Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether papaverine could mitigate cisplatin-induced kidney damage while preserving its chemotherapeutic efficacy. Integrative bioinformatics analysis predicted papaverine modulation of the mechanistic pathways related to cisplatin renal toxicity; notably, mitogen-activated protein kinase 1 (MAPK1) signaling. We validated protective effects in normal kidney cells without interfering with cisplatin cytotoxicity on a cancer cell line. Concurrent in vivo administration of papaverine alongside cisplatin in rats prevented elevations in nephrotoxicity markers, including serum creatinine, blood urea nitrogen, and renal oxidative stress markers (malondialdehyde, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines), as tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6). Papaverine also reduced apoptosis markers such as Bcl2 and Bcl-2–associated X protein (Bax) and kidney injury molecule-1 (KIM-1), and histological damage. In addition, it upregulates antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) while boosting anti-inflammatory signaling interleukin-10 (IL-10). These effects were underlined by the ability of Papaverine to downregulate MAPK-1 expression. Overall, these findings show papaverine could protect against cisplatin kidney damage without reducing its cytotoxic activity. Further research would allow the transition of these results to clinical practice.

Egypt has the greatest incidence of hepatitis C virus (HCV) infection globally, which is a considerable trigger of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The gut microbiome has been recognized for contributing to various hepatic conditions. Nevertheless, its correlation with HCV and HCC is not well understood. Our study is conducted to investigate the potential relevance of some biomarkers: matrix metalloproteinase 9 (MMP9), Signal transducer and activator of transcription 3 (STAT3), superoxide dismutase (SOD), vascular endothelial growth factor (VEGF), and nuclear factor-κB (NF-κB), along with gut microbial variations, for the differentiation between HCV-related cirrhosis and HCC. The 90 fecal and blood samples were collected from 30 healthy controls, 30 HCV-related cirrhosis, and 30 HCC for detecting gut microbial abundance and biochemical markers examination. Our findings displayed the existence of intestinal microbiome dysbiosis with marked enrichment of specific species, including Bifidobacterium , Fusobacterium , Providencia , E. faecium , and Pseudomonas aeruginosa in HCC patients. Furthermore, the most enriched genera in HCV-related cirrhosis patients were Bifidobacterium , Porphyromonas , and Bacteroides . MMP9 exhibited the highest diagnostic performance of the five measured biomarkers, discriminating against HCC vs. HCV-related cirrhosis with specificity and sensitivity of 100% and 90%, respectively, at a cut-off value > 166.8. Additionally, SOD and NF-κB were statistically significant discriminators of HCC from cirrhosis at cutoff values of ≤ 0.197 and > 166.8. A significant correlation between microbiome abundance and VEGF and MMP9 was observed. This study illustrated that gut microbiomes contribute to HCC and HCV-related cirrhosis pathogenesis, opening approaches for cancer management and prevention.