Introduction: Nephrotoxicity represents a major complication of using doxorubicin (DOX) in the management of several types of cancers. Increased oxidative stress and the activation of inflammatory mediators play outstanding roles in the development of DOX-induced kidney damage. This study aimed to investigate whether the two pathways of incretin-based therapy, glucagon-like peptide-1 receptor agonist (presented as semaglutide, SEM) and dipeptidyl peptidase-4 inhibitor (presented as alogliptin, ALO), differentially protect against DOX-induced nephrotoxicity in rats and to clarify the underlying molecular mechanisms.Methods: Adult male rats were divided into six groups: control (received the vehicle), DOX (20 mg/kg, single I.P. on day 8), DOX + ALO (20 mg/kg/day, P.O. for 10 days), DOX + SEM (12 μg/kg/day, S.C. for 10 days), ALO-alone, and SEM-alone groups. At the end of the study, the animals were sacrificed and their kidney functions, oxidative stress, and inflammatory markers were assessed. Kidney sections were also subjected to histopathological examinations.Results: The co-treatment with either ALO or SEM manifested an improvement in the kidney functions, as evidenced by lower serum concentrations of creatinine, urea, and cystatin C compared to the DOX group. Lower levels of MDA, higher levels of GSH, and increased SOD activity were observed in either ALO- or SEM-treated groups than those observed in the DOX group. DOX administration resulted in decreased renal expressions of sirtuin 1 (SIRT1) and Nrf2 with increased NF-κB and TNF-α expressions, and these effects were ameliorated by treatment with either ALO or SEM.Discussion: Co-treatment with either ALO or SEM showed a renoprotective effect that was mediated by their antioxidant and anti-inflammatory effects via the SIRT1/Nrf2/NF-κB/TNF-α pathway. The fact that both pathways of the incretin-based therapy demonstrate an equally positive effect in alleviating DOX-induced renal damage is equally noteworthy.

The purpose of this study was to investigate the anti-cancer property of grape seed extract (GSE) during early stages of developing liver cancer using a two-stage carcinogenic model combining diethylnitrosamine (DEN) and 2-Acetyl Aminofluorene (2-AAF). Administration of GSE at doses 25, 50 and 100 mg/kg per day started at the beginning of promotion periods and continued for 14 weeks. GSE dramatically inhibited pre-neoplastic foci formation as well as significantly decreased the number and the area of placental glutathione-S-transferase in livers of DEN-2AAF-treated rats by approximately 4 & 10 fold deductions, respectively. GSE’s effects were associated with induced apoptosis, reduced cell proliferation, decreased oxidative stress and down regulation of histone deacetylase activity and inflammation makers, such as cyclooxygenase 2, inducible nitric oxide synthase, nuclear factor-kappa B-p65 and p- phosphorylated tumor necrosis factor receptor expressions in liver. GSE treatment also decreased the viability of HepG2 cells and induced early and late apoptosis through activating caspase-3 and Bax. Furthermore, GSE induced G2/M and G1/S cell cycle arrest. The present study provides evidence that the GSE’s anticancer effect is mediated through the inhibition of cell proliferation, induction of apoptosis, modulating oxidative damage and suppressing inflammatory response.

Introduction: Methotrexate (MTX) is a frequently utilized anti-inflammatory and anticancer agent. Its potential liver and lung toxicity often limits its clinical effectiveness. We conducted this study to demonstrate the possible protective impacts of a natural galectin-3 (Gal-3) inhibitor, modified citrus pectin (MCP), against MTX-induced liver and lung toxicity and verify the potential signaling pathways of these suggested effects. In vitro, the cytotoxicity of MCP and its modulatory effect on MTX cytotoxic efficacy were assessed.Methods: Four groups of rats were used: control, MTX (40 mg/kg, single intraperitoneal injection on day 9), MTX + MCP (200 mg/kg/day, orally, for 2 weeks), and MCP alone. MCF7, Nalm6, and JEG3 cell lines were used for the in vitro cytotoxicity assay.Results: MCP counteracted liver and lung toxicity evidenced by ameliorating the markers of liver and lung functions. Moreover, MCP minimized oxidative stress elicited by MTX in lung and liver tissues, as indicated by reduced malondialdehyde levels, elevated levels of reduced glutathione, increased superoxide dismutase activity, and upregulated Nrf2 protein expression. In hepatic and pulmonary tissues, MCP downregulated the inflammatory signaling pathway, Gal-3/TLR-4/NF-κB/TNF-α. MCP pretreatment decreased TGF-β, collagen content, and cleaved caspase-3 levels. MCP enhanced the cytotoxicity of MTX in Nalm6 and JEG3 and did not interfere with its cytotoxicity in the MCF7 cell lines.Discussion: MCP attenuated MTX-induced liver and lung toxicity through antioxidant, anti-fibrotic, anti-inflammatory, and anti-apoptotic influences, as demonstrated by the improved histopathological changes induced by MTX in pulmonary and hepatic tissues. Moreover, it increased MTX cytotoxicity in different human cell lines.