LncRNA与心血管疾病的研究进展

研究发现,人基因组中具有编码蛋白质功能的转录产物仅占约2%,其余大部分均为非编码RNAs。长链非编码RNA(Long noncoding RNA,LncRNA)是一类长度大于200个核苷酸的非编码RNA。研究表明LncRNA在心血管疾病中存在差异表达,并且通过不同的作用机制在心血管疾病的调控网络中发挥作用,参与心血管疾病的发生发展。本综述对近年来LncRNA与心血管疾病的研究进展进行总结,并将对其作为心血管疾病新型分子标记物及治疗靶点的可行性进行探讨。     

Mitochondria-directed therapeutics

Mitochondria are key regulators of cell life and death and play an important role in a wide range of diseases, including cancer, diabetes, cardiovascular disease, and the age-related neurodegenerative diseases. The unique structural and functional characteristics of mitochondria enable the selective targeting of drugs designed to modulate the function of this organelle for therapeutic gain. This forum discusses (a) potential new mitochondrial targets for therapeutic intervention, including components of the electron transport chain, the permeability transition, and the membrane dynamics protein mitofusin-2; (b) the role of mitochondria-targeted antioxidants including MitoQ and SS peptides in modulating reactive oxygen and chlorine species induced mitochondrial permeabilization and cell death; and (c) the potential use of SS peptides in ischemia and reperfusion tissue injury. In the future, mitochondrial drug-targeting strategies will be expected to open up avenues for manipulating mitochondrial functions and allow for selective protection or eradication of cells for therapeutic gain in a variety of diseases.     

NADPH oxidases in cardiovascular health and disease

Increased oxidative stress plays an important role in the pathophysiology of cardiovascular diseases such as hypertension, atherosclerosis, diabetes, cardiac hypertrophy, heart failure, and ischemia-reperfusion. Although several sources of reactive oxygen species (ROS) may be involved, a family of NADPH oxidases appears to be especially important for redox signaling and may be amenable to specific therapeutic targeting. These include the prototypic Nox2 isoform-based NADPH oxidase, which was first characterized in neutrophils, as well as other NADPH oxidases such as Nox1 and Nox4. These Nox isoforms are expressed in a cell- and tissue-specific fashion, are subject to independent activation and regulation, and may subserve distinct functions. This article reviews the potential roles of NADPH oxidases in both cardiovascular physiological processes (such as the regulation of vascular tone and oxygen sensing) and pathophysiological processes such as endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, angiogenesis, and vascular and cardiac remodeling. The complexity of regulation of NADPH oxidases in these conditions may provide the possibility of targeted therapeutic manipulation in a cell-, tissue- and/or pathway-specific manner at appropriate points in the disease process.     

Clinical aspects of obesity in the gynecological endocrinologicaly practice

Obesity is epidemic of 21st century, its visceral form is associated with increased risk for type 2 diabetes, cardiovascular disease, hypertension and increased mortality due to consequences of the disease. This type of obesity is a common diagnostic and therapeutic problem in gynecological practice. This especially concerns polycystic ovary disease, in which this type of obesity with its metabolic consequences is one of the important factors in etiology and additionally may lead to remote metabolic and cardiovascular problems. Another group of women in which this type of obesity plays an important role are climacteric women in whom redistribution of adipose tissue with increase in visceral fat deposit occurs. On the basis of current viewpoints and own experiences, the authors propose a diagnostic-therapeutic algorithm in women with visceral obesity and polycystic ovary disease or climacteric period. In case with cardiovascular risk factors (waist circumference over than 80cm, serum triglycerides over 1.7mmol/l, HDL cholesterol lower than 1.0mmol/l, blood pressure over 130/85mmHg and fast serum glucose levels over 100mg/dl) the therapeutic model focuses on the recognize risk factors. It must be considered that diet and physical activity play a very important role in the therapy.     

Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease

Chronic inflammation is being shown to be increasingly involved in the onset and development of several pathological disturbances such as arteriosclerosis, obesity, diabetes, neurodegenerative diseases and even cancer. Treatment for chronic inflammatory disorders has not been solved, and there is an urgent need to find new and safe anti-inflammatory compounds. Flavonoids belong to a group of natural substances occurring normally in the diet that exhibit a variety of beneficial effects on health. The anti-inflammatory properties of flavonoids have been studied recently, in order to establish and characterize their potential utility as therapeutic agents in the treatment of inflammatory diseases. Several mechanisms of action have been proposed to explain in vivo flavonoid anti-inflammatory actions, such as antioxidant activity, inhibition of eicosanoid generating enzymes or the modulation of the production of proinflammatory molecules. Recent studies have also shown that some flavonoids are modulators of proinflammatory gene expression, thus leading to the attenuation of the inflammatory response. However, much work remains to be done in order to achieve definitive conclusions about their potential usefulness. This review summarizes the known mechanisms involved in the anti-inflammatory activity of flavonoids and the implications of these effects on the protection against cancer and cardiovascular disease.     

Periodontal disease and type 2 diabetes mellitus: Is the HMGB1–RAGE axis the missing link?

Periodontitis is a major chronic inflammatory disease associated with increased production of numerous proinflammatory cytokines, which leads to the destruction of the periodontal tissue and ultimately loss of teeth. Periodontitis has powerful and multiple influences on the occurrence and severity of systemic conditions and diseases, such as diabetes mellitus, cardiovascular disease and respiratory disease. Meanwhile, diabetes is associated with increased prevalence, severity and progression of periodontal disease. There is also abundant evidence showing that diabetes plays important etiological roles in periodontitis. High mobility group box 1 (HMGB1) was recently identified as a lethal mediator of severe sepsis and comprises a group of intracellular proteins that function as inflammatory cytokines when released into the extracellular milieu. From a clinical perspective, extracellular HMGB1 can cause multiple organ failure and contribute to the pathogenesis of sepsis, rheumatoid arthritis, cardiovascular disease and diabetes. We recently reported that HMGB1 expression in periodontal tissues was elevated in patients with severe periodontitis. In addition, the receptor for advanced glycation end-products (RAGE), a receptor for HMGB1, was strongly expressed in gingival tissues obtained from patients with type 2 diabetes and periodontitis compared with systemically healthy patients with chronic periodontitis patients. From these data, we hypothesize that HMGB1 might play a role in the development of diabetes-associated periodontitis.     

Heme oxygenase-1 in tumors: is it a false friend?

Heme oxygenase-1 (HO-1) catalyzes the oxidation of heme to biologically active products: carbon monoxide (CO), biliverdin, and ferrous iron. It participates in maintaining cellular homeostasis and plays an important protective role in the tissues by reducing oxidative injury, attenuating the inflammatory response, inhibiting cell apoptosis, and regulating cell proliferation. HO-1 is also an important proangiogenic mediator. Most studies have focused on the role of HO-1 in cardiovascular diseases, in which its significant, beneficial activity is well recognized. A growing body of evidence indicates, however, that HO-1 activation may play a role in carcinogenesis and can potently influence the growth and metastasis of tumors. HO-1 is very often upregulated in tumor tissues, and its expression is further increased in response to therapies. Although the exact effect can be tissue specific, HO-1 can be regarded as an enzyme facilitating tumor progression. Accordingly, inhibition of HO-1 can be suggested as a potential therapeutic approach sensitizing tumors to radiation, chemotherapy, or photodynamic therapy.     

An introduction of the role of probiotics in human infections and autoimmune diseases

Abstract

During the last decades, studies exploring the role of microorganisms inhabiting human body in different scenarios have demonstrated the great potential of modulating them to treat and prevent diseases. Among the most outstanding applications, probiotics have been used for over a century to treat infections and inflammation. Despite the beneficial role of other probiotics, Lactobacillus and Bifidobacterium species are the most frequently used, and have been effective as a therapeutic option in the treatment/prevention of dental caries, periodontal diseases, urogenital infections, and gastrointestinal infections. Additionally, as gastrointestinal tract harbors a great diversity of microbial species that directly or indirectly modulate host metabolism and immune response, the influence of intestinal microbiota, one of the targets of therapies using probiotics, on the biology of immune cells can be explored to treat inflammatory disorders or immune-mediated diseases. Thus, it is not surprising that probiotics have presented promising results in modulating human inflammatory diseases such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease, among others. Hence, the purpose of this review is to discuss the potential of therapeutic approaches using probiotics to constrain infection and development of inflammation on human subjects.     

Should visceral fat be reduced to increase longevity?

Several epidemiologic studies have implicated visceral fat as a major risk factor for insulin resistance, type 2 diabetes mellitus, cardiovascular disease, stroke, metabolic syndrome and death. Utilizing novel models of visceral obesity, numerous studies have demonstrated that the relationship between visceral fat and longevity is causal while the accrual of subcutaneous fat does not appear to play an important role in the etiology of disease risk. Specific recommended intake levels vary based on a number of factors, including current weight, activity levels, and weight loss goals. It is discussed the need of reducing the visceral fat as a potential treatment strategy to prevent or delay age-related diseases and to increase longevity.     

The 'novel' 'uncoupling' proteins UCP2 and UCP3: what do they really do? Pros and cons for suggested functions

The scientifically novel, but evolutionarily ancient, so-called uncoupling proteins 2 and 3 (UCP2, UCP3) are structurally similar to the archetypical uncoupling protein UCP1. A series of suggestions have been forwarded for their physiological function. We discuss systematically here the pros and cons for these suggestions. We conclude that the novel UCPs do not seem to be physiologically relevant uncoupling proteins; the uncoupling property was apparently a late introduction into the subfamily through the evolution of UCP1. Physiological functions ascribed to UCP2 and UCP3 based on their purported uncoupling property may have to be revised (i.e. any type of thermogenesis, including protection against obesity, protection against the formation of reactive oxygen species and thermogenic involvement in the fever response). The presence of a mixed genetic background in most published studies of UCP2 or UCP3 gene-ablated mice also means that data concerning marked differences in diabetes propensity, infection sensitivity and production of reactive oxygen species may require confirmation in backcrossed mice. The increased expression of UCP2 and UCP3 under conditions of increased fatty acid metabolism implies an as yet undefined role in lipid metabolism. Thus, the novel UCPs should probably be considered as mitochondrial carriers, and the challenge now is to identify the transported molecule.     

Melatonin and the metabolic syndrome: a tool for effective therapy in obesity‐associated abnormalities?

The metabolic syndrome (MetS) is a cluster of metabolic abnormalities associated with increased risk for cardiovascular diseases. Apart from its powerful antioxidant properties, the pineal gland hormone melatonin has recently attracted the interest of various investigators as a multifunctional molecule. Melatonin has been shown to have beneficial effects in cardiovascular disorders including ischaemic heart disease and hypertension. However, its role in cardiovascular risk factors including obesity and other related metabolic abnormalities is not yet established, particularly in humans. New emerging data show that melatonin may play an important role in body weight regulation and energy metabolism. This review will address the role of melatonin in the MetS focusing on its effects in obesity, insulin resistance and leptin resistance. The overall findings suggest that melatonin should be exploited as a therapeutic tool to prevent or reverse the harmful effects of obesity and its related metabolic disorders.     

The use of ACE inhibitor in cardiovascular disease

Competitive inhibition of Angiotensin Converting Enzyme has an important role in cardiovascular diseases, which has been demonstrated by various extensive studies. Based on pharmacologic and mechanism of action, the pharmacodynamic of ACE-inhibitor involves some specific system, such as hemodynamic, neurohormonal, anti- proliferation and renal effect, etc. ACE-inhibitor has beneficial effect in various cardiovascular diseases such as heart failure, hypertension, systolic and dyastolic left ventricle dysfunction and acute myocardial infarction. This article will discuss advantages of its therapeutic use, the adverse effects that might occur as well as how to overcome this effect and also when it should be stopped. Extensive studies also demonstrate that therapeutic use of ACE-inhibitor will improve the quality of life and survival rate in conjunction with the decrease of morbidity and mortality.     

Insights into the redox control of blood coagulation: role of vascular NADPH oxidase-derived reactive oxygen species in the thrombogenic cycle

Various cardiovascular diseases including thrombosis, atherosclerosis, (pulmonary) hypertension and diabetes, are associated with disturbed coagulation. Alterations in the vessel wall common to many cardiovascular disorders have been shown to initiate the activity of the coagulation system, but also to be the result of an abnormal coagulation system. The primary link between the coagulation and the vascular system appears to be tissue factor (TF), which is induced on the surface of vascular cells and initiates the extrinsic pathway of the blood coagulation cascade, leading to the formation of thrombin. Thrombin can also interact with the vascular wall via specific receptors and can increase vascular TF expression. Such a "thrombogenic cycle" may be essentially involved in the pathogenesis of cardiovascular disorders associated with an abnormal coagulation. Therefore, the identification of the signaling pathways regulating this cycle and each of its relevant connecting links is of fundamental importance for the understanding of these disorders and their putative therapeutic potential. Reactive oxygen species (ROS) and the ROS-generating NADPH oxidases have been shown to play important roles as signaling molecules in the vasculature. In this review, we summarize the data supporting a substantial role of ROS in promoting a thrombogenic cycle in the vascular system.     

Inhibition of postprandial hyperglycemia by acarbose is a promising therapeutic strategy for the treatment of patients with the metabolic syndrome

The metabolic syndrome is strongly associated with insulin resistance and has been recognized as a cluster of risk factors for cardiovascular diseases such as visceral obesity, hypertension, diabetes, and atherogenic dyslipidemia. Recently, insulin resistance in the absence of overt diabetes or the metabolic syndrome itself has been associated with endothelial dysfunction, one of the initial steps in the process of atherosclerosis. Postprandial hyperglycemia, one of the characteristic features of insulin resistance, induces oxidative stress generation and elicits vascular inflammation and platelet activation, thus being involved in the pathogenesis of atherosclerosis. A recent multicenter, placebo-controlled randomized trial, STOP-NIDDM trial, revealed that acarbose (Glucobay R), an alpha-glucosidase inhibitor, improved postprandial hyperglycemia and subsequently reduced the risk of development of type 2 diabetes in patients with impaired glucose tolerance (IGT). In this study, acarbose treatment was also found to slow the progression of intima-media thickness of the carotid arteries, a surrogate marker for atherosclerosis, and to reduce the incidence of cardiovascular diseases and newly diagnosed hypertension in subjects with IGT. Acarbose significantly reduced body mass index and waist circumference in these patients over 3 years. Furthermore, a meta-analysis of seven long-term studies has also shown that intervention with acarbose prevents myocardial infarction and cardiovascular diseases in type 2 diabetic patients. In this analysis, glycemic control, triglyceride levels, body weight and systolic blood pressure was also significantly improved during acarbose treatment. These observations suggest that prevention of postprandial hyperglycemia by acarbose may be a promising therapeutic strategy for reducing the increased risk for diabetes, hypertension, dyslipidemia, obesity, and cardiovascular diseases in patients with the metabolic syndrome. Acarbose improves postprandial hyperglycemia by delaying the release of glucose from complex carbohydrates in the absence of an increase in insulin secretion. Therefore, we would like to hypothesize here that this improvement in glucose metabolism could be associated with amelioration in insulin sensitivity, thus explaining the above-mentioned beneficial cardiometabolic actions of acarbose. Large clinical trials will provide us with more definite information whether acarbose treatment can improve insulin sensitivity and resultantly reduce the risk of diabetes, hypertension and cardiovascular diseases in patients with the metabolic syndrome.     

Functional foods for health: Focus on diabetes

Type 2 diabetes is one of the fastest growing public health problems worldwide. Menopause may present additional challenges for women who have diabetes by increasing the risk for cardiovascular disease (CVD) and making blood glucose control more difficult. Functional foods may have the potential to improve glycemic control, but little evidence is known about the efficacy of these foods. The purpose of this literature review is to establish a recommendation for the intake of functional foods in a healthy diet – such as nuts, omega-3 fatty acids (FAs) and cinnamon – for the glycemic control in type 2 diabetes. Nuts and omega-3 FAs appear to have an overall beneficial effect on CVD; however, their effect on glucose homeostasis is uncertain. In addition, cinnamon appears to inconsistently improve glycemic parameters in diabetic patients. Overall, more research on the potential effect of all of these functional foods on patients with type 2 diabetes is needed to able to make specific recommendations. In conclusion, there is reason to consider the inclusion of nuts and fish, as a source of omega-3 FAs, in the diets of individuals with diabetes in view of their potential to reduce CVD risk, even though their ability to influence overall glycemic control remains to be established.     

Oxidative stress, glucose metabolism, and the prevention of type 2 diabetes: pathophysiological insights

With the rising epidemic of type 2 diabetes worldwide, including the United States, the death and disability due to the suboptimal control of cardiovascular disease associated with this epidemic has made prevention of type 2 diabetes emerge as a primary strategic intervention. Several modalities have been assessed in large randomized controlled trials for diabetes prevention such as lifestyle interventions and various pharmacologic agents. Included in these agents are metformin, thiazolidinediones, acarbose, angiotensin converting enzyme inhibitors, as well as angiotensin receptor blockers. Abrogation of oxidative stress appears to be a common soil hypothesis that explains the favorable effects of these agents on glucose metabolism, including the prevention of diabetes and its complications. This comprehensive review highlights the role of oxidative stress in the pathogenesis of diabetes, with emphasis on the major clinical trials conducted on prevention of type 2 diabetes.     

Update in the management of obesity

Significant increase of obesity prevalence in almost all countries in the world recently has had obesity as a global health problem, and WHO in 1998 defined it as "the global epidemic". Simply, obesity is defined as an excessive fat accumulation in fat tissue due to imbalance of energy intake and expenditure. Body mass index is a simple method for defining the degree of overweight and obesity, however, waist circumference is the preferred measure of abdominal obesity because it has greater relationship with the risk of metabolic and cardiovascular diseases. Body fatness reflects the interactions of development, environment and genetic factors. The role of genetic factors has already existed, nevertheless, environment factors are likely more important in developing obesity. Increased mortality among the obese is evident for several life-threatening diseases including type 2 diabetes, cardiovascular disease, gallbladder disease, and hormone-sensitive and gastrointestinal cancers. Risks are also higher for some non-fatal conditions such as back pain, arthritis, infertility and, in many westernized countries, poor psychosocial functioning. Obesity is not only threatening health, also impacts on high economic and social cost. Effective prevention of obesity should be focused to high risk individuals or groups. Individuals who have some existing weight-related problems and those with a high risk of developing obesity co-morbidity such as cardiovascular disease and type 2 diabetes should be a key priority in this prevention strategy. Although weight loss in obese persons of any age can improve obesity-related medical complications, physical function, and quality of life, the primary purpose for weigh-loss therapy may differ across age group. The current therapeutic tools available for weight management are: (1) lifestyle intervention involving diet, physical activity, and behavior modification; (2) pharmacotherapy; and (3) surgery. Moderate weight loss (5-10% of initial weight) by any programs is a realistic target in management of obesity associated with improvement of risk factors of metabolic and cardiovascular diseases.     

Combinations of common chronic paediatric diseases deviate the immune response in diverging directions

The cytokine pattern of T lymphocytes has not been characterized in children with combinations of paediatric immunological disorders. We describe cytokine secretion in children with type 1 diabetes, coeliac disease and allergy and combinations of two of these diseases after stimulation with 'disease-specific' antigens. Peripheral blood mononuclear cells (PBMC) were collected from 68 children with type 1 diabetes, allergy or coeliac disease, two of these diseases in combination or none of these diseases. Using the enzyme-linked immunospot (ELISPOT) technique, interferon (IFN)-gamma and interleukin (IL)-4 were analysed from fresh PBMC spontaneously and after in vitro stimulation with antigens associated with one or more of these diseases (insulin, gluten, birch and cat extract, beta-lactoglobulin, ovalbumin and phytohaemagglutinin) in order to divide T helper (Th)1- from Th2-like lymphocytes. Stimulation with birch and cat extract caused increased IL-4 secretion in allergic children. A low IFN-gamma response to insulin was found in type 1 diabetic children, whereas allergic children responded to insulin by increased IL-4 secretion. Children suffering from both type 1 diabetes (Th1-prone) and allergy (Th2-prone) reacted distinctly to general mitogen stimulation. Children suffering from two Th1-dominated diseases (type 1 diabetes and coeliac disease) showed hardly any response to either food or inhalation allergens. Our results indicate an important interplay between common immunological diseases in children. The combination of two Th1-deviated diseases is associated with a suppressed immune response, whereas a combination of Th1- and Th2-dominated diseases appears to increase the general immune response.     

Unique atheroprotective property of azelnidipine, a dihydropyridine-based calcium antagonist

Insulin resistance and central obesity are often associated with hypertension. The metabolic syndrome is a cluster of these common clinical disorders, and is related with an increased risk for cardiovascular diseases. A number of pro-inflammatory cytokines derived from adipose tissues have been thought to contribute to the development of insulin resistance and accelerated atherosclerosis. Among them, TNF-alpha has been most widely studied; it not only suppresses the insulin signaling, but also elicits vascular inflammation. Indeed, inhibition of TNF-alpha was found to improve insulin resistance in obese rats and reduce the progression of atherosclerosis in apolipoprotein E knockout mice, respectively. These observations demonstrate that TNF-alpha could play a central role in the pathogenesis of insulin resistance and accelerated atherosclerosis in the metabolic syndrome. Considering that the primary goals of treatment for hypertensive patients with the metabolic syndrome are prevention of the development of diabetes and cardiovascular events, anti-hypertensive drugs that have abilities to block the TNF-alpha signaling would be desirable as a first-line therapy for these patients. In the process of the search for such a unique anti-hypertensive drug, we have recently found that azelnidipine, a newly developed and commercially used long-acting dihydropyridine-based calcium antagonist (DHP), inhibited TNF-alpha-induced activator protein-1 activation and interleukin-8 expression in human umbilical vein endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. The concentration of azelnidipine that was found effective in these in vitro-experiments is well within the therapeutic range. Since endothelial cells do not possess voltage-operated L-type calcium channels, these observations suggest that the beneficial effects of azelnidipine are not likely due to calcium channel blocking property, but due to its unique anti-oxidative ability. Furthermore, we have very recently found that serum levels of monocyte chemoattractant protein-1, a biomarker for subclinical atherosclerosis, were significantly decreased by the treatment of azelnidipine in patients with essential hypertension. In this paper, we would like to hypothesize that due to its unique TNF-alpha signal modulatory, anti-oxidative property, azelnidipine may be a promising DHP that targets diabetes and cardiovascular diseases in hypertensive patients with the metabolic syndrome.