Unraveling the biomechanistic role of Rac1/TWEAK/Fn14/NF‐κB intricate network in experimentally doxorubicin‐induced cardiotoxicity in rats: The role of curcumin

Abstract

Doxorubicin (DOX) is an important chemotherapeutic drug. Cardiotoxicity diminishes its clinical efficacy. We aimed to focus on the mechanism of DOX‐induced cardiotoxicity, in addition, to evaluate curcumin's protective effect against it. Twenty‐eight rats were divided into the normal control group I, curcumin‐treated (200 mg/kg body weight [b.w.]) group II, DOX‐treated (4 mg/kg b.w.) group III, and DOX + curcumin group IV. Cardiac injury markers, heart tissue oxidative stress indices, interferon‐gamma (INF‐γ), tumor necrosis factor‐like weak inducer of apoptosis (TWEAK), upregulated modulator of apoptosis (PUMA), p53 and nuclear factor kappa‐B p65 (NF‐κB p65) levels as well as messenger RNA gene expression of Rac1 and fibroblast growth factor‐inducible protein 14 (Fn14) were assayed, besides the assay of DNA damage, histopathological changes, survivin immunohistochemistry and electron microscopic examination. Curcumin significantly downregulated Rac1 and Fn14 gene expression and significantly decreased p53, NF‐κB p65, INF‐γ, and PUMA levels in the cardiac tissue. In addition, curcumin improved oxidative stress indices, DNA damage, and cardiac toxicity markers in the form of lactate dehydrogenase (LD), creatine kinase isoenzyme‐MB (CK‐MB), and cardiac troponin‐I (cTn‐I). Meanwhile, upregulated antiapoptotic marker survivin was observed. Light and electron microscopic findings confirmed our biochemical and molecular outcomes. The current study established the antioxidant, anti‐inflammatory, and antiapoptotic roles of curcumin against DOX cardiotoxicity.

Potential therapeutic role of spermine via Rac1 in osteoporosis: Insights from zebrafish and mice

“…The results showed that SPM had a dual effect by promoting both P53 expression and phosphorylation, while simultaneously inhibiting Rac1, thereby reversing the effect of SPM on P53 expression and phosphorylation. These results suggest that P53 is a potential downstream molecule of Rac1, with SPM promoting the expression of both, consistent with previous researches ( Mishra et al, 2019 ; Soliman et al, 2021 ).…”

p53 at the Crossroads between Doxorubicin-Induced Cardiotoxicity and Resistance: A Nutritional Balancing Act

“…Furthermore, CUR (below 50 μM) treatment induces p53/p21-dependent apoptosis and significantly inhibits SH-SY5Y cell growth and migration [ 151 ]. An in vitro study showed that CUR treatment (200 mg/kg/day, gavage) can significantly downregulate the expression of genes such as Rac1 and p53 in myocardial tissue, highlighting a potential application of CUR in the prevention of DIC [ 152 ]. Meanwhile, RES, an anthraquinone terpenoid that is highly abundant in grapes, was first reported to have an anticancer effect in 1997 [ 153 ].…”

Melatonin epigenetic potential on testicular functions and fertility profile in varicocele rat model is mediated by silent information regulator 1

“…Ten different non-overlapping randomly selected fields from each section were examined at a magnification of 400 to quantitatively evaluate the mean colour intensity of Bax, Bcl-2 and NFκB positive immunohistochemistry reaction. The colour intensity was calculated by subtracting the colour intensity of negative immunohistochemistry control from the colour intensity of positively stained specimens in serial sections while eliminating the background (Soliman et al, 2021).…”