Cyclosporine Ameliorates Silica-Induced Autoimmune Hepatitis in Rat Model by Altering the Expression of Toll-Like Receptor-4, Interleukin-2, and Tumor Necrosis Factor-α.

BACKGROUND: Autoimmune hepatitis (AIH) is an inflammatory liver disease that is characterized histologically by interface hepatitis, biochemically by elevated transaminase levels, and serologically by the presence of autoantibodies. Toll-like receptor (TLR)-4 is a TLR family member that, upon activation in hepatocytes, initiates a cascade of events. Interleukin-2 (IL-2) and tumour necrosis factor α (TNF-α) are potent inflammatory cytokines secreted in AIH, playing an important role in the early development of inflammation and hepatocyte damage. OBJECTIVES: This study examined the role of cyclosporine in AIH and illustrated its actions on altered hepatic function in the silica-induced AIH model. METHODS: AIH was induced in Wistar rats using sodium silicate. The rats were divided into four groups: the control group, silica-AIH group, cyclosporine-treated group, and prevention group. TLR-4 and IL-2 mRNA expressions in liver tissues were tested by RTPCR. RESULTS: AIH was associated with up-regulation of liver enzymes, IL-2 and TLR-4 gene expression, while cyclosporine significantly down-regulated the expression of both. The relative quantity of TLR-4 mRNA was 1±0, 13.57±1.91, 4±0.38, and 2±0 in control, AIH, cyclosporine, and prevention groups, respectively (p<0.001). Also, the relative quantity of IL-2 mRNA was 1±0, 14.79±1.42, 7.07±0.96, and 3.4±0.55 in control, AIH, cyclosporine, and prevention groups, respectively (p<0.001). Additionally, immunohistochemical staining for TNF-α in liver sections was increased in the silica-AIH group but was found to decrease in the cyclosporine-treated and prevention groups. CONCLUSION: This study advocates the therapeutic role of cyclosporine in treating immune-mediated hepatic diseases. Cyclosporine improves histological alterations in the liver and inhibits the production of proinflammatory cytokines.

Guanosine protects against glycerol-induced acute kidney injury via up-regulation of the klotho gene.

Objectives: Acute Kidney Injury (AKI) is characterized by a rapid and reversible decline in renal function with a rapid decrease in Glomerular Filtration Rate (GFR), which is associated with high mortality. Rhabdomyolysis accounts for 10-40% of AKI, to which the therapeutic approach is limited. Klotho is a protein that modulates sodium-phosphate co-transporters, ion channels that have been reported to have a renal protective effect. Guanosine, a purine nucleoside, has already been reported to have a renal protective effect; however, the mechanism of such protection and its relation to Klotho modification has not been evaluated yet. This study aims to evaluate the mechanism of the protective effect of guanosine against rhabdomyolysis-induced AKI and its relation to the expression of the Klotho gene. Materials and Methods: In the current study, rats were divided into three groups: control, glycerol-induced AKI, and guanosine-treated. Serum urea and creatinine levels, renal tissue Total Antioxidant Capacity (TAC), and Klotho and Cystatin C genes expression were evaluated. Furthermore, caspase-3 immunostaining and histopathological evaluations were done. Results: Results showed that guanosine treatment resulted in a significant reduction in serum urea and creatinine, Cystatin C genes expression, and caspase-3 immunoexpression, and an increase in TAC and Klotho genes expression. Results also revealed an improvement of renal histopathology when compared with the glycerol-induced AKI group. Conclusion: Guanosine may be a promising agent in the treatment of rhabdomyolysis-induced AKI. The proposed mechanism for guanosine may be through its ability to enhance Klotho gene expression in renal tissue, with subsequent antioxidant and anti-apoptotic activity.

A study of the hepatoprotective effect of Plantago psyllium L. seed extract against Carbon tetrachloride induced hepatic injury in rats.

BACKGROUND: The liver is the main metabolic organ involved in disposal and detoxification of various molecules. Plantago psyllium L. seed has been reported to exert positive effects in some pathological conditions. The current study aims to assess the hepatoprotective effect of Plantago psyllium L. seed extract against carbon tetrachloride-induced hepatotoxicity. METHODS: Male albino Wistar rats were randomly divided into five groups of 10 rats each. Hepatotoxicity was induced by orally administered carbon tetrachloride (CCl4) for nine weeks with or without the different treatments which were utilized daily for the whole nine weeks. Serum and tissue samples were then withdrawn and different liver biomarkers were investigated. RESULTS: Treatment of rats with Psyllium seed ethanolic extract significantly alleviated the toxic effects of CCl4. This was evidenced by its ability to restore liver biomarkers levels. Moreover, treatment with Psyllium seed extract normalized levels of oxidative biomarkers such as lipid peroxidation, hepatic content of reduced glutathione and catalase activity, as well as the expression level of the inflammatory marker TNF-α. Histopathological examination reflected the protective effect of the extract on liver architecture and confirmed the observed biochemical data. CONCLUSIONS: The presented data demonstrates a potential hepatoprotective effect of Psyllium seed extract compared to the standard hepatoprotective drug silymarin. This effect can be attributed to the antioxidant and anti-inflammatory effects of Psyllium extract.

Therapeutic effect of liraglutide on expression of CTGF and BMP-7 in induced diabetic nephropathy.

INTRODUCTION: Diabetic nephropathy (DN) is one of the critical complications of diabetes mellitus and the main cause of chronic renal dysfunction. The pathogenic mechanism causing the disease remains unclear and there is a lack of effective treatment methods so novel strategies are needed for DN management. The aim of this study, therefore, is to evaluate the effect of liraglutide as glucagon-like peptide-1 analogue and its underlying mechanisms on induced DN in rats MATERIALS AND METHODS: Sixty rats were divided into control group, diabetic group, and liraglutide-treated group. At the end of experiment, renal CTGF and BMP-7 messeger RNA expression were determined. Blood sugar, serum urea, and creatinine were measured. Also, histopathological changes were studied. RESULTS: Liraglutide can improve renal alterations associated with diabetes as it reduced CTGF expression and increased BMP-7 expression. In the same time, it could improve histopathological changes and renal function tests. CONCLUSION: These findings influence the beneficial use of liraglutide for the management of DN in patients with diabetes mellitus.

Inhibition of NF-κB/TNF-α pathway may be involved in the protective effect of resveratrol against cyclophosphamide-induced multi-organ toxicity.

CONTEXT: Cyclophosphamide (CyP), an efficient anticancer drug, may damage normal human cells. Resveratrol (RES), a natural polyphenol, has a diverse pharmacological properties. OBJECTIVE: To test possible protective effect of RES on multi-organ damage caused by CyP. MATERIALS AND METHODS: RES (10 mg/kg/day) was administered orally for 8 days. In independent rat groups, CyP toxicity was induced via a single dose of 150 mg/kg i.p. 3 days before the end of experiment, with or without RES treatment. RESULTS: Compared to control, CyP caused significant increase in organ-to-body weight ratios of heart, kidney and liver, with deterioration in their functional parameters; namely serum creatine kinase, blood urea nitrogen, creatinine, alanine aminotransferase and aspartate aminotransferase. CyP also caused distortion in these organs' histology, with significant tissue oxidative stress, manifested by decrease in reduced glutathione and catalase, as well as increase in malondialdehyde and nitric oxide levels. Furthermore, CyP caused multi-organ inflammatory effects as shown by increased tumor necrosis factor-α levels, as well as up-regulation of nuclear factor-κB expressions. Using RES concurrently with CyP restored heart, kidney and liver functional parameters, as well as their normal histology. RES also reversed oxidative stress, as well as inflammatory signs caused by CyP alone. CONCLUSIONS: RES may be beneficial adjuvant that confers multi-organ protection against CyP toxicity via antioxidant and anti-inflammatory mechanisms.