Cisplatin

This study aimed to evaluate site-specific changes in the methylation of the nephro-protective gene p21 (CDKN1a) after exposure to nephrotoxicants using a targeted bisulfite sequencing approach. A targeted gene bisulfite sequencing (TGBS) method was developed using the Illumina MiSeq platform and Bismark bisulfite mapper. Human embryonic kidney (HEK293) cells and freshly isolated human proximal tubular cells (hPT) were analyzed, and 5-aza-2’-deoxycytidine (5-Aza), a DNA methyltransferase inhibitor, served as a positive control. Methylation differences between human and rat p21 were also investigated. TGBS analysis identified a methylation-sensitive site in the p21 promoter region, sis-inducible element-1 (SIE-1), which regulates p21 expression via transcription factor binding. Treatment with 5-Aza altered methylation at this site, whereas nephrotoxicants cisplatin and bromate (BrO3?) did not, despite increasing p21 protein expression. No SIE-1 site was detected in normal rat kidney cells (NRK), indicating species-specific differences. Cisplatin and BrO3? exposure did not decrease promoter methylation in either HEK293 or NRK cells. These findings reveal species-specific differences in basal p21 promoter methylation and indicate that nephrotoxicant-induced changes in p21 expression are independent of promoter DNA methylation. The study also demonstrates the utility of TGBS for rapid analysis of locus-specific DNA methylation.

Overall, we are convinced that in the future the field of medicinal inorganic chemistry will be a key part of drug development for personalized medicine, allowing also considerable advances in predictive medicine. However, we should also fight against the prejudice associated to metal-based drugs, mostly in terms of in vivo toxicity. Thus, as bioinorganic chemists, we should be able to address the difference between the toxicity related to the “naked”, non-coordinated metal ion, and that of the corresponding metal stabilized by the coordinating ligand(s). Moreover, the toxicity of metal complexes is a multifaceted subject during the development of metal-based drugs as it primarily depends on the type of selected application. In the case of metal-based radiopharmaceuticals for diagnosis or therapy toxicity is not the main matter of concern due to the low concentrations of metal-complexes administered to the patients. In order to exert pharmacological effects (e.g. cisplatin is activated by hydrolysis inside cancer cells), however, further studies are necessary to “fine tune” the stability metal complexes while maintaining their biological activity and reduce their side-effects.

To appraise the nephroprotective and antioxidant activity of hydroalcoholicCissampelospareira (C.pareira) whole plant extract using cisplatin induced nephrotoxic rats. C.pareirais a well know medicinal plant of Menispermaceae family which is widely used for ayurvedic medicine to treat various kidney complications. In the present study C.pareirawas observedfor its acute toxicity studies by using OECD guidelines no.425. The nephroprotective activity was evaluated by using cisplatin induced nephrotoxic rats. In-vivo antioxidant activity was evaluated by using glutathione and lipid peroxidation estimation in cisplatin induced rats. One way ANOVA followed by Dunnett’s test using Graph pad prism software. Statistical significance was set at P ≤ 0.05. From the acute toxicity study two doses were selected as 200 and 400 mg/kg p.o. body weight for the present study. C.pareira extract significantly increases the body weights, decrease the elevated urinary glucose levels in the urine, decrease the urea and creatinine levels in blood and increase the urinary creatinine levels in cisplatin induced nephrotoxic rats. In the in-vivo antioxidant study there was a dose dependent decreasing and increasing of lipid peroxidation, glutathione levels in hydroalcoholic extract treated groups respectively. The histopathological investigation was also supported nephroprotective activity of C.pareira. All the results were shown that the plants C.pareirahydroalcoholic extract has significant nephroprotective activity.

In the current investigation, we have assessed the nephroprotective activity of the 70% ethanolic extract of Tecoma stans leaves (EETSL) against cisplatin, gentamicin and paracetamol (nephrotoxicants) induced nephrotoxicity in rats. Nephrotoxicity is confirmed by elevated kidney weight, blood urea, serum creatinine, lipid peroxidation (LPO), decreased tissue glutathione (GSH) and body weight levels at the administered doses. The ethanolic extract produced reduction in kidney weight, blood urea, serum creatinine, LPO levels and reversed the depleted GSH levels and body weight. This is further confirmed by histopathological studies. The results of the present study reveals that the ethanolic extract of Tecoma stans leaves significantly inhibited the cisplatin, gentamicin and paracetamol induced renal damage in rats and this may be attributed to its antioxidant properties. Key words: Tecoma stans, Lipid peroxidation, GSH, Cisplatin, Gentamicin, Paracetamol, Renal injury.