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.

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.

Chlorogenic acid abates male reproductive dysfunction in arsenic-exposed mice via attenuation of testicular oxido-inflammatory stress and apoptotic responses.

Arsenic, a major environmental pollutant of global concern, is well-known for its reproductive toxicity. In this study, the protective potential of chlorogenic acid (CGA), a caffeoylquinic acid isomer abundantly found in many plants, was investigated against sodium arsenite (NaAsO2)-induced testicular dysfunctions. Adult male Swiss mice were either administered NaAsO2 alone at 5 mg kg-1 or co-treated with CGA at 100 mg kg-1 or 200 mg kg-1 body weight for 4 weeks. Results showed that NaAsO2-treated mice exhibited marked declines in testes weight, sperm count, and viability accompanied by decreases in sexual hormonal levels. Moreover, NaAsO2 toxicity evoked exhaustion of antioxidant markers (SOD, CAT, GPx, GR, and GSH), down-regulation of Nrf2 (nuclear factor erythroid 2-related factor 2) gene expression level, and elevations in malondialdehyde. Further, elevations in inflammatory cytokines (IL-1, TNF-α, and IL-6) together with the up-regulation of pro-apoptotic biomarkers (Bax and caspase- 3) and down-regulation of anti-apoptotic Bcl-2 were observed in NaAsO2 intoxication. Immunohistochemical analysis of testis sections of NaAsO2-treated mice showed high caspase-3 expression. These findings were well supported with testicular histopathological examination. However, pretreatment of mice with CGA resulted in noteworthy improvements in testicular damage induced by arsenic in a dose-dependent manner possibly mediated by the Nrf2 signaling pathway. Conclusively, CGA counteracted arsenic-induced testicular injury through its antioxidant, anti-inflammatory, and anti-apoptotic properties. Therefore, CGA could serve as a favorable intervention in the alleviation of arsenic-induced reproductive toxicity.

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.

MicroRNAs in prostate cancer: From function to biomarker discovery.

MicroRNAs (miRNAs) are a small functional non-coding RNAs that post-transcriptionally regulate gene expression through mRNA degradation or translational repression. miRNAs are key regulatory components of various cellular networks. Current evidence support that multiple mammalian genome-encoded miRNAs impact the cellular biology, including proliferation, apoptosis, differentiation, and tumorigenesis, by targeting specific subsets of mRNAs. This minireview is focused on the current themes underlying the interactions between miRNAs and their mRNA targets and pathways in prostate tumorigenesis and progression, and their potential clinical utility as biomarkers for prostate cancer. Impact statement The primary goal of this article was to review recent literature on miRNA biogenesis and further elaborate on the identity of newly discovered miRNAs and their potential functional significance in the complex biological network associated with prostate tumorigenesis and disease progression and as biomarkers for prostate cancer.