Structure-based investigation of pyruvate dehydrogenase kinase-3 inhibitory potential of thymoquinone, targeting lung cancer therapy.

Protein kinases are an attractive therapeutic target for cardiovascular, cancer and neurodegenerative diseases. Cancer cells demand energy generation through aerobic glycolysis, surpassing "oxidative phosphorylation" (OXPHOS) in mitochondria. The pyruvate dehydrogenase kinases (PDKs) have many regulatory roles in energy generation balance by controlling the pyruvate dehydrogenase complex. Overexpression of PDKs is associated with the overall survival of cancer. PDK3, an isoform of PDK is highly expressed in various cancer types, is targeted for inhibition in this study. PDK3 has been shown to binds strongly with a natural compound, thymoquinone (TQ), which is known to exhibit anti-cancer potential. Detailed interaction between the PDK3 and TQ was carried out using spectroscopic and docking methods. The overall changes in the protein's structures after TQ binding were estimated by UV-Vis spectroscopy, circular dichroism and fluorescence binding studies. The kinase activity assay was also carried out to see the kinase inhibitory potential of TQ. The enzyme inhibition assay suggested an excellent inhibitory potential of TQ towards PDK3 (IC50 = 5.49 µM). We observed that TQ forms a stable complex with PDK3 without altering its structure and can be a potent PDK3 inhibitor which may be implicated in cancer therapy after desired clinical validation.

Sesamin's Therapeutic Actions on Cyclophosphamide-Induced Hepatotoxicity, Molecular Mechanisms, and Histopathological Characteristics.

Cyclophosphamide, an alkylating agent integral to specific cancer chemotherapy protocols, is often curtailed in application owing to its significant hepatotoxic side effects. Therefore, this study was conducted to assess the hepatoprotective potential of sesamin, a plant-originated antioxidant, using rat models. The rats were divided into five groups: a control group received only the vehicle for six days; a cyclophosphamide group received an intraperitoneal (i.p.) single injection of cyclophosphamide (150 mg/kg) on day four; a sesamin group received a daily high oral dose (20 mg/kg) of sesamin for six days; and two groups were pretreated with oral sesamin (10 and 20 mg/kg daily from day one to day six) followed by an i.p. injection of cyclophosphamide on day four. The final and last sesamin dose was administered 24 h before euthanasia. At the end of the experiment, blood and liver tissue were collected for biochemical and histopathological assessments. The results indicated significantly increased liver markers (AST, ALT, ALP, and BIL), cytokines (TNFα and IL-1ß), caspase-3, and malondialdehyde (MDA) in the cyclophosphamide group as compared to the normal control. Additionally, there was a significant decline in antioxidants (GSH) and antioxidant enzymes (CAT and SOD), but the sesamin treatment reduced liver marker enzymes, cytokines, and caspase-3 and improved antioxidants and antioxidant enzymes. Thus, sesamin effectively countered these alterations and helped to normalize the histopathological alterations. In conclusion, sesamin demonstrated the potential for attenuating cyclophosphamide-induced hepatotoxicity by modulating cytokine networks, apoptotic pathways, and oxidative stress, suggesting its potential role as an adjunct in chemotherapy to reduce hepatotoxicity.