7‐difluoromethyl‐5,4′‐dimethoxygenistein, a novel agent protecting against vascular endothelial injury caused by oxidative stress

Wang, Li; Zheng, Xiaohui; Hu, Xiang; Fu, Xiaohua; Cao, Ji

doi:10.1111/j.1440-1681.2009.05305.x

Cited by 4 publications

(1 citation statement)

References 36 publications

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“…Data suggested that DFMG possesses a protective effect against vascular endothelium injury caused by oxidative stress. Our team previously focused on the protective effects and mechanisms of DFMG as applied to the damaged endothelium 18,19,28,29. We had also previously revealed that DFMG has an antiatherosclerosis effect, decreasing hyperlipidemia and possessing antioxidant and plaque stabilization properties in a rabbit model of atherosclerosis 30.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang¹,

Li²,

You³

et al. 2013

DDDT

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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.

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Section: Discussionmentioning

confidence: 99%

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

Zhang¹,

Li²,

You³

et al. 2013

DDDT

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Spectroscopic and molecular docking study on the structure–affinity relationship and mechanism in the interaction of genistein and its derivatives with bovine serum albumin

Guo

Shen

et al. 2017

Luminescence

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In this paper, the interaction of genistein (GEN) and its four derivatives (GEN1-4) with bovine serum albumin (BSA) were investigated by ultraviolet-visible absorption spectra, fluorescence, synchronous fluorescence, three-dimensional fluorescence spectroscopy, circular dichroism and molecular docking techniques. The experimental results showed that the intrinsic fluorescence of BSA was quenched by genisteins and was due to the formation of a genisteins-BSA complex. The quenching constant, binding constants, binding sites, intermolecular distances and thermodynamic properties were calculated at 298 K, 306 K and 310 K. Site marker competitive experiments indicated that the binding site of genisteins to BSA was mainly located in subdomain IIA. The conformational investigation showed that the presence of 0020 genisteins led to changes in the secondary structure of BSA and induced the slight unfolding of protein polypeptides, which confirmed some micro-environmental and conformational changes of BSA molecules. Furthermore, the binding affinity decreased in the order GEN1 > GEN > GEN4 > GEN3 > GEN2, which revealed that different type and position of substituents of genistein significantly influenced the affinity of compounds to BSA. The number of hydroxyl groups on the ring A was the most important factor because increasing the hydroxyl groups on ring A clearly enhanced the binding affinity. However, trifluoromethylation did not much affect the affinity, alkylation, esterification and difluoromethylation slightly enhanced the binding affinity. The results obtained herein will provide valuable information about the pharmacokinetics at a molecular level and be a useful guideline for the further design of much more suitable genistein derivatives.

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Protective effects of 7-difluoromethyl-5,4′-dimethoxygenistein against human aorta endothelial injury caused by lysophosphatidyl choline

Liu

Cao

et al. 2011

Mol Cell Biochem

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7-Difluoromethyl-5,4'-dimethoxygenistein (DFMG) is an active new derivative of genistein (GEN). It has shown effective protection in vascular endothelial injury. To further investigate its potential protective effects and its mechanism probably related to atherosclerosis, in present study, human aorta endothelial cells (HAECs) were chosen and treated with various concentrations of lysophosphatidyl choline (LPC) to establish an experimental model. Results showed that 10.0 μmol/l of LPC was optimal for inducing HAEC injury. DFMG pretreatment was able to prevent HAEC injury induced by LPC and restore cell viability in a concentration-dependent manner. The protective efficacy of DFMG (10.0 μmol/l) was significantly greater than that of GEN (10.0 μmol/l) and vitamin E (50.0 μmol/l). The mechanisms underlying the protective effects of DFMG are related to the activation of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase and to the clearance of intracellular reactive oxygen species. DFMG inhibits the apoptosis of HAECs mediated by LPC involving the blockage of the mitochondrial apoptotic pathway.

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7‐difluoromethyl‐5,4′‐dimethoxygenistein, a novel agent protecting against vascular endothelial injury caused by oxidative stress

Cited by 4 publications

References 36 publications

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

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

Spectroscopic and molecular docking study on the structure–affinity relationship and mechanism in the interaction of genistein and its derivatives with bovine serum albumin

Protective effects of 7-difluoromethyl-5,4′-dimethoxygenistein against human aorta endothelial injury caused by lysophosphatidyl choline

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