Effect of Heat-Treated Garlic (Allium sativum L.) on Growth Parameters, Plasma Lipid Profile and Histological Changes in the Ileum of Atherogenic Rats.

Dietary supplementation with raw garlic has a preventive and healing effect in cardiovascular diseases, but it could also damage the intestinal mucosa, resulting in impairment of nutrient absorption. Garlic processing, including heat treatment, changes the content and biological activity of garlic, so it is crucial to find food-processing methods that will preserve the health-promoting properties of garlic while minimizing its negative impact on the digestive system. Therefore, in this study, the effect of garlic (Allium sativum L.) on growth parameters, plasma lipid profile, and morphological parameters in the ileum of Wistar rats subjected to various types of heat treatment (90 s blanching garlic, 10 min boiling in water, 10 min pan frying without fat, microwave heating fresh garlic, 90 s blanching and microwave heating garlic, 10 min boiling in water and microwave heating garlic, and 10 min pan frying without fat and microwave heating garlic) was determined in an atherogenic diet (containing 1% addition of cholesterol). In the conducted research, it was found that the diet supplemented with heat-treated garlic used in the atherogenic diet improved the consumption and growth parameters of rats, depending on the type and time of its use. The highest consumption was recorded in atherogenic groups supplemented with garlic subjected to a longer (10 min) heat treatment and was then heated in a microwave oven. Garlic subjected to the shortest heat treatment proved to be most effective, and a significant improvement in the lipid profiles of rats' plasma with atherogenic was observed. Extending the time of heat treatment of garlic and, additionally, its microwaving significantly weakened the action of garlic in the body, but still retained its hypolipidemic effect. The greatest influence on the structural changes in the mucosa of the rats' iliac intestine, manifested by degeneration of the mucosa, shortening the length of the intestinal villi, damage to the brush border, and thus impairment of the intestinal absorption, was exerted by supplementing the atherogenic diet with garlic subjected to short-term heat treatment. Among the processes used, blanching was the least favorable, and the long-lasting thermal processes (cooking, frying for 10 min) had a positive effect on the mucosa of the rats' intestines. The results obtained in this study confirm that the selection of an appropriate method of thermal processing of garlic may allow for the maintenance of preventive and therapeutic efficacy of garlic in cardiovascular diseases, while ensuring the safety of its long-term use in the context of degenerative changes in the gastrointestinal tract.

Endothelial Yin Yang 1 Phosphorylation at S118 Induces Atherosclerosis Under Flow.

RATIONALE: Disturbed flow occurring in arterial branches and curvatures induces vascular endothelial cell (EC) dysfunction and atherosclerosis. We postulated that disturbed flow plays important role in modulating phosphoprotein expression profiles to regulate endothelial functions and atherogenesis. OBJECTIVE: The goal of this study is to discover novel site-specific phosphorylation alterations induced by disturbed flow in ECs to contribute to atherosclerosis. METHODS AND RESULTS: Quantitative phosphoproteomics analysis of ECs exposed to disturbed flow with low and oscillatory shear stress (0.5±4 dynes/cm2) versus pulsatile shear stress (12±4 dynes/cm2) revealed that oscillatory shear stress induces phospho-YY1S118 (serine [S]118 phosphorylation of Yin Yang 1) in ECs. Elevated phospho-YY1S118 level in ECs was further confirmed to be present in the disturbed flow regions in experimental animals and human atherosclerotic arteries. This disturbed flow-induced EC phospho-YY1S118 is mediated by CK2α (casein kinase 2α) through its direct interaction with YY1. Yeast 2-hybrid library screening and in situ proximity ligation assays demonstrate that phospho-YY1S118 directly binds ZKSCAN4 (zinc finger with KRAB [krüppel-associated box] and SCAN [SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA] domains 4) to induce promoter activity and gene expression of HDM2 (human double minute 2), which consequently induces EC proliferation through downregulation of p53 and p21CIP1. Administration of apoE-deficient (ApoE-/-) mice with CK2-specific inhibitor tetrabromocinnamic acid or atorvastatin inhibits atherosclerosis formation through downregulations of EC phospho-YY1S118 and HDM2. Generation of novel transgenic mice bearing EC-specific overexpression of S118-nonphosphorylatable mutant of YY1 in ApoE-/- mice confirms the critical role of phospho-YY1S118 in promoting atherosclerosis through EC HDM2. CONCLUSIONS: Our findings provide new insights into the mechanisms by which disturbed flow induces endothelial phospho-YY1S118 to promote atherosclerosis, thus indicating phospho-YY1S118 as a potential molecular target for atherosclerosis treatment.

Nanotechnological approach to delivering nutraceuticals as promising drug candidates for the treatment of atherosclerosis.

Atherosclerosis is Caesar's sword, which poses a huge risk to the present generation. Understanding the atherosclerotic disease cycle would allow ensuring improved diagnosis, better care, and treatment. Unfortunately, a highly effective and safe way of treating atherosclerosis in the medical community remains a continuous challenge. Conventional treatments have shown considerable success, but have some adverse effects on the human body. Natural derived medications or nutraceuticals have gained immense popularity in the treatment of atherosclerosis due to their decreased side effects and toxicity-related issues. In hindsight, the contribution of nutraceuticals in imparting enhanced clinical efficacy against atherosclerosis warrants more experimental evidence. On the other hand, nanotechnology and drug delivery systems (DDS) have revolutionized the way therapeutics are performed and researchers have been constantly exploring the positive effects that DDS brings to the field of therapeutic techniques. It could be as exciting as ever to apply nano-mediated delivery of nutraceuticals as an additional strategy to target the atherosclerotic sites boasting high therapeutic efficiency of the nutraceuticals and fewer side effects.

Digestive n-6 Lipid Oxidation, a Key Trigger of Vascular Dysfunction and Atherosclerosis in the Western Diet: Protective Effects of Apple Polyphenols.

SCOPE: A main risk factor of atherosclerosis is a Western diet (WD) rich in n-6 polyunsaturated fatty acids (PUFAs) sensitive to oxidation. Their oxidation can be initiated by heme iron of red meat leading to the formation of 4-hydroxy-2-nonenal (4-HNE), a cytotoxic aldehyde. An increased 4-HNE production is implicated in endothelial dysfunction and atherosclerosis. By contrast, a diet rich in proanthocyanidins reduces oxidative stress and arterial diseases. This study evaluates the effects of a WD on vascular integrity in ApolipoproteinE (ApoE-/- ) mice and the protective capacity of apple extract and puree rich in antioxidant proanthocyanidins. METHODS AND RESULTS: ApoE-/- mice are fed during 12 weeks with a WD with or without n-6 PUFAs. Moreover, two WD + n-6 PUFAs groups are supplemented with apple puree or phenolic extract. An increase in digestive 4-HNE production associated with a rise in plasmatic 4-HNE and oxidized LDL concentrations is reported. Oxidizable n-6 PUFAs consumption is associated with a worsened endothelial dysfunction and atherosclerosis. Interestingly, supplementations with apple polyphenol extract or puree prevented these impairments while reducing oxidative stress. CONCLUSION: n-6 lipid oxidation during digestion may be a key factor of vascular impairments. Nevertheless, an antioxidant strategy can limit 4-HNE formation during digestion and thus durably protect vascular function.

Idebenone Protects against Atherosclerosis in Apolipoprotein E-Deficient Mice Via Activation of the SIRT3-SOD2-mtROS Pathway.

PURPOSE: Atherosclerosis, a chronic disease of the arteries, results from pathological processes including the accumulation and aggregation of oxidized low-density lipoprotein (oxLDL) in the vessel walls, development of neointima, formation of a fibrous cap, and migration of immune cells to damaged vascular endothelium. Recent studies have shown that mitochondrial dysfunction is closely associated with the development and progression of atherosclerosis. Idebenone, a short-chain benzoquinone similar in structure to coenzyme Q10, can effectively clear oxygen free radicals as an electron carrier and antioxidant. In the present study, we aim to investigate weather idebenone protects against atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. METHODS: apoE-/- mice receiving a high-fat diet (HFD) were treated with idebenone for 16 weeks. A total of 60 mice were randomized into the following four groups: (1) HFD, (2) HFD and low-dose idebenone (100 mg/kg/d), (3) HFD and medium-dose idebenone (200 mg/kg/d), and (4) HFD and high-dose (400 mg/kg/d). Proteomic analysis was performed between the HFD and idebenone-high-dose group. Plaque analysis was carried out by histological and immunohistochemical staining. Western blot, TUNEL staining, and MitoSOX assays were performed in human umbilical vein endothelial cells (HUVECs) to investigate the SIRT3-SOD2-mtROS pathway. RESULTS: Histological and morphological analysis demonstrated that idebenone significantly reduced plaque burden and plaque size. Idebenone treatment effectively stabilized the atherosclerotic plaques. In mice treated with idebenone, 351 up-regulated and 379 down-regulated proteins were found to be significantly altered in proteomic analysis. In particular, the expression of SIRT3, SOD2, and NLRP3 was significantly regulated in the idebenone treatment groups compared with the HFD group both in vivo and in vitro. We further confirmed that idebenone protected against endothelial cell damage and inhibited the production of mitochondrial reactive oxygen species (mtROS) in cholesterol-treated HUVECs. CONCLUSIONS: We demonstrated that idebenone acted as a mitochondrial protective agent by inhibiting the activation of NLPR3 via the SIRT3-SOD2-mtROS pathway. Idebenone may be a promising therapy for patients with atherosclerosis by improving mitochondrial dysfunction and inhibiting oxidative stress.

Omega-3 polyunsaturated fatty acids: anti-inflammatory and anti-hypertriglyceridemia mechanisms in cardiovascular disease.

Cardiovascular disease (CVD) is the world's most recognized and notorious cause of death. It is known that increased triglyceride-rich lipoproteins (TRLs) and remnants of triglyceride-rich lipoproteins (RLP) are the major risk factor for CVD. Furthermore, hypertriglyceridemia commonly leads to a reduction in HDL and an increase in atherogenic small dense low-density lipoprotein (sdLDL or LDL-III) levels. Thus, the evidence shows that Ω-3 fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have a beneficial effect on CVD through reprogramming of TRL metabolism, reducing inflammatory mediators (cytokines and leukotrienes), and modulation of cell adhesion molecules. Therefore, the purpose of this review is to provide the molecular mechanism related to the beneficial effect of Ω-3 PUFA on the lowering of plasma TAG levels and other atherogenic lipoproteins. Taking this into account, this study also provides the TRL lowering and anti-inflammatory mechanism of Ω-3 PUFA metabolites such as RvE1 and RvD2 as a cardioprotective function.

Regulatory effect of traditional Chinese medicine on gut microbiota in patients with atherosclerosis: A protocol for systematic review and meta-analysis.

BACKGROUND: Atherosclerosis is the pathological basis of many cardiovascular and cerebrovascular diseases, and its pathogenesis is complex. Recent studies revealed a significant role of gut microbiota in the onset and development of atherosclerosis. Traditional Chinese medicine has rich clinical experience and unique advantages in the treatment of atherosclerosis. A large number of studies have proved that traditional Chinese medicine has the functions of reducing blood lipid, regulating gut microbiota, and resisting inflammation. The aim of this systematic review is to observe the randomized controlled trial of traditional Chinese medicine in treating gut microbiota, so as to evaluate the effectiveness and safety of traditional Chinese medicine in treating atherosclerosis patients. METHODS: The English database (PubMed, Web of Science, Embase, the Cochrane Library) and Chinese database (China National Knowledge Infrastructure, the Chongqing VIP Chinese Science, and Technology Periodic Database, Wanfang Database, and China Biomedical Literature Database) will be searched up to October 2020. We will also manually search the Chinese clinical trial register, conference papers, and unpublished studies or references. Randomized control trials of traditional Chinese medicine treatment of atherosclerosis were collected comprehensively, and 2 researchers will independently screen literature, data extraction, and evaluation the quality of literature methodology. The primary outcomes are lipid metabolism and gut microbiota and their metabolites. The secondary outcomes are the change of inflammatory markers. Meta-analysis was performed by RevMan 5.3.5 software. The Grades of Recommendation, Assessment, Development, and Evaluation will be used to evaluate the outcome quality of evidence. RESULTS: This study will comprehensively review the existing evidence of traditional Chinese medicine in treating atherosclerosis from the perspective of gut microbiota. CONCLUSION: This study will provide information on the effectiveness and safety of traditional Chinese medicine in treating atherosclerosis from the perspective of gut microbiota. UNIQUE INPLASY NUMBER: INPLASY2020110056.

Vitamin D and Cardiovascular Disease, with Emphasis on Hypertension, Atherosclerosis, and Heart Failure.

Vitamin D deficiency is the most common nutritional deficiency, affecting almost one billion people worldwide. Vitamin D is mostly known for its role in intestinal calcium absorption and bone mineralization. However, the observation of seasonal changes in blood pressure and the subsequent identification of vitamin D receptor (VDR) and 1α-hydroxylase in cardiomyocytes, as well as endothelial and vascular smooth muscle cells, implicated a role of vitamin D in the cardiovascular system. Animal studies provided compelling evidence that vitamin D signaling is essential for cardiovascular integrity, especially for the regulation of vascular tone and as an antifibrotic and antihypertrophic signaling pathway in the heart. In addition, observational studies reported an association between vitamin D deficiency and risk of hypertension, atherosclerosis, and heart failure. However, recent clinical intervention studies failed to prove the causal relationship between vitamin D supplementation and beneficial effects on cardiovascular health. In this review, we aim to highlight our current understanding of the role of vitamin D in the cardiovascular system and to find potential explanations for the large discrepancies between the outcome of experimental studies and clinical intervention trials.

Bushen Jiangzhi formula reduces atherosclerosis in apoE-/- mice through autophagy.

OBJECTIVE: To study the effect of Bushen Jiangzhi formula (BSJZF) on atherosclerosis (AS) in apolipoprotein E knockout (apoE-/-) mice and the underlying mechanism. METHODS: We used a high fat diet to induce AS in apoE-/- mice. The mice were randomly divided into four groups: model, BSJZF, atorvastatin, and 3-methyladenine groups. Syngeneic C57BL/6 mice of the same age were used for the control group. Autophagosomes in the aorta were examined by transmission electron microscopy. Morphology, lipid accumulation, and collagen deposition in the aorta were examined by hematoxylin and eosin, Oil Red O, and Masson's staining, respectively. Serum levels of tumor necrosis factor alpha (TNF-), interferon gamma (IFN-), and interleukin 10 (IL-10) were measured by enzyme-linked immunoassays. Protein expression of microtubule-associated protein light chain 3 (LC3), Beclin 1, and p62 in the aorta were examined by Western blot analyses. RESULTS: ApoE-/- mice fed a high fat diet exhibited AS symptoms including less autophagosomes in the aorta, higher serum levels of TNF-a, IFN-r, and p62, and lower serum levels of IL-10, LC3, and Beclin 1. Treatment with BSJZF significantly reduced the area of the aortic plaque, decreased expression of TNF-a, IFN-r, and p62, and increased expression of IL-10, LC3, and Beclin 1. CONCLUSION: Our findings suggest that BSJZF promotes autophagy and reduces inflammation by regulating the expression of autophagy-related proteins LC3, Beclin 1, and p62, thereby effectively treating AS.

Rol de los fitoestrógenos en la calcificación vascular e interacciones óseo-vasculares / Role of phytoestrogens in vascular calcification and bonevascular interactions

La osteoporosis y las enfermedades cardiovasculares son patologías prevalentes en mujeres posmenopáusicas. La calcificación vascular es un proceso en el que se produce una distorsión de la arquitectura natural del tejido arterial con una transformación símil osteogénica. La fisiología vascular y la osteogénesis (formación y remodelación ósea) comparten una complejidad metabólica y funcional crítica, que ha sido poco explorada en forma conjunta, lo que ha impulsado la concepción del Eje Óseo-Vascular como nueva área de investigación, con una visión de estudio integradora con la finalidad de identificar vínculos entre ambos sistemas. En virtud de la controversia planteada sobre los riesgos/beneficios de la terapia de reemplazo hormonal para prevenir enfermedades asociadas a la menopausia, se ha incentivado la búsqueda de nuevas opciones de tratamiento. Los fitoestrógenos, como compuestos nutracéuticos, surgen como una potencial alternativa terapéutica. En particular, las isoflavonas presentan gran analogía estructural con el estrógeno humano 17ß-estradiol, lo que les permite unirse al receptor de estrógenos e inducir acciones estrogénicas tanto en células animales como humanas. Basado en la experiencia propia como en lo reportado en la bibliografía, este artículo analiza la información disponible sobre las acciones vasculares y óseas de los fitoestrógenos (específicamente la isoflavona genisteína), con una visión de ciencia traslacional. Es de esperar que los avances en el conocimiento derivado de la ciencia básica, en un futuro cercano, pueda contribuir a decisiones clínicas a favor de promover terapias naturales de potencial acción dual, para la prevención de enfermedades de alta prevalencia y significativo costo social y económico para la población. (AU)

Osteoporosis and cardiovascular diseases are prevalent diseases in postmenopausal women. Vascular calcification is a cellmediated process that leads to the loss of the natural architecture of the arterial vessels due to osteogenic transdifferentiation of smooth muscle cells, and matrix mineralization. Vascular physiology and osteogenesis (bone formation and remodeling) share a critical metabolic and functional complexity. Given the emerging integrative nature of the bonevascular axis, links between both systems are a matter of ongoing interest. In view of the controversy stated about the risks/benefits of hormone replacement therapy to prevent diseases associated with menopause, phytoestrogens arise as a potential natural therapeutic alternative. In particular, isoflavones have a strong structural analogy with the human estrogen 17ß-estradiol, that allows them to bind to the estrogen receptor and induce estrogenic actions in animal and human cells. Based in on our own experience and the information available in the literature, in this paper we provide an overview of the role of phytoestrogens on vascular and bone tissues, with focus on Genistein actions. We wish that the basic knowledge acquired may contribute to guide clinical decisions for the promotion of natural therapies for the treatment of diseases that conspire against human health. (AU)

Improvement of Endothelial Dysfunction of Berberine in Atherosclerotic Mice and Mechanism Exploring through TMT-Based Proteomics.

Atherosclerosis is a multifactorial vascular disease triggered by disordered lipid metabolism, characterized by chronic inflammatory injury, and initiated by endothelial dysfunction. Berberine is the main active alkaloid of the herbal medicine Coptidis Rhizoma (Huanglian). Notably, berberine has been shown to have beneficial effects against atherosclerosis. However, the mechanisms of berberine in preventing atherosclerosis are still unclear. This study is aimed at investigating the effects and mechanisms of berberine in protecting the aorta and ameliorating atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Here, we demonstrated that berberine reduced serum lipid levels, antagonized hepatic lipid accumulation, improved intima-media thickening, and alleviated atherosclerotic lesions in ApoE-/- mice fed a western-type diet for 12 weeks. Meanwhile, berberine reduced aortic reactive oxygen species (ROS) generation and reduced the serum levels of malondialdehyde (MDA), oxidized low-density lipoprotein (ox-LDL), and interleukin-6 (IL-6). In aortic ring assay, berberine restored aortic endothelium-dependent vasodilatation in vivo and in vitro. Furthermore, 4,956 proteins were identified by proteomic analysis, and 199 differentially expressed proteins regulated by berberine were found to be involved in many biological pathways, such as mitochondrial dysfunction, fatty acid ß-oxidation I, and FXR/RXR activation. Summarily, these data suggested that berberine ameliorates endothelial dysfunction and protects against atherosclerosis, and thus may be a promising therapeutic candidate for atherosclerosis.

Assessment of traditional and non-traditional risk factors for premature atherosclerosis in children with juvenile dermatomyositis and pediatric controls.

BACKGROUND: Children with juvenile dermatomyositis (JDM), the most common inflammatory myopathy of childhood, may be at increased risk of premature atherosclerosis given a host of traditional and non-traditional risk factors. The primary aim of this study was to determine the underlying frequency of premature atherosclerosis in children with JDM compared to pediatric controls using flow-mediated dilation as a measure of endothelial function. METHODS: Children and adolescents with and without JDM were evaluated for traditional atherosclerotic risk factors and assessment of endothelial function, using Endothelial Pulse Amplitude Testing (Endo-PAT). RESULTS: In this study, 75% of pediatric controls were of Black or Hispanic descent (compared to 55% in the JDM group) and 70% were found to live in a household with a medium income less than $50,000/year (compared to 45% in the JDM group). Among traditional atherogenic risk factors, lipoprotein A appeared to be different between controls and JDM patients (66 nmol/L and 16.5 nmol/L, respectively). Using a reactive hyperemia index (RHI) < 1.67 as evidence of endothelial dysfunction, 75% of controls were defined as having endothelial dysfunction compared to 50% in JDM group. When controlled for lipoprotein A as an atherogenic confounder, JDM patients were found to have a 41% increase in RHI, thus indicating less endothelial dysfunction compared to controls. CONCLUSIONS: In this study, we have shown that atherogenic risk factors are present in the pediatric population and may be associated with endothelial dysfunction, even at very young ages. Despite increasing concerns that children with rheumatologic disorders may be at increased risk of developing premature atherosclerosis, traditional and sociodemographic features may play a greater role in the ultimate development of cardiovascular disease.

Traditional Chinese medicine Shenqi compound to improve lower extremity atherosclerosis of patients with type 2 diabetes by affecting blood glucose fluctuation: Study protocol for a randomized controlled multicenter trial.

BACKGROUND: Clinical and basic research supports that blood glucose fluctuation is an important predictor of diabetic vascular disease and an etiology of lower extremity atherosclerosis, which is an important pathological basis for lower extremity vascular diseases. Previous Chinese National Natural Science Foundation trials (No. 81503566) have reported that the traditional Chinese medicine Shenqi compound can reduce blood glucose fluctuation and low-grade inflammation, and protect blood vessels; however, there are no high-quality clinical evidences available to support the same. This multicenter randomized controlled trial aims to obtain more clinical evidence to confirm the efficacy and safety of Shenqi compound in type 2 diabetes with lower extremity atherosclerosis. METHODS: A multicenter RCT will be implemented in this study for a 32-week study period (8 weeks for intervention and 24 weeks for follow-up). Participants will be recruited from the Teaching Hospital of Chengdu University of TCM, Mianyang Hospital of TCM, and Shuangliu Hospital of TCM. Sixty participants will be randomly divided into a treatment group (basic treatment combined with traditional Chinese medicine Shenqi Compound) or a control group (basic treatment combined with Chinese medicine placebo) with 30 participants in each group. Patients will be selected considering the following inclusion criteria: age between 35 and 65 years, and a positive diagnosis for type 2 diabetes with lower extremity atherosclerosis and TCM syndromes. Primary outcome indicator is an arterial color Doppler ultrasound. Secondary outcome indicators include: blood glucose fluctuation indicators (MBG, SDBG, LAGE), islet ß-cell function evaluation indicators (Homa-IR, Homa-islet, SG, SCP), inflammation indicators (NLR, CRP, IL-6), blood lipids, and HbA1c. Safety index includes vital signs (T, P, R, BP), blood, urine, stool routine, liver and renal function, electrocardiogram, and adverse event records. The endpoint event is defined as the presence of gangrene in the lower limbs. DISCUSSION: Explore the clinical effect of traditional Chinese medicine "Shenqi Compound" to reduce blood glucose fluctuation and use HOMA-IR, the area under the glucose curve, and the area under the C-peptide curve to evaluate the effect of protecting islet ß cell function. TRIAL REGISTRATION: Chinese clinical trial registry (ChiCTR-1900027693). Registered on November 23, 2019. http://www.chictr.org.cn.

Vitamin D and Endothelial Function.

Vitamin D is known to elicit a vasoprotective effect, while vitamin D deficiency is a risk factor for endothelial dysfunction (ED). ED is characterized by reduced bioavailability of a potent endothelium-dependent vasodilator, nitric oxide (NO), and is an early event in the development of atherosclerosis. In endothelial cells, vitamin D regulates NO synthesis by mediating the activity of the endothelial NO synthase (eNOS). Under pathogenic conditions, the oxidative stress caused by excessive production of reactive oxygen species (ROS) facilitates NO degradation and suppresses NO synthesis, consequently reducing NO bioavailability. Vitamin D, however, counteracts the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which produces ROS, and improves antioxidant capacity by enhancing the activity of antioxidative enzymes such as superoxide dismutase. In addition to ROS, proinflammatory mediators such as TNF-α and IL-6 are risk factors for ED, restraining NO and eNOS bioactivity and upregulating the expression of various atherosclerotic factors through the NF-κB pathway. These proinflammatory activities are inhibited by vitamin D by suppressing NF-κB signaling and production of proinflammatory cytokines. In this review, we discuss the diverse activities of vitamin D in regulating NO bioavailability and endothelial function.

Fish oil reduces subclinical inflammation, insulin resistance, and atherogenic factors in overweight/obese type 2 diabetes mellitus patients: A pre-post pilot study.

OBJECTIVE: Insulin resistance-associated obesity and type 2 diabetes mellitus (T2DM) are commonly accompanied with metabolic lipid abnormalities and are characterized by hypertriglyceridemia and low HDL-c levels (atherogenic index plasma, AIP). The primary molecular mechanism that is known to cause insulin resistance is chronic low-grade inflammation. Considering that omega-3 fatty acid reduces subclinical inflammation, we hypothesized that fish oil could affect insulin resistance and AIP. Therefore, the present study evaluated the effects of fish oil supplementation on the inflammatory, insulin resistance, and atherogenic factors in overweight/obese T2DM patients. RESEARCH DESIGNS AND METHODS: In this study, we recruited 32 overweight and/or obese patients diagnosed with T2DM for over one year and who exhibited hypertriglyceridemia. These patients received fish oil supplementation (4.0 g/day) for eight weeks. Anthropometric and body composition measurements were obtained. In addition, blood samples were collected before and after omega-3 supplementation for the evaluation of lipid profile, glycemia, insulin, and inflammation. RESULTS: As expected, patients showed reduction in the TNFα, IL-1ß, and Il-6 levels after fish oil supplementation and showed improved insulin sensitivity (HOMA-IR) without observed alterations in anthropometric and body composition. These observations were followed by reduction in the levels of triglycerides and non-esterified fatty acids, increase in HDL cholesterol levels, and a significant reduction in triglycerides/HDL-c ratio, and total cholesterol/HDL-c ratio. CONCLUSION: Fish oil supplementation is effective in reducing the levels of proinflammatory cytokines, improving insulin resistance, and reducing atherogenic factors in overweight/obese and T2DM patients independent of weight loss.

Protective Effect of Epigallocatechin Gallate on Endothelial Disorders in Atherosclerosis.

Healthy vascular endothelial cells regulate vascular tone and permeability, prevent vessel wall inflammation, enhance thromboresistance, and contribute to general vascular health. Furthermore, they perform important functions including the production of vasoactive substances such as nitric oxide (NO) and endothelium-derived hyperpolarizing factors, as well as the regulation of smooth muscle cell functions. Conversely, vascular endothelial dysfunction leads to atherosclerosis, thereby enhancing the risk of stroke, myocardial infarction, and other cardiovascular diseases (CVDs). Observational studies and randomized trials showed that green tea intake was inversely related to CVD risk. Furthermore, evidence indicates that epigallocatechin gallate (EGCG) found in green tea might exert a preventive effect against CVDs. EGCG acts as an antioxidant, inducing NO release and reducing endothelin-1 production in endothelial cells. EGCG enhances the bioavailability of normal NO by reducing levels of the endogenous NO inhibitor asymmetric dimethylarginine. Furthermore, it inhibits the enhanced expression of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and attenuates monocyte adhesion. In addition, EGCG prevents enhanced oxidative stress through the Nrf2/HO-1 pathway. These effects indicate that it might prevent the production of reactive oxygen species, inhibit inflammation, and reduce endothelial cell apoptosis during the initial stages of atherosclerosis. The current review summarizes recent research in this area and discusses novel findings regarding the protective effect of EGCG on endothelial dysfunction and CVDs in general.

Estrogenic and anti-inflammatory effects of pseudoprotodioscin in atherosclerosis-prone mice: Insights into endothelial cells and perivascular adipose tissues.

Pseudoprotodioscin (PPD), a phytoestrogen isolated from Dioscorea nipponica Makino, is recognized to possess anti-inflammatory and antiadipogenic capacities. However, little is known about the antiatherosclerotic effects of PPD and the underlying mechanisms. Here, the contribution of estrogen receptors (ERs) and inflammation to PPD-mediated amelioration of endothelial dysfunction has been fully assessed. PPD administration alleviated atherosclerotic lesions by lowering total cholesterol in ovariectomized apoE-/- mice fed a high-cholesterol diet. Molecular docking analysis suggested a selective interaction of PPD with ERα. Upon PPD treatment, ERα and endothelial nitric oxide synthase (eNOS) protein levels were increased, whereas cell adhesion molecule and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were suppressed in human umbilical vein endothelial cells (HUVECs) after injury caused by oxidized low-density lipoprotein (ox-LDL). These effects could be abolished by an ERα antagonist or a NOS inhibitor. Whereas, PPD can ERα-independently suppress TNFα expression in peritoneal macrophages upon LPS induction. Estrogen deficiency induced inflammatory phenotypes in perivascular adipose tissue (PAT), which could be partially attenuated by PPD. The increased release of adiponectin in PAT after PPD treatment is in accordance with previous reported data showing that adiponectin exerts anti-inflammatory effects in multiple cell types. ERα-dependent antiadipogenic effects of PPD were also detected in PAT-derived stromal cells. The present study reveals a novel mechanism through which PPD exerts estrogenic and anti-inflammatory properties in atherosclerosis-prone mice. Thus, PPD is a promising compound which has potential therapeutic effects on atherosclerotic cardiovascular diseases in postmenopausal women.

Effects of betalains on atherogenic risk factors in patients with atherosclerotic cardiovascular disease.

This study evaluated the potential impacts of supplementation with betalain-rich extracts of foods on some atherosclerotic risk factors in coronary artery disease patients. During an acute phase, 48 male patients received about 50 mg betalain/betacyanin, and their blood and urine samples were collected at 3, 8, and 24 hours after supplementations. Also, in a pilot randomized crossover trial, these participants were allocated to two-week interventions (a betacyanin-rich supplement of Opuntia stricta, a betalain-rich supplement of red beetroot and a placebo) with two-week washout periods. Then, their plasma samples were collected at the baseline after a two-week period. The concentrations of betanin in plasma and urine samples were determined using HPLC. Also, homocysteine and glucose levels, lipid profile, and blood pressure were analyzed. Additionally, quality of life and dietary intake were assessed. After these interventions, minimal amounts of betanin were found in plasma and about 0.13-0.93% in urine. Also, both supplements significantly decreased the concentration of homocysteine, glucose, total cholesterol, triglyceride, and LDL. Also, betalain-rich supplements lowered both systolic and diastolic blood pressures. Nevertheless, the clinically meaningful changes were only found in the case of Hcy, LDL, and non-HDL-c concentrations. It seems that food sources of betalains can be considered as functional foods because they improve the lipid profile and levels of homocysteine, glucose, blood pressure, and quality of life to some extent.

Therapeutic effects of garlic in cardiovascular atherosclerotic disease.

Garlic (Allium sativum) is a widely known medicinal plant, potential of which remains to be fully evaluated. Its wide-range beneficial effects appear to be relevant for treatment and prevention of atherosclerosis and related diseases. It is generally believed that garlic-based preparations are able to improve lipid profile in humans, inhibit cholesterol biosynthesis, suppress low density lipoprotein oxidation, modulate blood pressure, suppress platelet aggregation, lower plasma fibrinogen level and increase fibrinolytic activity, thus providing clinically relevant cardioprotective and anti-atherosclerotic effects. It is important to assess the level of evidence available for different protective effects of garlic and to understand the underlying mechanisms. This information will allow adequate integration of garlic-based preparations to clinical practice. In this review, we discuss the mechanisms of anti-atherosclerotic effects of garlic preparations, focusing on antihyperlipidemic, hypotensive, anti-platelet and direct anti-atherosclerotic activities of the medicinal plant. We also provide an overview of available meta-analyses and a number of clinical trials that assess the beneficial effects of garlic.

Mechanistic insights into the effect of lutein on atherosclerosis, vascular dysfunction, and related risk factors: A systematic review of in vivo, ex vivo and in vitro studies.

Lutein is an essential carotenoid commonly consumed in the diet; however, its dietary intake does not usually reach the minimum recommended intake to decrease the incidence of chronic diseases. Experimental and epidemiological evidence suggests an anti-atherosclerotic effect for lutein-rich foods or lutein supplementation. This systematic review aimed to assess the mechanistic pathways of lutein in the prevention of atherosclerosis. Electronic databases, including PubMed, SCOPUS, ProQuest, Embase, and Google Scholar were searched to May 2019. Original studies published in English-language journals that investigated the effects of lutein on atherosclerosis and related risk factors, including lipid profile, hemodynamic, glycemic and inflammatory measurements, and endothelial function indices, were considered. Two reviewers independently extracted data on study characteristics, methods and outcomes. The review protocol has been registered at PROSPERO database of Systematic Reviews (registration number: CRD42019121381). A total of 5818 articles were found in the first phase of the search; from these, 19 met the inclusion criteria: 3 in vitro, 1 ex vivo, 11 animal, and 4 human studies. Nine of ten studies showed positive effects of lutein on endothelial function by reducing blood pressure, arterial thickness, monocyte migration, and vascular smooth muscle cell migration. Twelve studies examined the anti-inflammatory properties of lutein and found a significant decrease in proinflammatory cytokines. Although few studies investigated the anti-hyperlipidemic effects of lutein, three animal studies and one clinical trial found a beneficial effect of lutein on lipid profile. Evidence supports positive effects of lutein on atherosclerosis development and some common risk factors of atherosclerosis, including inflammation and endothelial dysfunction. Further studies focused on the effects of lutein on hyperglycemia, lipid profile, blood pressure and coagulation are required.