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Scientific Reports May 2023N-acetylcysteine (NAC) has been used as an antioxidant drug in tumor cells and preclinical mice tumor xenografts, and it improves adaptive immunotherapy in melanoma. NAC...
N-acetylcysteine (NAC) has been used as an antioxidant drug in tumor cells and preclinical mice tumor xenografts, and it improves adaptive immunotherapy in melanoma. NAC is not readily bioavailable and is used in high concentrations. The effects of NAC have been attributed to its antioxidant and redox signaling role in mitochondria. New thiol-containing molecules targeted to mitochondria are needed. Here, mitochondria-targeted NAC with a 10-carbon alkyl side chain attached to a triphenylphosphonium group (Mito-NAC) that is functionally similar to NAC was synthesized and studied. Mito-NAC has a free sulfhydryl group and is more hydrophobic than NAC. Mito-NAC is nearly 2000-fold more effective than NAC in inhibiting several cancer cells, including pancreatic cancer cells. Methylation of NAC and Mito-NAC also inhibited cancer cell proliferation. Mito-NAC inhibits mitochondrial complex I-induced respiration and, in combination with monocarboxylate transporter 1 inhibitor, synergistically decreased pancreatic cancer cell proliferation. Results suggest that the antiproliferative effects of NAC and Mito-NAC are unlikely to be related to their antioxidant mechanism (i.e., scavenging of reactive oxygen species) or to the sulfhydryl group-dependent redox modulatory effects.
Topics: Humans; Mice; Animals; Acetylcysteine; Antioxidants; Reactive Oxygen Species; Mitochondria; Pancreatic Neoplasms
PubMed: 37142668
DOI: 10.1038/s41598-023-34266-w -
Pharmacological Reports : PR Oct 2021Substance use disorder (SUD) is a chronic brain condition, with compulsive and uncontrollable drug-seeking that leads to long-lasting and harmful consequences. The... (Review)
Review
Substance use disorder (SUD) is a chronic brain condition, with compulsive and uncontrollable drug-seeking that leads to long-lasting and harmful consequences. The factors contributing to the development of SUD, as well as its treatment settings, are not fully understood. Alterations in brain glutamate homeostasis in humans and animals implicate a key role of this neurotransmitter in SUD, while the modulation of glutamate transporters has been pointed as a new strategy to diminish the excitatory glutamatergic transmission observed after drugs of abuse. N-acetylcysteine (NAC), known as a safe mucolytic agent, is involved in the regulation of this system and may be taken into account as a novel pharmacotherapy for SUD. In this paper, we summarize the current knowledge on the ability of NAC to reduce drug-seeking behavior induced by psychostimulants, opioids, cannabinoids, nicotine, and alcohol in animals and humans. Preclinical studies showed a beneficial effect in animal models of SUD, while the clinical efficacy of NAC has not been fully established. In summary, NAC will be a small add-on to usual treatment and/or psychotherapy for SUD, however, further studies are required.
Topics: Acetylcysteine; Animals; Drug-Seeking Behavior; Expectorants; Extinction, Psychological; Humans; Substance-Related Disorders
PubMed: 34091880
DOI: 10.1007/s43440-021-00283-7 -
European Review For Medical and... Dec 2023The aim of the study was to determine the pharmacokinetics (PK) and safety of single and repeat doses of intravenous (IV) N-acetylcysteine (NAC) in Chinese subjects.
OBJECTIVE
The aim of the study was to determine the pharmacokinetics (PK) and safety of single and repeat doses of intravenous (IV) N-acetylcysteine (NAC) in Chinese subjects.
PATIENTS AND METHODS
A total of 24 healthy male and female Chinese subjects aged 19-40 years were enrolled in this open-label phase I study. All subjects received a single dose of NAC 600 mg IV on day 1 and, after a 3-day washout, received repeat doses of NAC 600 mg IV (twice daily on days 4 and 5 and once on day 6).
RESULTS
Following a single dose, plasma NAC concentrations peaked rapidly, starting to fall at the end of the 5-minute infusion in a multiphasic manner. Mean Cmax was 83.30 μg/mL (CV% 30.7%), median Tmax was 0.083 h (range 0.08-0.25 h), and mean AUC(0-12 h) was 81.87 h*μg/mL (CV 14.0%). Following repeat dosing, Cmax was approximately 20% higher than after a single dose, with similar Tmax. Total exposure AUC(0-12) was 13% higher at steady state than after single dosing. The accumulation ratio was approximately 1.13, indicating only a slight accumulation with multiple dosing. NAC was eliminated with T1/2 of approximately 8 hours. Around 15% of the total NAC dose was excreted in the urine in the 32 hours post-dose, keeping with extensive NAC metabolism and transformation. Renal clearance of NAC was 995.2 mL/h (CV 50.2%). IV NAC was well tolerated after both single and multiple dosing.
CONCLUSIONS
This is the first robust study evaluating the PK and safety of IV NAC 600 mg in Chinese subjects and provides important data if this agent is to be used IV as a mucolytic in this population.
Topics: Female; Humans; Male; Acetylcysteine; Administration, Intravenous; Administration, Oral; Area Under Curve; China; Dose-Response Relationship, Drug; Healthy Volunteers; East Asian People
PubMed: 38164872
DOI: 10.26355/eurrev_202312_34808 -
Experimental and Clinical... Mar 2023This study aimed to compare the effects of N-acetylcysteine and benfotiamine in protection of ovarian tissue from ischemia caused by slow neovascularization injury due...
OBJECTIVES
This study aimed to compare the effects of N-acetylcysteine and benfotiamine in protection of ovarian tissue from ischemia caused by slow neovascularization injury due to intraperitoneal ovarian autotransplant in rats.
MATERIALS AND METHODS
Twenty-eight female rats were divided into 4 groups, each containing 7 rats. Group 1 only had the abdomen opened and closed, group 2 was the transplant-only group, group 3 received benfotiamine for 3 weeks starting 1 day before the transplant procedure, and group 4 received N-acetylcysteine for 3 weeks starting 1 day before the transplant procedure. At the end of the experimental period, malondialdehyde levels in ovarian tissues together with the apoptosis and fibrosis, proliferating cell nuclear antigen and vascular endothelial growth factor immunoreactivity, and ovarian reserves were investigated.
RESULTS
Apoptosis was significantly increased in group 2 animals. Primordial follicle count was higher in groups 3 and 4 than in group 2. Vascular endothelial growth factor immunoreactivity was decreased in groups 3 and 4 compared with group 2. Proliferating cell nuclear antigen immunoreactivity was reduced in the secondary follicles in all transplant groups.
CONCLUSIONS
In autologous intraperitoneal ovarian transplant, both benfotiamine and N-acetylcysteine are equal and effective agents in protection of ovarian tissue against ischemic injury.
Topics: Rats; Female; Animals; Acetylcysteine; Autografts; Proliferating Cell Nuclear Antigen; Vascular Endothelial Growth Factor A; Reperfusion Injury
PubMed: 30295588
DOI: 10.6002/ect.2017.0320 -
The Journal of Pharmacology and... Jan 2024Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase-mediated conversion to the active...
Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase-mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been linked to AAP therapeutic benefits yet clearly leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (plus or minus NAC) were assessed for liver toxicity by histology and serum chemistry. The anticancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high-dose AAP with NAC/fomepizole rescue had profound antitumor activity against commonly used 4T1 breast tumor and lewis lung carcinoma lung tumor models, and no liver toxicity was detected. The antitumor efficacy was reduced in immune-compromised NOD-scid IL2Rgamma mice, suggesting an immune-mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity. SIGNIFICANCE STATEMENT: High-dose acetaminophen can be given concurrently with CYP2E1 inhibition to allow for safe dose escalation to levels needed for anticancer activity without detected evidence of toxicity.
Topics: Mice; Animals; Acetaminophen; Cytochrome P-450 CYP2E1; Fomepizole; Mice, Inbred NOD; Liver; Acetylcysteine
PubMed: 37918853
DOI: 10.1124/jpet.123.001772 -
Chemical Research in Toxicology Jul 2019-Acetylcysteine is a commonly used antioxidant that is broadly effective despite its limited reactive oxygen species (ROS) reactivity. Chemoprotection by -acetylcysteine...
-Acetylcysteine is a commonly used antioxidant that is broadly effective despite its limited reactive oxygen species (ROS) reactivity. Chemoprotection by -acetylcysteine frequently results from inactivation of primary toxicants or reactive electrophiles arising as metabolites or lipid peroxidation products. ROS are linked to the development of many human diseases and biological injury by numerous xenobiotics. Oxidative damage is the first mechanism that is often tested for toxicants. There is also a frequent projection of the established ROS mechanism for one member to a broader group to which this chemical belongs. However, the biological significance of oxidative processes is not always easy to establish, as oxidants could be a cause or result of cellular injury. The role of ROS is tested through genetic manipulations of oxidative stress-protective proteins and addition of small antioxidants. In general, genetic approaches produce protective effects weaker than those of small antioxidants, which can reflect different anti-ROS specificity. Another possibility is that chemical antioxidants have ROS-unrelated chemoprotective activities.
Topics: Acetylcysteine; Aldehydes; Disulfides; Free Radical Scavengers; Metals, Heavy; Oxidation-Reduction; Reactive Oxygen Species
PubMed: 31046246
DOI: 10.1021/acs.chemrestox.9b00152 -
International Journal of Molecular... Nov 2023Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress.... (Randomized Controlled Trial)
Randomized Controlled Trial
Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects.
Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1β, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFβ), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NO and NO), glutathione reductase, and superoxide dismutase decreased after treatment with Vit C, Vit E, NAC, and MT. The levels of thiols recovered with the use of Vit E, and all patients treated with antioxidants maintained their selenium levels, in contrast with controls ( = 0.04). The findings regarding oxidative stress markers and cytokines after treatment with antioxidants allow us to consider to future the combined use of antioxidants in a randomized clinical trial with a larger sample to demonstrate the reproducibility of these beneficial effects.
Topics: Humans; Antioxidants; Interleukin-6; Cytokine Release Syndrome; Interleukin-10; Shock, Septic; Reproducibility of Results; Oxidative Stress; Ascorbic Acid; Vitamin E; Acetylcysteine; Melatonin; Adjuvants, Immunologic
PubMed: 38068931
DOI: 10.3390/ijms242316610 -
Nature Communications Feb 2024Chronic wounds are often infected with biofilm bacteria and characterized by high oxidative stress. Current dressings that promote chronic wound healing either require...
Chronic wounds are often infected with biofilm bacteria and characterized by high oxidative stress. Current dressings that promote chronic wound healing either require additional processes such as photothermal irradiation or leave behind gross amounts of undesirable residues. We report a dual-functionality hydrogel dressing with intrinsic antibiofilm and antioxidative properties that are synergistic and low-leaching. The hydrogel is a crosslinked network with tethered antibacterial cationic polyimidazolium and antioxidative N-acetylcysteine. In a murine diabetic wound model, the hydrogel accelerates the closure of wounds infected with methicillin-resistant Staphylococcus aureus or carbapenem-resistant Pseudomonas aeruginosa biofilm. Furthermore, a three-dimensional ex vivo human skin equivalent model shows that N-acetylcysteine promotes the keratinocyte differentiation and accelerates the re-epithelialization process. Our hydrogel dressing can be made into different formats for the healing of both flat and deep infected chronic wounds without contamination of the wound or needing other modalities such as photothermal irradiation.
Topics: Humans; Animals; Mice; Antioxidants; Acetylcysteine; Hydrogels; Methicillin-Resistant Staphylococcus aureus; Wound Healing; Bandages; Anti-Bacterial Agents; Biofilms; Deafness; Wound Infection; Diabetes Mellitus
PubMed: 38296937
DOI: 10.1038/s41467-024-44968-y -
Biomolecules Nov 2023Recent evidence indicates that reactive oxygen species play an important causative role in the onset and progression of valvular diseases. Here, we analyzed the...
Recent evidence indicates that reactive oxygen species play an important causative role in the onset and progression of valvular diseases. Here, we analyzed the oxidative modifications of albumin (HSA) occurring on Cysteine 34 and the antioxidant capacity of the serum in 44 patients with severe aortic stenosis (36 patients underwent aortic valve replacement and 8 underwent a second aortic valve substitution due to a degenerated bioprosthetic valve), and in 10 healthy donors (controls). Before surgical intervention, patients showed an increase in the oxidized form of albumin (HSA-Cys), a decrease in the native reduced form (HSA-SH), and a significant reduction in serum free sulfhydryl groups and in the total serum antioxidant activity. Patients undergoing a second valve replacement showed levels of HSA-Cys, free sulfhydryl groups, and total antioxidant activity similar to those of controls. In vitro incubation of whole blood with aspirin (ASA) significantly increased the free sulfhydryl groups, suggesting that the in vivo treatment with ASA may contribute to reducing oxidative stress. We also found that N-acetylcysteine and its amide derivative were able to regenerate HSA-SH. In conclusion, the systemic oxidative stress reflected by high levels of HSA-Cys is increased in patients with aortic valve stenosis. Thiol-disulfide breaking agents regenerate HSA-SH, thus paving the way to the use these compounds to mitigate the oxidative stress occurring in the disease.
Topics: Humans; Antioxidants; Serum Albumin; Oxidative Stress; Acetylcysteine; Sulfhydryl Compounds; Aortic Valve Stenosis
PubMed: 38136584
DOI: 10.3390/biom13121713 -
Assessing combined effects of varenicline and N-acetylcysteine on reducing nicotine seeking in rats.Addiction Biology Mar 2022Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most...
Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most effective pharmacotherapy for smoking cessation is Varenicline (VRN), which reduces both positive and negative reinforcement by nicotine. Clinically, VRN attenuates withdrawal symptoms and promotes abstinence, but >50% of smokers relapse within 3 months following a quit attempt. This may indicate that VRN fails to ameliorate components of nicotine-induced neuroplasticity that promote relapse vulnerability. Animal models reveal that glutamate dysregulation in the nucleus accumbens is associated with nicotine relapse. N-acetylcysteine (NAC) normalizes glutamate transmission and prolongs cocaine abstinence. Thus, combining VRN and NAC may promote and maintain, respectively, nicotine abstinence. In rats, we found that VRN effectively reduced nicotine self-administration and seeking in early abstinence, but not seeking later in abstinence. In contrast, NAC reduced seeking only later in abstinence. Because VRN and NAC are sometimes associated with mild adverse effects, we also evaluated a sequential approach combining subthreshold doses of VRN during self-administration and early abstinence with subthreshold doses of NAC during late abstinence. As expected, subthreshold VRN did not reduce nicotine intake. However, subthreshold VRN and NAC reduced seeking in late abstinence, suggesting a combined effect. Overall, our results suggest that combining subthreshold VRN and NAC is a viable and drug-specific approach to promote abstinence and reduce relapse while minimizing adverse effects. Our data also suggest that different components and time points in addiction engage the different neurocircuits targeted by VRN and NAC.
Topics: Acetylcysteine; Animals; Nicotine; Rats; Smoking Cessation; Tobacco Use Disorder; Varenicline
PubMed: 35229943
DOI: 10.1111/adb.13151