Toxicity induced by orellanine from the mushroom Cortinarius orellanus in primary renal tubular proximal epithelial cells (RPTEC): Novel mechanisms of action.

The toxicity of Orellanine (OR), a significant factor in mushroom poisoning, has severe effects on the kidneys, particularly the proximal tubules. This study investigated the acute toxicity of OR from the Cortinarius orellanus mushroom in human Primary Renal Tubular Proximal Epithelial Cells (RPTEC). Additionally, the half maximal inhibitory concentration (IC50) of OR in MCF-7 cells was established. RPTEC were subjected to a 6.25 µg/ml dose of orellanine for 24 h, while Control cells were exposed to 0.05% DMSO (vehicle). The RT2 Profiler™ PCR Array Human Nephrotoxicity was utilized to identify genes that were upregulated or downregulated. Western blotting confirmed the protein product of some significantly regulated genes compared to control cells. The IC50 of OR was found to be 319.2 µg/ml. The mechanism of OR toxicity involved several pathways including apoptosis, metal ion binding, cell proliferation, tissue remodeling, xenobiotic metabolism, transporters, extracellular matrix molecules, and cytoskeleton pathways. Other genes from non-specific pathways were also identified. These findings enhance our understanding of OR nephrotoxicity and pave the way for future research into potential treatments or antidotes for natural mushroom poisoning.

Postmortem sampling time effect on toxicity biomarkers in rats exposed to an acute lethal methomyl dose.

Regulations often are imposing long postmortem times before autopsy leading to certain toxicity-unrelated changes in biomarkers, which in turn may affect the reliability of toxicity evaluation during forensic investigations. Since methomyl pesticide shows significant toxicity and is frequently encountered in poisoning cases, the current study evaluated different parameters in methomyl intoxicated rats at three different postmortem intervals (Hour 0, Hour 3 and Hour 6). Eighteen adult Sprague Dawley rats were poisoned with methomyl to simulate actual methomyl poisoning cases. The time of death was assigned as Hour 0. The animals were divided into 3 groups (n = 6) to collect blood and tissue samples at the selected time points. Body weight, relative organ weight, protein concentration, methomyl concentration and acetylcholinesterase activity (AChE) were assessed in blood and different tissues (liver, spleen, kidney, brain, eye, and bone marrow) to evaluate the effect of postmortem sampling time. Outcomes revealed significant decreases in methomyl concentration in blood and bone marrow with advanced sampling time (P < 0.001). Similarly, there were significant reductions in AChE activity in the kidney (P < 0.01), while the enzyme activity significantly increased in brain samples (P < 0.05). Findings illustrated the importance of sampling time in toxicity studies because it could alter experimental results and impact consequent interpretations, as well as it may alter postmortem biomarkers in related forensic cases.

Exploring the effects of edaravone in rats with contrast-induced acute kidney injury.

AIMS: Oxidative stress and inflammatory response play a vital role in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). This study investigated the effects of edaravone in rats with CI-AKI. MAIN METHODS: Male Sprague Dawley rats were randomly assigned into four groups (n = 11-14/group): control, edaravone (30 mg/kg/day intraperitoneally (IP)), CI-AKI, and edaravone with CI-AKI. The induction of CI-AKI was performed by dehydration and the administration of contrast media (iohexol) and inhibitors of prostaglandin (indomethacin) and nitric oxide synthesis (L-NAME: N-nitro L-arginine methyl ester). Edaravone was administered for two weeks before the induction of CI-AKI. Serum creatinine and urea, renal oxidative stress and inflammatory biomarkers, and histopathological alterations were evaluated after 48 h of contrast exposure. KEY FINDINGS: Rats with CI-AKI showed a significant increase in serum creatinine and urea. The levels of antioxidant biomarkers including glutathione peroxidase, superoxide dismutase and reduced glutathione were significantly decreased in CI-AKI group versus control. Pre-treatment of rats with edaravone normalized kidney function and protected the kidney from oxidative damage as demonstrated by normalization of previous biomarkers. Furthermore, edaravone partially ameliorated renal histopathological alterations relative to the CI-AKI group, notably in the nephrons. No changes were observed in inflammatory biomarkers including tumour necrosis factor-alpha and interleukin-6 among all groups. SIGNIFICANCE: The current findings suggest that edaravone could be a potential strategy to ameliorate developing CI-AKI possibly by improving renal antioxidant capacity. Further studies are warranted to expand the current understanding of the use of edaravone in the various models of AKI.

Evaluation of orellanine-induced toxicity from the mushroom Cortinarius orellanus and the antagonistic effect of Petroselinum crispum.

Mushroom poisoning is a worldwide public health problem that may cause serious toxic consequences on renal functions. The study aimed to evaluate the acute toxicity (24 h) of orellanine (OR) from Cortinarius orellanus in rat kidney and the ameliorative effect of parsley ethanolic extract. Twelve adult male Wistar rats were used to determine intraperitoneal (ip) median lethal dose (LD50) of OR, and 32 rats were divided into 4 groups (n = 8): OR group had 500 mg OR per kg bwt; OR + parsley group had the same dose of OR and after 1 h had 500 mg/kg parsley orally; parsley group had parsley only; and control had the vehicle 0.1% DMSO. Blood and kidney samples were collected at Hour 48. The LD50 dose was 1430 mg/kg for an observation period of 24 h. There were significant reductions (p < 0.01) in the body weight, and relative kidney weight of intoxicated rats compared to parsley treated rats and to controls. Similarly, this group had significantly higher levels of creatinine (p < 0.001), uric acid and urea (p < 0.05). The antioxidant glutathione peroxidase activity was significantly reduced (p < 0.01), while Cystatin C serum levels were significantly higher (p < 0.001) in the intoxicated untreated rats compared to all groups. Histopathological examination indicated necrotic damage in glomeruli and proximal tubules of rats given OR, which was relieved by parsley extract. Overall, the study showed that parsley extract ameliorated OR-induced kidney toxicity. This could be utilized in future research on adjunct therapy for toxicity-induced renal injury.

Evaluation of coenzyme Q10 combined with or without N-acetyl cysteine or atorvastatin for preventing contrast-induced kidney injury in diabetic rats.

Combined antioxidants effect for prevention of contrast-induced nephropathy (CIN) remains unclear. This study assessed the potential protective effects of coenzyme Q10 (CoQ10) alone or combined with N-acetyl cysteine (NAC) or atorvastatin against CIN in diabetic rats. Animals were randomly divided into five groups, including control and four disease groups with CIN and diabetes. Group 2 included diabetic rats with CIN. Groups 3-5 included diabetic rats that received CoQ10, CoQ10 and NAC, or CoQ10 and atorvastatin, respectively, before CIN induction. Serum, urine, and tissue were collected to evaluate renal protective effects of tested agents. Renal biomarkers, oxidative stress, and histopathological alterations were investigated. Rats with CIN showed significant renal impairment as revealed by the deleterious effects on kidney function and histology. While induction of CIN did not affect the renal levels of catalase, glutathione peroxidase (GPx), and thiobarbituric acid reactive substances, pretreatment of animals with CoQ10/NAC showed significant increase in GPx and catalase levels versus controls. Lastly, pretreatment with CoQ10/atorvastatin showed regenerative effect on distal tubules with mild kidney histology alterations relative to CIN rats. The combined use of CoQ10/atorvastatin could be a potential strategy to prevent CIN. However, future studies are warranted to test different combinations for longer prophylactic periods.