Keshav Raj Paudel

Reactive Oxygen Species: A Key Hallmark of Cardiovascular Disease

Cardiovascular diseases (CVDs) have been the prime cause of mortality worldwide for decades. However, the underlying mechanism of their pathogenesis is not fully clear yet. It has been already established that reactive oxygen species (ROS) play a vital role in the progression of CVDs. ROS are chemically unstable reactive free radicals containing oxygen, normally produced by xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidase, lipoxygenases, or mitochondria or due to the uncoupling of nitric oxide synthase in vascular cells. When the equilibrium between production of free radicals and antioxidant capacity of human physiology gets altered due to several pathophysiological conditions, oxidative stress is induced, which in turn leads to tissue injury. This review focuses on pathways behind the production of ROS, its involvement in various intracellular signaling cascades leading to several cardiovascular disorders (endothelial dysfunction, ischemia-reperfusion, and atherosclerosis), methods for its detection, and therapeutic strategies for treatment of CVDs targeting the sources of ROS. The information generated by this review aims to provide updated insights into the understanding of the mechanisms behind cardiovascular complications mediated by ROS.

Circulating Endothelial Microparticles: A Key Hallmark of Atherosclerosis Progression

The levels of circulating microparticles (MPs) are raised in various cardiovascular diseases. Their increased level in plasma is regarded as a biomarker of alteration in vascular function. The prominent MPs present in blood are endothelial microparticles (EMPs) described as complex submicron (0.1 to 1.0 μm) vesicles like structure, released in response to endothelium cell activation or apoptosis. EMPs possess both physiological and pathological effects and may promote oxidative stress and vascular inflammation. EMPs release is triggered by inducer like angiotensin II, lipopolysaccharide, and hydrogen peroxide leading to the progression of atherosclerosis. However, there are multiple physiological pathways for EMPs generation like NADPH oxidase derived endothelial ROS formation, Rho kinase pathway, and mitogen-activated protein kinases. Endothelial dysfunction is a key initiating event in atherosclerotic plaque formation. Atheroemboli, resulting from ruptured carotid plaques, is a major cause of stroke. Increasing evidence suggests that EMPs play an important role in the pathogenesis of cardiovascular disease, acting as a marker of damage, either exacerbating disease progression or triggering a repair response. In this regard, it has been suggested that EMPs have the potential to act as biomarkers of disease status. This review aims to provide updated information of EMPs in relation to atherosclerosis pathogenesis.

Terminalia chebula Fructus Inhibits Migration and Proliferation of Vascular Smooth Muscle Cells and Production of Inflammatory Mediators in RAW 264.7

Pathogenesis of atherosclerosis and neointima formation after angioplasty involves vascular smooth muscle cells (VSMCs) migration and proliferation followed by inflammatory responses mediated by recruited macrophages in the neointima. Terminalia chebula is widely used traditional medicine in Asia for its beneficial effects against cancer, diabetes, and bacterial infection. The study was designed to determine whether Terminalia chebula fructus water extract (TFW) suppresses VSMC migration and proliferation and inflammatory mediators production in macrophage (RAW 264.7). Our results showed that TFW possessed strong antioxidative effects in 1,1-diphenyl-2-picryl hydrazyl (DPPH) scavenging and lipid peroxidation assays. In addition, TFW reduced nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression in RAW 264.7 cells. Also, TFW inhibited platelet-derived growth factor (PDGF-BB) induced VSMC migration as determined by wound healing and Boyden chamber assays. The antimigratory effect of TFW was due to its inhibitory effect on metalloproteinase-9 (MMP-9) expression, focal adhesion kinase (FAK) activation, and Rho-family of small GTPases (Cdc42 and RhoA) expression in VSMCs. Furthermore, TFW suppressed PDGF-BB induced VSMC proliferation by downregulation of mitogen activated protein kinases (MAPKs) signaling molecules. These results suggest that TFW could be a beneficial resource in the prevention of atherosclerosis.

Cepharanthine inhibits in vitro VSMC proliferation and migration and vascular inflammatory responses mediated by RAW264.7.

Pathogenesis of atherosclerosis involves vascular smooth muscle cell (VSMC) migration and proliferation followed by an inflammation mediated by activated macrophages in the tunica intima of blood vessels. Cepharanthine (CEP) belongs to bisbenzylisoquinoline alkaloids found in the plant Stephania cepharantha, which has been used for various diseases like cancer, alopecia areata, venomous snakebites, and malaria. In this study, we investigated whether CEP suppresses VSMC migration and proliferation and inhibits inflammatory mediator production in macrophage (RAW264.7). Our results showed that CEP possessed significant DPPH scavenging and metal chelating activities. It also markedly inhibited lipid peroxidation. Similarly, CEP suppressed the nitric oxide (NO) production and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in RAW264.7 cells. Moreover, the level of prostaglandin E2 was also suppressed and the formation of macrophage derived foam cell was attenuated in RAW264.7 cells. Likewise, NO production in isolated peritoneal macrophage and VSMC migration in response to LPS stimulated RAW264.7 was also halted by CEP treatment. Also, VSMC migration induced by platelet-derived growth factor (PDGF-BB) was inhibited by CEP dose dependently. The anti-migratory effect of CEP on VSMCs was due to its inhibitory effect on metalloproteinase-9 (MMP-9) expression, preventing the degradation of extracellular matrix (ECM) component. Furthermore, CEP suppressed PDGF-BB induced VSMC proliferation by down-regulation of mitogen activated protein kinase (MAPK) signaling molecules. CEP also inhibited the translocation of NF-κB from cytosol to nucleus. Thus, our results suggest that CEP exerts potent anti-atherosclerotic effect through attenuation of inflammation, lipid peroxidation and VSMC migration and proliferation.

Phytochemical profile and biological activity of Juglans regia

Juglans regia Linn. (Juglandaceae), popularly known as English or Persian walnut, is a valuable medicinal plant with a potency to cure various diseases in traditional medicine. Since ancient time, different local ethnic groups have used various part of J. regia for a wide array of ailments including helminthiasis, diarrhea, sinusitis, stomach ache, arthritis, asthma, eczema, scrofula, skin disorders, diabetes mellitus, anorexia, thyroid dysfunction, cancer and infectious diseases. Biological activities of J. regia have been reported in several peer review journals and scientific attention is increasing. The present review attempts to provide comprehensive information on plant description, ethnobotanical use, toxicity, phytochemical profile, pharmacology, clinical studies and current research prospective of the J. regia. Currently, there is an immense interest on isolation/identification of active constituents from walnut and screening those active compounds for pharmacological activities. In addition, researchers are performing clinical trials as well as screening various solvent extracts or fractions of J. regia in several animal diseases models to identify promising therapeutic benefits. In the present work, we review the latest information based on published scientific investigations of J. regia.

Antiatherogenic Effect of Camellia japonica Fruit Extract in High Fat Diet-Fed Rats

Hypercholesterolemia is a well-known etiological factor for cardiovascular disease and a common symptom of most types of metabolic disorders. Camellia japonica is a traditional garden plant, and its flower and seed have been used as a base oil of traditional cosmetics in East Asia. The present study was carried out to evaluate the effect of C. japonica fruit extracts (CJF) in a high fat diet- (HFD-) induced hypercholesterolemic rat model. CJF was administered orally at three different doses: 100, 400, and 800 mg·kg−1·day−1 (CJF 100, 400, and 800, resp.). Our results showed that CJF possessed strong cholesterol-lowering potency as indicated by the decrease in serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL), accompanied by an increase in serum high-density lipoprotein (HDL). Furthermore, CJF reduced serum lipid peroxidation by suppressing the formation of thiobarbituric acid reactive substance. In addition, oil red O (ORO) staining of rat arteries showed decreased lipid-positive staining in the CJF-treated groups compared to the control HFD group. Taken together, these results suggest that CJF could be a potent herbal therapeutic option and source of a functional food for the prevention and treatment of atherosclerosis and other diseases associated with hypercholesterolemia.

Chungtaejeon, a Korean fermented tea, prevents the risk of atherosclerosis in rats fed a high-fat atherogenic diet

OBJECTIVE Hypercholesterolemia is one of the well-established risk factors for cardiovascular mortality and morbidity in coronary heart disease. The aim of this study was to investigate the anti-atherogenic effect of Chungtaejeon (CTJ, a Korean fermented tea) aqueous extract on proliferation and migration of human aortic smooth muscle cells (HASMCs) in vivo and in vitro. METHODS The authors used high-fat atherogenic diet (HFAD) to induce hyperlipidemia in Wistar rats in in vivo animal experiments and used HASMCs for in vitro cell experiments. For the in vitro cell experiment, the proliferation of HASMCs was evaluated using the MTT assay. Similarly, the expression of matrix metalloproteinases (MMPs) in HASMCs was measured using gelatin zymography. Antimigratory activity of CTJ was revealed using the wound-healing model and Boyden s chamber assay. In the in vivo experiment, CTJ was administered in three different doses for 20 d from the initiation of the HFAD. After 20 d, the serum lipid profile and total lipid contents in liver were measured. RESULTS Treatment with CTJ for 24 h dose-dependently inhibited the proliferation and migration of HASMCs and expression of MMP-2 in HASMCs. The oral administration of CTJ at concentrations of 200 and 400 mg/kg decreased the levels of low-density lipoprotein cholesterol, total serum cholesterol and hepatic cholesterol of HFAD-fed rats. CONCLUSION CTJ possessed strong antiproliferative, antimigratory, as well as lipid-lowering activities. Thus, CTJ can be considered as a therapeutic option in the treatment of high-fat diet-induced atherosclerosis.