chrysin and Cardiotoxicity

Cardiometabolic diseases (CMD) have caused a great burden in terms of morbidity and mortality worldwide. The vicious cycle of CMD consists of type II diabetes, hypertension, dyslipidemia, obesity, and atherosclerosis. They have interlinked pathways, interacting and interconnecting with each other. The natural flavonoid chrysin has been shown to possess a broad spectrum of therapeutic activities for human health. Herein, we did an in-depth investigation of the novel mechanisms of chrysin's cardioprotection against cardiometabolic disorders. Studies have shown that chrysin protects the cardiovascular system by enhancing the intrinsic antioxidative defense system. This antioxidant property enhanced by chrysin protects against several risk factors of cardiometabolic disorders, including atherosclerosis, vascular inflammation and dysfunction, platelet aggregation, hypertension, dyslipidemia, cardiotoxicity, myocardial infarction, injury, and remodeling, diabetes-induced injuries, and obesity. Chrysin also exhibited anti-inflammatory mechanisms through inhibiting pro-inflammatory pathways, including NF-κB, MAPK, and PI3k/Akt. Furthermore, chrysin modulated NO, RAS, AGE/RAGE, and PPARs pathways which contributed to the risk factors of cardiometabolic disorders. Taken together, the mechanisms in which chrysin protects against cardiometabolic disorder are more than merely antioxidation and anti-inflammation in the cardiovascular system.

Topics: Anti-Inflammatory Agents; Antioxidants; Atherosclerosis; Cardiotoxicity; Diabetes Mellitus, Type 2; Flavonoids; Humans; Hypertension; Obesity; Phosphatidylinositol 3-Kinases

Mounting evidences have indicated that cyclophosphamide (CyC)a potent anticancer and cytotoxic agent is associated with various organ and systemic toxicities and the cytotoxic effects observed after administration of CyC still challenges its clinical use. Chrysin (Chy) is a dietary flavonoid with prevailing antioxidant and anti-inflammatory properties. This study evaluated the protective properties of Chy against CyC-induced cardiotoxicity in rats. The animals were orally treated with Chy (25 and 50 mg/kg/day) for 35 days and exposed to CyC (i. p., 100 mg/kg) once a week for four weeks. The results indicated that CyC caused significant cardiotoxicity as manifested by notable increases in heart weight, cardiac function biomarkers such as lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), troponin T and aspartate transaminase (AST). In addition, cardiac malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL1 β) and interleukin 6 (IL-6) levels were considerably increased. Meanwhile, cardiac antioxidant enzymes activities such as superoxide dismutase (SOD) and catalase (CAT), as well as glutathione (GSH) level were suppressed, while H&E stained histopathological assessment showed marked alterations in cardiac tissues. CyC also significantly lowered red blood cells (RBC) and white blood cells (WBC) parameters, whereas treatment with Chy significantly restored the altered biochemical and histopathological features. Conclusively, aforementioned results inferred that Chy offered cardioprotective potentials against CyC-induced cardiotoxicity which may be due to its antioxidant, and anti-inflammatory properties.

Topics: Animals; Antioxidants; Apoptosis; Cardiotoxicity; Cyclophosphamide; Flavonoids; Oxidative Stress; Rats; Rats, Wistar

Mitochondrial dysfunction may lead to cardiomyocyte death in trastuzumab (TZM)-induced cardiotoxicity. Accordingly, this study was designed to evaluate the mitochondrial protective effects of curcumin, chrysin and thymoquinone alone in TZM-induced cardiotoxicity in the rats. Forty-eight male adult Wistar rats were divided into eight groups: control group (normal saline), TZM group (2.5 mg/kg I.P. injection, daily), TZM + curcumin group (10 mg/kg, I.P. injection, daily), TZM + chrysin (10 mg/kg, I.P. injection, daily), TZM + thymoquinone (0.5 mg/kg, I.P. injection, daily), curcumin group (10 mg/kg, I.P. injection, daily), chrysin group (10 mg/kg, I.P. injection, daily) and thymoquinone group (10 mg/kg, I.P. injection, daily). Blood and tissue were collected on day 11 and used for assessment of creatine phosphokinase, lactate dehydrogenase (LDH), troponin, malondialdehyde (MDA) amount, glutathione levels and mitochondrial toxicity parameters. TZM increased mitochondrial impairments (reactive oxygen species formation, mitochondrial swelling, mitochondrial membrane potential collapse and decline in succinate dehydrogenase activity) and histopathological alterations (hypertrophy, enlarged cell, disarrangement, myocytes degeneration, infiltration of fat in some areas, hemorrhage and focal vascular thrombosis) in rat heart. As well as TZM produced a significant increase in the level of CK, LDH, troponin, MDA, glutathione disulfide. In most experiments, the co-injection of curcumin, chrysin and thymoquinone with TZM restored the level of CK, LDH, troponin, MDA, GSH, mitochondrial impairments and histopathological alterations. The study revealed the cardioprotective effects of curcumin, chrysin and thymoquinone against TZM-induced cardiotoxicity which could be attributed to their antioxidant and mitochondrial protection activities.

Topics: Animals; Antioxidants; Benzoquinones; Cardiotoxicity; Curcumin; Doxorubicin; Flavonoids; Glutathione; Male; Mitochondria; Oxidative Stress; Rats; Rats, Wistar; Trastuzumab; Troponin

Apart from the anticancer, antioxidant, anti-inflammatory effects, and inhibition of aromatase, chrysin is involved in the protection of cardiovascular disorders. Cardiovascular complications are the main cause of death induced by aluminum phosphide (AlP) which is related to oxidative stress and mitochondrial damages. For this purpose, we investigated the effect of chrysin as an antioxidant and mitochondrial protective agent against AlP-induced toxicity in isolated cardiomyocytes and mitochondria obtained from rat heart ventricular. Using by biochemical and flow cytometry, cell viability, reactive oxygen species (ROS) formation, mitochondria membrane potential (MMP), lysosomal membrane integrity, malondialdehyde (MDA) content, and glutathione (GSH) and oxidized glutathione (GSSG) content were measured in isolated cardiomyocytes. Also, mitochondrial toxicity parameters such as mitochondrial NADH/succinate dehydrogenase activity, mitochondrial swelling, ROS formation, MMP collapse, and lipid peroxidation were analyzed in isolated mitochondria. Our results showed that the administration of chrysin (up to 10 μM) efficiently decreased (P < 0.05) cytotoxicity, oxidative, lysosomal, and mitochondrial damages induced by AlP, in isolated cardiomyocytes. Also, our finding in isolated mitochondria showed that chrysin (up to 10 μM) significantly (P < 0.05) decreased AlP-induced mitochondrial toxicity. These findings demonstrated that chrysin as an antioxidant and mitochondrial protective agent exert protective effect in wild-type cardiomyocyte treated with AlP. It was concluded that chrysin significantly reduced the toxicity of AlP in isolated cardiomyocytes and mitochondria. Due to the very low toxicity of chrysin for humans, it could be a promising agent in treatment of AlP poisoning.

Topics: Aluminum Compounds; Animals; Cardiotoxicity; Cells, Cultured; Flavonoids; Glutathione; Humans; Lipid Peroxidation; Lysosomes; Male; Membrane Potential, Mitochondrial; Mitochondria, Heart; Mitochondrial Swelling; Myocytes, Cardiac; Oxidative Stress; Phosphines; Protective Agents; Rats; Rats, Wistar; Reactive Oxygen Species

Doxorubicin (DOX) is the mainstay chemotherapeutic agent against a variety of human neoplasmas. However, its clinical utility is limited by its marked cardiotoxicity. Chrysin, is a natural flavone which possesses antioxidant, anti-inflammatory and anti-cancer properties. The current study aimed to investigate the potential protective effect of chrysin against DOX-induced chronic cardiotoxicity and the underlying molecular mechanisms. Male Sprague-Dawley rats were treated with either DOX (5 mg/kg, once a week) and/or chrysin (50 mg/kg, four times a week) for four weeks. Chrysin prevented DOX-induced cardiomyopathy which was evident by conduction abnormalities, elevated serum CKMB and LDH and histopathological changes. Chrysin also ameliorated DOX-induced oxidative stress by decreasing lipid peroxidation and upregulating the antioxidant enzymes. Moreover, chrysin attenuated DOX-induced apoptosis via decreasing expression of p53, Bax, Puma, Noxa, cytochrome c and caspase-3 while increasing expression of Bcl-2. DOX induced activation of MAPK; p38 and JNK and increased expression of NF-κB. Meanwhile, DOX suppressed AKT pathway via decreasing expression of its upstream activator VEGF and increasing expression of PTEN. Conversely, chrysin effectively neutralised all these effects. Collectively, these findings indicate that chrysin effectively protected against DOX-induced cardiomyopathy via suppressing oxidative stress, p53-dependent apoptotic pathway, MAPK and NF-κB pathways while augmenting the VEGF/AKT pathway.

Topics: Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Cardiomyopathies; Cardiotonic Agents; Cardiotoxicity; Caspase 3; Cytochromes c; Doxorubicin; Drug Administration Schedule; Flavonoids; Gene Expression Regulation; Male; Myocytes, Cardiac; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Signal Transduction; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A