1.
Natural products: The role and mechanism in low-density lipoprotein oxidation and atherosclerosis.
Zhang, S, Li, L, Chen, W, Xu, S, Feng, X, Zhang, L
Phytotherapy research : PTR. 2021;(6):2945-2967
Abstract
Atherosclerosis is a chronic inflammatory, metabolic, and epigenetic disease, which leads to the life-threatening coronary artery disease. Emerging studies from bench to bedside have demonstrated the pivotal role of low-density lipoprotein (LDL) oxidation in the initiation and progression of atherosclerosis. This article hereby reviews oxidation mechanism of LDL, and the pro-atherogenic and biomarker role of oxidized LDL in atherosclerosis. We also review the pharmacological effects of several representative natural products (vitamin E, resveratrol, quercetin, probucol, tanshinone IIA, epigallocatechin gallate, and Lycopene) in protecting against LDL oxidation and atherosclerosis. Clinical and basic research supports the beneficial effects of these natural products in inhibiting LDL oxidation and preventing atherosclerosis, but the data are still controversial. This may be related to factors such as the population and the dosage and time of taking natural products involved in different studies. Understanding the mechanism of LDL oxidation and effect of oxidized LDL help researchers to find novel therapies against atherosclerosis.
2.
Formononetin protects against ox-LDL-induced endothelial dysfunction by activating PPAR-γ signaling based on network pharmacology and experimental validation.
Zhang, B, Hao, Z, Zhou, W, Zhang, S, Sun, M, Li, H, Hou, N, Jing, C, Zhao, M
Bioengineered. 2021;(1):4887-4898
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Abstract
Formononetin (FMNT), a flavonoid identified from the Chinese herb Astragalus membranaceus, possesses anti-inflammatory or anti-oxidative properties in different human diseases. This study aims to comprehensively elucidate the function of FMNT in atherosclerosis and its underlying mechanisms. Online public databases were used to identify the drug-disease targets. Protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were applied to explore the potential targets and signaling pathways involved in FMNT against atherosclerosis. Human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low-density lipoprotein (ox-LDL) to construct an atherosclerosis cell model in vitro. Endothelial cell function was assessed via examining cell proliferation, inflammatory factors, oxidative markers, reactive oxygen species (ROS), and apoptosis. Western blot was performed to detect the expression of cyclooxygenase-2 (COX-2), endothelial nitric oxide synthase (eNOS), cleaved caspase-3, and peroxisome proliferator-activated receptor-γ (PPAR-γ). A total of 39 overlapping target genes of FMNT and atherosclerosis were identified. Through the PPI network analysis, 14 hub genes were screened and found to be closely relevant to inflammation, oxidative stress, and apoptosis. Results of KEGG pathway assays indicated that lots of targets were enriched in PPAR signaling. Functionally, FMNT could protect against ox-LDL-induced inflammatory reaction, oxidative stress, and apoptosis in HUVECs. Moreover, FMNT attenuated ox-LDL-mediated inactivation of PPAR-γ signaling. GW9662, a PPAR-γ antagonist, reversed the inhibitory effect of FMNT on ox-LDL-induced endothelial injury. In conclusion, FMNT alleviates ox-LDL-induced endothelial injury in HUVECs by stimulating PPAR-γ signaling, providing a theoretical basis for employing FMNT as a potential drug to combat atherosclerosis.Abbreviations: FMNT formononetin; PPI: protein-protein interaction; GO: Gene Ontology; KEGG Kyoto Encyclopedia of Genes and Genomes; HUVECs: human umbilical vein endothelial cells; ox-LDL: oxidized low-density lipoprotein; COX-2: cyclooxygenase-2; eNOS: endothelial nitric oxide synthase; PPAR-γ: peroxisome proliferator-activated receptor-γ; CVD: cardiovascular disease; TCM: traditional Chinese medicines; OGDR oxygen-glucose deprivation/reoxygenation; ROS: reactive oxygen species; FBS: fetal bovine serum; CCK-8: cell counting kit-8; EdU: 5-Ethynyl-2'-deoxyuridine; SOD: antioxidant enzymes superoxide dismutase; MDA: malondialdehyde; DCFH-DA: 2',7'-dichlorofluorescein-diacetate; PVDF polyvinylidene fluoride; ANOVA one-way analysis of variance; PPARs: peroxisome proliferation-activated receptors.