Abstract
Doxorubicin (DOX), a common chemotherapeutic agent, suffers serious adverse effects including hepatotoxicity. Mokko lactone (ML) is a guainolide sesquiterpene with promising biological activities. The study aimed to evaluate the protection offered by ML against hepatotoxicity induced by DOX in rats. Our data indicated ML exhibited protective effects as evidenced by ameliorating the rise in serum activities of alanine transaminase, aspartate transaminase and alkaline phosphatase. This was confirmed histologically as ML prevented DOX-induced pathological alteration in liver architecture. Further, ML administration significantly prevented malondialdehyde accumulation, glutathione depletion and superoxide dismutase and catalase exhaustion. Antioxidant action of ML was associated with enhanced expression of the nuclear translocation of NF-E2-related factor 2 (Nrf2) and a lower expression of forkhead box protein O1 (FOXO1). Also, ML showed potent anti-inflammatory activities highlighted by decreased expression of interleukin 6, tumor necrosis factor α and nuclear factor κB (NF-κB). The anti-apoptotic effects of ML were associated with decreased Bax and enhanced Bcl-2 mRNA expression in liver tissues. ML caused a significant up-regulation in the expression of silent information regulator 1 (Sirt-1). Therefore, it can be concluded that ML prevents liver injury caused by DOX. This could partially be due to the ML regulatory activities on Sirt-1/FOXO1/NF-κB axis.
Highlights
Doxorubicin (DOX) is a broad-spectrum anthracycline antibiotic commonly utilized in combination with several drugs for treating different tumors, including solid tumors, lymphomas, and leukemias [1]
At 15 mg/kg caused a significant decrease in the DOX-induced expression to the DOX-alone group, Mokko lactone (ML) at 15 mg/kg caused a significant decrease in the DOXof forkhead box protein O1 (FOXO1) by
To gain further insight into the protective activity of ML in DOX-stressed liver tissues, the expression of the master regulator silent information regulator 1 (Sirt-1) was assessed after the DOX and ML treatment via Western blotting
Summary
Doxorubicin (DOX) is a broad-spectrum anthracycline antibiotic commonly utilized in combination with several drugs for treating different tumors, including solid tumors, lymphomas, and leukemias [1]. The release of reactive oxygen species (ROS) during DOX metabolism is a culprit behind its hepatotoxicity These ROS lead to exhaustion of antioxidant enzymes resulting in redox imbalance and oxidative stress [8]. Another culprit is apoptosis induced by DOX via increasing apoptotic protein expression [9]. The ability of guainolides to affect cell signaling may be due to the α-methylene-γ-lactone group, as it reacts with cysteine sulfhydryl groups of cellular peptides and proteins [15] In this regard, Costus speciosus rhizomes are an excellent source of guaianolides sesquiterpenes. Because of the great importance of Dox in cancer chemotherapy, several approaches have been pursued to attenuate its toxicity These included dosage optimization and use of analogs or combined therapy. The current study aimed to investigate the potential protective activity of ML, purified from Costus speciosus rhizomes extract, against DOX-induced hepatotoxicity in rats
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