The protective effects of esculetin against Doxorubicin-Induced hepatotoxicity in rats: Insights into the modulation of Caspase, FOXOs, and heat shock protein pathways.

Doxorubicin (DOX) is an anthracycline antibiotic widely employed to treat carcinoma. Nevertheless, severe cardiotoxic side effects restrict its clinical use. Esculetin, a natural flavonoid, is found abundantly in plants. This study evaluated the protective effects of esculetin against DOX-induced hepatotoxicity in rat livers. Forty-eight rats were randomly divided into six groups with eight rats in each group: control (I), DOX (II), esculetin (III, 50 mg/kg), esculetin (IV, 100 mg/kg), DOX+esculetin 50 (V, DOX+esculetin 50 mg/kg), and DOX+esculetin 100 (VI, DOX+esculetin 100 mg/kg). The administration of esculetin effectively mitigated alterations in the measured biochemical parameters induced by DOX. Gene expression analyses demonstrated that esculetin treatment significantly reduced the DOX-induced expression of Foxo1, Hspa1a, Hsp4a, Hsp5a, Casp3, and Casp9 while increasing the DOX-induced expression of Foxo3. These findings suggest that esculetin, with its antioxidant and anti-inflammatory effects, might be a therapeutic option for protecting against DOX-induced hepatotoxicity.

The interplay between doxorubicin chemotherapy, antioxidant system, and cardiotoxicity: Unrevealing of the protective potential of tannic acid.

Cardiotoxicity is the leading side effect of anthracycline-based chemotherapy. Therefore, it has gained importance to reveal chemotherapy-supporting strategies and reliable agents with their mechanisms of action. Tannic acid (TA), a naturally occurring plant polyphenol, has diverse physiological effects, including anti-inflammatory, anticarcinogenic, antioxidant, and radical scavenging properties. Therefore, this study was designed to investigate whether TA exerts a protective effect on mechanisms contributing to anthracycline-induced cardiotoxicity in rat heart tissues exposed to doxorubicin (DOX). Rats were randomly divided into control and experimental groups and treated with (18 mg/kg) DOX, TA (50 mg/kg), and DOX + TA during the 2 weeks. Cardiac gene markers and mitochondrial DNA (mtDNA) content were evaluated in the heart tissues of all animals. In addition to major metabolites, mRNA expression changes and biological activity responses of components of antioxidant metabolism were examined in the heart tissues of all animals. The expression of cardiac gene markers increased by DOX exposure was significantly reduced by TA treatment, whereas mtDNA content, which was decreased by DOX exposure, was significantly increased. TA also improved antioxidant metabolism members' gene expression and enzymatic activity, including glutathione peroxidase, glutathione s-transferase, superoxide dismutase, catalase, and thioredoxin reductase. This study provides a detailed overview of the current understanding of DOX-induced cardiotoxicity and preventive or curative measures involving TA.

Investigation of the multi-targeted protection potential of tannic acid against doxorubicin-induced kidney damage in rats.

Doxorubicin (DOX) is an antitumor drug that is powerful but can cause worse outcomes, including nephrotoxicity, and therefore has limited clinical use. Therefore, it is necessary to identify safer agents that can minimize the damage caused by the drug without shifting the treatment performance, in addition to clarifying the underlying mechanisms of DOX-induced aberrant in vivo renal activation. In this study, we tested the prophylactic capacity and mechanisms of action of tannic acid (TA) against DOX-mediated kidney damage in rats and evaluated the nephrotoxic activity of DOX when used with TA. Rats were treated during the two weeks with cumulative (18 mg/kg with six different injections) DOX, daily TA (50 mg/kg), and the DOX + TA combination. Changes in major metabolites and components involved in antioxidant metabolism were evaluated in the kidney tissues of all animals. Further, the gene expression levels of regulatory factors that have critical importance in cell metabolism, inflammation, and apoptosis were investigated. Both biochemical and molecular examinations showed that TA improved DOX-induced dysregulations at both protein and gene levels in the kidneys. Increased lipid peroxidation and decreased glutathione levels were reversed. Consistent with oxidative stress marker metabolites, suppressed antioxidant enzyme activities and transcript levels of antioxidant system members were restored. Of note, combination treatment with TA could overcome doxorubicin-induced gene expressions markedly altered by DOX, suggesting that nephroprotection conferred by TA involved the remodeling of stress resistance, cell metabolism, inflammation, and apoptosis. Collectively, the present in vivo study suggests that TA could be used as a multitarget and effective agent for the mitigation of doxorubicin-induced nephrotoxicity without changing the therapeutic efficacy of the drug.