Low dose methotrexate is the cornerstone for the treatment of rheumatoid arthritis. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Dissatisfied arthritis patients are likely to seek the option of complementary and alternative medicine such as bee venom. The combination of natural products with modern medicine poses the possibility of potential interaction between the two groups and needs investigation. The present study was aimed to investigate the modulatory effect of bee venom acupuncture on efficacy, toxicity, and pharmacokinetics and tissue disposition of methotrexate. Complete Freund's adjuvant induced arthritic rats were treated for 3 weeks with methotrexate and/or bee venom. Arthritic score, ankle diameter, paw volume and tissue expression of NF-κB and TNF-α were determined to assess anti-arthritic effects, while anti-nociceptive effects were assessed by gait score and thermal hyperalgesia. Methotrexate toxicity was assessed by measuring serum TNF-α, liver enzymes and expression of NF-κB in liver. Combination therapy of bee venom with methotrexate significantly improved arthritic parameters and analgesic effect as compared to methotrexate alone. Bee venom ameliorated serum TNF-α and liver enzymes elevations as well as over expression of NF-κB in liver induced by methotrexate. Histological examination supported the results. And for the first time bee venom acupuncture was approved to increase methotrexate bioavailability with a significant decrease in its elimination. Conclusion: bee venom potentiates the anti-arthritic effects of methotrexate, possibly by increasing its bioavailability. Also, it provides a potent anti-nociceptive effect. Furthermore, bee venom protects against methotrexate induced hepatotoxicity mostly due to its inhibitory effect on TNF-α and NF-κB.
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.
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