Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/ß-catenin signalling pathway.

INTRODUCTION: Vascular calcification, a devastating vascular complication accompanying atherosclerotic cardiovascular disease and chronic kidney disease, increases the incidence of adverse cardiovascular events and compromises the efficacy of vascular interventions. However, effective therapeutic drugs and treatments to delay or prevent vascular calcification are lacking. OBJECTIVES: This study was designed to test the therapeutic effects and mechanism of Moscatilin (also known as dendrophenol) from Dendrobium huoshanense (an eminent traditional Chinese medicine) in suppressing vascular calcification in vitro, ex vivo and in vivo. METHODS: Male C57BL/6J mice (25-week-old) were subjected to nicotine and vitamin D3 (VD3) treatment to induce vascular calcification. In vitro, we established the cellular model of osteogenesis of human aortic smooth muscle cells (HASMCs) under phosphate conditions. RESULTS: By utilizing an in-house drug screening strategy, we identified Moscatilin as a new naturally-occurring chemical entity to reduce HASMC calcium accumulation. The protective effects of Moscatilin against vascular calcification were verified in cultured HASMCs. Unbiased transcriptional profiling analysis and cellular thermal shift assay suggested that Moscatilin suppresses vascular calcification via binding to interleukin 13 receptor subunit A2 (IL13RA2) and augmenting its expression. Furthermore, IL13RA2 was reduced during HASMC osteogenesis, thus promoting the secretion of inflammatory factors via STAT3. We further validated the participation of Moscatilin-inhibited vascular calcification by the classical WNT/ß-catenin pathway, among which WNT3 played a key role in this process. Moscatilin mitigated the crosstalk between WNT3/ß-catenin and IL13RA2/STAT3 to reduce osteogenic differentiation of HASMCs. CONCLUSION: This study supports the potential of Moscatilin as a new naturally-occurring candidate drug for treating vascular calcification via regulating the IL13RA2/STAT3 and WNT3/ß-catenin signalling pathways.

Curcumin and chemokines: mechanism of action and therapeutic potential in inflammatory diseases.

Chemokines belong to the family of cytokines with chemoattractant properties that regulate chemotaxis and leukocyte migration, as well as the induction of angiogenesis and maintenance of hemostasis. Curcumin, the major component of the Curcuma longa rhizome, has various pharmacological actions, including anti-inflammatory, immune-regulatory, anti-oxidative, and lipid-modifying properties. Chemokines and chemokine receptors are influenced/modulated by curcumin. Thus, the current review focuses on the molecular mechanisms associated with curcumin's effects on chemoattractant cytokines, as well as putting into context the many studies that have reported curcumin-mediated regulatory effects on inflammatory conditions in the organs/systems of the body (e.g., the central nervous system, liver, and cardiovascular system). Curcumin's effects on viral and bacterial infections, cancer, and adverse pregnancy outcomes are also reviewed.

Isoginkgetin, a bioactive constituent from Ginkgo Biloba, protects against obesity-induced cardiomyopathy via enhancing Nrf2/ARE signaling.

Obesity-induced metabolic cardiomyopathy (MC), characterized by lipotoxicity and excessive oxidative stress, emerges as the leading cause of heart failure in the obese patients. Yet, its therapy remains very limited. Here, we demonstrated that isoginkgetin (IGK), a bioactive biflavonoid isolated from medicinal herb Ginkgo Biloba, protected against obesity-induced cardiac diastolic dysfunction and adverse remodeling. Transcriptomics profiling revealed that IGK activated Nrf2 signaling in the heart tissues of the obese mice. Consistent with this observation, IGK treatment increased the nuclear translocation of Nrf2, which in turn trigger the activation of its downstream target genes (e. g. HO-1 and NQO1). In addition, IGK significantly rejuvenated mitochondrial defects in obese heart tissues as evidenced by enhancing mitochondrial respiratory capacity and resisting the collapse of mitochondrial potential and oxidative stress both in vitro and in vivo. Mechanistically, IGK stabilized Nrf2 protein via inhibiting the proteasomal degradation, independent of transcription regulation. Moreover, molecular docking and dynamics simulation assessment demonstrated a good binding mode between IGK and Nrf2/Keap1. Of note, the protective effects conferred by IGK against obesity-induced mitochondrial defects and cardiac dysfunction was compromised by Nrf2 gene silencing both in vitro and in vivo, consolidating a pivotal role of Nrf2 in IGK-elicited myocardial protection against MC. Thus, the present study identifies IGK as a promising drug candidate to alleviate obesity-induced oxidative stress and cardiomyocyte damage through Nrf2 activation, highlighting the therapeutic potential of IGK in ameliorating obesity-induced cardiomyopathy.

Kaempferol and atherosclerosis: From mechanism to medicine.

Natural products possess pleiotropic cardiovascular protective effects owing to their anti-oxidation, anti-inflammation and anti-thrombotic properties. Kaempferol, (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one), is a kind of naturally occurring flavonoid existing in many common fruits and vegetables (e.g., onions, broccoli, strawberries and grapes) and particularly in traditional Chinese medicine as exemplified by Ginkgo biloba. Epidemiological, preclinical and clinical studies have revealed an inverse association between the consumption of kaempferol-containing foods and medicines and the risk of developing cardiovascular diseases. Numerous translational studies in experimental animal models and cultured cells have demonstrated a wide range of pharmacological activities of kaempferol. In this article, we reviewed the antioxidant, anti-inflammatory and cardio-protective activities of kaempferol and elucidated the potential molecular basis of the therapeutic capacity of kaempferol by focusing on its anti-atherosclerotic effects. Overall, the review presents the health benefits of kaempferol-containing plants and medicines and reflects on the potential of kaempferol as a possible drug candidate to prevent and treat atherosclerosis, the underlying pathology of most cardiovascular diseases.

Citri Reticulatae Pericarpium (Chenpi): A multi-efficacy pericarp in treating cardiovascular diseases.

Citri Reticulatae Pericarpium (CRP) has been utilized as a versatile medicinal herb with wide cardiovascular benefits in Asian nations for centuries. Accumulating evidence suggests that CRP and its components are effective in preventing cardiovascular diseases (CVDs) such as atherosclerosis, myocardial infarction, myocardial ischemia, arrhythmia, cardiac hypertrophy, heart failure, and hypertension. Studies show that the two most bioactive components of CRP are flavonoids and volatile oils. The cardiovascular protective effects of CRP have attracted considerable research interest due to its hypolipidemic, antiplatelet activity, antioxidant and anti-inflammatory effects. Hereby, we provide a rigorous and up-to-date overview of the cardiovascular protective properties and the potential molecular targets of CRP, and finally highlight the pharmacokinetics and the therapeutic potential of the main pharmacologically active components of CRP to treat CVDs.

A review on therapeutical potential of paeonol in atherosclerosis.

The morbidity and mortality of atherosclerotic cardiovascular disease (ASCVD) is increasing year by year. Cortex Moutan is a traditional Chinese medicinal herb that has been widely used for thousands of years to treat a wide variety of diseases in Eastern countries due to its heat-clearing and detoxifying effects. Paeonol is a bioactive monomer extracted from Cortex Moutan, which has anti-atherosclerotic effects. In this article, we reviewed the pharmacological effects of paeonol against experimental atherosclerosis, as well as its protective effects on vascular endothelial cells, smooth muscle cells, macrophages, platelets, and other important cell types. The pleiotropic effects of paeonol in atherosclerosis suggest that it can be a promising therapeutic agent for atherosclerosis and its complications. Large-scale randomized clinical trials are warranted to elucidate whether paeonol are effective in patients with ASCVD.

Marijuana and endothelial dysfunction: new mechanism and therapy.

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.

Therapeutic potential of colchicine in cardiovascular medicine: a pharmacological review.

Colchicine is an ancient herbal drug derived from Colchicum autumnale. It was first used to treat familial Mediterranean fever and gout. Based on its unique efficacy as an anti-inflammatory agent, colchicine has been used in the therapy of cardiovascular diseases including coronary artery disease, atherosclerosis, recurrent pericarditis, vascular restenosis, heart failure, and myocardial infarction. More recently, colchicine has also shown therapeutic efficacy in alleviating cardiovascular complications of COVID-19. COLCOT and LoDoCo2 are two milestone clinical trials that confirm the curative effect of long-term administration of colchicine in reducing the incidence of cardiovascular events in patients with coronary artery disease. There is growing interest in studying the anti-inflammatory mechanisms of colchicine. The anti-inflammatory action of colchicine is mediated mainly through inhibiting the assembly of microtubules. At the cellular level, colchicine inhibits the following: (1) endothelial cell dysfunction and inflammation; (2) smooth muscle cell proliferation and migration; (3) macrophage chemotaxis, migration, and adhesion; (4) platelet activation. At the molecular level, colchicine reduces proinflammatory cytokine release and inhibits NF-κB signaling and NLRP3 inflammasome activation. In this review, we summarize the current clinical trials with proven curative effect of colchicine in treating cardiovascular diseases. We also systematically discuss the mechanisms of colchicine action in cardiovascular therapeutics. Altogether, colchicine, a bioactive constituent from an ancient medicinal herb, exerts unique anti-inflammatory effects and prominent cardiovascular actions, and will charter a new page in cardiovascular medicine.

Therapeutic potential of paeoniflorin in atherosclerosis: A cellular action and mechanism-based perspective.

Epidemiological studies have shown that the incidence, prevalence and mortality of atherosclerotic cardiovascular disease (ASCVD) are increasing globally. Atherosclerosis is characterized as a chronic inflammatory disease which involves inflammation and immune dysfunction. P. lactiflora Pall. is a plant origin traditional medicine that has been widely used for the treatment of various diseases for more than a millennium in China, Japan and Korean. Paeoniflorin is a bioactive monomer extracted from P. lactiflora Pall. with anti-atherosclerosis effects. In this article, we comprehensively reviewed the potential therapeutic effects and molecular mechanism whereby paeoniflorin protects against atherosclerosis from the unique angle of inflammation and immune-related pathway dysfunction in vascular endothelial cells, smooth muscle cells, monocytes, macrophages, platelets and mast cells. Paeoniflorin, with multiple protective effects in atherosclerosis, has the potential to be used as a promising therapeutic agent for the treatment of atherosclerosis and its complications. We conclude with a detailed discussion of the challenges and future perspective of paeoniflorin in translational cardiovascular medicine.

Curcumin as a Natural Remedy for Atherosclerosis: A Pharmacological Review.

Curcumin, a natural polyphenolic compound present in Curcuma longa L. rhizomes, shows potent antioxidant, anti-inflammatory, anti-cancer, and anti-atherosclerotic properties. Atherosclerosis is a comprehensive term for a series of degenerative and hyperplasic lesions such as thickening or sclerosis in large- and medium-sized arteries, causing decreased vascular-wall elasticity and lumen diameter. Atherosclerotic cerebro-cardiovascular disease has become a major concern for human health in recent years due to its clinical sequalae of strokes and heart attacks. Curcumin concoction treatment modulates several important signaling pathways related to cellular migration, proliferation, cholesterol homeostasis, inflammation, and gene transcription, among other relevant actions. Here, we provide an overview of curcumin in atherosclerosis prevention and disclose the underlying mechanisms of action of its anti-atherosclerotic effects.

Medicinal plants and bioactive natural products as inhibitors of NLRP3 inflammasome.

The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that induces caspase-1 activation and the downstream substrates involved with the processing and secretion of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 and tumor necrosis factor-α (TNF- α). The NLRP3 inflammasome is activated by a wide range of danger signals that derive from metabolic dysregulation. Activation of this complex often involves the adaptor ASC and upstream sensors including NLRP1, NLRP3, NLRC4, AIM2, and pyrin, which are activated by different stimuli including infectious agents and changes in cell homeostasis. It has been shown that nutraceuticals and medicinal plants have antiinflammatory properties and could be used as complementary therapy in the treatment of several chronic diseases that are related to inflammation, for example, cardiovascular diseases and diabetes mellitus. Herb-based medicine has demonstrated protective effects against NLRP3 inflammasome activation. Therefore, this review focuses on the effects of nutraceuticals and bioactive compounds derived from medicinal plants on NLRP3 inflammasome activation and the possible mechanisms of action of these natural products. Thus, herb-based, natural products/compounds can be considered novel, practical, and accessible agents in chronic inflammatory diseases by inhibiting NLRP3 inflammasome activation.

Epigenetic targeting of cancer stem cells by polyphenols (cancer stem cells targeting).

Epigenetic alterations are one of the main factors that disrupt the expression of genes and consequently, they have an important role in the carcinogenicity and the progression of different cancers. Cancer stem cells (CSCs) are accountable for the recurrence, metastasis, and therapeutic failure of cancer. The noticeable and specific pathways in CSCs can be organized by epigenetic mechanisms such as DNA methylation, chromatin remodeling, regulatory RNAs, among others. Since epigenetics modifications can be changed and reversed, it is a possible tool for cancer control and treatment. Epigenetic therapies against CSCs are emerging as a very new strategy with a good future expectation to treat cancer patients. Phenolic compounds are a vast group of substances with anticarcinogenic functions, antiinflammatory, and antioxidative activities. It seems these characteristics are related to neutralizing CSCs development, their microenvironment, and metabolism through epigenetic mechanisms. In the current work, the types of epigenetic changes known in these cells are introduced. In addition, some studies about the use of polyphenols acting through a variety of epigenetic mechanisms to counteract these cells will be reviewed. The reported results seem to indicate that the use of these phenolic compounds may be useful for CSCs defeat.

Natural products: The role and mechanism in low-density lipoprotein oxidation and atherosclerosis.

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.

Emodin in atherosclerosis prevention: Pharmacological actions and therapeutic potential.

Atherosclerotic plaque formation, destabilization and eventual rupture leads to the acute cardiovascular events including myocardial infarction and stroke. Emodin (PubChem CID#3220), (1,3,8-trihydroxy-6-methylanthracene-9,10-dione) is a pharmacologically bioactive constituent isolated from the traditional Chinese medicinal herb Radix rhizoma Rhei. This molecule has anti-oxidant, anti-inflammatory, anti-proliferative, anti-apoptotic and lipid-modulating effects. Experimental studies have demonstrated that emodin attenuates and stabilizes atherosclerotic plaques. In this mini-review, we provide a summary of the pharmacological actions of emodin in regulating vascular function and atherosclerosis, highlighting the therapeutic potential of this phytochemical in patients with cardiovascular disease.

Autophagy and cardiac diseases: Therapeutic potential of natural products.

The global incidence of cardiac diseases is expected to increase in the coming years, imposing a substantial socioeconomic burden on healthcare systems. Autophagy is a tightly regulated lysosomal degradation mechanism important for cell survival, homeostasis, and function. Accumulating pieces of evidence have indicated a major role of autophagy in the regulation of cardiac homeostasis and function. It is well established that dysregulation of autophagy in cardiomyocytes is involved in cardiac hypertrophy, myocardial infarction, diabetic cardiomyopathy, and heart failure. In this sense, autophagy seems to be an attractive therapeutic target for cardiac diseases. Recently, multiple natural products/phytochemicals, such as resveratrol, berberine, and curcumin have been shown to regulate cardiomyocyte autophagy via different pathways. The autophagy-modifying capacity of these compounds should be taken into consideration for designing novel therapeutic agents. This review focuses on the role of autophagy in various cardiac diseases and the pharmacological basis and therapeutic potential of reported natural products in cardiac diseases by modifying autophagic processes.

The Effect of Salvianolic Acid on Vascular Protection and Possible Mechanisms.

Salvia miltiorrhiza (Danshen), as an important traditional Chinese medicinal plant, has been used in China for the treatment of cardiovascular diseases for hundreds of years. Salvianolic acids (salvianolic acid A and salvianolic acid B) as the most abundant water-soluble component extracted from Salvia miltiorrhiza have attracted more and more attention from cardiovascular scientists due to its comprehensive cardiovascular actions. In vivo and in vitro studies have rendered salvianolic acid an excellent drug candidate for the treatment and prevention of cardiovascular diseases. In this review, we surveyed the protective effects of salvianolic acid A and salvianolic acid B against cardiovascular diseases and the pharmacological basis, providing a strong scientific rationale for elucidating the important role of Salvia miltiorrhiza in cardiovascular therapy. More importantly, we also hope to provide new inspiration and perspectives on the development and innovation of small-molecule cardiovascular drugs based on salvianolic acid.

Medicinal plants and bioactive natural compounds as inhibitors of HMG-CoA reductase: A literature review.

Cardiovascular diseases (CVDs) are one of the most important causes for mortality worldwide. Elevated levels of total cholesterol, and particularly LDL-cholesterol (LDL-C) are the main risk factor for acute myocardial infarction (AMI) and ischemic heart disease. The risk of CVDs could be reduced by decreasing the elevated cholesterol levels. ß-hydroxy ß-methylglutaryl-CoA reductase (HMGCoAR) is the primary and rate-limiting enzyme in the cholesterol biosynthesis pathway. Recently, the crucial role of nutraceuticals in maintaining normal physiological function was established. Nutraceuticals play an important role in preventing several non-communicable diseases such as obesity, CVDs, cancer, diabetes, and reducing hyperlipidemia. Although the effect of nutraceuticals and herbal medicine on CVDs and dyslipidemia was previously investigated thoroughly, the effect of these natural products on HMGCoAR as one of the important enzymes involved in CVDs etiopathogenesis has not yet been investigated. Therefore, the major aim of this paper was to review the effects of nutraceuticals and medicinal plants on HMGCoAR. Results indicate that different types of natural foods, isolated nutrients, herbal products, and dietary supplements as nutraceuticals decrease the expression and activity of HMGCoAR. This review shows that medicinal plants and nutraceuticals could be used to decrease HMGCoAR activity as accessible and convenient and economical natural compounds to prevent dyslipidemia and CVDs.

Traditional Chinese medicine in cardiovascular drug discovery.

In this virtual special issue entitled "Traditional Chinese Medicine in Cardiovascular Drug Discovery", a collection of 18 basic research, clinical research and review articles was published to highlight the therapeutic potential of traditional Chinese medicine (TCM) and their bioactive components in treating atherosclerosis, coronary artery disease, ischemic cardiomyopathy, heart failure and beyond.

Endothelial-specific YY1 governs sprouting angiogenesis through directly interacting with RBPJ.

Angiogenesis, the formation of new blood vessels, is tightly regulated by gene transcriptional programs. Yin Ying 1 (YY1) is a ubiquitously distributed transcription factor with diverse and complex biological functions; however, little is known about the cell-type-specific role of YY1 in vascular development and angiogenesis. Here we report that endothelial cell (EC)-specific YY1 deletion in mice led to embryonic lethality as a result of abnormal angiogenesis and vascular defects. Tamoxifen-inducible EC-specific YY1 knockout (YY1iΔEC ) mice exhibited a scarcity of retinal sprouting angiogenesis with fewer endothelial tip cells. YY1iΔEC mice also displayed severe impairment of retinal vessel maturation. In an ex vivo mouse aortic ring assay and a human EC culture system, YY1 depletion impaired endothelial sprouting and migration. Mechanistically, YY1 functions as a repressor protein of Notch signaling that controls EC tip-stalk fate determination. YY1 deficiency enhanced Notch-dependent gene expression and reduced tip cell formation. Specifically, YY1 bound to the N-terminal domain of RBPJ (recombination signal binding protein for Ig Kappa J region) and competed with the Notch coactivator MAML1 (mastermind-like protein 1) for binding to RBPJ, thereby impairing the NICD (intracellular domain of the Notch protein)/MAML1/RBPJ complex formation. Our study reveals an essential role of endothelial YY1 in controlling sprouting angiogenesis through directly interacting with RBPJ and forming a YY1-RBPJ nuclear repression complex.

Therapeutic potential of polyphenols in cardiovascular diseases: Regulation of mTOR signaling pathway.

Cardiovascular diseases comprise of non-communicable disorders that involve the heart and/or blood vessels and have become the leading cause of death worldwide with increased prevalence by age. mTOR is a serine/threonine-specific protein kinase which plays a central role in many physiological processes including cardiovascular diseases, and also integrates various proliferative signals, nutrient and energy abundance and stressful situations. mTOR also acts as central regulator during chronic stress, mitochondrial dysfunction and deregulated autophagy which are associated with senescence. Under oxidative stress, mTOR has been reported to exert protective effects regulating apoptosis and autophagy processes and favoring tissue repair. On the other hand, inhibition of mTOR has been suggested to have beneficial effects against atherosclerosis, cardiac hypertrophy and heart failure, and also in extending the lifespan. In this aspect, the use of drugs or natural compounds, which can target mTOR is an interesting approach in order to reduce the number of deaths caused by cardiovascular disease. In the present review, we intend to shed light on the possible effects and molecular mechanism of natural agents like polyphenols via regulating mTOR.