CD160/HVEM/BTLA/LIGHT通路在自身免疫病中的研究进展

共信号分子是免疫细胞表面信号传递分子及其配体，对调控T细胞或B细胞的活化有重要作用。近年来，研究显示多种共信号分子对T细胞的激活与免疫平衡有重要调控作用，这些分子的异常表达可以引起T细胞的过度激活并引发自身免疫病。CD160/HVEM/BTLA/LIGHT通路是近年来共信号分子领域的研究热点，该信号通路在免疫调节中起重要的作用，其功能异常或异常表达与自身免疫病的发生密切相关。本文对该通路在自身免疫病中的研究进展做一简要综述。     

基于整合药理学研究参麦注射液治疗心力衰竭的生物作用机制

本文利用中医药整合药理学研究平台(TCMIP V2.0)视角,探索参麦注射液治疗心衰的作用机制,借助于本平台的分析功能,构建参麦注射液治疗心衰的"中药-化学成分-核心靶标-关键通路"多维网络,从不同的角度探索参麦注射液干预心衰的潜在分子机制.在TCMIP V2.0分析参麦注射液治疗心衰的分子机制研究结果表明,参麦注射液...     

Novel molecular targets in the treatment of cardiac hypertrophy

Left ventricular hypertrophy represents the heart's response to increased biomechanical stress such as arterial hypertension or valvular heart disease. Cardiac hypertrophy has traditionally been considered a compensatory mechanism required to normalize wall tension and to maintain cardiac output. However, recent clinical studies as well as several animal models have shown that sustained cardiac hypertrophy is rather a maladaptive process, ultimately leading to heart failure and sudden death independent of the underlying cause of hypertrophy. Throughout the past decade, much effort has thus been spent on deciphering the molecular signaling pathways mediating cardiac growth. Identification of novel molecules regulating cardiac hypertrophy could offer the basis for a new generation of cardiovascular drugs. In this review we focus on recent insights into hypertrophic signaling and consider current and emerging approaches to inhibit hypertrophy with the ultimate goal to prevent or delay the onset of heart failure and sudden death in patients.     

Phosphodiesterases and cardiac cGMP: evolving roles and controversies

cGMP and its primary target kinase, protein kinase G (PKG), are well recognized modulators of cardiac function and the chronic stress response. Their enhancement appears to serve as a myocardial brake, reducing maladaptive hypertrophy, improving cell survival, signaling and mitochondrial function, protecting against ischemia/reperfusion injury, and blunting the stimulatory effects of catecholamines. Translation of these effects into a chronic treatment for patients with heart failure based on increasing the generation of cGMP has been difficult, however, with tolerance and hypotension effects occurring with nitrates and neutral responses to natriuretic peptides (at least B-type). Inhibition of cGMP-targeted phosphodiesterases (PDEs) such as PDE5A is an alternative approach that appears to have more potent effects. Recent studies in experimental models and patients are revealing benefits in heart failure syndromes, and ongoing multicenter trials are testing the efficacy of PDE5A inhibition. In this review we discuss recent research findings and controversies regarding the PDE/cGMP/PKG signaling pathway, and suggest directions for further research.     

The powerful cardioprotective effects of urocortin and the corticotropin releasing hormone (CRH) family

The urocortins are members of the corticotropin releasing hormone (CRH) family of peptide hormones. The archetypal member of this family, CRH, plays an important role in regulating thermogenesis and homeostasis by acting centrally and systemically in target organs via its two receptors CRH-R1 and CRH-R2. However, by virtue of their much greater relative affinity for CRH-R2, the physiological effects of the urocortin peptides are largely restricted to peripheral organs such as the heart. A powerful cytoprotective effect of urocortin peptide administration against ischemia and reperfusion injury has been demonstrated in isolated cardiomyocyte models, as well as in the intact heart both in vitro and in vivo. Extremely promising data has shown the beneficial effect of treating pacing-induced heart failure in sheep with urocortin molecules. Though the efficacy and specificity of these molecules in humans is not yet established, molecular dissection of the cytoprotective pathways activated by urocortin peptides suggests that the beneficial effects may be separable from potentially deleterious effects.     

Role of TGF-β in melanoma

Human malignant melanoma is highly resistant to chemotherapy and current immunotherapeutic approaches induce long term remission only in the minority of patients. The transforming growth factor-β (TGF-β) has attracted much attention as a therapeutic target because it plays an important and pleiotropic role in melanoma progression. TGF-β is a multifunctional cytokine involved in the regulation of many cellular processes including cell proliferation, differentiation and survival. Resistance to the growth inhibitory effects of TGF-β without alterations of TGF-β signaling molecules is characteristic of cutaneous melanoma. Melanoma produces increasing amounts of TGF-β with disease progression, inhibiting immune responses and providing an optimal microenvironment for undisturbed tumor growth. In addition, TGF-β exerts its tumor promoting functions via direct effects on tumor cell motility and invasiveness and indirectly by modulating tumor stroma and extracellular matrix, supporting angiogenesis and inhibiting immune surveillance. TGF-β acts through multiple intracellular signaling pathways and the outcome of TGF-β signaling is context-dependent. Defining the impact of the different TGF-β signaling pathways on melanoma progression will help to identify suitable therapeutic targets. Here we review the current knowledge of TGF-β in melanoma and discuss recent therapeutic approaches targeting the TGF-β pathway.     

Enhancement of calcium uptake via the sarcoplasmic reticulum is a potent therapeutic strategy for dilated cardiomyopathy and heart failure

Dilated cardiomyopathy (DCM), a distinct form of cardiomyopathy, is a myocardial disorder characterised by heart chamber dilation with severe contractile dysfunction and frequent association with heart failure. Analysing this subset of heart failure has provided mechanistic insights of intrinsic pathways for myocyte adaptation and survival. Despite the heterogeneous aetiologies, a calcium cycling defect is common in DCM. A growing body of evidence has shown that calcium homeostasis and calcium-dependent signalling pathways play a pivotal role in cardiac hypertrophy and heart failure. In this regard, recent studies demonstrate that a cardiac calcium cycling defect is identified as a critical regulator for the progression of heart failure in DCM and that enhancement of calcium uptake into the cardiac sarcoplasmic reticulum (SR) may have potential therapeutic value for cardiac dysfunction. This article will focus on the cardiac SR calcium ATPase (SERCA2a) and its regulatory protein, phospholamban (PLB), as new therapeutic targets for DCM and heart failure.     

Endothelin receptor antagonists in heart failure: current status and future directions

Experimental evidence suggests that endothelin substantially contributes to left ventricular remodelling and progression of heart failure. Plasma endothelin (ET)-1 levels are increased in patients with heart failure, independent of the aetiology, and correlate with the severity of the disease. Furthermore, tissue endothelin levels and endothelin receptors are upregulated in myocardium from animals and humans with heart failure. In several experimental models of left ventricular remodelling and/or heart failure, treatment with nonselective ET-A and -B as well as selective ET-A antagonists exerted beneficial cardiovascular effects. In patients with heart failure, short-term studies of treatment with endothelin antagonists demonstrated an improvement of haemodynamic parameters; however, long-term treatment with these drugs did not significantly improve combined morbidity/mortality endpoints. Furthermore, in the recently completed Endothelin-A Receptor Antagonist Trial in Heart Failure (EARTH) trial in patients with chronic heart failure, the selective ET-A receptor antagonist darusentan did not significantly affect left ventricular remodelling as assessed by cardiac magnetic resonance imaging. Potential reasons for the lack of beneficial effects of long-term treatment with ET antagonists in patients with heart failure include the following. Firstly, adverse effects on left ventricular healing have been observed when endothelin antagonist therapy was introduced early after myocardial infarction in rats. Secondly, the role of the ET-B receptor in the pathophysiology of heart failure and remodelling processes has not been clearly defined. Finally, for the detection of improvement in left ventricular remodelling, a study needs to be conducted in patients with recent myocardial infarction and signs of heart failure.     

Striking the target in Wnt-y conditions: Intervening in Wnt signaling during cancer progression

Wnt signaling can be divided into three pathways, namely the canonical Wnt/β-catenin pathway, and the non-canonical (or heretical) Wnt/Ca²⁺ and planar cell polarity (PCP) pathways. Although the canonical Wnt/β-catenin pathway is the best described in cancer, increasing data points to the importance of the heretical Wnt pathways in several aspects of tumor progression. The recent advances in understanding the players and mechanisms by which these Wnt pathways contribute to cancer progression have led to the identification of numerous molecules that are already, or could be considered, targets for cancer therapy.     

New pathways for reactive oxygen species generation in inflammation and potential novel pharmacological targets

Oxidative agents are generated in large amounts during inflammation. These highly reactive intermediates interact with several extracellular and intracellular molecules and with each other, thus generating a complex network of responses culminating in an outcome that may be detrimental or beneficial for the host. Alongside with the well known systems involved in production of reactive oxygen species or reactive nitrogen species, such as the NADPH oxidase or the nitric oxide synthase, novel enzymatic pathways have been discovered. This has unveiled new targets and functions for oxidant species, and has prompted the development of innovative anti-inflammatory drugs. In the new integrate scenario stemming from these studies oxidant species are increasingly recognized as true messengers, and even their toxic effects are viewed as the result of the perversion of an otherwise physiological extra/intra cellular signaling.     

AII antagonists in hypertension, heart failure, and diabetic nephropathy: focus on losartan

The goal of antihypertensive therapy is to prevent cardiovascular complications of hypertension, such as heart failure, stroke, end stage renal disease, and death, not just to normalize blood pressure. Recently, several clinical trials investigated the beneficial effects of angiotensin II antagonists (AIIAs) in patients with hypertension, heart failure or diabetic nephropathy utilizing proven clinical outcomes (e.g., all-cause mortality) rather than surrogate outcomes (e.g., blood pressure or proteinuria). The AIIAs may offer therapeutic advantages with respect to particular outcomes in certain types of patients. Evidence is also emerging that losartan may possess beneficial pharmacological properties such as effects on uric acid, platelets, sexual dysfunction, and cognitive function, that may set it apart from other members of the AIIA class. However, further studies are needed to delineate fully these potential pharmacological differences among the AIIAs and their possible clinical relevance. This paper reviews recent AIIA outcomes studies in patients with hypertension, heart failure, or diabetic nephropathy and also examines data suggesting that molecular differences exist within the AIIA class, differences that may assist in explaining the outcomes achieved in these recent trials.     

Intercepting neoplastic progression in lung malignancies via the beta adrenergic (β-AR) pathway: implications for anti-cancer drug targets

The understanding of signaling cascades involved in the induction, promotion, and progression of cancer, although advanced in recent years, is still incomplete. Tracing the imbalance of the impaired, physiologically-essential cellular signaling that drives the neoplastic process is a complex issue. This review discusses the role of the regulator of the fight or flight response, the beta-adrenergic signaling cascade, as a mediator of cancer growth and progression in in vitro and in vivo cancer models. We review a series of experiments from our own laboratory and those of others examining the contribution of this signaling network to lung and other human malignancies and thereby identifying potential targets for chemotherapeutic interventions. The stimulation of the β-adrenergic receptor by lifestyle and environmental factors, as well as a preexisting risk for neoplasm, activates downstream effector molecules (adenylyl cyclase/cAMP/PKA/CREB) concomitant to the transactivation of related pathways (EGFR) that lead to pro-oncogenic signaling; this β-adrenergic pathway thereby encourages cancer growth by evasion of apoptosis, invasion, angiogenesis, and metastasis. GABAergic signaling acts as an antagonist to the β-adrenergic cascade by intercepting adenylyl cyclase activation, and thereby neutralizing the pro-oncogenic effects of β-adrenergic stimulation. The regulation of cancer cell growth by neurobiological signals expands the possibilities for pharmacological interventions in cancer therapy.     

Matrix metallopropteinases in heart failure

Heart failure (HF) represents a complex multifactorial syndrome, characterized by crucial structural and functional abnormalities of the myocardium. Matrix metalloproteinases are associated with left ventricular dysfunction, adverse left ventricular remodelling and prognosis after acute myocardial infarction. There is a strong association between oxidative stress and MMPs in the pathophysiology of HF. As MMPs are strongly associated to the pathogenesis and pathophysiology of HF, several agents have been proposed as potential modulators of these molecules. Classical agents such as statins, angiotensin converting enzyme inhibitors (ACEIS) and beta-blockers and a variety of novel agents have been implicated in the pathogenesis and progression of heart failure via the matrix metalloproteinases pathway and consist of possible future therapeutic targets.     

MicroRNA and receptor mediated signaling pathways as potential therapeutic targets in heart failure

Introduction: Cardiac remodelling is a complex pathogenetic pathway involving genome expression, molecular, cellular, and interstitial changes that cause changes in size, shape and function of the heart after cardiac injury.

Areas covered: We will review recent advances in understanding the role of several receptor-mediated signaling pathways and micro-RNAs, in addition to their potential as candidate target pathways in the pathogenesis of heart failure. The myocyte is the main target cell involved in the remodelling process via ischemia, cell necrosis and apoptosis (by means of various receptor pathways), and other mechanisms mediated by micro-RNAs. We will analyze the role of some receptor mediated signaling pathways such as natriuretic peptides, mediators of glycogen synthase kinase 3 and ERK1/2 pathways, beta-adrenergic receptor subtypes and relaxin receptor signaling mechanisms, TNF/TNF receptor family and TWEAK/Fn14 axis, and some micro-RNAs as candidate target pathways in pathogenesis of heart failure. These mediators of receptor-mediated pathways and micro-RNA are the most addressed targets of emerging therapies in modern heart failure treatment strategies.

Expert opinion: Future treatment strategies should address mediators involved in multiple steps within heart failure pathogenetic pathways.     

AII antagonists in hypertension,heart failure,and diabetic nephropathy: focus on losartan

SUMMARY

The goal of antihypertensive therapy is to prevent cardiovascular complications of hypertension, such as heart failure, stroke, end stage renal disease, and death, not just to normalize blood pressure. Recently, several clinical trials investigated the beneficial effects of angiotensin II antagonists (AIIAs) in patients with hypertension, heart failure or diabetic nephropathy utilizing proven clinical outcomes (e.g., all-cause mortality) rather than surrogate outcomes (e.g., blood pressure or proteinuria). The AIIAs may offer therapeutic advantages with respect to particular outcomes in certain types of patients. Evidence is also emerging that losartan may possess

beneficial pharmacological properties such as effects on uric acid, platelets, sexual dysfunction, and cognitive function, that may set it apart from other members of the AIIA class. However, further studies are needed to delineate fully these potential pharmacological differences among the AIIAs and their possible clinical relevance. This paper reviews recent AIIA outcomes studies in patients with hypertension, heart failure, or diabetic nephropathy and also examines data suggesting that molecular differences exist within the AIIA class, differences that may assist in explaining the outcomes achieved in these recent trials.     

Carvedilol versus other beta-blockers in heart failure

Carvedilol is a beta-blocker with ancillary properties. Pilot clinical studies with carvedilol, added to the standard therapy of digoxin, diuretics and ACE inhibitors, showed beneficial effects in mild, moderate and severe heart failure. Patients consistently showed improvement in LV ejection fraction and NYHA functional class. Subsequently large clinical trials showed decreased morbidity and mortality with carvedilol in mild and moderate and more recently, severe heart failure. However, there is little or no improvement in exercise tolerance with carvedilol. The beneficial effects of carvedilol in heart failure are associated with cardiac remodelling. Metoprolol and bisoprolol are selective beta(1)-blockers without ancillary properties. Early studies showed benefits with metoprolol and bisoprolol in heart failure. Large clinical trials established that metoprolol and bisoprolol decreased mortality and morbidity in heart failure. In contrast no benefit has been shown with celiprolol, a selective beta(1)-blocker and beta(2)-stimulant in heart failure. There is a debate as to whether the ancillary properties of carvedilol contribute to its beneficial effect in heart failure, making it a better drug to use than metoprolol. Short-term studies suggested that carvedilol and metoprolol were equivalent in heart failure but short-term is probably not an appropriate way to compare the drugs. A recent long-term study and study in poor responders to metoprolol, suggest that carvedilol may be better than metoprolol in heart failure.