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Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4 and HMGB1. On the basis of summarizing these studies, we further discussed the future research directions of metformin: single-cell RNA sequencing, neutrophil extracellular traps (NETs), epigenetic modification, and metformin-based combination drugs. In short, macrophages play an important role in a variety of diseases, and improving macrophage dysfunction may be an important mechanism for metformin to expand its pleiotropic pharmacological profile. In addition, the combination of metformin with other drugs that improve the function of macrophages (such as SGLT2 inhibitors, statins and IL-1β inhibitors/monoclonal antibodies) may further enhance the pleiotropic therapeutic potential of metformin in conditions such as atherosclerosis, obesity, cancer, dementia and aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Feng, Chen, Ni, Little, Xu, Tang and Weng.)

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., (© 2020 John Wiley & Sons, Ltd.)

ATP citrate lyase (ACLY) is an important enzyme linking carbohydrate to lipid metabolism by generating acetyl-CoA from citrate for fatty acid and cholesterol biosynthesis. Mendelian randomization of large human cohorts has validated ACLY as a promising target for low-density-lipoprotein-cholesterol (LDL-C) lowering and cardiovascular protection. Among current ACLY inhibitors, Bempedoic acid (ETC-1002) is a first-in-class, prodrug-based direct competitive inhibitor of ACLY which regulates lipid metabolism by upregulating hepatic LDL receptor (LDLr) expression and activity. ACLY deficiency in hepatocytes protects from hepatic steatosis and dyslipidemia. In addition, pharmacological inhibition of ACLY by bempedoic acid, prevents dyslipidemia and attenuates atherosclerosis in hypercholesterolemic ApoE -/- mice, LDLr -/- mice, and LDLr -/- miniature pigs. Convincing data from clinical trials have revealed that bempedoic acid significantly lowers LDL-C as monotherapy, combination therapy, and add-on with statin therapy in statin-intolerant patients. More recently, a phase 3 CLEAR Harmony clinical trial ("Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol") has shown that bempedoic acid reduces the level of LDL-C in hypercholesterolemic patients receiving guideline-recommended statin therapy with a good safety profile. Hereby, we provide a updated review of the expression, regulation, genetics, functions of ACLY in lipid metabolism and atherosclerosis, and highlight the therapeutic potential of ACLY inhibitors (such as bempedoic acid, SB-204990, and other naturally-occuring inhibitors) to treat atherosclerotic cardiovascular diseases. It must be pointed out that long-term large-scale clinical trials in high-risk patients, are warranted to validate whether ACLY represent a promising therapeutic target for pharmaceutic intervention of dyslipidemia and atherosclerosis; and assess the safety and efficacy profile of ACLY inhibitors in improving cardiovascular outcome of patients., (Copyright © 2019. Published by Elsevier Ltd.)

Marijuana (cannabis) can cause cardiovascular side effects, yet the mechanisms and treatments remain poorly understood. In a recent study published in Cell , Wei et al. discovered that soy isoflavone genistein attenuates Δ9-tetrahydrocannabinol (Δ9-THC, a main constituent from marijuana)-induced endothelial dysfunction and atherosclerosis by directly antagonizing peripheral cannabinoid receptor 1, demonstrating a therapeutic potential for ameliorating the cardiovascular side effects of cannabis. [ABSTRACT FROM AUTHOR]

Metformin has been used in diabetes for more than 60 years and has excellent safety in the therapy of human type 2 diabetes (T2D). There is growing evidence that the beneficial health effects of metformin are beyond its ability to improve glucose metabolism. Metformin not only reduces the incidence of cardiovascular diseases (CVD) in T2D patients, but also reduces the burden of atherosclerosis (AS) in pre-diabetes patients. Vascular smooth muscle cells (VSMCs) function is an important factor in determining the characteristics of the entire arterial vessel. Its excessive proliferation contributes to the etiology of several types of CVD, including AS, restenosis, and pulmonary hypertension. Current studies show that metformin has a beneficial effect on VSMCs function. Therefore, this review provides a timely overview of the role and molecular mechanisms by which metformin acts through VSMCs to protect CVD. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Cardiovascular and cerebrovascular diseases are the main cause of mortality worldwide, currently with less than optimum therapeutic options. Danhong injection (DHI) is a medicinal preparation based on two eminent Chinese herbal medicines, Salviae Miltiorrhizae (Dan Shen; family: Lamiaceae) and Flos Carthami (Hong Hua; family: Compositae/Asteraceae). DHI has been mainly used in the clinical therapy of cardiovascular (such as acute coronary syndrome and angina pectoris) and cerebrovascular diseases (such as stroke) in China for many years. The pharmacological properties of DHI include anti-inflammatory, anti-oxidant, anti-coagulatory, hypolipidemic, anti-apoptotic, vasodilatory, and angiogenesis-promoting actions. DHI offers a safe and effective therapeutic agent against cardiovascular and cerebrovascular diseases by modulating multiple disease-relevant signaling pathways and molecular targets. Herein, we provide a comprehensive review of the phytochemistry, therapeutic effects, molecular mechanisms, and adverse reactions of DHI in cardiovascular and cerebrovascular diseases. We also highlight the latest pharmacological advances and therapeutic potential of this promising herb-derived cardiovascular drug preparation. [ABSTRACT FROM AUTHOR]

Receptor-interacting protein 140 (RIP140) is a multifunctional coregulator of lipid metabolism and inflammation. However, the potential role of RIP140 in atherosclerosis remains unknown. The present study investigated the impact of RIP140 on foam cell formation, a critical step in pathogenesis of atherosclerosis. The expression of RIP140 was increased in foam cells. RIP140 overexpression resulted in decreased cholesterol efflux in macrophages and their concomitant differentiation into foam cells. Moreover, RIP140 negatively regulated the macrophage expression of ATP-binding cassette transporters A1 and G1 (ABCA1/G1), by suppressing the expression and activity of liver X receptor (LXR). These findings shed light onto the contribution of RIP140 to the development and progression of atherosclerosis, and suggest a novel therapeutic target for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]