Protective Effect Of N-acetylcysteine Research Articles

Ameliorative effects ofN‐acetyl cysteine on diclofenac‐induced renal injury in male rats based on serum biochemical parameters, oxidative biomarkers, and histopathological study

Diclofenac (DIC) can cause nephrotoxicity in humans. In this study, we evaluated the protective effects of N-acetyl cysteine (NAC) on DIC-induced nephrotoxicity. Rats were assigned to four groups. Group 1 was control group; group 2 administrated with DIC only; group 3 administrated with DIC plus NAC and group 4 was treated with DIC and silymarin. Then, the oxidative biomarkers in serum and kidney were evaluated. In group 2, DIC caused a remarkable elevation (p<0.05) in the levels of serum uric acid, TNF-α, creatinine, urea, GOT, and GPT, protein carbonyl, malondialdehyde (MDA), and renal TNF-α gene expression, relative to control group. In treated groups with NAC and silymarin, a noticeable reduction (p<0.05) was seen in mentioned levels of biochemical parameters. NAC showed that it could reduce the abnormality of biochemical parameters and histopathological changes which is induced by DIC. PRACTICAL APPLICATIONS: N-acetyl cysteine (NAC) has a potential to ameliorate renal histopathological changes and improving renal activity of antioxidant enzymes in nephrotoxicity bydiclofenac. Also, NAC has a potential to reduce inflammatory gene expression in the diclofenac-induced nephrotoxicity. Additionally, NAC can be considered as an antioxidant which reduces renal MDA and serum protein carbonyl due to nephrotoxicity bydiclofenac.

Protective effect of N-acetylcysteine on fenitrothion-induced toxicity: The antioxidant status and metabolizing enzymes expression in rats

The existence of fenitrothion (FNT) in the soil, water, and food products has harmful effects on non-target organisms. Therefore, this study was conducted to evaluate the hepatotoxic, nephrotoxic and neurotoxic effects of FNT and the possible ameliorative effect of N-acetylcysteine (NAC), a precursor of intracellular GSH, on FNT-induced toxicity. For this purpose, thirty-two adult male albino rats were allocated into control group and groups treated with NAC (200 mg/kg), FNT (10 mg/kg) and FNT + NAC via gastric tube daily for 28 days. FNT intoxication significantly reduced food intake, water intake, body weight, and body weight gain and altered the expression of phase I and phase II xenobiotic-metabolizing enzymes—cytochrome P450 (CYP1A1) and glutathione S-transferase (GSTA4-4). In hepatic, renal and brain tissues, FNT induced oxidative stress, hepatopathy, nephropathy, and encephalopathy, and significantly increased pro-inflammatory cytokines. Furthermore, FNT exposure significantly elevated the level of hepatic and renal injury biomarkers and significantly inhibited the brain acetylcholinesterase activity. Co-administration of NAC with FNT modulated most of these altered biochemical, oxidative and inflammatory markers and restored the xenobiotic-metabolizing enzymes expression and histological structures. Our study indicated the involvement of oxidative damage, inflammation, and alteration of xenobiotic-metabolizing enzymes expression in FNT-induced toxicity and revealed that they were significantly improved by NAC co-treatment. These findings suggest that NAC administration might protect against FNT-induced toxicity in non-target organisms, including humans.

Protective Effect of N-Acetyl Cysteine on Chlorpyrifos-Induced Testicular Toxicity in Mice.

BackgroundChlorpyrifos (CPF), an organophosphate pesticide, is widely used in farms in order to preserve crops and fruits. Previous studies have shown that CPF exposure might cause chronic toxicity in male genital system. The present study investigated the protective effect of N-Acetyl Cysteine (NAC), a potent antioxidant against testicular toxicity of CPF in male mice.Materials and MethodsIn this experimental study, 42 adult male mice were divided into seven groups, CPF low (0.5 mg/kg.b.w) and high (5 mg/kg.b.w) doses groups, NAC group (35 mg/kg.b.w), NAC+CPF 0/5 mg/kg.b.w, NAC+CPF 5 mg/kg.b.w, dimethyl sulfoxide (DMSO, 0.75% solution mg/kg.b.w) and control group. All treatment were done intraperitoneally. Treatment was conducted for four consecutive weeks (five days each week). However NAC was injected to NAC+CPF groups five days before initiation of the treatment procedure. One week after the last injection, mice were sacrificed using anesthetic gas to evaluate alterations in testicular histology and sperm parameters.ResultsSeminiferous tubules area and diameter were significantly diminished in the group treated with 5 mg/kg CPF (P<0.05). CPF also statistically reduced sperm parameters (count and motility) and damaged sperm morphology) at both doses (P<0.05). However, NAC significantly improved spermatogonia, spermatocytes, spermatid cell counts as well as sperm parameters in mice treated with both CPF concentrations (P<0.05).ConclusionAccording to our results, NAC may significantly ameliorate CPF-induced damages to spermatogonia, spermatocytes, spermatids cell counts and sperm parameters.

The Protective Effect of N-acetylcysteine Against Methotrexate-Induced Hepatotoxicity in Rat

The Protective Effect of N-acetylcysteine Against Methotrexate-Induced Hepatotoxicity in Rat

Protective effects of N-acetyl-cysteine in mitochondria bioenergetics, oxidative stress, dynamics and S-glutathionylation alterations in acute kidney damage induced by folic acid

Folic acid (FA)-induced acute kidney injury (AKI) is a widely used model for studies of the renal damage and its progression to chronic state. However, the molecular mechanisms by which FA induces AKI remain poorly understood. Since renal function depends on mitochondrial homeostasis, it has been suggested that mitochondrial alterations contribute to AKI development. Additionally, N-acetyl-cysteine (NAC) can be a protective agent to prevent mitochondrial and renal dysfunction in this model, given its ability to increase mitochondrial glutathione (GSH) and to control the S-glutathionylation levels, a reversible post-translational modification that has emerged as a mechanism able to link mitochondrial energy metabolism and redox homeostasis. However, this hypothesis has not been explored. The present study demonstrates for the first time that, at 24 h, FA induced mitochondrial bioenergetics, redox state, dynamics and mitophagy alterations, which are involved in the mechanisms responsible for the AKI development. On the other hand, NAC preadministration was able to prevent mitochondrial bioenergetics, redox state and dynamics alterations as well as renal damage. The protective effects of NAC on mitochondria and renal function could be related to its observed capacity to preserve the S-glutathionylation process and GSH levels in mitochondria. Taken together, our results support the idea that these mitochondrial processes can be targets for the prevention of the renal damage and its progression in FA-induced AKI model.

SAH-Induced Electrophysiological Changes of Ventricular Myocytes and Role of N-acetylcysteine Protection.

Electrocardiogram (ECG) changes in patients with subarachnoid hemorrhage (SAH) are frequent. ST- and/or T-wave changes in ECG seem to predominate. To investigate the ion channel mechanisms of SAH-induced ventricular excitation-contraction coupling changes and the possible protective effect of N-acetylcysteine (NAC). Three groups of rabbits were used for the experiments. In two groups, SAH was induced by replacing the cerebrospinal fluid (CSF) with fresh autologous blood. In the control group, CSF was replaced with isotonic saline. In one SAH group, NAC was administered daily beginning at SAH induction. On day 5, ventricular action potentials, ionic currents, contractions, and intracellular free ion concentrations were recorded from the myocytes. In the SAH group, no change was found in the sodium currents, but the transient outward potassium currents were depressed, rapid repolarizing currents were increased, and t-type calcium currents were increased. Contractions and the intracellular free calcium concentration were depressed. NAC treatment, in contrast, not only restores these electrical remodeling changes but also the contractile abnormalities in the cardiac myocytes. The changes in the action potential duration can be attributed to the measured ionic current changes. However, the exact mechanism, other than the oxidative stress, by which the NAC treatment protects the cardiac muscle needs additional investigations.

Protective Effect of N-Acetylcysteine against Oxidative Stress Induced by Zearalenone via Mitochondrial Apoptosis Pathway in SIEC02 Cells.

Zearalenone (ZEN), a nonsteroidal estrogen mycotoxin, is widely found in feed and foodstuffs. Intestinal cells may become the primary target of toxin attack after ingesting food containing ZEN. Porcine small intestinal epithelial (SIEC02) cells were selected to assess the effect of ZEN exposure on the intestine. Cells were exposed to ZEN (20 µg/mL) or pretreated with (81, 162, and 324 µg/mL) N-acetylcysteine (NAC) prior to ZEN treatment. Results indicated that the activities of glutathione peroxidase (Gpx) and glutathione reductase (GR) were reduced by ZEN, which induced reactive oxygen species (ROS) and malondialdehyde (MDA) production. Moreover, these activities increased apoptosis and mitochondrial membrane potential (ΔΨm), and regulated the messenger RNA (mRNA) expression of Bax, Bcl-2, caspase-3, caspase-9, and cytochrome c (cyto c). Additionally, NAC pretreatment reduced the oxidative damage and inhibited the apoptosis induced by ZEN. It can be concluded that ZEN-induced oxidative stress and damage may further induce mitochondrial apoptosis, and pretreatment of NAC can degrade this damage to some extent.

Protective effect of N-acetylcysteine against cisplatin ototoxicity in rats: a study with hearing tests and scanning electron microscopy

IntroductionOtotoxicity is a health problem appearing after powerful treatments in serious health conditions. It is sometimes inevitable when treatment of the serious disease is required. Cisplatin is an antineoplastic agent which was investigated previously to reveal increased nitrogen and reactive oxygen radicals that damages hair cells, resulting in ototoxicity. N-acetylcysteine, previously shown to decrease ototoxicity caused by different agents, is known to be a powerful in vitro antioxidant. Probably N-acetylcysteine, in addition to its antioxidant effect, blocks a cascade where reactive oxygen species result in apoptosis in the cochlea. ObjectivesThe possible preventive effect of N-acetylcysteine in cisplatin ototoxicity was studied with auditory brain stem responses, otoacoustic emissions, and histopathological investigation of the cochlea in a scanning electron microscopy. MethodsThis study was conducted on 21 Wistar Albino rats in four groups. 1mL/kg/day three times in total intraperitoneal (i.p.) Saline (n=5), 500mg/kg/day i.p. three times in total N-acetylcysteine (n=5), i.p. 15mg/kg cisplatin alone (single dose) (n=5) and i.p. 15mg/kg cisplatin plus 500mg/kg/day N-acetylcysteine (n=6) were administered. The rats were anesthetized to study the hearing tests before and after the experiment. The rats were sacrificed to investigate the cochleas by scanning electron microscopy. ResultsAuditory brain stem responses and otoacoustic emissions values were attenuated in the cisplatin group. The group that received N-acetylcysteine in addition to cisplatin had better auditory brain stem responses thresholds and otoacoustic emissions. The samples obtained from the cisplatin group showed surface irregularities, degeneration areas, and total or partial severe stereocilia losses. The changes were milder in the cisplatin+N-acetylcysteine group. ConclusionCisplatin ototoxicity can be detected by auditory brain stem responses and otoacoustic emissions testing in rats. N-acetylcysteine may protect the cochlear cells from histopathological changes. We concluded that N-acetylcysteine given 4h after cisplatin injection has a potential otoprotective effect against cisplatin ototoxicity. which suggests it could be used in clinical trials.

Protective effect of N-acetylcysteine in prosthetic joint infection: A nationwide population-based cohort study.

This nationwide population-based retrospective cohort study evaluated the protective effect of N-acetylcysteine against prosthetic joint infection after hip or knee joint replacement. Patients receiving N-acetylcysteine after hip or knee joint replacement between 2000 and 2015 were identified from the Taiwan National Health Insurance Research Database. Each patient receiving N-acetylcysteine was matched to four controls based on age, sex, and index year. All subjects were followed-up from the index date to December 31, 2015. The Cox proportional hazards regression model was used to assess the risk of prosthetic joint infection. A total of 1478 patients were included in the study group, and 5912 matched subjects not receiving N-acetylcysteine were included in the control group. After adjusting for age, sex, insured premium, comorbidities, and immunosuppressive agent use, no significant difference in the risk of prosthetic joint infection was found between the two groups. A higher N-acetylcysteine dose (>360 cumulative defined daily dose) significantly decreased the risk of prosthetic joint infection (adjusted hazard ratio=0.891; 95% confidence interval=0.599-0.989; p=0.042). The protective effect of N-acetylcysteine was observed only in the group of prosthetic joint infection within 5 years (adjusted hazard ratio=0.801; 95% confidence interval=0.581-0.980; p=0.040). High cumulative dose of N-acetylcysteine (>360 cumulative defined daily dose) can effectively reduce the risk of prosthetic joint infection in patients undergoing knee or hip joint replacement surgery within 5 years.

N-acetylcysteine suppresses colistimethate sodium-induced nephrotoxicity via activation of SOD2, eNOS, and MMP3 protein expressions

Objective: To investigate the molecular mechanisms of colistimethate sodium-induced nephrotoxicity and the protective effect of N-acetylcysteine (NAC) against nephrotoxicity.Methods: Twenty-eight Wistar rats were divided into four groups comprised of control, colistin, NAC, and colistin–NAC co-treatment, respectively. Serum creatinine and urine N-acetyl-β-d-glucosaminidase (NAG) levels were measured at different time intervals. Histological changes, apoptosis, total oxidant and antioxidant status, and the expression levels of endothelial nitric oxide synthase (eNOS), superoxide dismutase 2 (SOD2), and matrix metalloproteinase 3 (MMP3) were evaluated in renal tissue.Results: In the colistin group, post-treatment creatinine levels were higher than pretreatment levels (p = .001). There was a significant increase in urine NAG level following colistin treatment on day 10, compared to the baseline value and the first day of treatment (p = .001 and .0001, respectively). Urine NAG levels were higher in the colistin group on the 10th day of treatment than in the other groups (p < .01). Colistin treatment increased the apoptosis index and renal histological damage score (RHDS) significantly and these changes were reversed in NAC co-treatment (RHSD and apoptosis index were 45 and 0 for sterile saline group, 29 and 2 for NAC group, 122 and 7 for colistin group, and 66 and 2 for colistin + NAC group). We observed no difference between groups regarding total antioxidant and total oxidant status in the kidneys. The expression levels of eNOS, SOD2, and MMP3 decreased significantly in the kidneys of colistin-treated rats; these changes were reversed in the kidneys of NAC co-treated rats.Conclusions: N-acetylcysteine prevented colistin-induced nephrotoxicity through activation of expression levels of SOD2, eNOS, and MMP3.

The gastroprotective effect of N-acetylcysteine and genistein in indomethacin-induced gastric injury in rats.

The protective effect of N-acetylcysteine (NAC) and genistein (GEN) on an experimental model of indomethacin (IND)-induced gastric injury was investigated. A total of 50 male rats were divided into 5 groups: (1) control, (2) IND, (3) NAC pretreated, (4) GEN pretreated, and (5) NAC+GEN pretreated. Rats in groups 3-5 were orally administered NAC (500 mg/kg), GEN (10 mg/kg), or both, respectively, once daily for 7 days before the induction of gastric injury by IND (50 mg/kg). The stomach was removed for biochemical analysis and histopathological examination. Pretreatment with NAC, GEN, or both significantly improved ulcer indices and increased nitric oxide level and superoxide dismutase activity. They also significantly decreased malondialdehyde, tumour necrosis factor α levels, and myeloperoxidase activity, and downregulated matrix metalloproteinase 9 (MMP-9) gene expression compared to the IND group. NAC alone ameliorated IND-induced apoptosis, whereas GEN only significantly increased prostaglandin E2 level. Further, coadministration of both resulted in a significantly better gastroprotective effect versus solo administration. Coadministration of NAC and GEN has an additive gastroprotective effect in IND-induced gastric injury, which may be through interaction of their potential cytoprotective, antioxidant, anti-inflammatory, and antiapoptotic mechanisms together with regulation of MMP-9 expression.

The protective effect of N-acetyl cysteine against carbon tetrachloride toxicity in rats

BackgroundCarbon tetrachloride (CCL4) is used as a solvent for oils and fats, as a refrigerant, and as a dry-cleaning agent. Inhalation of its vapors can depress central nervous system activity and cause degeneration of the liver and kidneys.AimThe aim of this study was to investigate whether N-acetyl cysteine (NAC) has a protective effect on the toxicity caused by carbon tetrachloride.MethodsMale rats were used in this experiment. Animals were divided into five groups, 5 animals each: G1 received olive oil, G2 was treated with CCL4 (1 ml/kg body wt) dissolved in olive oil (1:1), G3 received NAC (300 mg/kg body wt), G4 received CCL4 plus NAC, and G5 received NAC for 1 week then administrated to the same treatment of G4. All administrations were performed by gavage and maintained for 4 weeks.ResultsThe present study revealed that administration of CCL4 caused a significant increase in liver marker enzymes Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), and alkaline phosphatase (ALP); also, malondialdehyde (MDA) content in the liver tissue was increased. However, serum total protein showed no change in all groups. Also, histopathological investigation of CCL4 on the liver, testis, and kidney showed different deleterious effects. Additionally, CCl4 induced a highly significant increase in the percentage of sperm shape abnormality and sperm DNA tail moment values. Alternatively, result revealed that the two routes of NAC administrations caused a significant decrease in liver marker enzymes as well as MDA contents; improvement in liver, kidney, and testes architecture; a significant decrease in the percentage of sperm head abnormalities; and decline in the DNA tail moment values.ConclusionThe present study pointed out the protective effect of NAC against the toxicity of CCL4.

Histopathological Effects of Titanium Dioxide Nanoparticles and The Possible Protective Role of N-Acetylcysteine on The Testes of Male Albino Rats.

BackgroundTitanium dioxide (TiO2) is a white pigment which is used in paints, plastics, etc. It is reported that TiO2 induces oxidative stress and DNA damage. N-acetylcysteine (NAC) has been used to fight oxidative stress-induced damage in different tissues. The objective of this study was to evaluate the toxic effects of orally administered TiO2 nanoparticles and the possible protective effect of NAC on the testes of adult male albino rats.Materials and MethodsIn this experimental study, 50 adult male albino rats were classified into five groups. Group I was the negative control, group II was treated with gum acacia solution , group III was treated with NAC, group IV was treated with TiO2nanoparticles, and group V was treated with 100 mg/kg of NAC and 1200 mg/kg TiO2nanoparticles. Total testosterone, glutathione (GSH), and serum malondialdehyde (MDA) levels were estimated. The testes were subjected to histopathological, electron microscopic examinations, and immunohistochemical detection for tumor necrosis factor (TNF)-α. Cells from the left testis were examined to detect the degree of DNA impairment by using the comet assay.ResultsTiO2nanoparticles induced histopathological and ultrastructure changes in the testes as well as positive TNF-α immunoreaction in the testicular tissue. Moreover, there was an increase in serum MDA while a decrease in testosterone and GSH levels in TiO2nanoparticles-treated group. TiO2resulted in DNA damage. Administration of NAC to TiO2- treated rats led to improvement of the previous parameters with modest protective effects against DNA damage.ConclusionTiO2-induced damage to the testes was mediated by oxidative stress. Notably, administration of NAC protected against TiO2’s damaging effects.

DNA damage in homocystinuria: 8-oxo-7,8-dihydro-2 -deoxyguanosine levels in cystathionine-²-synthase deficient patients and the in vitro protective effect of N-acetyl-L-cysteine

Introduction: Homocysteine (Hcy) tissue accumulation occurs in a metabolic disease characterized biochemically by cystathionine β-synthase (CBS) deficiency and clinically by mental retardation, vascular problems, and skeletal abnormalities. Previous studies indicate the occurrence of DNA damage secondary to hyperhomocysteinemia and it was observed that DNA damage occurs in leukocytes from CBS-deficient patients. This study aimed to investigate whether an oxidative mechanism could be involved in DNA damage previously found and investigated the in vitro effect of N-acety-L-cysteine (NAC) on DNA damage caused by high Hcy levels. Methods: We evaluated a biomarker of oxidative DNA damage in the urine of CBS‑deficient patients, as well as the in vitro effect of NAC on DNA damage caused by high levels of Hcy. Moreover, a biomarker of lipid oxidative damage was also measured in urine of CBS deficient patients. Results: There was an increase in parameters of DNA (8-oxo-7,8-dihydro-2’- deoxyguanosine) and lipid (15-F2t-isoprostanes levels) oxidative damage in CBS-deficient patients when compared to controls. In addition, a significant positive correlation was found between 15-F2t-isoprostanes levels and total Hcy concentrations. Besides, an in vitro protective effect of NAC at concentrations of 1 and 5 mM was observed on DNA damage caused by Hcy 50 μM and 200 μM. Additionally, we showed a decrease in sulfhydryl content in plasma from CBS-deficient patients when compared to controls. Discussion: These results demonstrated that DNA damage occurs by an oxidative mechanism in CBS deficiency together with lipid oxidative damage, highlighting the NAC beneficial action upon DNA oxidative process, contributing with a new treatment perspective of the patients affected by classic homocystinuria. Keywords: Cystathionine-β-synthase deficiency; oxidative stress; 8-oxo-7,8-dihydro- 2’-deoxyguanosine; homocysteine; DNA damage; N-acetyl-L-cysteine

Individual and combined effects of Fusarium toxins on apoptosis in PK15 cells and the protective role of N-acetylcysteine

Deoxynivalenol (DON), zearalenone (ZEN) and fumonisin B1 (FB1) are among the most toxicologically important Fusarium toxins commonly found in nature that lead to nephrotoxicity in animals. The present study investigated that the individual and combined effects of subcytotoxic DON (0.25 μM), ZEN (20 μM) and FB1 (10 μM) on oxidative stress and apoptosis in porcine kidney cells (PK15). In addition, the protective effect of N-acetylcysteine (NAC) against the toxicity of Fusarium toxins was also evaluated. Our results showed that the activities of glutathione reductase (GR) and total superoxide dismutase (SOD) were affected by DON, ZEN and FB1, and this change in activity induced reactive oxygen species (ROS) and malondialdehyde (MDA) production, increased apoptosis and regulated the mRNA expression of Bax, Bcl-2, caspase-3, caspase-9, cytochrome c (cyto c) and P53. This study demonstrated the complexity of combined mycotoxin infection since the combination of toxins exhibited more profound defects in the oxidative stress responses and apoptosis. Moreover, NAC reduced the oxidative damage and inhibited the apoptosis induced by Fusarium toxins. It was concluded that oxidative damage and apoptosis through the mitochondria-dependent channel were the mechanisms of Fusarium toxin mediated toxicity, and NAC reversed these damages to some extent.

The cathepsin B inhibitor z-FA-CMK induces cell death in leukemic T cells via oxidative stress.

The cathepsin B inhibitor benzyloxycarbonyl-phenylalanine-alanine-chloromethyl ketone (z-FA-CMK) was recently found to induce apoptosis at low concentrations in Jurkat T cells, while at higher concentrations, the cells die of necrosis. In the present study, we showed that z-FA-CMK readily depletes intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) generation. The toxicity of z-FA-CMK in Jurkat T cells was completely abrogated by N-acetylcysteine (NAC), suggesting that the toxicity mediated by z-FA-CMK is due to oxidative stress. We found that L-buthionine sulfoximine (BSO) which depletes intracellular GSH through the inhibition of GSH biosynthesis in Jurkat T cells did not promote ROS increase or induce cell death. However, NAC was still able to block z-FA-CMK toxicity in Jurkat T cells in the presence of BSO, indicating that the protective effect of NAC does not involve GSH biosynthesis. This is further corroborated by the protective effect of the non-metabolically active D-cysteine on z-FA-CMK toxicity. Furthermore, in BSO-treated cells, z-FA-CMK-induced ROS increased which remains unchanged, suggesting that the depletion of GSH and increase in ROS generation mediated by z-FA-CMK may be two separate events. Collectively, our results demonstrated that z-FA-CMK toxicity is mediated by oxidative stress through the increase in ROS generation.

PROTECTIVE EFFECT OF SOME CHELATING AGENTS AND ANTIOXIDANTS ON THE BIOHAZARDS PRODUCED FROM WATER POLLUTION BY HEAVY METALS IN WISTAR RATS: BIOLOGICAL, GENETIC AND HISTOPATHOLOGICAL STUDY

Background: Heavy metals that normally cause problems are mercury (HgCl2) and lead acetate (LA). Chelating&#x0D; and inhibitor agents are the target to treat and overcome metal toxicity. The current study has been carried out to&#x0D; evaluate the protective effects of N-acetyl cysteine (NAC) and meso 2,3 dimercaptosuccinic acid (DMSA) against&#x0D; HgCl2 and LA toxicity.&#x0D; Materials and Methods: Ninety male Wistar rats were divided into nine equal groups. The groups were administered&#x0D; NAC and/or DMSA in presence or absence of LA (LA; 0.2% in drinking water) or HgCl2 (2 mg/kg BW) for 2&#x0D; consecutive months. Serum and organs were collected for biochemical, genetic and histopathological changes.&#x0D; Results: Biochemical results revealed that LA and HgCl2 significantly increased the levels of liver and kidney&#x0D; biomarkers. Administration of NAC and DMSA considerably improved these altered changes. LA and HgCl2 decreased&#x0D; serum levels of antioxidants and were ameliorated in NAC and DMSA administered rats. LA and HgCl2 administration&#x0D; upregulated expression of IL-1β and IL-8 that were normalized by NAC and DMSA. Kidneys of LA and HgCl2 groups&#x0D; showed intraluminal hyaline casts. Kidneys of DMSA-administrated rats showed mild hydropic degeneration of renal&#x0D; tubular epithelium in LA and HgCl2 groups. Kidneys of NAC administrated rats showed atrophy of capillary tufts.&#x0D; Kidneys of LA and HgCl2 administered rats which received DMSA and NAC showed normal glomerular structure.&#x0D; Liver histopathology showed sever changes that were ameliorated by NAC and DMSA.&#x0D; Conclusion: Taken together, usage of NAC and DMSA provide significant protection against LA and HgCl2-induced&#x0D; hepatotoxicity and nephrotoxicity in male Wistar rats.

Potential protective effect of N-acetyl cysteine in acoustic trauma: An experimental study using scanning electron microscopy.

Oxidative stress has been associated with pathological processes involved in acoustic trauma. In this prospective experimental study, we investigated the potential preventive effect of N-acetyl cysteine (NAC) in rats exposed to acoustic trauma (AT). Light microscopic and scanning electron microscopic (SEM) evaluations were performed. Healthy Wistar albino rats (n = 18) were divided into 3 groups: group 1 (control group, n = 6), group 2 (acoustic trauma group, n = 6), and group 3 (AT+NAC group, n = 6). The rats in group 2 were exposed to AT. The rats in group 3 received NAC at a dose of 100 mg/kg/day by gavage for 7 days, and then 10 min after the 7th-day dose, they were exposed to AT. From light and scanning electron microscopy evaluations in the control group, the cochlear structure and epithelium were normal. In group 2 (AT group), extensive hair cell loss was observed in the cochlea by light microscopy evaluation. In the SEM evaluation, various epithelial damage and loss of stereocilia were also observed. In group 3 (AT+NAC group), decreased damage with preserved cochlear structures was seen by light microscopy. In the SEM evaluation, although stereocilia loss was also seen, nearly normal cell structures and vertical and symmetrical alignment of stereocilia structures were observed compared to the AT group. NAC reduced cochlear damage due to acoustic trauma. Because NAC has antioxidant capacity, AT mat have caused an increase in free radicals and death of outer hair cells. NAC is an antioxidant agent and it prevented cochlear damage due to AT in rats.

Abstract LB-170: A novel, nontoxic RXR agonist, UAB30, targets Fanconi anemia DNA repair pathway to act as potent cancer chemopreventive agent

Abstract UAB30, a synthetic analog of 9-cis-RA is a potent retinoid X receptors (RXR) agonist. It was found to have significantly low retinoic acid receptor (RAR)-binding activity. This unique property of UAB30 is responsible for its low lipid toxicity. Thus, it does not cause elevation in serum triglycerides both in humans and in experimental animals. These properties with favorable pharmacokinetics make it a suitable candidate for chronic use as chemopreventive agent. Here, we show that UAB30 is highly effective in inhibiting UVB-induced pathogenesis of skin cancers in Ptch1+/-/SKH-1 hairless mice. Similar to humans, this unique genetically engineered murine model develops both basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin following chronic UVB irradiation. Compared to controls, the UAB30-treated group showed a 48% reduction in tumor number and a 78% reduction in tumor volume. The number of papillomas, BCCs, and SCCs were reduced by 33%, 74%, and 76%, respectively. UAB30 also diminished UVB-induced skin inflammation, hyperplasia, and enhanced differentiation of suprabasal epidermal cells. The expression of cyclins A, D1, D2, and D3, and cdc25A were decreased in UAB30 treated SCCs, while pro-apoptotic proteins, Bax and cleaved caspase 3 were increased. UAB30 when topically applied 30 min after each UVB irradiation for 30 weeks, it showed significant reduction in cancer development. A 57% reduction in tumor number and 72% reduction in tumor volume were observed. BCCs and SCCs were reduced by 55% and 60%, respectively. We also demonstrate that UAB30 acts by a unique molecular mechanism. Induction of lethal DNA double strand breaks (DSBs) characterized by the presence of p-γH2AX was observed following UAB30 treatment. These effects were more prominent in cancer cells than normal keratinocytes. Induction of DSBs was associated with the activation of DNA damage response (DDR) signaling leading to increased phosphorylation of ATM, Rad50, and Chk2. These effects paralleled with the reduction in cell cycle proteins and cell cycle arrest in G2/M phase followed by apoptosis of arrested cells. UAB30-induced DSBs and DDR were not dependent on ROS as we did not observe significant induction of ROS in UAB30-treated cells and did not notice any protective effect of N-acetyl cysteine. These effects were similar to DDR and changes in proliferation/apoptosis response observed following treatment with cisplatin which is known inducer of DSBs. Moreover, other RXR agonists were significantly less potent in inducing DSBs and DDR responses. The underlying mechanism for the accumulation of DSBs was the diminished ability of cancer cells to repair these DNA lesions. Reduction in FANCD2 and FANCC, the Fanconi anemia core complex proteins which are known to be involved in DSBs repair appear to be the cause of extensive DNA damage associated tumor cell death. Citation Format: Sandeep C. Chaudhary, Craig A. Elmets, Mohammad Athar. A novel, nontoxic RXR agonist, UAB30, targets Fanconi anemia DNA repair pathway to act as potent cancer chemopreventive agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-170. doi:10.1158/1538-7445.AM2017-LB-170

Protective effect of N-acetylcysteine on progression to end-stage renal disease: Necessity for prospective clinical trial

BackgroundWe aimed to evaluate the potential benefits of N-acetylcysteine (NAC) on the risk of chronic kidney disease (CKD) progression to dialysis-requiring end-stage renal disease (ESRDd). MethodsIn a population-based cohort study of 145,062 individuals, 123,608 CKD patients who were followed up for 10years were included, and CKD patients treated with NAC (ICD-9-CM) were compared with those who were not treated. Using propensity score matching, we analyzed the predictors of CKD progression to ESRDd by Cox proportional hazards regression with adjustments for sex, age, and comorbidities, and evaluated the effect of NAC using cumulative defined daily dose (cDDD). ResultsNAC use was associated with a reduced risk for progression to ESRDd [hazard ratio (HR), 0.819; 95% confidence interval (CI), 0.781–0.965; P=0.017]. Risk reduction was proportional to cDDD in NAC users compared with that in NAC non users (HR, 0.835, 0.811, and 0.799 for cDDD 91–180, 181–360, and >360, respectively; P for trend=0.018). Risk reduction was apparent in women (P=0.001) and in younger-aged patients of 18–29years (P=0.021) and 30–39years (P=0.033), in the presence of hypertension (P=0.003), and in the absence of diabetes mellitus (P=0.042) and congestive heart failure (P=0.036). ConclusionNAC use was associated with a reduced risk for progression to ESRDd. These results, obtained from retrospective data, indicate that a prospective study is warranted.