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.

Effect of tannic acid on doxorubicin-induced cellular stress: Expression levels of heat shock genes in rat spleen.

Doxorubicin (DOX), an anthracycline group antibiotic, has been extensively employed as a potent chemotherapeutic agent for treating solid and hematopoietic tumors in humans. Amid exposure to diverse stress conditions, living organisms swiftly initiate the synthesis of heat shock proteins (HSPs), a set of highly conserved proteins. Tannic acid (TA) has garnered increasing study attention due to its special chemical properties, health benefits, and wide availability. This study's primary aim is to elucidate the impact of DOX and TA on the expression levels of Hsp90aa1, Hspa1a, Hspa4, and Hspa5 in the spleen tissues of rats. Sprague Dawley rats (Rattus norvegicus, male, 9-10 weeks old, 180 ± 20 g) were randomly divided into 4 groups: control, DOX (30 mg/kg cumulative), TA (50 mg/kg), and DOX + TA (5 mg/kg and 50 mg/kg, respectively). Subsequently, spleen tissues were collected from rats, and complementary DNA libraries were generated after the application process. The quantitative real-time PCR method was used to detect and quantify the mRNA expression changes of the Hsp90aa1, Hspa1a, Hspa4, and Hspa5 genes our results showed that the mRNA expressions of the targeted genes were up-regulated in rat spleen tissues exposed to DOX. However, this increase was remarkably suppressed by TA treatment. These findings suggest that TA may serve as a protective agent, mitigating the toxic effects of DOX in the rat spleen.

Protective effects of esculetin against doxorubicin-induced toxicity correlated with oxidative stress in rat liver: In vivo and in silico studies.

Doxorubicin (DOX) is widely used in cancer treatment but the dose-related toxicity of DOX on organs including the liver limit its use. Therefore, there is great interest in combining DOX with natural compounds with antioxidant properties to reduce toxicity and increase drug efficacy. Esculetin is a natural coumarin derivative with biological properties encompassing anti-inflammatory and antioxidant activities. In light of these properties, this study was meticulously crafted to investigate the potential of esculetin in preventing doxorubicin (DOX)-induced hepatotoxicity in Sprague-Dawley rats. The rats were divided into a total of six groups: control group, DOX group (administered DOX at a cumulative dose of 5 mg/kg intraperitoneally every other day for 2 weeks), E50 group (administered 50 mg/kg of esculetin intraperitoneally every day), E100 group (administered 100 mg/kg of esculetin intraperitoneally every day) and combined groups (DOX + E50 and DOX + E100) in which esculetin was administered together with DOX. The treatments, both with DOX alone and in combination with E50, manifested a reduction in catalase (CAT mRNA) levels in comparison to the control group. Notably, the enzymatic activities of superoxide dismutase (SOD), CAT, and glutathione peroxidase (GPx) witnessed significant decreases in the liver of rats treated with DOX. Moreover, DOX treatment induced a statistically significant elevation in malondialdehyde (MDA) levels, coupled with a concurrent decrease in glutathione (GSH) levels. Additionally, molecular docking studies were conducted. However, further studies are needed to confirm the hepatoprotective properties of esculetin and to precisely elucidate its mechanisms of action.

Tannic acid may ameliorate doxorubicin-induced changes in oxidative stress parameters in rat spleen.

Doxorubicin (DOX) is a potent and broad-spectrum drug widely used in the treatment of cancer. However, the toxicity and side effects of DOX on various organs limit its clinical use. Approaches using natural antioxidants with these drugs have the potential to alleviate negative side effects. The aim of this study was to investigate the potential protective effect of tannic acid, a polyphenolic compound found naturally in plants, against DOX-induced spleen toxicity. Expression levels of Alox5, Inos, IL-6, Tnf-α, Casp-3, Bax, SOD, GST, CAT and GPx genes were determined using cDNAs obtained from spleen tissues of rats treated with DOX, tannic acid and both. In addition, SOD, CAT, GPx and GST enzyme activities, and GSH and MDA levels were measured in tissues. In the spleen tissues, DOX caused a decrease in the level of GSH and an increase in the level of MDA. In addition, it was determined that DOX had a suppressive effect on CAT, GST, SOD and GPx mRNA levels and its enzyme activities, which are antioxidant system components. The mRNA expression levels of proinflammatory cytokine markers, apoptotic genes, and some factors involved in cell metabolism showed a change compared to the control after DOX application. However, as a result of tannic acid treatment with DOX, these changes approached the values of the control group. The findings showed that tannic acid had a protective effect on the changes in the oxidative stress and inflammation system in the rat spleen as a result of the application of tannic acid together with DOX.