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1.
B‐type natriuretic peptide (BNP) is a naturally secreted regulatory hormone that influences blood pressure and vascular water retention in human physiology. The plasma BNP concentration is a clinically recognized biomarker for various cardiovascular diseases. Quantitative detection of BNP can be achieved in immunoassays using the high‐affinity monoclonal IgG1 antibody 106.3, which binds an epitope spanning residues 5‐13 of the mature bioactive peptide. To understand the structural basis of this molecular recognition, we crystallized the Fab fragment complexed with the peptide epitope and determined the three‐dimensional structure by X‐ray diffraction to 2.1 Å resolution. The structure reveals the detailed interactions that five of the complementarity‐determining regions make with the partially folded peptide. Thermodynamic measurements using fluorescence spectroscopy suggest that the interaction is enthalpy driven, with an overall change in free energy of binding, ΔG = ?54 kJ/mol, at room temperature. The parameters are interpreted on the basis of the structural information. The kinetics of binding suggest a diffusion‐limited mechanism, whereby the peptide easily adopts a bound conformation upon interaction with the antibody. Moreover, comparative analysis with alanine‐scanning results of the epitope explains the basis of selectivity for BNP over other related natriuretic peptides. Proteins 2009. © 2009 Wiley‐Liss, Inc.  相似文献   

2.
Juan Valcárcel 《EMBO reports》2015,16(12):1640-1655
Removal of introns from pre‐mRNA precursors (pre‐mRNA splicing) is a necessary step for the expression of most genes in multicellular organisms, and alternative patterns of intron removal diversify and regulate the output of genomic information. Mutation or natural variation in pre‐mRNA sequences, as well as in spliceosomal components and regulatory factors, has been implicated in the etiology and progression of numerous pathologies. These range from monogenic to multifactorial genetic diseases, including metabolic syndromes, muscular dystrophies, neurodegenerative and cardiovascular diseases, and cancer. Understanding the molecular mechanisms associated with splicing‐related pathologies can provide key insights into the normal function and physiological context of the complex splicing machinery and establish sound basis for novel therapeutic approaches.  相似文献   

3.
Thrombospondin‐1 (TSP‐1), a matricellular protein and one of the first endogenous anti‐angiogenic molecules identified, has long been considered a potent modulator of human diseases. While the therapeutic effect of TSP‐1 to suppress cancer was investigated in both research and clinical settings, the mechanisms of how TSP‐1 is regulated in cancer remain elusive, and the scientific answers to the question of whether TSP‐1 expressions can be utilized as diagnostic or prognostic marker for patients with cancer are largely inconsistent. Moreover, TSP‐1 plays crucial functions in angiogenesis, inflammation and tissue remodelling, which are essential biological processes in the progression of many cardiovascular diseases, and therefore, its dysregulated expressions in such conditions may have therapeutic significance. Herein, we critically analysed the literature pertaining to TSP‐1 expression in circulating blood and pathological tissues in various types of cancer as well as cardiovascular and inflammation‐related diseases in humans. We compare the secretion rates of TSP‐1 by different cancer and non‐cancer cells and discuss the potential connection between the expression changes of TSP‐1 and vascular endothelial growth factor (VEGF) observed in patients with cancer. Moreover, the pattern and emerging significance of TSP‐1 profiles in cardiovascular disease, such as peripheral arterial disease, diabetes and other related non‐cancer disorders, are highlighted. The analysis of published TSP‐1 data presented in this review may have implications for the future exploration of novel TSP‐1‐based treatment strategies for cancer and cardiovascular‐related diseases.  相似文献   

4.
The aim of this paper was to analyse the regional variations and trends in mortality from cardiovascular diseases in the population aged 0-64 years in Dalmatia and Slavonia, over the period 1998 to 2009. Mortality data were derived from Central Bureau of Statistics. The results show that age-standardized mortality rates from total cardiovascular diseases, ischaemic heart diseases and cerebrovascular diseases were lower in Dalmatia than rates for Slavonia, for both genders. All mortality rates, except rates for ischaemic heart diseases mortality for men in both regions, showed the trend of decline. Dalmatia has a more protective factors in pattern of Mediterranean diet. The improvement of cardiovascular health and reduction of premature mortality from cardiovascular diseases requires a system and comprehensive intervention approach at all levels of health care and multisectorial coordination.  相似文献   

5.
PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor and has been suggested recently to be involved in the regulation of cardiovascular diseases. The molecular mechanisms of this regulation are however poorly understood. This study shows that down regulation of PTEN expression and activity by angiotensin II (Ang II) increased proliferation and migration of vascular smooth muscle cells (VSMCs). The presence of Ang II induced rapid PTEN phosphorylation and oxidation in accordance with increased AKT and FAK phosphorylation. The Ang II‐mediated VSMC proliferation and migration was inhibited when cellular PTEN expression was increased by AT1 inhibitor losartan, PPARγ agonist rosiglitazone, NF‐κB inhibitor BAY 11‐7082. Over expression of PTEN in VSMCs by adenovirus transduction also resulted in inhibition of cell proliferation and migration in response to Ang II. These results suggest that PTEN down‐regulation is involved in proliferation and migration of VSMCs induced by Ang II. This provides insight into the molecular regulation of PTEN in vascular smooth muscle cells and suggests that targeting the action of PTEN may represent an effective therapeutic approach for the treatment of cardiovascular diseases. J. Cell. Biochem. 114: 174–182, 2012. © 2012 Wiley Periodicals, Inc.  相似文献   

6.
Evolutionary morphologists and physiologists have long recognized the phylogenetic significance of the ectothermic sauropsids. Sauropids have been classically considered to bridge between early tetrapods, ectotherms, and the evolution of endotherms. This transition has been associated with many modifications in cardiovascular form and function, which have changed dramatically during the course of vertebrate evolution. Most cardiovascular studies have focused upon adults, leaving the development of this critical system largely unexplored. In this essay, we attempt a synthesis of sauropsid cardiovascular development based on the limited literature and indicate fertile regions for future studies. Early morphological cardiovascular development, i.e., the basic formation of the tube heart and the major pulmonary and systemic vessels, is similar across tetrapods. Subsequent cardiac chamber development, however, varies considerably between developing chelonians, squamates, crocodilians, and birds, reflected in the diversity of adult ventricular structure across these taxa. The details of how these differences in morphology develop, including the molecular regulation of cardiac and vascular growth and differentiation, are still poorly understood. In terms of the functional maturation of the cardiovascular system, reflected in physiological mechanisms for regulating heart rate and cardiac output, recent work has illustrated that changes during ontogeny in parameters such as heart rate and arterial blood pressure are somewhat species‐dependent. However, there are commonalities, such as a β‐adrenergic receptor tone on the embryonic heart appearing prior to 60% of development. Differential gross morphological responses to environmental stressors (oxygen, hydration, temperature) have been investigated interspecifically, revealing that cardiac development is relatively plastic, especially, with respect to change in heart growth. Collectively, the data assembled here reflects the current limited morphological and physiological understanding of cardiovascular development in sauropsids and identifies key areas for future studies of this diverse vertebrate lineage. J. Morphol., 2009. © 2009 Wiley‐Liss, Inc.  相似文献   

7.
A major question in the biology of stress and environmental adaptation concerns the neurobiological basis of how neuroendocrine systems governing physiological regulatory mechanisms essential for life (metabolism, immune response, organ function) become harmful. The current view is that a switch from protection to damage occurs when vulnerable phenotypes are exposed to adverse environmental conditions. In accordance with this theory, sequelae of early life social and environmental stressors, such as childhood abuse, neglect, poverty, and poor nutrition, have been associated with the emergence of mental and physical illness (i.e., anxiety, mood disorders, poor impulse control, psychosis, and drug abuse) and an increased risk of common metabolic and cardiovascular diseases later in life. Evidence from animal and human studies investigating the associations between early life experiences (including parent‐infant bonding), hypothalamus‐pituitary‐adrenal axis activity, brain development, and health outcome provide important clues into the neurobiological mechanisms that mediate the contribution of stressful experiences to personality development and the manifestation of illness. This review summarizes our current molecular understanding of how early environment influences brain development in a manner that persists through life and highlights recent evidence from rodent studies suggesting that maternal care in the first week of postnatal life establishes diverse and stable phenotypes in the offspring through epigenetic modification of genes expressed in the brain that shape neuroendocrine and behavioral stress responsivity throughout life. Birth Defects Research (Part C) 87:314–326, 2009. © 2009 Wiley‐Liss, Inc.  相似文献   

8.
Transforming growth factor β1 (TGFβ1) is a multifunctional growth factor involved in wound healing, tissue fibrosis, and in the pathogenesis of many syndromic diseases (e.g., Marfan syndrome, Camurati‐Engelmann disease) and muscular, neurological, ophthalmic, cardiovascular and immunological disorders, and cancer. Since the generation of Tgfb1 knockout mice, there has been extraordinary progress in understanding its physiological and pathophysiological function. Here, we report the generation of a conditional knockout allele for Tgfb1 in which its exon 6 is flanked with LoxP sites. As proof of principle, we crossed these mice to LckCre transgenic mice and specifically disrupted Tgfb1 in T cells. The results indicate that T‐cell‐produced TGFβ1 is required for normal in vivo regulation of peripheral T‐cell activation, maintenance of T‐cell homeostasis, and suppression of autoimmunity. genesis 47:423–431, 2009. © 2009 Wiley‐Liss, Inc.  相似文献   

9.
While NLRP3‐inflammasome has been implicated in cardiovascular diseases, its role in physiological cardiac aging is largely unknown. During aging, many alterations occur in the organism, which are associated with progressive impairment of metabolic pathways related to insulin resistance, autophagy dysfunction, and inflammation. Here, we investigated the molecular mechanisms through which NLRP3 inhibition may attenuate cardiac aging. Ablation of NLRP3‐inflammasome protected mice from age‐related increased insulin sensitivity, reduced IGF‐1 and leptin/adiponectin ratio levels, and reduced cardiac damage with protection of the prolongation of the age‐dependent PR interval, which is associated with atrial fibrillation by cardiovascular aging and reduced telomere shortening. Furthermore, old NLRP3 KO mice showed an inhibition of the PI3K/AKT/mTOR pathway and autophagy improvement, compared with old wild mice and preserved Nampt‐mediated NAD+ levels with increased SIRT1 protein expression. These findings suggest that suppression of NLRP3 prevented many age‐associated changes in the heart, preserved cardiac function of aged mice and increased lifespan.  相似文献   

10.
Embryonic stem cells (ESCs) are endowed with the ability to generate multiple cell lineages and carry great therapeutic potentials in regenerative medicine. Future application of ESCs in human health and diseases will embark on the delineation of molecular mechanisms that define the biology of ESCs. Here, we discuss how the finite ESC components mediate the intriguing task of brain development and exhibit biomedical potentials to cure diverse neurological disorders. Birth Defects Research (Part C) 87:182–191, 2009. © 2009 Wiley‐Liss, Inc.  相似文献   

11.
Using endothelial cells for therapeutic angiogenesis/vasculogenesis of ischemia diseases has led to exploring human embryonic stem cells (hESCs) as a potentially unlimited source for endothelial progenitor cells. With their capacity for self‐renewal and pluripotency, hESCs and their derived endothelial cells (hESC‐ECs) may be more advantageous than other endothelial cells obtained from diseased populations. However, hESC‐ECs' poor differentiation efficiency and poorly characterized in vivo function after transplantation present significant challenges for their future clinical application. This review will focus on the differentiation pathways of hESCs and their therapeutic potential for vascular diseases, as well as the monitoring of transplanted cells' fate via molecular imaging. Finally, cell enhancement strategies to improve the engraftment efficiency of hESC‐ECs will be discussed. J. Cell. Biochem. 106: 194–199, 2009. © 2008 Wiley‐Liss, Inc.  相似文献   

12.
There are many different types of cardiovascular diseases, which impose a huge economic burden due to their extremely high mortality rates, so it is necessary to explore the underlying mechanisms to achieve better supportive and curative care outcomes. Sphingosine 1‐phosphate (S1P) is a bioactive lipid mediator with paracrine and autocrine activities that acts through its cell surface S1P receptors (S1PRs) and intracellular signals. In the circulatory system, S1P is indispensable for both normal and disease conditions; however, there are very different views on its diverse roles, and its specific relevance to cardiovascular pathogenesis remains elusive. Here, we review the synthesis, release and functions of S1P, specifically detail the roles of S1P and S1PRs in some common cardiovascular diseases, and then address several controversial points, finally, we focus on the development of S1P‐based therapeutic approaches in cardiovascular diseases, such as the selective S1PR1 modulator amiselimod (MT‐1303) and the non‐selective S1PR1 and S1PR3 agonist fingolimod, which may provide valuable insights into potential therapeutic strategies for cardiovascular diseases.  相似文献   

13.
The increasing incidence of metabolic and cardiovascular diseases has severely affected global human health and life safety. In recent years, some effective drugs with remarkable curative effects and few side effects found in natural compounds have attracted attention. Salidroside (SAL), a phenylpropane glycoside, is the main active ingredient of the plateau plant Rhodiola. So far, many animal experiments proved that SAL has good biological activity against some metabolic and cardiovascular diseases. However, most of these reports are scattered. This review systematically summarizes the pharmacological progress of SAL in the treatment of several metabolic (e. g., diabetes and non-alcoholic fatty liver disease) and cardiovascular (e. g., atherosclerosis) diseases in a timely manner to promote the clinical application and basic research of SAL. Accumulating evidence proves that SAL has beneficial effects on these diseases. It can improve glucose tolerance, insulin sensitivity, and β-cell and liver functions, and inhibit adipogenesis, inflammation and oxidative stress. Overall, SAL may be a valuable and potential drug candidate for the treatment of metabolic and cardiovascular diseases. However, more studies especially clinical trials are needed to further confirm its therapeutic effects and molecular mechanisms.  相似文献   

14.
近年来,越来越多的研究表明肠道菌群在心血管疾病、2型糖尿病、肥胖等疾病的发病过程中起着主要作用,肠道菌群组成改变以及肠道菌群代谢物水平改变是导致疾病发生发展的重要因素,人们对肠道菌群与宿主之间的相互作用产生极大兴趣。本文系统总结了肠道菌群组成结构改变及肠道菌群代谢物改变与动脉粥样硬化、高血压、心肌梗死、心力衰竭等心血管疾病的相关性,阐明了肠道菌群可能是促进心血管疾病发病的原因之一。因此,通过改变饮食结构和使用抗生素、益生菌制剂及肠道菌群代谢物氧化三甲胺(TMAO)小分子抑制剂,来调控肠道菌群组成及代谢物水平有望作为心血管疾病治疗的新靶点。  相似文献   

15.
Maternal thromboembolism and a spectrum of placenta‐mediated complications including the pre‐eclampsia syndromes, fetal growth restriction, fetal loss, and abruption manifest a shared etiopathogenesis and predisposing risk factors. Furthermore, these maternal and fetal complications are often linked to subsequent maternal health consequences that comprise the metabolic syndrome, namely, thromboembolism, chronic hypertension, and type II diabetes. Traditionally, several lines of evidence have linked vasoconstriction, excessive thrombosis and inflammation, and impaired trophoblast invasion at the uteroplacental interface as hallmark features of the placental complications. “Omic” technologies and biomarker development have been largely based upon advances in vascular biology, improved understanding of the molecular basis and biochemical pathways responsible for the clinically relevant diseases, and increasingly robust large cohort and/or registry based studies. Advances in understanding of innate and adaptive immunity appear to play an important role in several pregnancy complications. Strategies aimed at improving prediction of these pregnancy complications are often incorporating hemodynamic blood flow data using non‐invasive imaging technologies of the utero‐placental and maternal circulations early in pregnancy. Some evidence suggests that a multiple marker approach will yield the best performing prediction tools, which may then in turn offer the possibility of early intervention to prevent or ameliorate these pregnancy complications. Prediction of maternal cardiovascular and non‐cardiovascular consequences following pregnancy represents an important area of future research, which may have significant public health consequences not only for cardiovascular disease, but also for a variety of other disorders, such as autoimmune and neurodegenerative diseases. Birth Defects Research (Part C) 105:209–225, 2015. © 2015 Wiley Periodicals, Inc.  相似文献   

16.
Dramatic changes in the life expectancy of cystic fibrosis (CF) patients are occurring, creating a cohort of aging individuals experiencing long‐term complications of this chronic disease. The two most common of these complications include CF‐related diabetes and CF bone disease. The clinical implications of each have become better understood, as have potential therapies. However, data obtained from the basic science studies of both diseases have not been widely recognized. In this review, we focus on the known and hypothesized pathogenesis of these two disorders. Additionally, the molecular underpinnings of CF will be explained along with the potential interactions with endocrine disease phenotypes. J. Cell. Biochem. 108: 353–361, 2009. © 2009 Wiley‐Liss, Inc.  相似文献   

17.
Gender differences are present in many diseases and are especially prevalent in cardiovascular disease. Males tend to suffer from myocardial infarctions earlier than females, and a woman's risk of cardiovascular disease increases after menopause, suggesting a cardio‐protective role of estrogen. However, hormone replacement therapy did not decrease the risk of cardiovascular disease in post‐menopausal women; thus, other mechanisms may be involved besides estrogen. Oxidative stress plays an important role in the development of cardiovascular diseases such as coronary artery disease. Gender is also associated with differences in oxidative stress. Under physiological conditions, females appear to be less susceptible to oxidative stress. This may be due to the antioxidant properties of estrogen, gender differences in NADPH‐oxidase activity or other mechanism(s) yet to be defined. This review strives to discuss gender differences in general terms followed by a more detailed examination of gender differences with oxidative stress and various associated diseases and the possible mechanisms underlying these differences.  相似文献   

18.
Over the past three decades, the increasing rates of obesity have led to an alarming obesity epidemic worldwide. Obesity is associated with an increased risk of cardiovascular diseases; thus, it is essential to define the molecular mechanisms by which obesity affects heart function. Individuals with obesity and overweight have shown changes in cardiac structure and function, leading to cardiomyopathy, hypertrophy, atrial fibrillation, and arrhythmia. Autophagy is a highly conserved recycling mechanism that delivers proteins and damaged organelles to lysosomes for degradation. In the hearts of patients and mouse models with obesity, this process is impaired. Furthermore, it has been shown that autophagy flux restoration in obesity models improves cardiac function. Therefore, autophagy may play an important role in mitigating the adverse effects of obesity on the heart. Throughout this review, we will discuss the benefits of autophagy on the heart in obesity and how regulating autophagy might be a therapeutic tool to reduce the risk of obesity‐associated cardiovascular diseases.  相似文献   

19.
Cardiac hypertrophy is an important risk factor for heart failure. Epidermal growth factor receptor (EGFR) has been found to play a role in the pathogenesis of various cardiovascular diseases. The aim of this current study was to examine the role of EGFR in angiotensin II (Ang II)‐induced cardiac hypertrophy and identify the underlying molecular mechanisms. In this study, we observed that both Ang II and EGF could increase the phospohorylation of EGFR and protein kinase B (AKT)/extracellular signal‐regulated kinase (ERK), and then induce cell hypertrophy in H9c2 cells. Both pharmacological inhibitors and genetic silencing significantly reduced Ang II‐induced EGFR signalling pathway activation, hypertrophic marker overexpression, and cell hypertrophy. In addition, our results showed that Ang II‐induced EGFR activation is mediated by c‐Src phosphorylation. In vivo, Ang II treatment significantly led to cardiac remodelling including cardiac hypertrophy, disorganization and fibrosis, accompanied by the activation of EGFR signalling pathway in the heart tissues, while all these molecular and pathological alterations were attenuated by the oral administration with EGFR inhibitors. In conclusion, the c‐Src‐dependent EGFR activation may play an important role in Ang II‐induced cardiac hypertrophy, and inhibition of EGFR by specific molecules may be an effective strategy for the treatment of Ang II‐associated cardiac diseases.  相似文献   

20.
3‐Hydroxy 3‐methylglutaryl coenzyme A reductase (HMG‐CoAR) is the key and rate‐limiting enzyme of cholesterol biosynthetic pathway. Although HMG‐CoAR activity has already been related to the differentiation of some cellular lines there are no studies that analyze the role of HMG‐CoAR, and the pathway it is involved with in a fully characterized muscle differentiation model. Thus, the aim of this work is to evaluate such role and delineate the pathway involved in foetal rat myoblasts (L6) induced to differentiate by insulin—a standard and feasible model of the myogenic process. The results obtained by biochemical and morphological approaches demonstrate that (i) HMG‐CoAR increase is crucial for differentiation induction, (ii) p21waf, whose increase is a necessary requisite for differentiation to occur, rises downstream HMG‐CoAR activation, (iii) the main role of p38/MAPK as key regulator also for HMG‐CoAR. Pathologies characterized by muscle degeneration might benefit from therapeutic programmes committed to muscle function restoration, such as modulation and planning myoblast differentiation. Thus, the important role of HMG‐CoAR in muscular differentiation providing new molecular basis for the control of muscle development can help in the design of therapeutic treatment for diseases characterized by the weakening of muscular fibers and aging‐related disorders (sarcopenia). J. Cell. Physiol. 220: 524–530, 2009. © 2009 Wiley‐Liss, Inc.  相似文献   

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