Vitexin attenuates acute doxorubicin cardiotoxicity in rats via the suppression of oxidative stress, inflammation and apoptosis and the activation of FOXO3a

Abstract

Abstract. Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs. However, its clinical use has been hampered due to the development of cardiotoxicity. Vitexin, which is the active ingredient of hawthorn leaf extract, has various biological activities, including antioxidant and anti-inflammatory actions. The present study aimed to investigate whether vitexin was able to protect against DOX-induced acute cardiotoxicity in model rats and the mechanisms of this protective effect were assessed. Adult Sprague-Dawley rats were randomly assigned into the control (saline only), model (DOX only) and vitexin-treated (DOX plus vitexin) groups. Rats in the model and vitexin-treated groups were injected with DOX (2 mg/kg; i.p.) once a week for 4 weeks. Rats in the vitexin-treated group were administered 30 mg/kg oral vitexin once daily at doses for 4 weeks. The levels of lactate dehydrogenase, creatine kinase isoenzyme-MB, malondialdehyde, superoxide dismutase, catalase and myeloperoxidase were assessed using assay kits. The levels of inflammatory mediators, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, nuclear factor (NF)-κB, and caspase-3, were assayed by the enzyme-linked immunosorbent assay method. Western blot analysis was performed to assess the protein expression levels of p-FOXO3a. Vitexin pretreatment significantly protected against DOX-induced myocardial damage, which was characterized by increased serum creatine kinase isoenzyme-MB and lactate dehydrogenase. Vitexin significantly ameliorated oxidative stress injury evoked by DOX, demonstrated by the inhibition of lipid peroxidation and the elevation of antioxidant enzyme activities. Furthermore, DOX provoked inflammatory responses by increasing the expression levels of IL-1β, IL-6, NF-κB and tumor necrosis factor-α, whereas vitexin pretreatment significantly inhibited these inflammatory responses. Notably, DOX induced apoptotic tissue damage by increasing caspase-3 activity, whereas vitexin administration was able to decrease caspase-3 activity. In addition, vitexin induced elevated FOXO3a protein expression levels in the vitexin-treated group. In conclusion, the findings of the present study suggested that vitexin possesses cardioprotective action against DOX-induced cardiotoxicity by suppressing oxidative stress, inflammation and apoptotic signals. IntroductionDoxorubicin (DOX), which belongs to the anthracyclines family, has been used to treat cancer since the late 1960s. It is a well-established and highly effective antineopalstic agent that is used to treat various adult and pediatric cancers, including solid tumors, leukemia, lymphomas and breast cancer (1). However, DOX causes various toxic effects, the most common of which is cardiotoxicity (2). Multiple mechanisms are involved in DOX-induced cardiomyopathy, including the increase in cardiac oxidative stress, as evidenced by reactive oxygen species that induce damage such as lipid peroxidation, and changes in adenylate cyclase activity leading to apoptosis and inflammation-re...

Protective effect of vitexin reduces sevoflurane-induced neuronal apoptosis through HIF-1α, VEGF and p38 MAPK signaling pathway in�vitro and in newborn rats

“…Treatment with Vitexin significantly inhibited MDA level and increased SOD and GSH-px levels in sevoflurane-induced newborn rat or human neuroglioma cells. Sun et al suggested that vitexin possesses cardioprotective action against DOX-induced cardiotoxicity through anti-oxidative effects (10). Bax is a Bcl-2 superfamily.…”

“…Vitexin has anti-tumor, anti-oxidation, anti-virus, anti-inflammatory, anti-bacterial, antihypertensive and antispasmodic and other biological activities (10). In recent years, it has been reported that vitexin has anti-inflammatory effect (10). The present study was designed to investigate whether the protective effect of vitexin protects against sevoflurane-induced neuronal apoptosis and the mechanisms of this protective effect.…”

“…In addition, they are also widely found in other plants, such as Trollius, Cajan leaves, willow leaves, short bamboo leaves and Humulus (9). Vitexin has anti-tumor, anti-oxidation, anti-virus, anti-inflammatory, anti-bacterial, antihypertensive and antispasmodic and other biological activities (10). In recent years, it has been reported that vitexin has anti-inflammatory effect (10).…”

Anti-oxidant and anti-inflammatory effects of Salix Koreensis Andersson in DC. leaf methanol extract in vitro models

“…Though synthetic antioxidants are widely used yet it is suspected to induce tumor formation in animals (Clayson et al, 1993;Hocman, 1988). Oxidative stress also generate inflammatory cascades, which are primarily mediated via inflammatory molecules including nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 (Sun et al, 2016). During inflammation processes, NO, TNF-α, and IL-6 were produced from activated macrophages (Kitanaka, 2016).…”

“…Oxidative stress is tightly connected with inflammatory reactions (Sun et al, 2016). SK has anti-oxidative and antiinflammatory effects and is traditionally used to treat neuralgia, edema, pain, and inflammatory diseases in Korea.…”