Cisplatin (Cis) is one of the most potent and effective broad‐spectrum antitumor drugs, but its use is limited due to nephrotoxicity. The current study investigated the renoprotective effect of umbelliferone (UMB) on Cis‐induced nephrotoxicity in rats. Renal injury was induced by a single injection of Cis (7 mg/kg, ip). Our results exhibited that the injection of Cis significantly disrupted renal function biomarkers as well as KIM‐1 expression. The expressions of TNF‐α, IL‐1β, NF‐kB‐p65, and IKKβ were elevated along with downregulation of IkBα expression. Also, Cis disrupted cellular oxidant/antioxidant balance through the reduction of glutathione (GSH), glutathione‐S‐transferase (GST), and superoxide dismutase (SOD) levels and elevation of malondialdehyde (MDA) content. On the contrary, the levels of renal function biomarkers, cytokines, NF‐kB‐p65, IkBα, IKKβ, and oxidant/antioxidant status have been improved after UMB treatment. Mechanistically, rats administered Cis only exhibited a significant decrease in NRF2 and cytoglobin expressions as well as the CREB, SIRT1, FOXO‐3, and PPAR‐γ genes. Treatment with UMB significantly upregulated NRF2 and cytoglobin proteins, as well as effectively increased the expression of CREB, SIRT1, FOXO‐3, PPAR‐γ, and NRF2 genes. Histopathological findings strongly supported our biochemical results, as evidenced by attenuation of renal hemorrhage, cast diffusion, and inflammatory cell infiltration. Interestingly, UMB significantly enhanced Cis cytotoxicity in both HL‐60 and HeLa cells in a dose‐dependent manner. Together, our results demonstrated that UMB can protect against Cis‐induced nephrotoxicity in normal rats along with the enhancement of its in vitro antitumor activity. These findings suggested that UMB could be used as a potential adjuvant therapy in Cis chemotherapeutic protocols.

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This study targeted to examine the protective effects of acetovanillone (AV) against methotrexate (MTX)-induced hepatotoxicity. Thirty-two rats were allocated into four groups of eight animals; Group 1: Normal; Group 2: administered AV (100 ml/kg; P.O.) for 10 days; Group 3: challenged with MTX (20 mg/kg, i.p; single dose); Group 4: administered AV 5 days before and 5 days after MTX. For the first time, this study affords evidence for AV's hepatoprotective effects on MTX-induced hepatotoxicity.The underlined mechanisms behind its hepatic protection include counteracting MTX-induced oxidative injury via down-regulation of NADPH oxidase and upregulation of Nrf2/ARE, SIRT1, PPARγ, and cytoglobin signals. Additionally, AV attenuated hepatic inflammation through down-regulation of IL-6/STAT-3 and NF-κB/AP-1 signaling. Network pharmacology analysis exhibited a high enrichment score between the interacting proteins and strongly suggested the intricate and essential role of the target proteins regulating MTX-induced oxidative damage and inflammatory perturbation. Besides, AV increased the in vitro cytotoxic activity of MTX toward PC-3, HeLa, and K562 cancer cell lines. On the whole, our investigation suggested that AV might be regarded as a promising adjuvant for the amelioration of MTX hepatotoxicity and/or increased its in vitro antitumor efficacy, and it could be used in patients receiving MTX.

Introduction: Carbon tetrachloride (CCL4) is used for induction of liver fibrosis. Liver fibrosis has no standard treatment. Gallic acid (GA) is a naturally occurring phenolic compound having anti-inflammatory and anti-cancer activities. Aim of the work: This work aimed to evaluate the preventive role of GA against CCL4 induced liver fibrosis. Materials and Methods: Forty adult male albino rats were divided into 4 groups; Group I: without treatment .GroupII: received olive oil. Group III: received 1.5 mL/kg of CCL4 twice a week. Group IV: received CCL4 with GA 100mg/kg. Animals were sacrificed after 8 weeks. Liver specimens were processed for light and electron microscopic (EM) study. Area % of collagen and α-SMA expression, levels of AST, ALT, ALP, reduced GSH, MDA, SOD and hydroxyproline were measured and evaluated statistically. Results: Group III revealed foci of altered hepatocytes with dense nuclei and vacuolated cytoplasm. Dilatation and congestion of central and portal veins with mononuclear cell infiltration were observed. There was increased collagen deposition around the central vein. Intense stained α-SMA-positive cells were observed. CCL4 increased collagen and α-SMA expression area %. EM showed electronlucent areas in the cytoplasm of the hepatocytes, vacuolation and margination of nuclear chromatin. CCL4 increased AST, ALT, ALP, hepatic MDA and hydroxyproline levels. Moreover, it decreased the activities of SOD and reduced GSH. The co-administration of GA prevented most of these histological and biochemical changes. Conclusions: The use of natural antioxidants as GA can be promising in ameliorating liver fibrosis better than the drugs and their side effects.