Effects of N-Acetylcysteine on Humanin and Endostatin in Rats Exposed to Formaldehyde.

INTRODUCTION: People are constantly exposed to formaldehyde, a volatile and poisonous gas, in indoor environments. In particular, anatomists, pathologists, histologists, and those involved in embalming are exposed to higher amounts of formaldehyde continuously due to their work. This study aimed to investigate the effect of N-acetylcysteine on endostatin and humanin values in male rats exposed to experimental formaldehyde. METHODS: In the study, 28 male Spraque-Dawley rats aged 12-14 weeks (seven animals in each group: control group, formaldehyde group, N-acetylcysteine group, formaldehyde+N-acetylcysteine group) were used. Four weeks later, the animals were sacrificed by decapitation. Following decapitation, endostatin and humanin levels in the serum of rats were studied by the enzyme-linked immunoassay (ELISA) method. In all analyses, p<0.05 was accepted as statistically significant. RESULTS: Humanin and endostatin values were checked in the serum of rats. When humanin levels were compared between groups, a statistically significant difference was found between the formaldehyde group and both the control group (p<0.05) and the N-acetylcysteine group (p<0.05). In the formaldehyde+N-acetylcysteine group, it was determined that the humanin level was impaired due to formaldehyde exposure, approaching the control group values with the administered N-acetylcysteine. When the endostatin level was compared between the groups, a statistical significance (p<0.05) was found only between the formaldehyde group and the N-acetylcysteine group. In the formaldehyde+N-acetylcysteine group, it was determined that the endostatin level was impaired due to formaldehyde exposure, approaching the control group values with the administered N-acetylcysteine. CONCLUSION: In this study, the effects of N-acetylcysteine on humanin and endostatin on rats exposed to formaldehyde were demonstrated for the first time. Formaldehyde exposure negatively affected humanin and endostatin levels in rat sera. N-acetylcysteine ameliorated the negative effects of formaldehyde, bringing humanin and endostatin levels closer to the healthy control group.

Safety and Pharmacokinetics of a Combined Antioxidant Therapy against Myocardial Reperfusion Injury: A Phase I Randomized Clinical Trial in Healthy Humans.

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Effect of N-acetylcysteine on neural alcohol cue reactivity and craving in adolescents who drink heavily: A preliminary randomized clinical trial.

BACKGROUND: Alcohol craving is related to problematic alcohol use; therefore, pharmacotherapies that modulate alcohol craving are of interest. N-acetylcysteine, an over-the-counter antioxidant, is a candidate pharmacotherapy for adolescent alcohol use with the potential to impact craving. Cue-reactivity paradigms using functional magnetic resonance imaging (fMRI) can identify neural regions implicated in craving and serve as a screening tool for novel pharmacotherapy options. METHODS: This preliminary study examined the effect of N-acetylcysteine on neural reactivity to alcohol cues and subjective craving among 31 non-treatment-seeking adolescents (17.6-19.9 years old, 55% female) who use alcohol heavily. In a randomized cross-over design, participants completed three fMRI sessions: baseline and after a 10-day course of N-acetylcysteine (1200 mg twice daily) and matched placebo. The primary outcome was neural response to alcohol versus non-alcohol beverage cues after N-acetylcysteine versus placebo, with a secondary outcome of self-reported subjective craving. RESULTS: In the full sample (n = 31), there was no effect of N-acetylcysteine versus placebo on neural alcohol reactivity (ps ≥ 0.49; η p 2 $$ {\upeta_{\mathrm{p}}}^2 $$ s = 0.00-0.07) or self-reported acute alcohol craving (p = 0.18, η p 2 $$ {\upeta_{\mathrm{p}}}^2 $$ = 0.06). However, N-acetylcysteine did reduce self-reported generalized alcohol craving (p = 0.03, η p 2 $$ {\upeta_{\mathrm{p}}}^2 $$ = 0.15). In a subsample of youth who met criteria for past-year alcohol use disorder (n = 19), results remained unchanged. CONCLUSIONS: N-acetylcysteine may not alter neural reactivity to alcohol cues or acute craving; however, it may reduce general subjective alcohol craving among adolescents who consume alcohol heavily.

Use of N-acetylcysteine plus simethicone to improve mucosal visibility in upper digestive endoscopy via systematic alphanumeric-coded endoscopy: a randomized, double-blind controlled trial.

Background: The use of antifoaming and mucolytic agents prior to upper gastrointestinal (GI) endoscopy and a thorough systematic review are essential to optimize lesion detection. This study evaluated the effect of simethicone and N-acetylcysteine on the adequate mucosal visibility (AMV) of the upper GI tract by an innovative systematic method. Methods: This randomized, double-blind controlled trial included consecutive patients who underwent diagnostic upper GI endoscopy for screening for early neoplasms between August 2019 and December 2019. The upper GI tract was systematically assessed by systematic alphanumeric-coded endoscopy. Patients were divided into 4 groups: 1) water; 2) only simethicone; 3) N-acetylcysteine + simethicone; and 4) only N-acetylcysteine. The following parameters were assessed in each group: age, sex, body mass index, level of adequate mucosal visibility, and side-effects. Results: A total of 4564 images from upper GI areas were obtained for evaluation. The mean AMV in the 4 groups was 93.98±7.36%. The N-acetylcysteine + simethicone group had a higher cleaning percentage compared with the other groups (P=0.001). There was no significant difference among the remaining groups, but several areas had better cleaning when a mucolytic or antifoam alone was used. No side-effects were found in any group. Conclusion: The combination of N-acetylcysteine plus simethicone optimizes the visibility of the mucosa of the upper GI tract, which could potentially increase diagnostic yield.

Should high-dose N-acetylcysteine be given in cases of massive paracetamol overdoses: A narrative review.

N-acetylcysteine (NAC) is regarded as an effective treatment of paracetamol overdoses. However, in cases of "massive" paracetamol overdoses, recent studies indicate that patients may not be sufficiently treated with the standard dose of NAC (300 mg/kg over 20-21 h). The subject is further complicated because "massive overdoses" and "high-risk" are defined differently; some studies use the ingested amount (e.g., >40 g), and some studies use blood concentrations of paracetamol and transaminases. This narrative review investigates whether high-dose NAC significantly decreases the risk of hepatotoxicity in patients with massive paracetamol overdoses. Three observational studies were analysed; one study with 373 patients found no significant difference (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 0.49-3.29). One study with 79 patients found a significant difference (OR: 0.27, 95% CI: 0.08-0.94). The third study with 89 patients found a significant difference in hepatoxicity between the groups (p = 0.043). There are no solid evidence to support that treatment with high-dose NAC significantly reduces the rate of hepatotoxicity in patients presenting with massive paracetamol overdoses. Differences in inclusion criteria in the included studies make the studies incomparable. This paper shows that standardized inclusion is needed to determine whether a high-dose NAC regimen should be included in clinical practice.

S-glutathionylation in hepatocytes is involved in arsenic-induced liver fibrosis through activation of the NLRP3 inflammasome, an effect alleviated by NAC.

Arsenic, a toxicant widely distributed in the environment, is considered as a risk factor for liver fibrosis. At present, the underlying mechanism still needs to be explored. In the present study, we found that, for mice, chronic exposure to arsenic induced liver fibrosis, activated the NLRP3 inflammasome, and increased the levels of reactive oxygen species (ROS). After hepatocytes were co-cultured with hepatic stellate cells (HSCs), we observed the arsenic-activated NLRP3 inflammasome in hepatocytes, and the co-cultured HSCs were activated. Further, we found that, in livers of mice, arsenic disturbed GSH metabolism and promoted protein S-glutathionylation. A 3D molecular docking simulation suggested that NLRP3 binds with GSH, which was confirmed by immunoprecipitation experiments. N-acetylcysteine (NAC) increased the levels of GSH in hepatocytes, which suppressed the S-glutathionylation of NLRP3 and blocked arsenic-induced activation of the NLRP3 inflammasome. Mechanistically, an imbalance of the redox state induced by arsenic promotes the S-glutathionylation of NLRP3, which regulates activation of the NLRP3 inflammasome, leading into the activation of HSCs. Moreover, NAC increases the levels of GSH to block arsenic-induced S-glutathionylation of NLRP3, thereby blocking arsenic-induced liver fibrosis. Thus, via activating HSCs, the S-glutathionylation of NLRP3 in hepatocytes is involved in arsenic-induced liver fibrosis, and, for hepatocytes, NAC alleviates these effects by increasing the levels of GSH. These results reveal a new mechanism and provide a possible therapeutic target for the liver fibrosis induced by environmental factors.

The role of N-acetylcysteine on adhesion and biofilm formation of Candida parapsilosis isolated from catheter-related candidemia.

Objectives. Anti-fungal agents are increasingly becoming less effective due to the development of resistance. In addition, it is difficult to treat Candida organisms that form biofilms due to a lack of ability of drugs to penetrate the biofilms. We are attempting to assess the effect of a new therapeutic agent, N-acetylcysteine (NAC), on adhesion and biofilm formation in Candida parapsilosis clinical strains. Meanwhile, to detect the transcription level changes of adhesion and biofilm formation-associated genes (CpALS6, CpALS7, CpEFG1 and CpBCR1) when administrated with NAC in C. parapsilosis strains, furthermore, to explore the mechanism of drug interference on biofilms.Hypothesis/Gap statement. N-acetylcysteine (NAC) exhibits certain inhibitory effects on adhesion and biofilm formation in C. parapsilosis clinical strains from CRBSIs through: (1) down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections (CRBSIs), (2) regulating the metabolism and biofilm -forming factors of cell structure.Methods. To determine whether non-antifungal agents can exhibit inhibitory effects on adhesion, amounts of total biofilm formation and metabolic activities of C. parapsilosis isolates from candidemia patients, NAC was added to the yeast suspensions at different concentrations, respectively. Reverse transcription was used to detect the transcriptional levels of adhesion-related genes (CpALS6 and CpALS7) and biofilm formation-related factors (CpEFG1 and CpBCR1) in the BCR1 knockout strain, CP7 and CP5 clinical strains in the presence of NAC. To further explore the mechanism of NAC on the biofilms of C. parapsilosis, RNA sequencing was used to calculate gene expression, comparing the differences among samples. Gene Ontology (GO) enrichment analysis helps to illustrate the difference between two particular samples on functional levels.Results. A high concentration of NAC reduces the total amount of biofilm formation in C. parapsilosis. Following co-incubation with NAC, the expression of CpEFG1 in both CP7 and CP5 clinical strains decreased, while there were no significant changes in the transcriptional levels of CpBCR1 compared with the untreated strain. GO enrichment analysis showed that the metabolism and biofilm-forming factors of cell structure were all regulated after NAC intervention.Conclusions. The non-antifungal agent NAC exhibits certain inhibitory effects on clinical isolate biofilm formation by down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections.

Investigating a Novel Two-Bag N-Acetylcysteine Regimen for Acetaminophen Toxicity.

BACKGROUND: Acetaminophen toxicity remains one of the most common causes of liver failure and is treated with a course of n-acetylcysteine (NAC). This exceptionally effective medication is traditionally administered using a complicated three-bag protocol that is prone to administration errors. OBJECTIVE: We aimed to assess whether switching to a novel two-bag protocol (150 mg/kg over 1 h followed by 150 mg/kg over 20 h) reduced administration errors while not increasing liver injury or anaphylactoid reactions. METHODS: This was a retrospective chart review of hospital encounters for patients with acetaminophen toxicity, comparing outcomes before and after the change from a three-bag protocol to a two-bag protocol at two affiliated institutions. The primary outcome was incidence of medication errors with secondary outcomes including acute liver injury (ALI) and incidence of non-anaphylactoid allergic reactions (NAAR). The study was approved by the health system's Institutional Review Board. RESULTS: 483 encounters were included for analysis (239 in the three-bag and 244 in the two-bag groups). NAAR were identified in 11 patients with no difference seen between groups. Similarly, no differences were seen in ALI. Medication administration errors were observed significantly less often in the two-bag group (OR 0.24) after adjusting for confounders. CONCLUSION: Transitioning to a novel two-bag NAC regimen decreased administration errors. This adds to the literature that two-bag NAC regimens are not only safe but also may have significant benefits over the traditional NAC protocol.

Ultrasonographic and histopathological investigation of the effect of N-acetylcysteine on doxorubicin-induced ovarian and uterine toxicity in rats.

BACKGROUND: This study aimed to investigate the mitigating effect of N-acetylcysteine (NAC) on doxorubicin (DOX)-induced ovarian and uterine toxicity in rats using laboratory tests, ultrasonographic (US) imaging, and histopathology analysis. METHODS: Forty-eight rats were divided into six groups (n = 8) as follows: Group A (control) (0.5 mL saline administered intraperitoneally [IP]), Group B (a single 10 mg/kg dose of DOX administered IP on day 1), Group C (a single 10 mg/kg dose of DOX administered IP 24 h before sacrifice), Group D (100 mg/kg of NAC administered IP for 21 days), Group E ( a single 10 mg/kg dose of DOX administered IP on day 1 and 100 mg/kg of NAC administered IP for 21 days), and Group F (100 mg/kg of NAC administered IP for 21 days and a single 10 mg/kg dose of DOX administered IP 24 h before sacrifice). The ovaries were examined using B-mode US on days 1, 14, and 21, and the histopathological examinations of the ovaries and the uterus were undertaken after sacrifice on day 22. RESULTS: Histomorphological analyses showed that ovarian weight decreased after DOX administration in Group B but not in Group E. US revealed a transient increase in ovarian size in Group B and E, reverting to baseline levels over time, as well as a progressive increase in peritoneal fluid in Groups B and E. Group B exhibited a significant decrease in the thickness of the endometrium and myometrium and uterine cornual length, which was not observed in Group E. Histopathological examination showed that DOX caused a decline in follicular count, especially in primordial, secondary, and Graafian follicles, and resulted in follicular atresia, predominantly in Group B. Destructive degeneration/necrosis and vascular changes were most prominently seen in the corpus luteum of Groups C and B. In NAC-treated rats (Groups E and F), although germ cell damage was present, atretic follicles and vascular changes, such as hyperemia and congestion, were reduced. The anti-müllerian hormone (AMH) level was the highest in Group F. CONCLUSIONS: NAC, an antioxidant, attenuated DOX-induced gonadotoxicity in rats.

Hump-Nosed Pit Viper (Hypnale hypnale) Venom-Induced Irreversible Red Blood Cell Aggregation, Inhibition by Monovalent Anti-Venom and N-Acetylcysteine.

Envenomation by the Hypnale hypnale in the Western Ghats of India (particularly in the Malabar region of Kerala) and the subcontinent island nation of Sri Lanka is known to inflict devastating mortality and morbidity. Currently, H. hypnale bites in India are devoid of anti-venom regimens. A detailed characterization of the venom is essential to stress the need for therapeutic anti-venom. Notably, the deleterious effects of this venom on human blood cells have largely remained less explored. Therefore, in continuation of our previous study, in the present study, we envisioned investigating the effect of venom on the morphological and physiological properties of red blood cells (RBCs). The venom readily induced deleterious morphological changes and, finally, the aggregation of washed RBCs. The aggregation process was independent of the ROS and the intracellular Ca2+ ion concentration. Confocal and scanning electron microscopy (SEM) images revealed the loss of biconcave morphology and massive cytoskeletal disarray. Crenation or serrated plasma membrane projections were evenly distributed on the surface of the RBCs. The venom did not cause the formation of methemoglobin in washed RBCs but was significantly induced in whole blood. Venom did not affect glucose uptake and Na+/K+ -ATPase activity but inhibited glucose 6 phosphate dehydrogenase activity and decreased the fluidity of the plasma membrane. Venom-induced RBC aggregates exhibited pro-coagulant activity but without affecting platelet aggregation. In pre-incubation or co-treatment studies, none of the bioactive compounds, such as melatonin, curcumin, fisetin, berberine, and quercetin, sugars such as mannose and galactose, and therapeutic polyvalent anti-venoms (Bharat and VINS) were inhibited, whereas only N-acetylcysteine and H. hypnale monovalent anti-venom could inhibit venom-induced deleterious morphological changes and aggregation of RBCs. In post-treatment studies, paradoxically, none of the bioactives and anti-venoms, including N-acetylcysteine and H. hypnale monovalent anti-venom, reversed the venom-induced RBC aggregates.

N-acetylcysteine as a potentially safe adjuvant in the treatment of neurotoxicity due to pirimiphos-methyl poisoning.

Exogenous, well-established antioxidant N-acetylcysteine can reduce or prevent the deleterious effects of pesticides. In this study, utilizing a mouse model of daily single dose of N-acetylcysteine administration, we investigated the impact of this adjuvant on the treatment with atropine and/or obidoxime as well as oxidative stress response in pyrimiphos-methyl-induced toxicity. We found that N-acetylcysteine significantly reduces the oxidative stress generated by pyrimiphos-methyl. The therapy consisting of atropine and/or obidoxime routinely used in organophosphorous insecticide poisonings, including pyrimiphos-methyl, had no effect on the antioxidant properties of N-acetylcysteine. Adjunctive treatment offered by N-acetylcysteine fills therapeutic gap and may provide the full potential against pyrimiphos-methyl-induced toxicity.

Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds.

Objective: This study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds. Methods: We treated 10 IDMs who were gastrostomy tube candidates in an open-label trial of NAC and taVNS paired with oral feeding. NAC (75 or 100 mg/kg/dose) was given by nasogastric (NG) administration every 6 h for 4 days, then combined with taVNS paired with 2 daily feeds for another 14 days. NAC pharmacokinetic (PK) parameters were determined from plasma concentrations at baseline and at steady state on day 4 of treatment in conjunction with magnetic resonance spectroscopic (MRS) quantification of CNS glutathione (GSH) as a marker of oxidative stress. We compared increases in oral feeding volumes before and during taVNS treatment and with a prior cohort of 12 IDMs who largely failed to achieve full oral feeds with taVNS alone. Results: NAC 100 mg/kg/dose every 6 h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13 ± 0.08 mM (p = 0.01, compared to baseline). Mean daily feeding volumes increased over 14 days of NAC + taVNS compared to the 14 days before treatment and compared to the prior cohort of 12 IDMs treated with taVNS alone. Seven IDMs reached full oral feeds sufficient for discharge, while three continued to have inadequate intake. Conclusion: In IDM failing oral feeds, NAC 100 mg/kg/dose every 6 h NG for 4 days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.

A Clinical Course of Repeated Supratherapeutic Ingestion of Acetaminophen.

Acute liver failure (ALF) exemplifies a rapid decline in liver function among individuals with previously healthy livers, often manifesting through symptoms such as jaundice, confusion, and potentially life-threatening complications. Timely medical intervention, and, in severe instances, liver transplantation, are essential for enhancing outcomes and averting further deterioration. While the causes of ALF are multifaceted, in developed nations, it predominantly arises from drug-induced liver injury. Treatment primarily revolves around supportive measures, with severe cases necessitating liver transplantation. In instances where acute overdose with acetaminophen serves as the instigating factor, N-acetylcysteine (NAC) emerges as a pivotal component of management, as indicated by the Rumack-Matthew nomogram. The Rumack-Matthew nomogram guides treatment for acetaminophen overdose by correlating serum levels with the risk of liver damage. If levels exceed a set threshold, NAC is administered to prevent toxicity by replenishing glutathione. The decision to administer NAC is typically guided by this clinical tool, which aids healthcare providers in determining the appropriate course of action. NAC assumes a critical role in ameliorating the detrimental effects of acetaminophen overdose, particularly in averting liver damage, thus holding significant importance in patient care and recovery. While chronic acetaminophen overdose cases leading to ALF may also benefit from NAC, the supporting evidence remains weak. In this context, we present a case of ALF stemming from chronic acetaminophen ingestion, managed with NAC when liver transplantation was not a viable option.

In Vitro Investigation of the Effects of Various Reducing Agents on Dentin Treated with Hydrogen Peroxide.

We assessed the effect of non-protein thiols (NPSH), reduced glutathione (GSH) and n-acetylcysteine (NAC), on resin shear bond strength (SBS) to hydrogen peroxide (H2O2)-treated dentin, and their effects on the characteristics of dentin in comparison to ascorbic acid (AA) and sodium thiosulfate (STS). H2O2-treated dentin was conditioned with 5% AA, GSH, NAC, or STS applied for 1 or 5 min. The positive control group received H2O2 without antioxidant application, and the first negative control group received distilled water (DW). The specimens received resin bonding immediately after treatment except for the second negative control group (delayed bonding). Microhardness, roughness, and topography were studied. The SBS values of all antioxidants were statistically greater than the positive control group (p < 0.05); however, NAC and AA applied for 1 min demonstrated the highest values, which were comparable to delayed bonding. All treatments removed the smear layer except DW, H2O2, and STS. The negative effect of H2O2 on resin-dentin bonding was mitigated by the application of the antioxidants; however, their efficiencies were dependent on the antioxidant type and time of application. NAC was more effective in optimizing resin bonding to bleached dentin compared to GSH at 1 min application and STS at both application times but was comparable to AA. Negligible negative effects on the substrate's roughness and microhardness were detected. The antioxidant properties of the agent and its capacity to remove the smear layer are the processes underpinning the ability of a certain antioxidant to reverse the effect of H2O2 on bonding.

The effect of N-acetylcysteine on the neurotoxicity of sevoflurane in developing hippocampus cells.

Sevoflurane, a common pediatric anesthetic, has been linked to neurodegeneration, raising safety concerns. This study explored N-acetylcysteine's protective potential against sevoflurane-induced neurotoxicity in rat hippocampi. Four groups were examined: Control: Received 6 hours of 3 l/min gas (air and 30 % O2) and intraperitoneal saline. NAC: Received 6 hours of 3 l/min gas and 150 mg/kg NAC intraperitoneally. Sev: Exposed to 6 hours of 3 l/min gas and 3 % sevoflurane. Sev+NAC: Received 6 hours of 3 l/min gas, 3 % sevoflurane, and 150 mg/kg NAC. Protein levels of NRF-2, NLRP3, IL-1ß, caspase-1, Beclin 1, p62, LC3A, and apoptosis markers were assessed. Sevoflurane and NAC alone reduced autophagy, while Sev+NAC group maintained autophagy levels. Sev group had elevated NRF-2, NLRP3, pNRF2, Caspase-1, and IL-1ß, which were reduced in Sev+NAC. Apoptosis was higher in Sev, but Sev+NAC showed reduced apoptosis compared to the control. In summary, sevoflurane induced neurotoxicity in developing hippocampus, which was mitigated by N-acetylcysteine administration.

N-Acetylcysteine assists muscle development in offspring of mice subjected to maternal heat stress during pregnancy.

BACKGROUND: Heat stress (HS) has been shown to affect reproductive performance and muscle development negatively in animals. N-Acetylcysteine (NAC) plays a pivotal role in enhancing the antioxidant performance in animals as a recognized antioxidant. The present study assesses the potential of NAC to modulate the reproductive performance and antioxidant function in pregnant mice exposed to HS. The role of NAC in muscle development of offspring mice was also explored. RESULTS: The results showed that NAC supplementation from day 12 to day 18 of gestation increased the number of litters and enhanced the antioxidant function in pregnant mice under HS exposure. It improved the weight and body condition significantly in the offspring mice (P < 0.05). The alleviation of HS-induced muscle impairment with NAC was consistent with the alleviation of apoptosis, the enrichment of the proliferation and differentiation in the offspring mice muscle. N-Acetylcysteine also reversed HS-induced reduction in the cross-sectional area of the leg muscle and increased the proportion of myosin heavy chain IIx (MYHCIIx) in the muscle fiber. CONCLUSION: The results of the present study support the use of NAC at a dose of 100 mg kg-1 body weight as supplement for protecting the offspring derived from pregnant mice exposed to HS from muscle impairment by accelerating proliferation and differentiation. © 2024 Society of Chemical Industry.

N-Acetylcysteine Attenuates Cisplatin Toxicity in the Cerebrum and Lung of Young Rats with Artificially Induced Protein Deficiency.

Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the main mechanisms involved in brain and lung toxicity. The aim of the present work was to study the influence of the amount of protein on some oxidative parameters in the brain and lungs of rats treated with Cisplatin (CP) and N-Acetylcysteine (NAC) as neuroprotectors. Four groups of Wistar rats, each containing six animals, were fed with a protein diet at 7% for 15 days. Thereafter, the groups were given either a unique dose of CP® 5 mg/kg or NAC® 5 mg/kg as follows: group 1 (control), NaCl 0.9% vehicle; group 2, CP; group 3, NAC; and group 4, NAC + CP. The animals were sacrificed immediately after the treatments. Blood samples were collected upon sacrifice and used to measure blood triglycerides and glucose. The brain and lungs of each animal were obtained and used to assay lipid peroxidation (TBARS), glutathione (GSH), serotonin metabolite (5-HIAA), catalase, and the activity of Ca+2, and Mg+2 ATPase using validated methods. TBARS, H2O2, and GSH were found to be significantly decreased in the cortex and cerebellum/medulla oblongata of the groups treated with CP and NAC. The total ATPase showed a significant increase in the lung and cerebellum/medulla oblongata, while 5-HIAA showed the same tendency in the cortex of the same group of animals. The increase in 5-HIAA and ATPase during NAC and CP administration resulted in brain protection. This effect could be even more powerful when membrane fluidity is increased, thus proving the efficacy of combined NAC and CP drug therapy, which appears to be a promising strategy for future chemotherapy in malnourished patients.

Prophylactic Effects of n-Acethylcysteine on Inflammation-induced Depression-like Behaviors in Mice.

Depression, affecting individuals worldwide, is a prevalent mental disease, with an increasing incidence. Numerous studies have been conducted on depression, yet its pathogenesis remains elusive. Recent advancements in research indicate that disturbances in synaptic transmission, synaptic plasticity, and reduced neurotrophic factor expression significantly contribute to depression's pathogenesis. In our study, we utilized adult male C57BL/6J mice. Lipopolysaccharide (LPS) can induce both chronic and acute depression-like symptoms in mice, a widely used model for studying depression associated with inflammation. N-acetylcysteine (NAC) exhibits anti-inflammatory and ameliorative effects on depressive symptoms. This study sought to determine whether NAC use could mitigate inflammatory depressive behavior through the enhancement of synaptic transmission, synaptic plasticity, and increasing levels of brain-derived neurotrophic factor (BDNF). In this study, we discovered that in mice modeled with depression-like symptoms, the expression levels of dendrites, BDNF, and miniature excitatory postsynaptic potential (mEPSC) in glutamatergic neurons, as well as the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPARs) GluA1 and GluA2 subunits, were significantly decreased. These findings suggest an impairment in the synaptic transmission of glutamatergic neurons. Following treatment with NAC, the previously mentioned levels improved, indicating an enhancement in both synaptic transmission and synaptic plasticity. Our results suggest that NAC exerts a protective effect on mouse models of inflammatory depression, potentially through the enhancement of synaptic transmission and plasticity, as well as the restoration of neurotrophic factor expression. These findings offer vital animal experimental evidence supporting NAC's role in mitigating inflammatory depressive behaviors.

Oxidized Low-Density Lipoprotein Decreases the Survival of Bone Marrow Stem Cells via Inhibition of Bcl-2 Expression.

Therapy with mesenchymal stem cells (MSCs) is considered an attractive strategy for the repair or regeneration of damaged tissues. However, low survival of MSCs limits their applications clinically. Oxidized low-density lipoprotein (ox-LDL) is significantly increased in patients with hyperlipidemia and decreases the survival of MSCs. Bcl-2 is critically involved in important cell functions, including cell membrane integrity and cell survival. The present study was designed to test the hypothesis that ox-LDL attenuates the survival of MSCs through suppression of Bcl-2 expression. Bone marrow MSCs from C57BL/6 mice were cultured with ox-LDL at different concentrations (0-140 µg/mL) for 24 h with native LDL as control. Ox-LDL treatment substantially decreased the survival of MSCs dose-dependently and enhanced the release of intracellular lactate dehydrogenase (LDH) in association with a significant decrease in Bcl-2 protein level without change in BAX protein expression in MSCs. Bcl-2 overexpression effectively protected MSCs against ox-LDL-induced damages with preserved cell numbers without significant increase in LDH release. Treatment with N-acetylcysteine (NAC) (1 mM) effectively preserved Bcl-2 protein expression in MSCs and significantly attenuated ox-LDL-induced decrease of cell number and increase in the release of intracellular LDH. These data indicated that ox-LDL treatment resulted in a significant damage of cell membrane and dramatically decreased the survival of MSCs dose-dependently through inhibition of Bcl-2 expression. NAC treatment significantly protected MSCs against the damage of cell membrane by ox-LDL and promoted the survival of MSCs in association with preserved Bcl-2 expression.

Ex vivo Anti-Senescence Activity of N-Acetylcysteine in Visceral Adipose Tissue of Obese Volunteers.

INTRODUCTION: Excessive visceral adiposity is known to drive the onset of metabolic derangements, mostly involving oxidative stress, prolonged inflammation, and cellular senescence. N-acetylcysteine (NAC) is a synthetic form of l-cysteine with potential antioxidant, anti-inflammatory, and anti-senescence properties. This ex-vivo study aimed to determine the effect of NAC on some markers of senescence including ß-galactosidase activity and p16, p53, p21, IL-6, and TNF-α gene expressions in visceral adipose tissue in obese adults. METHODS: This ex-vivo experimental study involved 10 obese participants who were candidates for bariatric surgery. Duplicate biopsies from the abdominal visceral adipose tissue were obtained from the omentum. The biopsies were treated with or without NAC (5 and 10 mm). To evaluate adipose tissue senescence, beta-galactosidase (ß-gal) activity and the expression of P16, P21, P53, IL-6, and TNF-α were determined. ANOVA test was employed to analyze the varying markers of cellular senescence and inflammation between treatment groups. RESULTS: The NAC at concentrations of 5 mm and 10 mm resulted in a noteworthy reduction ß-gal activity compared to the control group (p < 0.001). Additionally, the expression of P16, P21, and IL-6 was significantly reduced following treatment with NAC (5 mm) and NAC (10 mm) compared to the control group (All p < 0.001). DISCUSSION/CONCLUSION: Taken together, these data suggest the senotherapeutic effect of NAC, as it effectively reduces the activity of SA-ß-gal and the expression of IL-6, P16, and P21 genes in the visceral adipose tissue of obese individuals.