Effect of 7-Difluoromethyl-5, 4΄-dimethoxygenistein on aorta atherosclerosis in hyperlipidemia ApoE-/- mice induced by a cholesterol-rich diet

Abstract

Purpose7-Difluoromethyl–5, 4′-dimethoxygenistein (DFMG), prepared by the difluoromethylation and alkylation of Genistein, is an active new chemical entity. Its anti-atherosclerosis effect was found in a series of studies in vitro. In this article, we explored and evaluated the anti-atherosclerosis effect via its protection of endothelial function in ApoE−/− mice that were fed a high-fat diet.MethodsFive C57BL/6J mice were selected as a control group and were fed a 1% high-fat diet (control group, n = 5). Five ApoE−/− mice that were fed a high-fat diet for 16 weeks were selected as the atherosclerosis model group (model group, n = 5). In the phase I study, 25 ApoE−/− mice were provided a prophylactic treatment with different drugs at the beginning of the 16 week high-fat diet: 5 mg/gk genistein (genistein 1 group, n = 5), 5 mg/kg lovastatin (lovastatin1 group, n = 5), 2.5 mg/kg DFMG (DFMG L1 group, n = 5), 5 mg/kg DFMG (DFMG M1 group, n = 5), and 10 mg/kg DFMG (DFMG H1 group, n = 5). In the phase II study, 25 atherosclerosis model, ApoE−/− mice were treated with different drugs and fed a high-fat diet for 16 weeks: 5 mg/gk genistein (genistein 2 group, n = 5), 5 mg/kg lovastatin (lovastatin 2 group, n = 5), 2.5 mg/kg DFMG (DFMG L2 group, n = 5), 5 mg/kg DFMG (DFMG M2 group, n = 5), and 10 mg/kg DFMG (DFMG H2 group, n = 5). The plasma levels of lipids, von Willebrand factor (vWF), and nitrite were compared between phases I and II. Endothelium-dependent relaxation (EDR), aortic lesion development, and quantification in thoracic aortas were measured during these two phase studies.ResultsCompared to the model group, the lipid and vWF plasma levels were significantly lower, the plasma nitrite levels were significantly higher, the fatty streaks of aortic lesions were significantly lower, and the endothelium dependent relaxation was significantly higher after both phase studies (P < 0.05). The DFMG supplementation led to significant plasma nitrite increment in all groups after both phase studies (P < 0.05). There were significantly decreased fatty streaks of aortic lesions in DFMG-prevented and DFMG-treated mice (P < 0.05). There was a significant increase in EDR in all prophylactic treatment groups and treatment groups (P < 0.05). We further demonstrated that the preventative effect was more obvious than the therapeutic effect.ConclusionOur results suggest that DFMG could work in prophylactic and therapeutic treatments for atherosclerosis development.

Hypocholesterolemic and Antiatherosclerotic Potential ofBasella albaLeaf Extract in Hypercholesterolemia-Induced Rabbits

“…HCD feeding showed significant elevation of TC, LDL, and TG, which increase lipid peroxidation and influence the development of atherosclerosis, in agreement with several studies [ 12 ]. In contrast, a significant decrease noted in serum HDL in hypercholesterolemic rabbits was also reported by Ismail et al [ 4 ].…”

Antioxidant and anti-inflammatory effects of dimethyl fumarate in hypercholesterolemic rabbits

“…These results support the findings of previous studies, which reported that HCD increased MDA level but decreased the activity of SOD level [31,32]. HCD-feeding causes oxidative stress by increasing the production of reactive oxygen species (ROS), mediated lipoprotein oxidation, particularly LDL particles that cause lipid peroxidation and subsequent influence the development of atherosclerosis [33]. Lipid peroxidation plays an important role in the pathophysiology of atherosclerosis so a decrease in lipid peroxidation leads to a reduction of hypercholesterolemia-induced atherosclerosis [34].…”

DFMG reverses proliferation and migration of vascular smooth muscle cells induced by co-culture with injured vascular endothelial cells via suppression of the TLR4-mediated signaling pathway

“…The authors of the present study, also previously reported that DFMG could protect VECs through inhibition of the mitochondrial apoptotic pathway ( 24 , 25 ). Furthermore, the preventive effect of DFMG was more apparent compared with the therapeutic effect within apolipoprotein E −/− mice induced by a cholesterol-rich diet ( 26 ).…”