DNA甲基化在药物效应和新药研发中的研究进展

DNA甲基化对药物作用的影响日渐受到关注。许多编码药物代谢酶、药物转运体、核受体及药物靶点的基因受DNA甲基化调控。DNA甲基化在影响细胞色素P450酶(CYP450)的表达水平上起着重要的作用,而CYP450酶系催化多种药物代谢反应,能显著影响药物疗效。目前的研究也发现DNA甲基化水平在个体间的差异与药物疗效和不良反应在个体间的差异是紧密相关的。DNA甲基化状态会受药物作用影响,进而引起不同程度的药物不良反应。近年来,以DNA甲基化为靶向的药物研发呈增长态势,DNA甲基转移酶抑制剂对肿瘤等重大疾病治疗具决定性作用。临床试验结果显示,DNA甲基化药物治疗已在改善药物疗效、稳定药理作用及减少药物不良反应上初见成效。DNA甲基化可能成为早期预测药物效应的潜在生物标记,将成为实现临床个体化用药的有力工具。     

Potential directions for drug development against galectin-7 in cancer

Background: Galectins are a family of proteins defined by having at least one characteristic carbohydrate recognition domain (CRD) with an affinity for beta-galactosides. Over the recent years, with a better understanding of their role in normal and pathological conditions, they have emerged as promising diagnostic and therapeutic targets in cancer. Whereas most of these studies have focused on galectin-1 and galectin-3, very little attention has been paid to galectin-7, a member of the family that has recently been associated with various forms of cancer. Objective: We review the role of galectin-7 in cancer and examine the possible directions that could be exploited to inhibit its role in cancer on the basis of recently identified galectin ligands. Conclusion: Although efforts have been made to develop drugs aimed at inhibiting the cancer-promoting propensity of galectins, most of these inhibitors were specific for the CRD region of the molecule and have focused on extracellular functions of galectins. However, galectins may also be involved in protein–protein interactions, most notably in the nucleus. As galectin-7 is expressed in the cytoplasm and the nucleus in cancer cells, it will be important to investigate its nucleocytoplasmic trafficking and how putative drugs will affect its functions in cancer.     

Strontium ranelate,a promising disease modifying osteoarthritis drug

Introduction: The articular cartilage and subchondral bone may have potential crosstalk in the development and progression of osteoarthritis (OA). Strontium ranelate (SrR) has the ability to dissociate the bone remodeling process and to change the balance between bone resorption and bone formation. Its effect on subchondral bone makes it a potential disease- modifying osteoarthritis drug (DMOAD) in the treatment of OA. The aim of the current review is to summarize up-to-date pharmacological and clinical data of SrR for OA treatment.

Areas covered: A literature search was performed on PubMed and European Medicines Agency (EMA) website for all publications and documents related to SrR and OA. References of related studies were searched by hand. Treatment with SrR, especially at the dosage of 2 g/day, was associated with reduced radiographic knee OA progression, and with meaningful clinical improvement. It was also significantly associated with decreased MRI-assessed cartilage volume loss (CVL) and bone marrow lesions (BMLs).

Expert opinion: SrR could be a promising DMOAD particularly for OA patients with bone phenotypes. The clinical efficacy and side effects of SrR for OA treatment need to be further investigated in future clinical trials before clinical application.     

表观遗传修饰在胚胎发育过程中的调控作用研究进展

表观遗传修饰是生命现象中普遍存在的一类基因调控方式,对维持哺乳动物正常生命活动至关重要。表观遗传修饰方式主要包括DNA甲基化、组蛋白乙酰化和组蛋白甲基化修饰,通常协同调控基因表达,且易受到营养和外源物等多种环境因素的影响,在胚胎正常发育中扮演重要角色。胚胎时期表观遗传修饰异常可能诱导胚胎甚至成年后多种疾病的发生。本文重点从DNA甲基化、组蛋白乙酰化和组蛋白甲基化修饰方面,综述表观遗传修饰在基因调控、胚胎发育过程中的作用及其可能的临床意义。     

Structure-based design,discovery and development of checkpoint kinase inhibitors as potential anticancer therapies

Psychiatric disorders have a heterogeneous biological basis, where environmental factors interplay with non-mendelian genetics to produce complex cognitive/behavioural syndromes such as schizophrenia. Recent findings indicate a proportion of schizophrenia is associated with genomic copy number variation, suggesting that alteration of gene expression levels rather than direct mutation may play a role. Epigenetic mechanisms could be the crucial link between external stimuli and gene expression, influencing schizophrenia risk. These are dynamic reversible systems that offer much promise as targets for future therapies.     

Glucosamine sulfate: the first clinical proven disease modifying drug for osteoarthritis

Overthelastdecade, thedrugresearchhasbeenfocussedontwobasicaims. Fromoneside, thedevel opmentofpotentbutrelativelysafesymptomaticagentsthatunspecificallymaycontrolpartofthediseasesymptoms, butdonotchangediseaseprogression(e.g. coxibsofnon steroidalant…     

硫酸氨基葡萄糖:第1个经临床证明的骨关节炎疾病改善药物

综述了近年发表的关于硫酸氨基葡萄糖临床研究的3项回顾性分析以及最为瞩目的关于硫酸氨基葡萄糖的临床研究报告,给出了骨关节炎疾病改善药物(DMOAD)发展的过去、现状和期望的一个侧面,一个最有希望的侧面,希望有助于推动DMOAD在中国的应用、评价与发展。     

DNA甲基化与药物效应的表观遗传药理学研究进展

除遗传多态性外,DNA序列的表观遗传修饰,也可造成基因表达水平的改变,从而影响个体对药物的反应,造成药物效应的个体差异。表观遗传药理学研究整个环境因素对药物的影响,为临床药物效应的个体差异提供了新的作用机制学说。DNA甲基化是表观遗传修饰的主要机制之一,本文综述了DNA甲基化对药物效应的影响及环境因素对DNA甲基化的影响。     

microRNA——药物开发的新靶点

微小RNA(microRNA)是一类长约22 nt的非编码单链RNA,由前体经酶作用而得,它是细胞的内源性物质,普遍存在于动植物中,高度保守,在生命体的生长、发育、疾病发生发展的过程中起到了基因调控作用,它与重大疾病,如肿瘤、心脏疾病、神经性疾病等都有着密切的关联,因此成为新药开发的一个重要新靶点,以它为靶点的药物设计和药物研发工作也在不断探索中.本文就其研究的历史、生物合成和作用机制、生物功能、与疾病的关系以及以microRNA为靶点的药物设计的研究情况做一个简单的综述.     

表观遗传学药物的研究进展

随着表观遗传学研究的不断深入,表观遗传学药物的研究取得了巨大进展。目前已有研究并批准上市的表观遗传学药物主要针对DNA异常甲基化和组蛋白的异常修饰。潜在的药物有DNA甲基转移酶抑制剂、赖氨酸去甲基化酶抑制剂、蛋白质甲基转移酶抑制剂、组蛋白去乙酰化酶抑制剂、组蛋白乙酰基转移酶抑制剂、含溴结构域蛋白抑制剂及甲基化组蛋白结合蛋白的抑制剂等。该文综述了近年来表观遗传学治疗在药理学上的进展,以期为疾病防治和基础研究提供一些新的思路。     

Antiosteoarthritic effect of Punica granatum L. peel extract on collagenase induced osteoarthritis rat by modulation of COL‐2, MMP‐3, and COX‐2 expression

Osteoarthritis (OA) is a chronic degenerative and musculoskeletal disorder. The toxicity associated with nonsteroidal antiinflammatory drugs (NSAIDs) limits its use in the management of OA. To ameliorate these toxicities, natural antioxidants can be used as substitutes for the management of OA. Therefore, this study is aimed to investigate the prophylactic mechanisms of Punica granatum L. peel (PGP) in collagenase‐induced OA rat compared with indomethacin. OA was induced in female Sprague Dawley rats by intraarticular injection of collagenase type‐II and treated with PGP (250 and 500 mg/kg body wt) and a positive control (PC) indomethacin (3 mg/kg body wt). The results demonstrated that PGP reduced the collagenase induced OA as compared with indomethacin treated group through reducing blood ALP (P < .001) and significantly (P < .001) inhibited cartilage erosion as indicated in histological slides with retention of collagen and proteoglycan content. Quantitative real‐time PCR analysis revealed the considerable (P < .05) upregulation in the expression of COL‐2 gene and downregulation of MMP‐3 and COX‐2 genes in the PGP treated group. The high phenolic content (633 ± 1.16 mg/GAE) and flavonoid content (420.3 ± 2.14 mg/RE) contribute to the strong antioxidant activity with IC₅₀ value (320 ± 2.2 μg/mL) of DPPH free radical scavenging activity. These results need further validation in clinical studies and thus, PGP could be developed as a preventive drug treatment for OA.     

患者参与药物研发

患者参与药物研发,这里的患者是广义的,包括患者个体、患者组织及其家属等.患者参与药物研发涉及从立题到上市后研究的全生命周期各阶段,而不仅局限在临床研究期间.在这方面,欧美的药物研发已经积累了相当的经验,日本的药品主管当局和工业界在近年已经开始实践.我国尚无相关规范或者指导原则等出台.本文将针对国外和我国患者参与药物研发...     

神经系统疾病治疗药物开发品种

神经系统疾病是临床常见的难治性疾病,由于认知功能障碍等退行性病变不断被认识和重视,以及人们对生存质量的关注,该领域医药市场潜力不容忽视.本文依据中国新药研发临测数据库,按大类分别汇总针对认知功能障碍、多发性硬化、癫痫以及帕金森病和偏头痛等疾病的处于开发阶段的治疗药物品种.     

药物转运体表观遗传调控机制的研究进展

药物转运体在体内药物吸收、分布和排泄过程中发挥着重要的作用。转运体在各组织器官的分布和表达受到表观遗传修饰调控,导致某些药物体内处置过程出现明显的个体差异。随着表观遗传学的发展,基于表观遗传修饰（如DNA甲基化、组蛋白修饰、microRNA干预等）调控药物转运体的相关研究越来越多。对表观遗传调控药物转运体研究进行综述。     

Inter-ethnic differences in drug response: Implications for drug development and complying with drug regulation

Abstract

The two key components of the pharmacology of a drug—dose–concentration (pharmacokinetic) and/or concentration–response (pharmacodynamic) relationships—are often influenced by genetic variations. These account for a substantial fraction of variability in dose–response or drug response, not only between individuals, but also between different ethnic groups. The approval of ‘BiDil’ for the treatment of cardiac failure in self-identified black patients is a spectacular example of inter-ethnic differences in drug response and regulatory awareness of ethnicity of the study population. Drug development programs are increasingly undertaken globally to reduce costs, shorten timeframes, and address issues concerning global prescribing. Regulatory authorities have responded to this globalization of drug development by promulgating guidelines that recommend sponsors of new drugs to explore the role of genetic variations, and potential differences in drug response, between different ethnic populations. They may refuse to accept an application, or require bridging studies, when such differences are anticipated but not adequately addressed. These bridging studies may include (i) pharmacokinetic studies, (ii) pharmacodynamic studies, (iii) dose–response studies, and/or (iv) in extreme cases, pivotal phase III studies in order to extrapolate efficacy and/or safety data from one population to another.     

Parallel drug development

In the pharmaceutical industry, it is common practice to pursue sequentially, within a family of compounds, a number of candidate compounds for further development. This article challenges the sequential tradition, and instead proposes a parallel drug development paradigm, in which several candidate compounds are nominated at the same time, and are simultaneously evaluated through the development process. Evaluating several compounds as candidate drugs (CDs) simultaneously, and in particular in the same studies, will potentially bring huge productivity benefits. The average time to a successful launch, or time to the closure of research on a futile target (family of CDs), may be substantially reduced. Other benefits imply substantially reduced costs as a result of fewer studies, fewer patients receiving placebo, and fewer animals receiving vehicle. A further benefit of the parallel drug development approach is the potential for head‐to‐head comparison of CDs, leading to improved accuracy in the selection of which compounds to progress through development. A modeling framework has been developed by which development strategies can be compared. Simulations have been performed based on the model. Results are summarized to allow quantitative comparisons of the performance of the parallel development and the traditional sequential development approaches. Drug Dev Res 73: 24–34, 2012. © 2011 Wiley Periodicals, Inc.     

Tuberculosis susceptibility – implications for drug development and therapy

Psoriasis is a chronic inflammatory condition affecting 1 – 3% of the world’s population. Despite the availability of several agents, therapeutic options remain limited. With a better understanding of the pathophysiology of psoriasis, several potential therapeutic targets have been identified. Peroxisome proliferator activated receptors have been shown to play a role in cutaneous homeostasis. This review focuses on the potential therapeutic role of peroxisome proliferator activated receptor-γ agonists in psoriasis and the possibility for the future prospects.