N-Acetyl Cysteine (Wikipedia)
NAC as a precursor to the antioxidant glutathione modulates glutamatergic neurotrophic, and inflammatory pathways. NAC reduces pro-inflammatory markers including Cytokines - IL-1, IL-6, 7, 8 and Tumor Necrosis Factor -alpha (TNF-alpha).
NAC improves mitochondrial function with potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson’s disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht–Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease.
Table 1. Summary of NAC mechanisms of action across different neurological disorders.
Neurodegenerative disorders: SCD, tardive dyskinesia, myoclonus epilepsy, Unverricht–Lundbor type
Antioxidant effect by free-radical scavenging and increased levels of glutathione (Arakawa and Ito 2007)
Amyotrophic lateral sclerosis
Focal cerebral ischemia
NOS inhibition, regeneration of endothelium-derived relaxing factor, increasing glutathione levels, improving microcirculatory blood flow, and tissue oxygenation (Dawson and Dawson 1997; Cuzzocrea et al. 2000b)
Free-radicals scavenger, endothelial apoptosis inhibition, lipid peroxidation reduction, increasing glutathione levels, and SOD enzymatic activities, endothelial integrity protection (Findlay et al. 1989; Sen et al. 2006)
Traumatic brain injury
Repair of TBI-induced mitochondrial dysfunction, increasing the reduced antioxidant enzyme and glutathione levels, inhibition of the activation of NF-κB and TNF-α (Hoffer et al. 2002; Akca et al. 2005; Hsu et al. 2006; Chen et al. 2008)
Further Clinical Evidence
Plast Reconstr Surg. 2015 Aug;136(2):179e-88e. doi: 10.1097/PRS.0000000000001443.
Effect of N-Acetylcysteine on Adipose-Derived Stem Cell and Autologous Fat Graft Survival in a Mouse Model
1Halifax, Nova Scotia, Canada From the Divisions of Plastic and Reconstructive Surgery and Otolaryngology, IWK Health Centre, the Departments of Microbiology and Immunology, Pharmacology, and Pediatrics, and the Faculty of Medicine, Dalhousie University.
Autologous fat grafting is a popular reconstructive technique, but is limited by inconsistent graft retention. The authors examined whether a widely available, clinically safe antioxidant, N-acetylcysteine, could improve adipose-derived stem cell survival and graft take when added to tumescent solution during fat harvest.
Inguinal fat pads were harvested from C57BL/6 mice using tumescent solution with or without N-acetylcysteine. Flow cytometric, proliferation, and differentiation assays were performed on isolated primary adipose-derived stem cells and 3T3-L1 preadipocytes treated with or without hydrogen peroxide and/or N-acetylcysteine. N-Acetylcysteine-treated or control grafts were injected under recipient mouse scalps and assessed by serial micro-computed tomographic volumetric analysis. Explanted grafts underwent immunohistochemical analysis.
In culture, N-acetylcysteine protected adipose-derived stem cells from oxidative stress and improved cell survival following hydrogen peroxide treatment. Combined exposure to both N-acetylcysteine and hydrogen peroxide led to a 200-fold increase in adipose-derived stem cell proliferation, significantly higher than with either agent alone. N-Acetylcysteine decreased differentiation of adipose-derived stem cells into mature adipocytes, as evidenced by decreased transcription of adipocyte differentiation markers and reduced Oil Red-O staining. In vivo, N-acetylcysteine treatment resulted in improved graft retention at 3 months compared with control (46 versus 17 percent; p = 0.027). N-Acetylcysteine-treated grafts demonstrated less fibrosis and inflammation, and a 33 percent increase in adipocyte density compared with controls (p < 0.001) that was not associated with increased vascularity.
These findings provide proof of principle for the addition of N-acetylcysteine to tumescent harvest solution in the clinical setting to optimize fat graft yields.
Clin Res Hepatol Gastroenterol. 2015 Jul 24. pii: S2210-7401(15)00157-6. doi: 10.1016/j.clinre.2015.06.020. [Epub ahead of print]
Potential targeted therapies for the inflammatory pathogenesis of hepatic encephalopathy
1Department of Gastroenterology, Ningxia People's Hospital, 301 Zhengyuan North Street, Jinfeng District, 750021 Yinchuan, Ningxia, PR China. Electronic address: email@example.com.
2Endoscopy Center, Ningxia People's Hospital, Yinchuan, PR China.
3Department of Gastroenterology, Ningxia People's Hospital, 301 Zhengyuan North Street, Jinfeng District, 750021 Yinchuan, Ningxia, PR China.
4Department of Gastroenterology, Ningxia People's Hospital, 301 Zhengyuan North Street, Jinfeng District, 750021 Yinchuan, Ningxia, PR China. Electronic address: firstname.lastname@example.org.
Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of acute and chronic liver dysfunction, and is characterized by a spectrum that ranges from mild neuropsychological disturbances to coma. Although ammonia plays a critical role in the pathogenesis of HE, the plasma concentrations of ammonia and manifest symptoms of HE are not always consistent in patients with HE. Recently, a substantial body of evidence has indicated that inflammation acts in concert with ammonia in the pathogenesis of HE. Meanwhile, emerging novel and potential therapeutic strategies, including N-acetylcysteine, hypothermia, minocycline, non-steroidal anti-inflammatory drugs, tumour necrosis factor-alpha antagonists and p38 inhibitors, have been reported to ameliorate systemic inflammation and neuroinflammation, improve or reverse neuropsychiatric manifestations, and prevent the onset and progression of HE in patients and/or animal models of acute or chronic liver failure. These results point to the possible therapeutic utility of decreasing inflammation in the treatment of HE, and translation of these experimental results to the clinic may provide novel and promising therapeutic approaches for patients with HE secondary to acute or chronic liver failure. This review will provide an overview of these potential targeted therapies in the prophylaxis and treatment of HE.
Invest Ophthalmol Vis Sci. 2015 Aug 1;56(9):5614-21. doi: 10.1167/iovs.15-16909.
The Antioxidant N-Acetylcysteine Inhibits Inflammatory and Apoptotic Processes in Human Conjunctival Epithelial Cells in a High-Glucose Environment
1Department of Ophthalmology, University of Ulsan College of Medicine, Gangneng Asan Hospital, Gangneng, Republic of Korea.
2Research Institute for Biomacromolecules, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
3Research Institute for Biomacromolecules, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea 3Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
We evaluated the effects of N-acetylcysteine (NAC), which is known to inhibit reactive oxygen species (ROS)-dependent apoptosis, on high glucose-induced ROS, apoptosis, inflammation, and delayed-wounding closure in primary cultured human conjunctival epithelial cells (pHCECs), and the regulatory effects of cleaved caspase-3, BAX, nuclear factor κB (NF-κB), IL-6, and TNF-α on these processes.
High glucose-induced ROS generation was measured using 2',7'-dichlorofluorescein diacetate (DCFH-DA). The effects of NAC on high glucose-induced apoptosis were investigated in pHCECs using Annexin-V and PI staining, and cleaved caspase-3 and BAX expression levels using immunoblotting. To evaluate the inflammatory response, IL-6 and TNF-α expression levels were quantified by multiplex cytokine analysis, and NF-κB activation and IkB-α degradation were assessed by Western blot analysis. The effects of NAC on high glucose-delayed conjunctival epithelial wound healing were assessed by a scratch-induced directional wounding assay.
Compared to the untreated control and normal glucose (5 mM), high glucose at 25 mM stimulated ROS generation, apoptosis, and release of inflammatory cytokines, and delayed wound healing in pHCECs. The addition of NAC markedly reduced the high glucose-induced ROS activation, Annexin-PI-positive cells, and levels of cleaved caspase-3, BAX, IL-6, and TNF-α. N-acetylcysteine also prevented high glucose-delayed wound healing.
High glucose levels promote apoptosis by affecting mitochondria-dependent caspase activity through elevation of ROS production, a process that can be reversed by the antioxidant NAC. These findings demonstrate that NAC has a beneficial effect on conjunctival epithelial cell wound healing, antiapoptosis, and anti-inflammation in the conjunctival epithelial cell.
J Clin Exp Hepatol. 2015 Mar;5(Suppl 1):S96-S103. doi: 10.1016/j.jceh.2014.02.004. Epub 2014 Jul 9.
Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure
1Neuroscience Research Unit, Hopital St-Luc (CHUM) and Department of Medicine, University of Montreal, Montreal, QC H2W 3J4, Canada.
Neuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines.
Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed.
Mild hypothermia and N-Acetyl cysteine have both hepato-protective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited.
Urology. 2015 Jul 20. pii: S0090-4295(15)00667-6. doi: 10.1016/j.urology.2015.07.013. [Epub ahead of print]
N-acetylcysteine ameliorates the erectile dysfunction caused by chronic intermittent hypoxia in rats: Partly involvement of endoplasmic reticulum stress
1Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan 430030, China.
2Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan 430030, China. Electronic address: email@example.com.
To conduct a study using a rodent model of chronic intermittent hypoxia (CIH) to define whether endoplasmic reticulum stress (ERS) is involved in the CIH-induced apoptosis of penile tissue and erectile dysfunction (ED), and whether treatment with N-acetylcysteine (NAC) alleviates pathological variations in corpus cavernosa (CC). Previous work has prompted that CIH acted as the major trigger linking obstructive sleep apnea syndrome (OSAS) and ED.
Five-month-old Sprague-Dawley male rats were subjected to 8 hours of intermittent hypoxia per day, with or without NAC for 5 weeks. Erectile function, apoptosis of penile tissue, levels of ERS-associated proapoptotic effectors, nitric oxide (NO) and nitric oxide synthase (NOS) activity were determined.
Treatment with NAC inhibited apoptosis of penile tissue, the expressions of ERS-related products: BIP, CHOP, caspase12 and Bax, NO and endothelial NOS. Administration of NAC before CIH significantly improved the CIH-induced impaired erectile function.
Our results show that pre-CIH NAC administration ameliorates the erectile dysfunction following CIH partly by alleviating CIH-induced ERS and cell apoptosis via regulating the expressions of BIP, CHOP, caspase12 and Bax.
Hum Exp Toxicol. 2013 Oct;32(10):1107-16. doi: 10.1177/0960327113499167. Epub 2013 Aug 7.
Hyperbaric oxygen treatment and N-acetylcysteine ameliorate acetaminophen-induced liver injury in a rat model
11Department of Biochemistry, Diskapi Yildirim Beyazit Training and Research Hospital, Diskapi, Ankara, Turkey.
An overdose of acetaminophen (APAP) produces centrilobular hepatocellular necrosis. We aimed to investigate the hepatoprotective effects of N-acetylcysteine (NAC) only and hyperbaric oxygen (O(2)) treatment (HBOT) combined with NAC, and their anti-inflammatory properties in liver tissue. In the current study, a total of 32 male Sprague Dawley rats were divided into 4 groups: sham, APAP, NAC, and NAC + HBOT. In the APAP, NAC, and NAC + HBOT groups, liver injury was induced by oral administration of 1 g/kg APAP. The NAC group received 100 mg/kg NAC per day. NAC + HBOT group received intraperitoneal injection of 100 mg/kg/day NAC and were given HBOT at 2.8 ATA pressure with 100% O(2) inhalation for 90 min every 12 h for 5 days. Rats in the sham group received distilled water only by gastric tube. All animals were killed on day 6 after APAP or distilled water administration. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, hepatic neopterin, tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) levels were measured. There was a significant increase in serum AST and ALT activities in the APAP group compared with the sham group (in both p = 0.001). NAC and NAC + HBOT groups had significant decreases in hepatic neopterin, TNF-α, and IL-6 levels compared with the APAP group. APAP administration caused extensive hepatic necrosis. NAC and NAC + HBO treatments significantly reduced APAP-induced liver injury. Our results showed that the liver damage in APAP toxicity was attenuated by NAC and NAC + HBO treatments. NAC + HBOT exhibit hepatoprotective activity against APAP-induced liver injury in rats.
Free Radic Biol Med. 2014 Mar;68:8-21. doi: 10.1016/j.freeradbiomed.2013.11.007. Epub 2013 Dec 1.
Hypoxia-inducible factor 1 contributes to N-acetylcysteine's protection in stroke.
1Department of Pharmacology & Toxicology, University of Kansas, Lawrence, KS 66045, USA.
2Department of Radiology, Medical University of South Carolina, Charleston, SC 29401, USA.
3Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA.
4Department of Pharmacology & Toxicology, University of Kansas, Lawrence, KS 66045, USA. Electronic address: firstname.lastname@example.org.
Stroke is a leading cause of adult morbidity and mortality with very limited treatment options. Evidence from preclinical models of ischemic stroke has demonstrated that the antioxidant N-acetylcysteine (NAC) effectively protects the brain from ischemic injury. Here, we evaluated a new pathway through which NAC exerted its neuroprotection in a transient cerebral ischemia animal model.
Our results demonstrated that pretreatment with NAC increased protein levels of hypoxia-inducible factor-1α (HIF-1α), the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3, in the ipsilateral hemispheres of rodents subjected to 90min middle cerebral artery occlusion (MCAO) and 24h reperfusion.
Interestingly, after NAC pretreatment and stroke, the contralateral hemisphere also demonstrated increased levels of HIF-1α, EPO, and GLUT-3, but to a lesser extent. Suppressing HIF-1 activity with two widely used pharmacological inhibitors, YC-1 and 2ME2, and specific knockout of neuronal HIF-1α abolished NAC's neuroprotective effects. The results also showed that YC-1 and 2ME2 massively enlarged infarcts, indicating that their toxic effect was larger than just abolishing NAC's neuroprotective effects. Furthermore, we determined the mechanism of NAC-mediated HIF-1α induction.
We observed that NAC pretreatment upregulated heat-shock protein 90 (Hsp90) expression and increased the interaction of Hsp90 with HIF-1α in ischemic brains. The enhanced association of Hsp90 with HIF-1α increased HIF-1α stability. Moreover, Hsp90 inhibition attenuated NAC-induced HIF-1α protein accumulation and diminished NAC-induced neuroprotection in the MCAO model. These results strongly indicate that HIF-1 plays an important role in NAC-mediated neuroprotection and provide a new molecular mechanism involved in the antioxidant's neuroprotection in ischemic stroke.
Life Sci. 2014 Jun 27;107(1-2):50-8. doi: 10.1016/j.lfs.2014.04.033. Epub 2014 May 5.
Antioxidant and anti-inflammatory effects of N-acetylcysteine against malathion-induced liver damages and immunotoxicity in rats
1Laboratory of Aggression Physiology and Endocrine Metabolic Studies, Department of Biology, Faculty of Sciences, Tunis, Tunisia. Electronic address: email@example.com.
2Laboratory of Aggression Physiology and Endocrine Metabolic Studies, Department of Biology, Faculty of Sciences, Tunis, Tunisia.
3Laboratory of Aggression Physiology and Endocrine Metabolic Studies, Department of Biology, Faculty of Sciences, Tunis, Tunisia; Laboratory of Clinical Immunology, Pasteur Institute of Tunis, Tunis, Tunisia.
4Laboratory of Clinical Biochemistry, Charles Nicolle Hospital, Tunis, Tunisia.
5Laboratory of Clinical Immunology, Pasteur Institute of Tunis, Tunis, Tunisia.
6Laboratory of Aggression Physiology and Endocrine Metabolic Studies, Department of Biology, Faculty of Sciences, Tunis, Tunisia. Electronic address: firstname.lastname@example.org.
7Laboratory of Aggression Physiology and Endocrine Metabolic Studies, Department of Biology, Faculty of Sciences, Tunis, Tunisia. Electronic address: email@example.com.
Occupational exposure to organophosphate pesticides is becoming a common and increasingly alarming world-wide phenomenon. The present study is designed to investigate the preventive effect of N-acetylcysteine on malathion-induced hepatic injury and inflammation in rats.
Adult male Wistar rats of body weight 200-230g were used for the study. Malathion (200mg/kg b.w./day) was administered to rats by oral intubation and N-acetylcysteine (2g/l) in drinking water for 28days. Rats were sacrificed on the 28th day, 2h after the last administration. Markers of liver injury (aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate desyhdogenase), inflammation (leukocyte counts, myeloperoxidase, immunophenotyping of CD4(+) and CD8(+), interleukin-1β, interleukin-6 and interferon-γ expression) and oxidative stress (lipid peroxidation, reduced glutathione and antioxidant status) were assessed.
Malathion induced an increase in activities of hepatocellular enzymes in plasma, lipid peroxidation index, CD3(+)/CD4(+) and CD3(+)/CD4(+) percent and pro-inflammatory cytokines, when decreased antioxidant status in liver was noted. When malathion-treated rats were compared to NAC supplemented rats, leukocytosis, T cell count and IL-1β, IL-6, INF-γ expression were reduced. Furthermore, NAC restored liver enzyme activities and oxidative stress markers.
Malathion induces hepatotoxicity, oxidative stress and liver inflammation. N-acetylcysteine showed therapeutic effects against malathion toxicity.
Exp Cell Res. 2014 Apr 15;323(1):77-86. doi: 10.1016/j.yexcr.2014.02.019. Epub 2014 Feb 26.
Redox regulation of MMP-3/TIMP-1 ratio in intestinal myofibroblasts: effect of N-acetylcysteine and curcumin
1Dipartimento di Scienze Biomediche Sperimentali e Cliniche (Sezione Biochimica), Università degli Studi di Firenze, viale Morgagni 50, 50134 Firenze, Italia.
2Dipartimento di Chirurgia e Medicina Traslazionale (DCMT) Largo Brambilla 3, 50134 Firenze, Italia.
3Dipartimento di Scienze Biomediche Sperimentali e Cliniche (Sezione Cubo) viale Morgagni 85, 50134 Firenze, Italia.
4Dipartimento di Scienze Biomediche Sperimentali e Cliniche (Sezione Biochimica), Università degli Studi di Firenze, viale Morgagni 50, 50134 Firenze, Italia. Electronic address: firstname.lastname@example.org.
Matrix metalloproteinases (MMPs) play a critical role in inflammation and ulcerations in gut of Crohn׳s disease (CD) patients. Intestinal subepithelial myofibroblasts (ISEMFs) secrete MMPs in response to inflammatory stimuli. Previous data showed in CD-ISEMFs increased oxidative status. The aim of this study was to investigate the role of ISEMFs in modulating the production of MMP-3 and TIMP-1, an inhibitor of MMPs activity. A relationship among oxidative stress, activity of antioxidants and MMP-3/TIMP-1 was also studied. ISEMFs isolated from CD patient colon and human colonic cell line of myofibroblasts (18Co) were used. Oxidative state was modulated by buthionine sulfoximine, an inhibitor of glutathione (GSH) synthesis, and N-acetylcysteine (NAC), GSH precursor. An up-regulation of MMP-3 due to increased oxidative state was found in CD-ISEMFs. Stimulation by tumor necrosis factor (TNF)α increased further MMP-3 levels. On the contrary, no change in TIMP-1 production was determined.
NAC treatment decreased MMP-3 production in CD-ISMEFs and removed the enhancement due to TNFα. Similar effects were observed in 18Co cells treated with curcumin, antioxidant with anti-inflammatory properties. The involvement of MAPKs on MMP-3 redox regulation was also shown. This study demonstrates the involvement of ISEMFs and high oxidative state in the increased MMP-3 production found in intestinal mucosa of CD patients.
NAC and curcumin normalize MMP-3 levels mainly in TNFα stimulated cells. A modulation of MMP-3 production by NAC and curcumin due to their direct action on transcriptional factors has been also suggested. Therefore, they could have a therapeutic use for the prevention and treatment of fistulaes in CD.
Saudi J Kidney Dis Transpl. 2014 Jan;25(1):66-72.
The effect of treatment with N-acetylcysteine on the serum levels of C-reactive protein and interleukin-6 in patients on hemodialysis
1Nephrology Department, Dr. Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Patients with end-stage renal disease (ESRD) are at an increased risk of cardiovascular disease due to many factors including inflammation and oxidative stress. N-acetylcysteine (NAC) is a thiol-containing anti-oxidant with anti-inflammatory properties. We aimed to assess the effect of three months treatment with oral NAC on the plasma levels of inflammatory mediators like interleukin-6 (IL-6) and C-reactive protein (hs-CRP) in patients on hemodialysis (HD). Twenty-four patients (nine males and 15 females) on maintenance HD were recruited in the study. Their mean age was 55.3 years.
All the patients received oral NAC (600 mg twice a day) for a period of three months. The serum levels of biomedical parameters and IL-6 and hs-CRP were measured at baseline and three months after initiation of treatment. A significant decrease in serum levels of hs-CRP (22.4 vs. 5.2), IL-6 (8.1 vs. 3.6), parathyroid hormone (iPTH) (257.2 vs. 158.8), ferritin (632.0 vs. 515.1) and erythrocyte sedimentation rate (ESR) (54.2 vs. 38.3) was observed following NAC treatment. Female subjects presented with a significantly higher change in serum levels of hs-CRP compared with males (23 vs. 5.4). In three subjects who were less than 40 years old, the hs-CRP and IL-6 levels showed an increase following NAC treatment.
Our study found that short-term oral NAC treatment might result in the reduction of IL-6 and hs-CRP in patients who are on regular HD. This suggests that patients with ESRD may benefit from the anti-inflammatory effects of NAC.
Cancer Prev Res (Phila). 2014 Mar;7(3):330-40. doi: 10.1158/1940-6207.CAPR-13-0259. Epub 2014 Jan 15.
Curcumin: a double hit on malignant mesothelioma
1Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, HSRF 216, Burlington, VT 05405-0068. email@example.com.
Inflammation is a key mediator in the development of malignant mesothelioma, which has a dismal prognosis and poor therapeutic strategies. Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anticarcinogenic properties through its anti-inflammatory effects.
Inflammasomes, a component of inflammation, control the activation of caspase-1 leading to pyroptosis and processing of proinflammatory cytokines, interleukin (IL)-1β and IL-18. In the present study, we investigate the role of curcumin in pyroptotic cell death of malignant mesothelioma cells. Using in vitro models with mouse and human malignant mesothelioma cells, curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of high-mobility group box 1 (HMGB1) without processing of IL-1β and IL-18. Absence of IL-1β processing in response to curcumin-mediated caspase-1 activation is attributed to blockade of pro-IL-1β priming through inhibition of the NF-κB pathway. Furthermore, curcumin's cytotoxicity in malignant mesothelioma cells is demonstrated to be dependent on pyroptosis as inhibition of caspase-1 resulted in protection against curcumin-induced cell death. We also demonstrate that curcumin-mediated caspase-1 activation is oxidant dependent by using N-acetyl-L-cysteine (NAC) to inhibit pyroptosis. PCR array analysis using the human inflammasome template revealed that curcumin significantly downregulated levels of inflammasome-related gene expression involved in inflammation, e.g., NF-κB, toll-like receptors (TLR), and IL-1β.
Our data indicate that curcumin has a double effect on malignant mesothelioma cells through induction of pyroptosis while subsequently protecting against inflammation.
Drugs R D. 2013 Sep;13(3):199-205. doi: 10.1007/s40268-013-0025-5.
N-Acetylcysteine effects on transforming growth factor-β and tumor necrosis factor-α serum levels as pro-fibrotic and inflammatory biomarkers in patients following ST-segment elevation myocardial infarction
1Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran, firstname.lastname@example.org.
BACKGROUND AND AIMS:
Ischemia following acute myocardial infarction (AMI) increases the level of pro-fibrotic and inflammatory cytokines, including transforming growth factor (TGF)-β and tumor necrosis factor (TNF)-α. N-acetylcysteine (NAC) has therapeutic benefits in the management of patients with AMI. To the best of our knowledge, this is the first study that has evaluated the effect of NAC on TNF-α and TGF-β levels in patients with AMI.
Following confirmation of AMI, 88 patients were randomly administered NAC 600 mg (Fluimucil(®), Zambon, Ticino, Switzerland) or placebo orally twice daily for 3 days. For quantification of TGF-β and TNF-α serum levels after 24 and 72 h of NAC or placebo administration, peripheral venous blood (10 mL) samples were collected at these time points.
Comparisons between levels of TGF-β and TNF-α after 24 and 72 h within the NAC or placebo groups revealed that there was not any significant difference except for TGF-β levels in the placebo group, which increased significantly over time (p = 0.042). Significant relationships existed between patients' ejection fraction (p = 0.005) and TGF-β levels.
Receiving NAC could prevent TGF-β levels from increasing after 72 h as compared with not receiving NAC. As TGF-β had strong correlations with the ejection fraction, its antagonism seems to be important in the prevention of remodeling.