Combined β-sitosterol and trimetazidine mitigate potassium dichromate-induced cardiotoxicity in rats through the interplay between NF-κB/AMPK/mTOR/TLR4 and HO-1/NADPH signaling pathways

Abstract

Hexavalent chromium salt, like potassium dichromate (PD), is chromium’s most precarious valence state in industrial wastes. Recently, there has been increasing interest in β-sitosterol (BSS), a bioactive phytosterol, as a dietary supplement. BSS is recommended in treating cardiovascular disorders due to its antioxidant effect. Trimetazidine (TMZ) was used traditionally for cardioprotection. Through the administration of BSS and TMZ, the cardiotoxic effects of PD were to be countered in this study, in addition to examining the precise mechanism of PD-induced cardiotoxicity. Thirty male albino rats were divided into five groups; the control group: administered normal saline daily (3 mL/kg); the PD group: administered normal saline daily (3 mL/kg); BSS group: administered BSS daily (20 mg/kg); TMZ group: administered TMZ daily (15 mg/kg); and the BSS + TMZ group: administered both BSS (20 mg/kg) and TMZ (15 mg/kg) daily. All experimental groups, except the control, received on the 19th day a single dose of PD (30 mg/kg/day, S.C.). Normal saline, BSS, and TMZ were received daily for 21 consecutive days p.o. The exposure to PD promoted different oxidative stresses, pro-inflammatory, and cardiotoxicity biomarkers. BSS or TMZ succeeded solely in reducing these deleterious effects; however, their combination notably returned measured biomarkers close to normal values. The histopathological investigations have supported the biochemical findings. The combination of BSS and TMZ protects against PD cardiotoxicity in rats by reducing oxidative stress and apoptotic and inflammatory biomarkers. It may be promising for alleviating and protecting against PD-induced cardiotoxicity in people at an early stage; however, these findings need further clinical studies to be confirmed. Highlights • Potassium dichromate induces cardiotoxicity in rats through the upregulation of oxidative stress, proinflammatory, and apoptotic pathways biomarkers. • β-Sitosterol possesses a possible cardioprotective effect by modulating several signaling pathways. • Trimetazidine, the antianginal agent, has a potential cardioprotective impact on PD-intoxicated rat model. • The combination of β-Sitosterol and trimetazidine was the best in modulating different pathways involved in PD cardiotoxicity in rats via the interplay between NF-κB/AMPK/mTOR/TLR4 and HO-1/NADPH signaling pathways. Graphical Abstract

Nicorandil mitigates arsenic trioxide‐induced lung injury via modulating vital signalling pathways SIRT1/PGC‐1α/TFAM, JAK1/STAT3, and miRNA‐132 expression

“…The present results highlight the pronounced effects of nicorandil on AMPK phosphorylation in ATO-treated rats. This aligns with other studies demonstrating the protective antioxidant role of AMPK, which suppresses NF-κB activity and impedes its migration from the cytosol of activated macrophages to the nucleus, thereby restraining the initiation of the pro-inflammatory cascade (El-Shoura et al, 2023;Xiang et al, 2019).…”

“…Furthermore, disturbed redox balance and heightened levels of oxidative stress biomarkers are known to trigger NF-κB activation via TLR-4. This activation exacerbates the redox status imbalance, stimulating an increased influx of inflammatory cells and cytokines, including TNF-α, IL-6, and IL-1β, while concurrently decreasing levels of anti-inflammatory cytokines (Atwa et al, 2022;Baeuerle & Baichwal, 1997;El-Shoura et al, 2023). Cytokine activation stimulates STATs through JAK activation via tyrosine phosphorylation (Liu et al, 2023;Morris et al, 2018).…”