Antioxidant capacity of N-acetylcysteine against the molecular and cytotoxic implications of cadmium chloride leading to hepatotoxicity and vital progression.

Many studies have reported that cadmium (Cd) can induce liver cell injury; however, the toxicity mechanisms of Cd on the liver have not been fully explained. Thirty-two male albino rats were divided into four groups: the control group, the N-acetylcysteine (NAC) group orally as effervescent instant sachets with a concentration of 200 mg dissolved in distilled water and dosage was 200 mg/kg body weight freshly prepared, the cadmium chloride (CdCl2) group (treated with 3 mg/kg orally), and the N-acetylcysteine (NAC) + cadmium chloride group (treated with 200 mg/kg orally post to CdCl2) for 60 days. The NAC alone did not make notable changes in most of the parameters. The CdCl2 alone, compared to control, induced significant alterations in oxidative stress markers (increment in lipid peroxidation (LPO) and nitric oxide (NO)) and antioxidant defense system (decrement in superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx)), which resulted in a downregulation of pro-apoptotic Bcl2-associated X protein (Bax) and caspase-3 and upregulation of anti-apoptotic B-cell leukemia/lymphoma 2 (Bcl2) protein as well as the survival fate of hepatic cells. Post-administration of NAC to CdCl2 resulted in a reduction in oxidative stress markers, shifting of cells from the G2/M phase to the G0/G1 inhibiting signal-regulated kinase activation, and impairment of the anti-apoptotic signaling pathway when compared to the CdCl2 group alone. Accordingly, the Bcl2/Bax ratio was reduced to 1.17-fold change, as an adaptive process to hepatic tissue injury. These findings demonstrated that NAC would attenuate the possibility of oxidative stress and cytotoxicity of hepatic tissue induced by CdCl2.

Zingerone alleviates cadmium-induced nephrotoxicity in rats via its antioxidant and anti-apoptotic properties

Objectives: Cadmium is an essential industrial metal and acts as an environmental toxicant that is a major cause of kidney diseases. Hence, we aimed to evaluate the possible nephroprotective effects of zingerone (ZGO), a major flavonoid constituent in ginger (Zingiber officinale) dry roots, against cadmium-induced nephrotoxicity in rats. Methods: In this study, Wistar albino rats [ACUC: HU2020/Z/FMS0120-01] were allocated randomly to 4 groups with seven animals in each group. The control group which received physiological saline; cadmium chloride (CdCl2) treatment group which received CdCl2 at a dose of 6.5 mg/kg intraperitoneally (i.p.) for 7 consecutive days; zingerone treatment group which received 25 mg/kg of zingerone orally for 7 consecutive days and CdCl2(6.5 mg/kg; i.p.)+ZGO (25 mg/kg; p.o.) treatment group which received CdCl2 and ZGO for 7 consecutive days. Results: Co-administration of ZGO along with CdCl2 resulted in a significant reduction in creatinine and urea levels of serum. Additionally, ZGO significantly diminished the tissue levels of Cd concentration, lipid peroxidation, and nitric oxide and significantly recovered the enzymatic and nonenzymatic antioxidant molecules, namely glutathione, total superoxide dismutase, catalase, and glutathione recycling enzymes peroxidase and reductase, in kidney tissue. Furthermore, ZGO treatment prevented the inflammation produced by CdCl2 by restraining the elevation in the level of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin1beta). Moreover, ZGO improved histopathological alternations in the kidney by preventing apoptosis cascade in kidney tissue by stimulating Bcl-2 and suppressing Bax and caspase-3. Conclusions: Our findings suggest that ZGO has nephroprotective activity in cadmium-induced nephrotoxicity mostly via modulating of oxidant/antioxidant balance, inflammatory response, and apoptosis.

N-Acetylcysteine Reduces miR-146a and NF-κB p65 Inflammatory Signaling Following Cadmium Hepatotoxicity in Rats.

We performed a thorough screening and analysis of the impact of cadmium chloride (CdCl2) and N-acetylcysteine (NAC) on the miR146a/NF-κB p65 inflammatory pathway and mitochondrial biogenesis dysfunction in male albino rats. A total of 24 male albino rats were divided into three groups: a control group, a CdCl2-treated group (3 mg/kg, orally), and a CdCl2 + NAC-treated group (200 mg/kg of NAC, 1 h after CdCl2 treatment), for 60 consecutive days. Real-time quantitative PCR was used to analyze the expression of miR146a, Irak1, Traf6, Nrf1, Nfe2l2, Pparg, Prkaa, Stat3, Tfam, Tnfa, and Il1b, whereas tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 protein levels were assessed using ELISA, and NF-κB p65 was detected using western blotting. A significant restoration of homeostatic inflammatory processes as well as mitochondrial biogenesis was observed after NAC and CdCl2 treatment. Decreased miR146a and NF-κB p65 were also found after treatment with NAC and CdCl2 compared with CdCl2 treatment alone. Collectively, our findings demonstrate that CdCl2 caused mtDNA release because of Tfam loss, leading to NF-κB p65 activation. Co-treatment with NAC could alleviate Cd-induced genotoxicity in liver tissue. We concluded that adding NAC to CdCl2 resulted in a decreased signaling of the NF-κB p65 signaling pathway.

Exposure to arsenite and cadmium induces organotoxicity and miRNAs deregulation in male rats.

Sodium arsenite (NaAsO2) and cadmium chloride (CdCl2) are two prime examples of un-biodegradable compounds that accumulate in the ecosystems causing great threats to human health and produce severe adverse effects. However, their joint toxicities are poorly understood in mammals. This study aimed to identify the effect of exposure to NaAsO2 (5 mg/kg, by oral gavage) and CdCl2 (1 mg/kg injected interperitoneal, i.p.) either alone or in combinations after 14 and 28 days on oxidative stress, antioxidant enzyme activities, and histopathological changes. The results revealed a downregulation of miR-146a also, in miR-let7a after 14 days and a notable upregulation after 28 days. However, administrations of their combinations for 14 days caused downregulated miR-146a and miR-let7a. However, upregulation miR-let7a was observed only after 28 days. Organotoxicity of liver results in a remarkable increase in oxidative stress biomarkers by the two metals either alone or in combinations. A remarkable decrease was noted in an antioxidant enzyme activity indicating a defect in the antioxidant defense system. Also, CdCl2 alone showed remarkable liver histopathological changes. This study concluded that there was a close relationship of high epigenetic changes as deregulation of both miR-146a and miR-let7a as a result of the joint toxicity of both compounds, and ultimately major changes in hepatic tissues that may lead to cell transformations. However, further studies are needed to investigate the target genes for those miRNAs.