疼痛性别差异的表观遗传学研究进展

人类急慢性疼痛存在明显的性别差异,女性与男性疼痛相比患病率更高、疼痛更甚且持续时间更长,其发生发展机制目前尚不清楚,越来越多的研究表明,表观遗传学机制参与了疼痛性别差异的调控。本文将综述参与疼痛性别差异表观遗传学研究的最新进展,包括X染色体失活、DNA甲基化、组蛋白修饰和非编码RNA。有助于更好地阐明疼痛病因学,为疼痛的个体化及靶向治疗提供参考,为攻克疼痛提供新思路,有利于最终解决人类疼痛这个复杂临床问题。     

外周T细胞淋巴瘤的表观遗传机制及治疗进展

外周T细胞淋巴瘤(PTCL)是一组高度异质且预后极差的恶性肿瘤,基因异常和分子生物学改变是其发生、发展的重要因素.目前,PTCL的治疗仍然借鉴侵袭性B细胞淋巴瘤的化疗方案,但是疗效并不显著.表观遗传学作为一门涉及基因表达调控的新兴学科,为PTCL的发生、发展机制的研究与临床诊断治疗提供了新的思路.同时,针对PTCL的新型表观遗传学靶向药物的研发及新药联合应用方案的研究亦在进行中.因此,表观遗传学调控为PTCL的诊断及治疗提供了新的治疗切入点.笔者拟就PTCL的表观遗传学机制研究及相关靶向新药的应用前景进行综述.     

OPRM1基因甲基化在疼痛及阿片类镇痛药物应用中的研究进展

OPRM1基因是编码μ阿片受体的基因,OPRM1基因甲基化是其重要的表观遗传学调控机制,会影响OPRM1基因的功能及μ阿片受体的表达。近年来,多项临床和基础研究显示,OPRM1基因甲基化在疼痛及机体对阿片类药物的镇痛反应中具有重要作用,并可能参与酒精依赖症与阿片类药物成瘾。本文就OPRM1基因甲基化相关研究进展进行综述,以探讨其在疼痛和阿片类药物反应中的作用及临床价值。     

骨髓增生异常综合征发病机制研究进展

骨髓增生异常综合征是一种克隆性骨髓干细胞异常的疾病,以无效造血和血细胞减少为临床特征。作为血液病学中信息度较低的一组"灰色病",随着近年来研究工作的不断深入,对其发病机制的探讨从分子遗传学、免疫表型特征转移到表观遗传学和微环境等方面。然而,目前对MDS的发病机制仍然无明确的定论,通常应用的分子遗传学、免疫表型的研究已经不能满足MDS的实验和临床应用。目前针对造血干细胞、细胞因子、表观遗传等方面的研究更为深入,而且成果丰硕,相应的靶向药物如去甲基化药物氮杂胞苷和地西他滨等已经在MDS临床应用并已取得了令人满意的疗效。本文就近年来有关MDS发病机制中的造血干细胞、细胞因子、表观遗传改变等方面的研究进展进行综述,以便优化对MDS疾病进展的监控和指导其临床用药策略等。     

周围神经损伤后再生的表观遗传学调控机制研究进展

周围神经损伤反应及影响再生的表观遗传学机制尚未被阐明。本文着眼于表观遗传学调控机制，从DNA甲基化、组蛋白修饰、非编码RNA等方面对周围神经损伤后再生的表观遗传学调控机制进行综述，为优化周围神经损伤后再生的临床治疗提供基础知识。     

慢性疼痛与抑郁症的共同病理机制

慢性疼痛和抑郁症关系紧密,并在临床上常同时出现,严重影响病人的生活质量的同时加大了临床治疗难度。研究发现在慢性疼痛和抑郁症之间存在一定的基因重叠,这可能是两者共病的基础。此外还发现了两者共享的病理机制,如炎症机制、下丘脑-垂体-肾上腺轴(hypothalamic-pituitary-adrenal axis, HPA)失调、神经递质减少等。在临床治疗上,已使用认知行为疗法及抗抑郁药物干预疼痛,抑郁症病人存在过度使用阿片类药物的风险,这使得药物管理复杂化。本文从多方面对慢性疼痛和抑郁症共病的可能机制进行综述,为临床治疗提供依据。     

Graves病表观遗传学的进展

Graves病（GD）又称毒性弥漫性甲状腺肿,是引起甲状腺功能亢进最常见的原因。最近研究表明遗传易感性和环境诱发因素的相互作用被认为是导致GD发病的关键原因;而表观遗传学是环境与遗传之间的桥梁,越来越多的证据表明表观遗传修饰,包括DNA甲基化、组蛋白共价修饰以及由非编码的RNA分子介导的基因沉默,在GD的发病机制中扮演着重要的角色。本文主要阐述表观遗传学参与GD发病的机制以及相关的临床潜在应用。     

老年人为何易发皮肤瘙痒:机械敏感离子通道Piezo2-Merkel细胞调控触觉到痒觉的转化

躯体感觉系统负责传递从轻触、疼痛和瘙痒的多种信号。触觉对空间意识和交流至关重要。然而,在疾病状态下,无害的机械刺激可引发诸如机械性瘙痒(触诱发痒)等病理性感觉。目前控制这种转化的分子细胞机制仍属未知。研究者发现,在小鼠中衰老和干皮病诱发的机械性瘙痒与Merkel细胞(皮肤中的触觉感受器)的丧失有关。靶向遗传性删除皮肤中Merkel细胞或相关的机械敏感离子通道Piezo2足以产生机械性瘙痒。化学遗传学激活残存的Merkel细胞可治疗干皮病诱导的机械性瘙痒。该研究揭示了皮肤触觉感受器先前未知的功能,并提供了机械性瘙痒发生发展的新见解。     

特应性皮炎瘙痒机制及相关治疗研究进展

特应性皮炎(atopic dermatitis, AD)是一种慢性复发性炎症性皮肤病, 慢性瘙痒是其特征性症状之一。AD瘙痒的发生机制复杂, 目前认为与皮肤屏障功能障碍、免疫调节异常及外界环境因素相关; 瘙痒-搔抓恶性循环可加重皮肤屏障的破坏、促进皮肤炎症反应及神经失调过程, 是AD瘙痒不易控制的原因之一。目前控制AD瘙痒的药物包括外用药物和系统药物, AD瘙痒机制的研究为其治疗提供了新靶点, 如IL-4、IL-13、IL-31、JAK、IL-33等。本文就AD瘙痒机制及相关治疗研究进展进行综述。     

以秀丽线虫为模式生物的机械痛研究进展

疼痛是伴随着不愉快生理感觉和相应情绪状态的基础体验,其发生机制至今尚未完全清楚.机械感觉在疼痛的各个方面都起着关键的作用,但哺乳动物的机械感觉分子传导机制尚未明确,哺乳动物机械感受的研究常常由于外周神经末端体积较小、分布弥散而难以开展.目前机械感觉研究在细胞和分子水平上突破主要来源于以秀丽线虫和果蝇为模式生物的遗传学研究.本文将以秀丽线虫作为模式生物为例,对近年来机械感觉中轻触觉的遗传学研究进展作一个概述.     

Neural correlates of perceptual difference between itching and pain: a human fMRI study

It has been wondered why we can discriminate between itching and pain as different sensations. Several researchers have investigated neural mechanisms underlying their perceptual differences, and found that some C fibers and spinothalamic tract neurons had different sensitivity between itching and pain. These findings suggest that such differences in ascending pathways are partly associated with perceptual difference between itching and pain. However, it was still unclear how our brains distinguish itching from pain. Thus, by functional magnetic resonance imaging (fMRI) time series analysis, we investigated the neural substrates of perceptual differences between itching and pain. The anterior cingulate cortex, the anterior insula, the basal ganglia and the pre-supplementary motor area were commonly activated by itching and pain. Neural activity in the posterior cingulate cortex (PCC) and the posterior insula associated with itching was significantly higher than that associated with pain and significantly proportional to itching sensation. Pain, but not itching, induced an activation of the thalamus for several minutes, and neural activity of this brain region significantly correlated to pain sensation. These findings demonstrate that the difference in the sensitivity of PCC, the posterior insula and the thalamus between itching and pain would be responsible for the perceptual difference between these sensations. The previous itching studies did not observe an activation of the secondary somatosensory cortex (S2) by itching. However, we observed that an activation of S2 by pain was not significantly different from that by itching, indicating that S2 was associated with not only pain but also itching.     

Comparative psychological aspects of itching and pain

Itching is a major symptom of chronic skin diseases such as atopic dermatitis and leads to considerable psychological strain. Chronic itching lowers patient's quality of life similar to chronic pain and influences the medical treatment. The frequently resulting scratching behavior (short-term avoidance of itch) leads to continuation and exacerbation of the disease, just as with specific pain behavior. For the development of itching and pain psychosocial factors have been identified in addition to somatic ones. However, recent data suggest that there is a complex interaction between pain and itching and comparable mechanisms of neuronal sensitization. In contrast to traditional biomedical one-dimensional models which focus mainly on physical and not psychological factors of a disease, recent data support a biopsychosocial model of development and maintenance for itching and pain. Biopsychosocial understanding of a disease should consequently be taken as the basis for treatment and the importance of interdisciplinary treatment is emphasized. This article will focus on chronic itching and pain with particular consideration of psychological factors.     

Vergleichende psychologische Aspekte von Juckreiz und Schmerz

Itching is a major symptom of chronic skin diseases such as atopic dermatitis and leads to considerable psychological strain. Chronic itching lowers patient??s quality of life similar to chronic pain and influences the medical treatment. The frequently resulting scratching behavior (short-term avoidance of itch) leads to continuation and exacerbation of the disease, just as with specific pain behavior. For the development of itching and pain psychosocial factors have been identified in addition to somatic ones. However, recent data suggest that there is a complex interaction between pain and itching and comparable mechanisms of neuronal sensitization. In contrast to traditional biomedical one-dimensional models which focus mainly on physical and not psychological factors of a disease, recent data support a biopsychosocial model of development and maintenance for itching and pain. Biopsychosocial understanding of a disease should consequently be taken as the basis for treatment and the importance of interdisciplinary treatment is emphasized. This article will focus on chronic itching and pain with particular consideration of psychological factors.     

Epigenetic and miRNA Expression Changes in People with Pain: A Systematic Review

Accumulating evidence suggests that epigenetic mechanisms may hold great potential in the field of pain. We systematically reviewed the literature exploring epigenetic mechanisms in people with pain. Four databases have been interrogated: MEDLINE, The Cochrane Central Register of Controlled Trial, Scopus, and Web of Science, following PRISMA guidelines in conducting study selection and assessment. Thirty-seven studies were included. Studies explored epigenetics in conditions such as fibromyalgia, CRPS, neuropathies, or osteoarthritis. Research focussed on genome-wide and gene-specific DNA methylation, and miRNA expression. Bioinformatics analyses exploring miRNA-associated molecular pathways were also performed. Several genes already known for their role in pain (BDNF, HDAC4, PRKG1, IL-17, TNFRSF13B, etc.), and several miRNAs linked to inflammatory regulation, nociceptive signalling and protein kinases functions have been found to differ significantly between people with chronic pain and healthy controls. Although the studies included were cross-sectional in nature, and no conclusion on causal links between epigenetic changes and pain could be drawn, we summarised the large amount of data available in literature on the topic, highlighting results that have been replicated by independent investigations. The field of pain epigenetics appears very exciting and has all the potential to lead to remarkable scientific advances. However, high-quality, well-powered, longitudinal studies are warranted.PerspectiveThough more high-quality research is needed, available research exploring epigenetic mechanisms or miRNAs in people with pain shows that genes regulating synaptic plasticity and excitability, protein kinases, and elements of the immune system might hold great potential in understanding the pathophysiology of different conditions.     

Decoding the Role of Epigenetics and Genomics in Pain Management

Persistent pain is a costly epidemic, affecting >50 million Americans with estimated expenditures of >$200 billion annually for direct care and lost productivity. Recent advances in epigenetic/genomic understanding of pain and analgesic response may lead to improvements in pain management and help curtail costs by providing more precise detection of the pain mechanisms involved and thereby more personalized and effective treatments. However, the translation of epigenetic and genomic strategies for pain management into clinical practice will depend on understanding their potential applications. The purpose of this article is to examine current knowledge about epigenetic and genomic mechanisms of persistent pain and potential opportunities for improving pain management. The initial discussion focuses on present understanding of nociceptive pathways and alterations that lead to pathologic pain. The discussion then moves to a review of epigenetic mechanisms that have been identified in the transition to and maintenance of persistent pain as well as in the individual’s response to analgesics. Potential applications of epigenetics/genomics to identify people at risk and possibly prevent persistent pain and guide diagnosis and the selection of therapeutic modalities are presented.     

Would depression management relieve pain and improve function

Chronic pain represents an important clinical, social, and economic problem that often is confounded by affective disorders. While clinicians do not know if chronic pain induces depression or depression initiates pain, co-morbidity is common and the burden of illness increases when patients suffer from both illnesses. The patient's quality of life dramatically decreases leading to decreased functioning which makes the treatment for pain more complicated. Patients who have chronic pain also may benefits from antidepressant medications for improved function and quality of life. To obtain optimal clinical outcomes, it is imperative to address both conditions when planning therapy for and studies of chronic pain.     

Epigenetics in pain and analgesia: An imminent research field

Heritable phenotypes resulting from environment‐caused changes in a chromosome without alterations in the DNA sequence are increasingly recognized as a basis of personalized therapy. Epigenetic mechanisms include covalent modifications of the DNA (methylation) or of the DNA‐packaging histones (e.g., deacetylation or phosphorylation). In addition, regulatory non‐coding RNA molecules (micro‐RNAs) exert epigenetic actions. This leads to disruption or otherwise modified expression of genes. Environmental influences such as nutritional factors, exposure to chemicals or drugs, but also social factors appear to exert epigenetic actions. Histone modifications and DNA methylation are associated with the subject's age. Epigenetic mechanisms can silence the expression of pro‐ or antinociceptive genes. To the epigenetic control of nociception adds its control of the pharmacodynamics or pharmacokinetics of analgesics by epigenetic control of drug targets and analgesics metabolizing enzymes. Although epigenetics‐based strategies for pain therapy are not yet available, experiments in rodents suggest that RNA interference may become a new therapy approach for neuropathic and other pain. Another epigenetic approach to analgesic treatment employs inhibitors of histone deacetylase that act on the epigenome by indirectly remodeling the spatial conformation of the chromatin. Finally, epigenetic techniques such as RNA interference have been employed in pain research to proof the contribution of certain proteins to nociception. Thus, the new field of epigenetics becomes increasingly used in research and management of pain and will complement genetics. This article introduces epigenetics to pain and summarizes the current and future utility.     

Modulation of oral cancer and periodontitis using chemotherapeutic agents - A narrative review

Periodontitis, an inflammatory condition, is linked to a higher risk of developing oral cancer. Periodontitis may be a precipitating factor for tumorigenesis and the aggressiveness of specific cancer variants. Although genetics is considered the primary etiologic factor for the development of most cancers, many factors have come to be recognized in the initiation and progression of oral cancer. Consecutively, it is suggestive that periodontitis and oral cancer are distinct disease entities but share common pathogenic mechanisms. Oxidative stress and epigenetic mechanisms are among the most researched mechanisms responsible for initiating apoptotic mechanisms implicated in periodontitis and oral cancer. Current research aims to formulate therapeutic agents to intercede in these mechanisms via host modulation therapy and epigenetic therapy. These advances can revolutionize the treatment of periodontitis and oral cancer. This review aims to shed light on the common pathogenic mechanisms of these diseases and the various host modulation agents that could be beneficial in their treatment.     

Mental disorders in chronic pain patients

Prominent and distressing emotions, cognitions, and behaviors frequently accompany chronic pain. In many cases, these psychological symptoms will be sufficiently severe to qualify the patient for a diagnosis of a mental disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). This article introduces mental disorders that are frequently diagnosed in patients with chronic pain. Mental disorders are common co-morbidities with chronic pain. This paper presents an overview of the extent and nature of co-morbidity between mental disorders and chronic pain, as well as an outline of the structure of DSM-IV-TR, especially with respect to its use of a five-axis system for structuring mental disorder diagnoses.     

Mécanismes épigénétiques impliqués dans la douleur chronique

Epigenetics define inheritable and reversible gene expression modifications that do not involve change the DNA sequence. This review proposes a state of art of current knowledge on different epigenetic mechanisms involved in the transition from acute to chronic pain. Considering epigenetic modifications reversibility, identification of disrupted epigenetic regulations in chronic pain might contribute to the development of new therapeutic strategies for the restoration of altered neuronal functions.