascular dysfunction, mitochondrial reprogramming, and inflammasome activation as critical regulators of ischemic stroke severity induced by chronic exposure to prescription opioids.

The Journal of neuroscience : the official journal of the Society for Neuroscience pii:JNEUROSCI.0614-24.2024 [Epub ahead of print].

The opioid epidemic endangers not only public health but also social and economic welfare. Growing clinical evidence indicates that chronic use of prescription opioids may contribute to an elevated risk of ischemic stroke and negatively impact post-stroke recovery. In addition, NLRP3 inflammasome activation has been related to several cerebrovascular diseases, including ischemic stroke. Interestingly, an increase in NLRP3 inflammasome activation has also been reported in chronic opioid exposure. Given the pivotal roles of the blood-brain barrier (BBB) and oxidative stress in ischemic stroke pathophysiology, this study focuses on the impact of chronic exposure to prescription opioids on the integrity of cerebrovascular microvasculature, endothelial mitochondrial homeostasis, and the outcomes of ischemic stroke in male wild type and NLRP3-deficient mice. Our results demonstrate that chronic opioid exposure can compromise the integrity of the BBB and elevate the generation of reactive oxygen species (ROS), resulting in endothelial mitochondrial dysfunction and apoptosis activation. We also provide evidence that opioid exposure enhances inflammasome activation, inflammatory responses, and increases the severity of an ischemic stroke. The antioxidant N-acetylcysteine (NAC) ameliorated these opioid-induced alterations and accelerated the post-stroke tissue restoration and functional recovery processes in opioid-exposed mice. Importantly, there was also a significant decrease in ischemic stroke damage in the NLRP3-deficient mice with chronic opioid exposure as compared to wild-type controls. These findings indicate that chronic exposure to prescription opioids impacts the outcome of ischemic stroke by damaging microvascular cerebral integrity through inflammasome activation and mitochondrial dysfunction.Significance Statement Misuse of opioids has become one of the most important public health problems. Growing evidence indicates that chronic use of prescription opioids may contribute to an elevated risk of ischemic stroke, and negatively impact post-stroke recovery. In the present study, we hypothesize that microvascular dysfunction can underlie the impact of prescription opioid on an ischemic stroke. Our novel results demonstrate that opioid exposure leads to mitochondrial dysfunction in the brain microvascular endothelium, compromised blood-brain barrier integrity, enhanced inflammatory responses, and more severe effects of an ischemic stroke. Importantly, the NLRP3 inflammasome-deficient mice or treatment with N-acetylcysteine attenuated these alterations and enhanced post-stroke tissue and functional recovery, providing valuable therapeutic options for people with opioid use disorder.

RevDate: 2025-01-03

Lin J, Zhang T, L Zhang (2024)

Arsenite-induced liver apoptosis via oxidative stress and the MAPK signaling pathway in marine medaka.

Aquatic toxicology (Amsterdam, Netherlands), 279:107226 pii:S0166-445X(24)00395-3 [Epub ahead of print].

Arsenic (As) is widely recognized for its hazards to aquatic organisms; however, its toxicological impacts on apoptosis in marine fish remain inadequately explored. This study investigated the effects of in vivo dietary exposure to 50 or 500 mg/kg AsIII (as NaAsO2) over 28 days in marine medaka, alongside in vitro exposure to 50-750 μg/L AsIII for 48 h in a hepatic cell line derived from marine medaka, to elucidate the toxicity and underlying molecular mechanisms. In vivo, As significantly accumulated in liver tissue (1.79-fold compared to the control), causing hepatic lesions and increased apoptosis (4.85 ± 0.56 % and 9.29 ± 1.82 %, respectively). Gene expression analysis showed downregulation of bcl2l1 and upregulation of bax, caspase-3 and caspase-9, indicating mitochondrial pathway-mediated apoptosis. In vitro, As exposure induced hepatocyte morphological changes, reactive oxygen species (ROS) production, and apoptosis. Additionally, mapk1 and mapk3 (ERK pathway) were downregulated both in vivo and in vitro, while mapk14a (P38 pathway), mapk8b and mapk9 (JNK pathway) were upregulated exclusively in hepatocytes. Furthermore, n-acetyl cysteine (NAC) attenuated As-induced apoptosis and modulated the expression of MAPK signaling pathway genes, including mapk3 and mapk8b, suggesting that As-induced oxidative stress regulates apoptosis via the MAPK signaling pathway. In contrast, phenylbutyric acid (PBA) was ineffective in preventing apoptosis. Overall, these results demonstrate that As induces endogenous apoptosis through oxidative stress and the MAPK signaling pathway in marine medaka.

RevDate: 2025-01-04

Shokoohi M, Khaki AA, Roshangar L, et al (2024)

The impact of N-acetylcysteine on hypoxia-induced testicular apoptosis in male rats: TUNEL and IHC findings.

Heliyon, 10(22):e40097.

The present study aimed to evaluate the impact of N-acetylcysteine (NAC) on testicular hypoxia caused by varicocele, focusing specifically on the regulation of genes related to apoptosis and oxidative stress in the testes of mature Wistar rats. Thirty-two rats were divided into four groups: Control (Sham), hypoxia, testicular hypoxia treated with NAC (Hypoxia + NAC), and healthy animals treated with NAC. After the 8-week treatment period, testicular histopathology and the levels of oxidative stress markers-superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA)-in serum were examined. The expression of Bax and Bcl-2 mRNA was analyzed using immunocytochemistry and RT-qPCR assays, while the apoptosis rate was determined using the TUNEL method. Histopathological evaluations showed that parameters such as Johnsen's score, epithelium width, and seminiferous tubule diameter indicated significant improvement in the Hypoxia + NAC group compared to the Hypoxia group. NAC administration resulted in elevated serum levels of GPx and SOD, accompanied by a reduction in MDA levels (p < 0.003). Furthermore, the study revealed that NAC decreased Bax expression and enhanced Bcl-2 gene and protein expression compared to the varicocele group (p < 0.05). Additionally, NAC administration significantly decreased the rate of apoptosis in germ cells (p < 0.05). These findings suggest that NAC administration can mitigate testicular damage induced by hypoxia from varicocele in rats, primarily due to its antioxidant properties.

RevDate: 2025-01-05
CmpDate: 2025-01-03

Bahramibanan F, Rad MV, Ranjbar A, et al (2025)

Comparison of oxidative stress status in the kidney tissue of male rats treated with paraquat and nanoparaquat.

Scientific reports, 15(1):389.

The study aimed to compare the oxidative stress status in the kidney tissue of rats treated with paraquat and nanoparaquat. The levels of oxidative stress markers, including malondialdehyde (MDA), total antioxidant capacity (TAC), and thiol groups (TTG), were measured in the kidney tissue samples. A total of forty male Wistar rats were randomly assigned to eight groups, each consisting of five rats: a control group, a paraquat (PQ) group, an N-acetylcysteine (NAC) group, groups receiving nanoparaquat α and β (α and β), groups receiving PQ and NAC (PQ + NAC), and groups receiving nanoparaquat α and β with NAC (+ NACα and β). Paraquat, a widely used herbicide, induces severe oxidative damage in kidneys through radical formation and cellular stress. Newly developed nanoparaquat formulations may modify its toxicity profile and tissue distribution patterns. The results revealed that rats treated with paraquat showed a significant increase in Lipid Peroxidation Oxidation (LPO) levels compared to the control group and those treated with NAC. However, treatment with nanoparaquat α and β resulted in a decrease in LPO levels compared to the paraquat-treated group. Additionally, when nanoparaquat α and β were administered in combination with NAC, a further reduction in LPO levels was observed compared to the PQ treated group. Regarding TAC levels, the PQ group exhibited a significant decrease compared to the control group and the NAC-treated group. However, treatment with nanoparaquat β resulted in higher TAC levels compared to the PQ group. Moreover, when nanoparaquat α and β were administered in combination with NAC, there was an increase in TAC levels compared to the PQ group. In terms of TTG levels, the PQ group showed a significant decrease compared to the control group and the NAC group. However, treatment with nanoparaquat β led to an increase in TTG levels compared to the PQ group. Furthermore, when nanoparaquat α and β were administered in combination with NAC, there was an increase in TTG levels compared to the PQ group. Overall, the results suggest that treatment with nanoparaquat, especially nanoparaquat β, may have a protective effect against oxidative stress induced by PQ toxicity in the kidney tissue of rats. Further studies are warranted to elucidate the underlying mechanisms and potential therapeutic implications of nanoparaquat in oxidative stress-related kidney disorders.

RevDate: 2025-01-01

Yang X, Li Y, Shen R, et al (2024)

New insights into the tenderization pattern of yak meat by ROS-ERS: Promotion of ERS-associated apoptosis through feedback regulation of PERK/IRE1/ATF6 and caspase-12 activity.

Food chemistry, 470:142705 pii:S0308-8146(24)04355-3 [Epub ahead of print].

This study aimed to investigate the molecular mechanisms of reactive oxygen species (ROS)-induced endoplasmic reticulum stress (ERS) in apoptosis and meat tenderization during postmortem aging. Yak longissimus dorsi muscle was incubated with N-acetylcysteine (NAC), 4-phenylbutyric acid (4-PBA) and NAC + 4-PBA, respectively, and stored at 4 °C for 0 h, 12 h, 24 h, 72 h, 120 h and 168 h. The results showed that NAC and 4-PBA treatments significantly reduced ROS content and endoplasmic reticulum stress levels. Meanwhile, the specific inhibitory effect of 4-PBA affected Ca[2+] content, caspase-12 activity, endoplasmic reticulum apoptotic cascade reaction and meat tenderization by preventing myogenic fiber degradation. Additionally, the combined treatment of NAC + 4-PBA had a more significant effect than the other groups, confirming the necessity of targeted regulation of the ROS-ERS axis. Overall, our findings provide new insights into the critical role of ROS-mediated ERS in caspase-12-dependent apoptosis and yak meat tenderization during yak meat postmortem.

RevDate: 2025-01-02
CmpDate: 2024-12-31

Essam R, Nasr M, Khater MW, et al (2024)

Anti-microbial impact of non-antibiotic agents; salicylic acid, N-acetylcysteine, and isotretinoin against Cutibacterium acnes in patients with acne vulgaris.

Archives of dermatological research, 317(1):155.

There are two main strategies to eliminate Cutibacterium acnes and to reduce antibiotic resistance in acne treatment. The first is to target the pathogenic bacteria and the second is to change the environment for their growth. The present study aimed to evaluate the anti-microbial role of non-antibiotic agents against Cutibacterium acnes (C. acnes) in acne vulgaris patients. The three agents of interest in the study were isotretinoin, salicylic acid, and N-acetylcysteine (NAC). The study included forty-eight patients with acne vulgaris with ages ranging from 16 to 30 years, and they had different grades of the disease. Azithromycin and Doxycycline sensitivity and the ability of biofilm formation of C. acnes isolated from all patients were assessed before and after adding the 3 agents. Azithromycin and Doxycycline sensitivity was improved after adding the 3 agents and the ability of biofilm formation of C. acnes was also reduced. Isotretinoin, salicylic acid, and NAC can be promising adjuvants in treating acne vulgaris by their anti-microbial effect in reducing biofilm formation and improving antibiotic sensitivity. Clinical Trial NCT06179056.

RevDate: 2025-01-04
CmpDate: 2024-12-31

Higazy D, Ahmed MN, O Ciofu (2024)

The impact of antioxidant-ciprofloxacin combinations on the evolution of antibiotic resistance in Pseudomonas aeruginosa biofilms.

NPJ biofilms and microbiomes, 10(1):156.

The evolution of antimicrobial resistance (AMR) in biofilms, driven by mechanisms like oxidative stress, is a major challenge. This study investigates whether antioxidants (AOs) such as N-acetyl-cysteine (NAC) and Edaravone (ED) can reduce AMR in Pseudomonas aeruginosa biofilms exposed to sub-inhibitory concentrations of ciprofloxacin (CIP). In vitro experimental evolution studies were conducted using flow cells and glass beads biofilm models. Results showed that combining CIP with antioxidants (CIP-AOs) effectively reduced the development of CIP resistance. Isolates from biofilms treated with CIP-AO had significantly lower minimum inhibitory concentrations (MICs) of CIP compared to those treated with CIP alone. Whole-genome sequencing (WGS) revealed mutations in the negative regulators of efflux pumps, nfxB, and nalC, in CIP-only treated biofilm populations. The occurrence of nfxB mutations was significantly lower in flow cell biofilms treated with CIP-AO compared to CIP alone. These findings suggest that antioxidants could play a role in mitigating AMR development in biofilms.

RevDate: 2025-01-04
CmpDate: 2024-12-31

Xing T, Hu LJ, Zhao HY, et al (2024)

Bone Marrow Endothelial Progenitor Cells remodelling facilitates normal hematopoiesis during Acute Myeloid Leukemia Complete Remission.

Nature communications, 15(1):10832.

Although acute myeloid leukemia (AML) affects hematopoietic stem cell (HSC)-supportive microenvironment, it is largely unknown whether leukemia-modified bone marrow (BM) microenvironment can be remodeled to support normal hematopoiesis after complete remission (CR). As a key element of BM microenvironment, endothelial progenitor cells (EPCs) provide a feasible way to investigate BM microenvironment remodeling. Here, we find reduced and dysfunctional BM EPCs in AML patients, characterized by impaired angiogenesis and high ROS levels, could be partially remodeled after CR and improved by N-acetyl-L-cysteine (NAC). Importantly, HSC-supporting ability of BM EPCs is partially recovered, whereas leukemia-supporting ability is decreased in CR patients. Mechanistically, the transcriptome characteristics of leukemia-modified BM EPCs return to near-normal after CR. In a classic AML mouse and chemotherapy model, BM vasculature and normal hematopoiesis are reversed after CR. In summary, we provide further insights into how leukemia-modified BM microenvironment can be remodeled to support normal hematopoiesis after CR, which can be further improved by NAC.

RevDate: 2025-01-03
CmpDate: 2024-12-31

Coşkun Ç, Aksu T, Gülhan B, et al (2025)

Plasma Exchange and N-Acetylcysteine Therapy in a Case of Congenital Thrombotic Thrombocytopenic Purpura Presenting With Acute Renal Failure.

Journal of pediatric hematology/oncology, 47(1):e65-e67.

Congenital thrombotic thrombocytopenic purpura (cTTP), which is associated with mutations in the gene for a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13), is a chronic and lifelong disease. The clinical course is variable. Regularly using ADAMTS13-containing products such as fresh frozen plasma (FFP) for long-term prophylaxis is the most important treatment to prevent thrombotic microangiopathy (TMA) episodes. Here, we identified novel pathogenic mutations of ADAMTS13 in our patients who experienced severe acute renal failure. Infections can trigger acute hemolytic episodes, and if the initiation of FFP therapy is delayed, this leads to severe organ dysfunction, as in our case. We have shown that regular use of products containing ADAMTS13 can reverse TMA episodes and long-term morbidity and mortality. When severe acute renal failure occurs, daily plasma exchange and N-acetylcysteine (NAC) are useful.

RevDate: 2024-12-30

Mao K, Huang Y, Liu Z, et al (2024)

Oxidative stress mediates retinal damage after corneal alkali burn through the activation of the cGAS/STING pathway.

Experimental eye research pii:S0014-4835(24)00450-0 [Epub ahead of print].

Retinal damage accounts for irreversible vision loss following ocular alkali burn (OAB), but the underlying mechanisms remain largely unexplored. Herein, using an OAB mouse model, we examined the impact of oxidative stress (OS) in retinal damage and its molecular mechanism. Results revealed that OS in the retina was enhanced soon after alkali injury. Antioxidant therapy with N-acetylcysteine (NAC) preserved the retinal structure, suppressed cell apoptosis and decreased retinal inflammation, confirming the role of OS. Moreover, enhanced OS was linked to mitochondrial dysfunction, mtDNA leakage and initiation of the cytosolic DNA-sensing signaling. The activation of the major DNA sensors cyclic GMP-AMP Synthase (cGas) and cGAS-Stimulator of Interferon Genes (cGAS/STING) pathway was then identified. Notably, inhibiting cGAS/STING signaling with C-176 markedly reduced inflammation and cell apoptosis and ultimately protected the retina against OAB. Overall, our study reveals the vital function of OS in the occurence of OAB-induced retinal damage and the involvement of cGAS/STING activation. Furthermore, our provides preclinical validation of the use of an antioxidant or a STING inhibitor as a potential therapeutic approach to protect the retina after OAB.

RevDate: 2024-12-31

Li Z, Nie J, Zhou R, et al (2024)

Thiostrepton suppresses colorectal cancer progression through reactive oxygen species related endoplasmic reticulum stress.

Toxicology and applied pharmacology, 495:117221 pii:S0041-008X(24)00420-4 [Epub ahead of print].

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Due to the poor therapeutic efficacy of CRC treatments and poor prognosis of the disease, effective treatment strategies are urgently needed. As long-term proteotoxic stress is a major cause of cell death, agents that induce proteotoxic stress offer a promising strategy for cancer intervention. Thiostrepton is a natural antibiotic derived from the Streptomyces genus. In the present study, we found that thiostrepton triggered apoptosis, reduced the migration of CRC cells, and inhibited xenograft tumour growth in vivo. Mechanistically, thiostrepton reduced proteasome activity; induced the aggregation of ubiquitinated proteins; caused endoplasmic reticulum (ER) stress, which was characterized by increased protein levels of GRP78, ATF4, P-eIF2α, and CHOP and cytosolic calcium release; and ultimately resulted in cell death. Thiostrepton-related changes in cell survival and cell migration, as well as mechanistical processes, were almost completely reversed by treatment with the antioxidant N-acetylcysteine (NAC), suggesting that the mechanism is dependent on reactive oxygen species (ROS). These results demonstrated that thiostrepton induced apoptosis and inhibited migration through ROS-induced ER stress and proteotoxic stress in colorectal cancer.

RevDate: 2024-12-28
CmpDate: 2024-12-28

Rasheed H, Ijaz M, Ahmed A, et al (2024)

Antimicrobial resistance, virulence profiling, and drug repurposing analysis of Staphylococcus aureus from camel mastitis.

Veterinary research communications, 49(1):59.

Camel mastitis especially caused by Staphylococcus aureus (S. aureus), is a major risk to animal health and milk production. The current investigation evaluated the antibiotic susceptibility and virulence factors of S. aureus isolates from subclinical mastitis in camels. A total of 384 milk samples were collected and submitted to isolate S. aureus. The S. aureus isolates exhibiting resistance to Penicillin and Cefoxitin disc on Kirby-Bauer disc diffusion method were considered as β-lactam resistant S. aureus (BRSA) and methicillin-resistant S. aureus (MRSA) which were further confirmed by PCR targeting blaZ and mecA genes, respectively. The results showed that S. aureus was found in 57.06% of subclinical (SCM) positive camel milk samples. A high molecular prevalence of BRSA and MRSA were found to be 48.51% and 46.53% respectively depicting that treating these infections is challenging due to their high resistance levels. The phylogenetic analysis revealed a significant resemblance of the study isolates with each other and with already reported sequences from different countries which shows the potential for the spread of pathogen. Virulence profiling of antibiotic resistance strains showed the presence of virulence markers (nuc and coag genes), intercellular adhesion genes (icaA, icaD), Panton-Valentine leukocidin (pvl) gene, and enterotoxin-producing genes including sea, seb, sec, and sed. In-vitro antibiotic susceptibility testing revealed that the most resistant antibiotic group was penicillin followed by aminoglycosides and cephalosporins. Drug repurposing analysis of different non-antibiotics for combination therapies with resistant antibiotics was done to combat the S. aureus isolates harboring the mecA and blaZ genes. The results revealed the synergistic effect of amoxicillin, sulfamethoxazole, gentamicin, and doxycycline with ketoprofen, amikacin with flunixin meglumine, and gentamicin with N-acetylcysteine (NAC) against study isolates. The current investigation provides the status of antibiotic-resistant strains and virulence factors of S. aureus in the udder of dromedary camels. The combinational therapy of resistant antibiotics with non-antibiotics provides a potential therapeutic option for the treatment of resistant strains.

RevDate: 2025-01-04
CmpDate: 2024-12-27

Li M, Liu Z, Cao X, et al (2024)

[Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6.

Scientific reports, 14(1):30924.

High glucose (HG) induced endothelial senescence is related to endothelial dysfunction and cardiovascular complications in diabetic patients. Humanin, a member of mitochondrial derived peptides (MDPs), is thought to contribute to aging-related cardiovascular protection. The goal of the study is to explore the pathogenesis of HG-induced endothelial senescence and potential anti-senescent effects of Humanin. Human umbilical vein endothelial cells (HUVECs) were exposed to glucose to induce senescence, determined by β-galactosidase staining and the expressions of p21, p53, and p16. A clinically relevant dose of HG (15 mM, HG) induced endothelial senescence after 72 h incubation without elevated apoptosis. HG-induced senescence was attributed to the induction of reactive oxygen species (ROS) caused by SIRT6 downregulation, as ROS inhibitor N-acetyl cysteine blocked HG-induced senescence, while inactivation of SIRT6 increased ROS levels and promoted senescence. Strikingly. pretreatment with [Gly14]-Humanin (HNG) antagonized the downregulation of SIRT6 in response to HG and alleviated ROS production and cell senescence. HG-induced reduction of SIRT6 results in ROS overproduction and endothelial senescence. Humanin protects against HG-induced endothelial senescence via SIRT6. This study provides new directions for biological products related to Humanin to be a potential candidate for the prevention of vascular aging in diabetes.

RevDate: 2024-12-27

Muhammad W, Liang M, Wang B, et al (2024)

NAC-Grafted ROS-Scavenging Polymer Nanoparticles for Modulation of Acute Lung Injury Microenvironment In Vivo.

Biomacromolecules [Epub ahead of print].

N-Acetyl cysteine (NAC) is an essential molecule that boosts acute lung injury (ALI) defense via its direct antioxidant capability. Nevertheless, the therapeutic use of NAC is limited due to its poor bioavailability and short half-life. In this study, NAC was grafted to the polyurethane consisting of poly(propylene fumarate), poly(thioketal), and 1,6-hexamethylene diisocyanate (PFTU) to reduce excessive oxidative stress and inflammatory factors in ALI. The NAC-grafted polymer nanoparticles (NPT@NPs) were prepared as a drug delivery system, which could effectively scavenge free radicals and reduce inflammation in vitro. The administration of NPT@NPs exhibited notable efficacy in ameliorating pulmonary edema, attenuating the presence of inflammatory cells, suppressing myeloperoxidase expression, diminishing the levels of pro-inflammatory cytokines, and reversing cell apoptosis in an ALI model induced by lipopolysaccharide (LPS). The NPT@NPs demonstrated significantly better efficacy compared to the free NAC in mitigating the deleterious effects of LPS on pulmonary tissue, thereby providing more effective protection against pulmonary inflammation.

RevDate: 2024-12-27

Alrashed M, Alyousef A, Badreldin HA, et al (2024)

Comparison of Three-Bag Method Acetylcysteine Versus Two-Bag Method Acetylcysteine for the Treatment of Acetaminophen Toxicity: An Updated Systematic Review and Meta-Analysis.

Diseases (Basel, Switzerland), 12(12): pii:diseases12120332.

BACKGROUND: Acetaminophen is generally considered safe when used according to the recommended guidelines. Consumption in excessive doses can lead to severe liver damage and, in critical cases, may even result in death. To reduce the effects of acetaminophen overdose, N-acetylcysteine (NAC) has been established as the preferred intervention to prevent liver damage.

OBJECTIVES: The purpose of this updated systematic review and meta-analysis is to evaluate the potential benefits of a two-bag N-acetylcysteine (NAC) dosing regimen compared to the traditional three-bag protocol in the treatment of acetaminophen-induced liver toxicity.

METHODS: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The research team utilized the PubMed and Cochrane databases to perform a thorough and comprehensive search of the relevant literature from the inception of these databases up until January 2024.

RESULTS: Nine studies were included. The overall use of two-bag NAC was associated with lower anaphylactic reactions and gastrointestinal symptoms compared to the three-bag method. The rate of liver toxicity resolution was the same between the two treatment groups.

CONCLUSIONS: The two-bag NAC regimen can be considered a safe and effective method for managing acetaminophen toxicity.

RevDate: 2025-01-04

Ntchana A, R Muhumza (2024)

Use of N-Acetylcysteine in the Management of Isoniazid-Induced Liver Injury in a Tuberculosis Patient: A Case Report.

Cureus, 16(11):e74445.

Drug-induced liver injury (DILI) is a rare but significant cause of acute liver failure, often challenging to diagnose due to its clinical similarity to other liver conditions. Since most drugs are metabolized by liver enzymes, the liver is at risk for hepatotoxicity. Although DILI has a low incidence in clinical practice, it remains a critical consideration for patients on potentially hepatotoxic medications. Acetaminophen is the most commonly implicated drug in DILI cases and is prioritized in toxicology screenings. Effective management of DILI requires the prompt discontinuation of the offending drug and supportive care. This case report discusses a 65-year-old male patient who developed elevated liver enzymes three weeks after starting tuberculosis treatment, raising suspicion of DILI. This report explores the diagnostic process, management strategies, and therapeutic role of N-acetylcysteine (NAC), emphasizing its mechanism of action, current clinical applications, and potential future uses in treating DILI.

RevDate: 2025-01-07

Khanal S, Shin EJ, Yoo CJ, et al (2024)

Inosine exerts dopaminergic neuroprotective effects via mitigation of NLRP3 inflammasome activation.

Neuropharmacology, 266:110278 pii:S0028-3908(24)00447-7 [Epub ahead of print].

Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Transformation of pro-interleukin (IL)-1β into a mature IL-1β via active inflammasome may be related to the progression of PD. Therefore, the modification of inflammasome activity may be a potential therapeutic strategy for PD. Inosine has been shown to exert anti-inflammatory effects in various disease models. In this study, we evaluated inosine's inhibitory effects on the microglial NLRP3 inflammasome, which may be related to the dopaminergic neuroprotective effects of inosine. Inosine suppresses lipopolysaccharides (LPS)-induced NLRP3 inflammasome activation in BV-2 microglial cells dose dependently. When SH-SY5Y cells were treated with conditioned medium from BV-2 cells treated with LPS and inosine, an NLRP3 inhibitor, or a caspase-1 inhibitor, the viability of SH-SY5Y cells was reduced indicating that LPS-induced microglial inflammasome activation could contribute to neuronal death. Inosine's modulatory effect on NLRP3 inflammasome activity appears to rely on the adenosine A2A and A3 receptors activation, as A2A or A3 receptor antagonists reversed the amelioration of NLRP3 activation by inosine. In addition, inosine treatment attenuated intracellular and mitochondrial ROS production mediated by LPS and this effect might be related to attenuation of NLRP3 inflammasome activity, as the antioxidant, N-acetyl cysteine ameliorated LPS-induced activation of the inflammasome. Finally, we assessed the inosine's neuroprotective effects via inflammasome activity modulation in mice receiving an intranigral injection of LPS. Immunohistochemical analysis revealed that LPS caused a significant loss of nigral dopaminergic neurons, which was mitigated by inosine treatment. LPS increased NLRP3 expression in IBA1-positive microglial cells, which was attenuated by inosine injection. These findings indicate that inosine can rescue neurons from LPS-induced injury by ameliorating NLRP3 inflammasome activity. Therefore, inosine could be applied as an intervention for neuroinflammatory diseases such as Parkinson's disease.

RevDate: 2024-12-26

Kokurcan A, Sandıkçı F, Yılmaz MŞ, et al (2024)

Protective effects of tadalafil and N-acetyl cysteine therapy on cisplatin-induced testicular toxicity.

International urology and nephrology [Epub ahead of print].

PURPOSE: To investigate whether tadalafil (TAD) and N-acetyl cysteine (NAC) can prevent cisplatin (CIS)-induced testicular toxicity.

METHODS: Forty Wistar-Albino rats were divided into five groups: Control group, CIS group, TAD group, NAC group and TAD + NAC group. All groups were compared regarding body and testicular weights, testicular volumes, blood testosterone levels, testicular tissue malondialdehyde (MDA) levels, histopathological features, and testicular Cosentino and Johnsen scores.

RESULTS: There was no significant difference between the groups regarding body weights and Johnsen scores. It was observed that TAD and NAC affected the apoptotic index, and Cosentino scores were lower in these groups than in the control group. This effect was most prominent in the TAD + NAC group. The CIS treatment led to a decrease in serum testosterone levels. While testosterone levels were higher in the TAD Group, no statistically significant difference was found between the groups. Combination therapy and NAC did not affect blood testosterone levels.

CONCLUSIONS: Cisplatin has adverse effects on the testicular tissue. The histopathological changes caused by this agent can be prevented by TAD + NAC combination therapy.

RevDate: 2024-12-25

Zhu Y, Dutta S, Han Y, et al (2024)

Oxidative stress promotes lipid-laden macrophage formation via CYP1B1.

Redox biology, 79:103481 pii:S2213-2317(24)00459-2 [Epub ahead of print].

Emerging evidence suggests that lipid-laden macrophages (LLM) participate in lung damage in various clinical conditions. However, the mechanisms involved in LLM formation are not fully understood. In this study, we aimed to investigate the link between reactive oxygen species (ROS) and LLM formation. We found that ROS triggered by cigarette smoke extract (CSE) or H2O2 significantly promoted LLM formation. Given the key role of ROS in LLM formation, we further demonstrated that LLM formation is induced by various ROS-producing stimuli, including bacteria, oxidized low-density lipoprotein (OxLDL), hyperoxia, and E-cigarette vapor extract (EVE). Meanwhile, cytochrome P450 family-1 subfamily B member 1 (CYP1B1) was highly upregulated in lung macrophages from chronic obstructive pulmonary disease (COPD) patients and CSE-treated macrophages. Functionally, CYP1B1 contributes to the CSE-induced lipid accumulation and LLM formation. CYP1B1 expression and LLM formation were effectively suppressed by antioxidant N-acetylcysteine (NAC) and carvedilol. The formation of LLM was also associated with classically activated M1 but not the M2 state. CSE-induced LLM showed time-dependent alterations in inflammatory response and phagocytic ability. In summary, our study highlights the role of oxidative stress in LLM formation. CYP1B1 contributes to ROS-induced LLM formation and may serve as a therapeutic target for reducing LLM-induced lung damage.

RevDate: 2025-01-04

Qiu X, Yao Y, Chen Y, et al (2024)

TRPC5 Promotes Intermittent Hypoxia-Induced Cardiomyocyte Injury Through Oxidative Stress.

Nature and science of sleep, 16:2125-2141.

PURPOSE: Intermittent hypoxia (IH), a defining feature of obstructive sleep apnea (OSA), is associated with heart damage and linked to transient receptor potential canonical channel 5 (TRPC5). Nonetheless, the function of TRPC5 in OSA-induced cardiac injury remains uncertain. For this research, we aimed to explore the role and potential mechanism of TRPC5 in cardiomyocyte injury induced by intermittent hypoxia.

METHODS: 30 patients with newly diagnosed OSA and 30 patients with primary snoring(PS) were included in this study. Participants were subjected to polysomnography (PSG) for OSA diagnosis. Echocardiography was used to evaluate the structure and function of the heart, while peripheral blood samples were obtained. Additionally, RT-qPCR was utilized to quantify the relative expression level of TRPC5 mRNA in peripheral blood. H9c2 cells experienced IH or normoxia. TRPC5 levels in H9c2 cells were determined via RT-qPCR and Western blotting (WB) methods. H9c2 cells overexpressing TRPC5 were subjected to either normoxic or intermittent hypoxia conditions. Cell viability was determined by CCK8, the apoptosis rate, reactive oxygen species(ROS) levels, and Ca[2+] concentration were assessed by flow cytometry, and the protein levels of TRPC5, Bcl-2, Bax, and Caspase-3 were analyzed by WB. Mitochondrial membrane potential(MMP), mitochondrial membrane permeability transition pore(mPTP), and transmission electron microscopy(TEM) were employed to observe mitochondrial function and structure. After inhibiting ROS with N-acetylcysteine (NAC), apoptosis, mitochondrial function and structure, and the concentration of Ca[2+] were further detected.

RESULTS: TRPC5 and left atrial diameter (LAD) were higher in OSA individuals, while the E/A ratio was lower(all P<0.05). IH impaired cell viability, triggered cell apoptosis, and enhanced TRPC5 expression in H9c2 cells(all P<0.05). The effects of IH on apoptosis, cell viability, mitochondrial function and structure damage, and oxidative stress (OxS) in H9c2 cells were accelerated by the overexpression of TRPC5(all P<0.05). Furthermore, cell apoptosis and mitochondrial structural and functional damage caused by overexpression of TRPC5 were attenuated by ROS inhibition.

CONCLUSION: TRPC5 is associated with structural and functional cardiac damage in patients with OSA, and TRPC5 promotes IH-induced apoptosis and mitochondrial damage in cardiomyocytes through OxS. TRPC5 may be a novel target for the diagnosis and treatment of OSA-induced myocardial injury.

RevDate: 2024-12-26

Xu M, Yu S, Li P, et al (2024)

Tailored multilayer nanoparticles against resistant P. aeruginosa by disrupting the thickened mucus, dense biofilm and hyperinflammation.

Journal of controlled release : official journal of the Controlled Release Society, 378:588-604 pii:S0168-3659(24)00892-7 [Epub ahead of print].

Therapeutic challenges of chronic pulmonary infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRP. aeruginosa) biofilms due to significantly enhanced antibiotic resistance. This resistance is driven by reduced outer membrane permeability, biofilm barriers, and excessive secretion of virulence factors. Thickened mucus in the airways exacerbates the problem by impeding antibiotic penetration, providing a breeding ground for biofilms, consequently aggravating infection. Moreover, biofilms recruit numerous immune cells, resulting in chronic inflammation and lung tissue damage. In turn, damaged airway further facilitates bacterial colonization and elevated mucus production. To thoroughly disintegrate the stubborn triad of "thickened mucus & dense biofilm & excessive inflammation" and address drug resistance, tailored multilayer nanoparticles (NPVC/PBIP NPs) were developed. NPVC/PBIP NPs were engineered through self-assembly of vanillin-chitosan amphiphilic polymer loading polymyxin B-linoleic acid ion pairs in. Then polyaspartic acid and N-acetylcysteine-ε-poly-l-lysine were coated by layer-by-layer on the surface of vanillin-chitosan NPs via electrostatic interactions. As expected, the NAC units on NPVC/PBIP NPs effectively thinned human clinical sputum and porcine sputum, resulting in rapid sputum penetration followed by biofilm permeation. NPVC/PBIP NPs achieved over 99 % eradication of mature biofilms in vitro. Furthermore, they effectively inhibited virulence factors production and bacteria re-adhesion (biofilm reformation) while exhibiting superior anti-inflammatory and antioxidant activities. In a chronic pulmonary infection model, NPVC/PBIP NPs remarkably thinned airway mucus, reduced bacterial burden by 99.7 %, alleviated inflammatory cell infiltration, and minimized lung tissue damage. In summary, the NPVC/PBIP NPs represent a novel and promising strategy to manage MDRP. aeruginosa biofilms associated infections by disintegrating the stubborn triad of "thickened mucus & dense biofilm & excessive inflammation".

LOAD NEXT 100 CITATIONS

RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

Support this website:
Order from Amazon
We will earn a commission.

Focusing on the practical use of N-Acetyl-Cysteine (NAC) in medicine, this book provides a comprehensive review of the basic biological and clinical studies documenting its benefits in treating medical disease. NAC is perhaps best known as an antidote for acetaminophen, but its therapeutic effect in a wide range of medical diseases has recently been realized. In addition to its well recognized use in radiological contrast prophylaxis for renal disease and pulmonary disorders, studies have suggested significant promise in psychiatric and neurological disorders such as addiction, Alzheimer’s disease, ataxia, autism, bipolar disorder, depression, epilepsy, neuropathy, obsessive-compulsive disorder, schizophrenia, traumatic brain injury and trichotillomania in addition to promising studies in audiology, cardiology, exercise physiology, gastroenterology, hematology, infectious disease, infertility and ophthalmology. Given the promising studies for a wide range of medical conditions, coupled with a excellent safety profile, the potential for NAC in the treatment of human disease appears considerable. Amazon

963 Red Tail Lane
Bellingham, WA 98226

206-300-3443

E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

RJR Picks from Around the Web (updated 11 MAY 2018 )