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Celiac disease: Role of genetics and immunity and update on novel strategies for treatment 乳糜泻:遗传和免疫的作用以及新治疗策略的最新进展
Pub Date : 2014-12-31 DOI: 10.14748/BMR.V25.1047
E. Sequeira, Ginpreet Kaur, H. Buttar
Celiac disease (CD) is one of the most common inflammatory diseases of the small intestine which causes abdominal pain, diarrhoea, malabsorption, weight loss, anorexia, and iron deficiency anaemia in humans. It is a human leukocyte antigen (HLA)-linked disorder that is triggered by the gluten and gliadin proteins from wheat and related cereals. The presence of other genetic factors such as HLA-DQ2 and HLA-DQ8 have also been identified for the generation of circulating autoantibodies to the enzyme transglutaminase (TG2). The TG2 enzyme deamidates the gluten peptides and increases their affinity for the HLA-DQ2 or HLA-DQ8, which in turn cause a more vigorous activation of CD4+ T-helper 1 (Th1) cells and trigger the immune response, and such immune cascade eventually leads to intestinal membrane damage and malabsorption. Generally, CD is managed by lifelong gluten-free diet. However, strict adherence to a gluten-free diet is difficult and is not always effective. Several pharmacological agents and alternative therapies for treating CD are currently under development and are in clinical trials, The purpose of this review is to highlight the complex involvement of genetics and immunity in CD and to focus on the novel strategies being used for developing adjunct and alternative therapies for the treatment of CD. Biomedical Reviews 2014; 25: 45-58.
乳糜泻(CD)是最常见的小肠炎症性疾病之一,可导致人类腹痛、腹泻、吸收不良、体重减轻、厌食和缺铁性贫血。它是一种人类白细胞抗原(HLA)相关的疾病,由小麦和相关谷物中的麸质和麦胶蛋白引发。其他遗传因素如HLA-DQ2和HLA-DQ8的存在也被确定为产生循环自身抗体转谷氨酰胺酶(TG2)。TG2酶使谷蛋白肽脱酰胺并增加其对HLA-DQ2或HLA-DQ8的亲和力,进而引起CD4+ t -辅助性1 (Th1)细胞更强烈的激活并触发免疫反应,这种免疫级联最终导致肠膜损伤和吸收不良。一般来说,乳糜泻需要终生无谷蛋白饮食。然而,严格遵守无麸质饮食是困难的,并不总是有效的。一些治疗乳糜泻的药物和替代疗法目前正在开发和临床试验中,本综述的目的是强调遗传和免疫在乳糜泻中的复杂参与,并重点介绍用于开发治疗乳糜泻的辅助和替代疗法的新策略。25: 45-58。
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引用次数: 1
Computational modelling: moonlighting on the neuroscience and medicine 计算建模:神经科学和医学的兼职
Pub Date : 2013-12-31 DOI: 10.14748/BMR.V24.19
P. Hassanzadeh
Computational modelling has emerged as a powerful tool to study the behaviour of complex systems. Computer simulation may lead to a better understanding of the function of biological systems and the pathophysiological mechanisms underlying various diseases. In neuroscience, modelling techniques have provided knowledge about the electrical properties of neurons, activity of ion channels, synaptic function, information processing, and signalling pathways. Using simulations and analysis in network models has resulted in greater understanding of the behaviour of neural networks and dynamics of synaptic connectivity. Moreover, the correlation between the neurobiological mechanisms and a cluster of physiological, cognitive, and behavioural phenomena may be explored by the computational modelling of the neuronal systems. In this context, a significant progress has been made in understanding of the neural network architectures including those with a high degree of connectivity between the units, information processing, performance of complex cognitive tasks, integration of brain signals, as well as the dynamic mechanisms and computations implemented in the brain for making goal-directed choices. Computational models are able to explore the interactions between the brain areas which are involved in predictive processes and high-level skills. In this review, the significance of computational modelling in the study of neural networks, decision-making procedure, nerve growth factor signalling, and endocannabinoid system along with its medical applications have been highlighted. Biomedical Reviews 2013; 24: 25-31.
计算模型已经成为研究复杂系统行为的有力工具。计算机模拟可以更好地理解生物系统的功能和各种疾病的病理生理机制。在神经科学中,建模技术提供了关于神经元电特性、离子通道活动、突触功能、信息处理和信号通路的知识。在网络模型中使用模拟和分析导致了对神经网络行为和突触连接动力学的更好理解。此外,神经生物学机制与一系列生理、认知和行为现象之间的相关性可以通过神经元系统的计算建模来探索。在此背景下,对神经网络架构的理解取得了重大进展,包括单元之间的高度连接、信息处理、复杂认知任务的执行、大脑信号的整合,以及在大脑中实现目标导向选择的动态机制和计算。计算模型能够探索涉及预测过程和高级技能的大脑区域之间的相互作用。本文综述了计算模型在神经网络、决策过程、神经生长因子信号和内源性大麻素系统研究中的重要意义及其医学应用。生物医学评论2013;24: 25-31。
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引用次数: 13
The roles of micro RNA in pancreas development and regeneration 微RNA在胰腺发育和再生中的作用
Pub Date : 2013-12-31 DOI: 10.14748/BMR.V24.22
Tamara I Rabe, Farnaz Shamsi, A. Mansouri
Presence of sufficient number of functional glucose responsive β-cells is indispensable for normal glucose homeostasis. Diabetes mellitus is a chronic disease associated with loss or reduction of β-cell mass and not β-cell mass. MicroRNAs are small non-coding RNAs that are involved in different biological processes including development, cell proliferation, stress response, and tumor pathogenesis. MicroRNAs fine-tune the gene expression level post-transcriptionally either by mRNA degradation or translational repression. In the past few years, several miRNAs have been introduced as new critical players for pancreas development, function, and regeneration. Deregulation of several microRNAs is found in animal models of diabetes, as well as in diabetic patients. Therefore, it is essential to understand the roles of these microRNAs in β-cell generation and physiology, as well as the biological consequences of their functional impairment. Biomedical Reviews 2013; 24: 57-65.
足够数量的功能性葡萄糖反应β细胞的存在对于正常的葡萄糖稳态是必不可少的。糖尿病是一种慢性疾病,与β细胞团块的丢失或减少有关,而不是β细胞团块。MicroRNAs是一种小的非编码rna,参与不同的生物学过程,包括发育、细胞增殖、应激反应和肿瘤发病。MicroRNAs在转录后通过mRNA降解或翻译抑制来微调基因表达水平。在过去的几年中,一些mirna作为胰腺发育、功能和再生的新关键参与者被引入。在糖尿病动物模型和糖尿病患者中发现了几种microrna的失调。因此,有必要了解这些microrna在β细胞生成和生理中的作用,以及它们的功能损伤的生物学后果。生物医学评论2013;24: 57 - 65。
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引用次数: 1
YKL-40 in health and disease: a challenge for joint inflammation YKL-40在健康和疾病:对关节炎症的挑战
Pub Date : 2013-12-31 DOI: 10.14748/BMR.V24.21
M. Kazakova, V. Sarafian
There is a need of biomarkers to detect early joint inflammation and destruction of cartilage in different types of arthritis. YKL-40, a 39 kD heparin- and chitin-binding secreted glycoprotein (also known as cartilage gp39), was recently discovered. Its exact biological function is still unclear. Specific receptors for YKL-40 have not been identified yet. The clinical significance of YKL-40 as a biomarker is discussed in different aspects. High level of YKL-40 was found in various human diseases associated with inflammatory and neoplastic processes. The review highlights the information available about YKL-40 and its significance in inflammatory joint diseases. We suggest that this glycoprotein might have a promising value as a novel biomarker and could provide additional evidence for inflammation activity in different types of arthritis. Biomedical Reviews 2013, 24: 49-56.
在不同类型的关节炎中,需要生物标志物来检测早期关节炎症和软骨破坏。YKL-40是最近发现的一种39kd的肝素和几丁质结合分泌糖蛋白(也称为软骨gp39)。其确切的生物学功能尚不清楚。YKL-40的特异性受体尚未确定。本文从不同方面探讨了YKL-40作为生物标志物的临床意义。高水平的YKL-40在各种与炎症和肿瘤过程相关的人类疾病中被发现。本文综述了关于YKL-40的现有信息及其在炎性关节疾病中的意义。我们认为这种糖蛋白作为一种新的生物标志物可能具有很好的价值,并且可以为不同类型关节炎的炎症活性提供额外的证据。生物医学评论,2013,24(4):49-56。
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引用次数: 9
Postnatal development of the inner ear efferent innervation in mammals 哺乳动物内耳传出神经支配的产后发育
Pub Date : 2013-12-31 DOI: 10.14748/BMR.V24.20
E. Ivanov, Svetla P. Doseva, N. Lazarov
Efferent innervation of the inner ear is extensively studied but the whole model revealing the development of efferent synapses is not clear yet. In mammals the lateral and medial olivocochlear systems are known as the source of efferent fibers. The lateral olivocochlear system innervates the ipsilateral cochlea, terminating on the dendrites beneath the inner hair cells (IHCs), the dendrites being spiral ganglion neuron compounds. The medial olivocochlear system is involved in forming synapses directly on the outer hair cells (OHCs). To reach the final targets efferent axons use the afferent fibers as a scaffold. Efferent synaptogenesis occurs just before the onset of hearing. At P0 in rats we observed synaptic-like contacts lacking typical features. At P3 the synapses were immature. At P4-P5 efferent contacts with IHCs were clearly defined. At P6-P7 the efferent terminals were larger with distinct synaptic vesicles. During maturation, at P8-P10, the number of efferent synapses at the base of the ICHs reduced alongside with a decrease in the synaptic cisternae. After P12 efferent terminals formed axodendritic synapses below IHCs and large axosomatic synapses on OHCs. The innervation of OHCs underwent two stages, i.e. transitional with simultaneous innervation of IHCs and OHCs and a final OHC-targeted innervation. These results support the idea for a waiting period of efferent innervation before its final establishment in adult organ of Corti. We also summarize the role of neurotrophic factors, specific neurotransmitter systems, their receptors and transporters for refinement of cochlear efferent innervation. Biomedical Reviews 2013; 24: 33-48.
内耳的传出神经支配已被广泛研究,但揭示传出突触发育的整个模型尚不清楚。在哺乳动物中,外侧和内侧耳蜗系统被认为是传出纤维的来源。侧耳蜗系统支配同侧耳蜗,止于内毛细胞(IHCs)下的树突,树突为螺旋神经节神经元化合物。内侧耳蜗系统直接参与形成外毛细胞(ohc)上的突触。为了达到最终目标,传出轴突使用传入纤维作为支架。传出突触发生在听力出现之前。在大鼠P0,我们观察到突触样接触缺乏典型特征。P3时突触未成熟。在P4-P5时与ihc的不同接触被明确定义。P6-P7时传出端变大,突触囊泡明显。在成熟过程中,在P8-P10时,ICHs基部的传出突触数量随着突触池的减少而减少。P12后传出终端形成ihc下方的轴突突触和OHCs上的大轴体突触。ohc的神经支配经历了两个阶段,即间充质干细胞和ohc同时神经支配的过渡阶段和ohc靶向神经支配的最终阶段。这些结果支持了Corti成体器官传出神经支配在最终建立之前存在等待期的观点。我们还总结了神经营养因子、特定的神经递质系统及其受体和转运体在耳蜗传出神经支配中的作用。生物医学评论2013;24: 33-48。
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引用次数: 0
GENOME-WIDE PROFILING OF COPY NUMBER ALTERATIONS IN CANCER: FOCUS ON MELANOMA 癌症中拷贝数改变的全基因组分析:重点是黑色素瘤
Pub Date : 2013-12-31 DOI: 10.14748/BMR.V24.18
L. Pasini
Thanks to a never-before detailed view of the human genome, the last decade has brought to light the notion of DNA copy number variation (CNV) as the pivotal force contributing to population genomic diversity and evolution. It is as well clear now that cancer typically results in loosened control over genomic integrity and that the acquisition of somatic copy number alterations (SCNAs), whether confined to specific genes or affecting entire chromosome arms, is likely to be a fundamental prerequisite to the adaptive pressure that drives oncogenesis. This review gives a brief overview of key developments in genome-wide SCNA profiling, with specific emphasis on array-based techniques and deep-sequencing, which indeed enabled us to identify the large majority of genomic regions undergoing frequent alteration in human cancers and defining recognizable clinical phenotype. Alongside with the prospective to take advantage for future personalized precision medicine, high-throughput SCNA analysis have already proven diagnostic and prognostic potential, particularly for those clinically unpredictable and therapy-refractory tumors, such us cutaneous melanoma. Biomedical Reviews 2013; 24: 11-24.
由于人类基因组前所未有的详细视图,在过去的十年中,DNA拷贝数变异(CNV)的概念被揭示为促进种群基因组多样性和进化的关键力量。同样清楚的是,癌症通常导致对基因组完整性的控制松动,体细胞拷贝数改变(SCNAs)的获得,无论是局限于特定基因还是影响整个染色体臂,都可能是驱动肿瘤发生的适应性压力的基本先决条件。这篇综述简要概述了全基因组SCNA分析的关键进展,特别强调了基于阵列的技术和深度测序,这确实使我们能够识别人类癌症中发生频繁改变的大部分基因组区域,并定义可识别的临床表型。除了利用未来个性化精准医疗的前景外,高通量SCNA分析已经证明了诊断和预后的潜力,特别是对于那些临床不可预测和治疗难治性的肿瘤,如皮肤黑色素瘤。生物医学评论2013;24: 11-24。
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引用次数: 1
"Rediscovery" of a forgotten organelle, the primary cilium: the root cause of a plethora of disorders “重新发现”了一个被遗忘的细胞器,初级纤毛:许多疾病的根本原因
Pub Date : 2013-12-31 DOI: 10.14748/BMR.V24.16
D. Wheatley
The primary cilium was recognised in the late 19th century. Conclusive evidence of its existence required the advent of the electron microscope (1950s-1960s), after which its comparison with motile cilia of the (9 + 2) variety was made by Sorokin. Although a small group of devotees researched the primary cilium from this period until the late 1990s, its function as a sensor (previously advocated by Tony Poole) was established because it produced Ca 2+ transients in intracellular signalling. The pathobiological consequences of ciliary agenesis or dysfunction was emphasised in the mid 1990s. But it was only after the recognition that agenesis could be due to mutations in intraflagellar transport proteins several years later that the pathological sequelae were appreciated. Since the early 2000s, the primary cilium has now been implicated as having many functions in cellular behaviour and development, such that disorder in this almost ubiquitous organelle in many tissues of the body leads to an astonishingly wide range of symptoms, from polycystic kidney disease to Alzheimer's. This organelle, dismissed as vestigial or rudimentary by most cell biologists for well over a century, can no longer be ignored in almost any medical and development condition. There is also very much more to learn about the biology of this fascinating organelle. Biomedical Reviews 2013; 24: 1-7.
初级纤毛是在19世纪后期被发现的。其存在的确凿证据需要电子显微镜的出现(20世纪50年代至60年代),之后由Sorokin将其与(9 + 2)品种的活动纤毛进行比较。尽管从这一时期到20世纪90年代末,只有一小群研究人员对初级纤毛进行了研究,但由于它在细胞内信号传导中产生ca2 +瞬态,它作为传感器的功能(之前由Tony Poole提倡)得以确立。纤毛发育不全或功能障碍的病理生物学后果在20世纪90年代中期得到强调。但直到几年后认识到发育不全可能是由于鞭毛内转运蛋白的突变引起的,病理后遗症才得到认识。自21世纪初以来,初级纤毛已经被认为在细胞行为和发育中具有许多功能,因此,在身体的许多组织中,这种几乎无处不在的细胞器的紊乱会导致从多囊肾病到阿尔茨海默氏症的惊人广泛的症状。一个多世纪以来,这种细胞器被大多数细胞生物学家视为退化或初级,但在几乎任何医学和发育条件下都不能再被忽视。关于这个迷人的细胞器的生物学,还有很多东西需要学习。生物医学评论2013;24: 1 - 7。
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引用次数: 2
SOS for SOC: the renaissance of a seemingly ubiquitous organelle SOS代表SOC:看似无处不在的细胞器的复兴
Pub Date : 2013-12-31 DOI: 10.14748/BMR.V24.17
G. Chaldakov, K. Dikranian
In this volume of Biomedical Reviews Denys Wheatley presents a short review "Rediscovery" of a forgotten organelle, the primary cilium: the root cause of a plethora of disorders . Dr Wheatley has extensively published cilium-related research papers, reviews and book chapters. Quite naturally has been an advocate for attracting scientific interest to this beautiful biological structure for decades. Therefore he is well suited to provide a world-class view on this scientific problem. He does that in an elegant manner in his review, and states the future direction of research into the ubiquitous nature and involvement of this organelle in health and disease. Biomedical Reviews 2013; 24: 9-10.
在这一卷的生物医学评论丹尼斯·惠特利提出了一个简短的回顾“重新发现”一个被遗忘的细胞器,初级纤毛:疾病的根源过多。惠特利博士广泛发表了与纤毛有关的研究论文、评论和书籍章节。很自然地,几十年来一直是吸引科学家对这种美丽生物结构感兴趣的倡导者。因此,他非常适合为这个科学问题提供世界级的观点。在他的评论中,他以一种优雅的方式做到了这一点,并指出了未来研究的方向,即这种细胞器在健康和疾病中的无处不在的性质和参与。生物医学评论2013;24: 9。
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引用次数: 0
Adipotoxicology of obesity and related diseases 肥胖及相关疾病的脂肪毒理学
Pub Date : 2012-12-31 DOI: 10.14748/BMR.V23.28
S. Yanev, G. Chaldakov
The human genome project's big promise was that it could improve our understanding of the pathogenesis and therapy of diseases. However, the genes have been found to account for only about 10% of diseases, and the remaining causes appear to be from environmental exposures, hence the exposure science (exposome concept) emerges. Indeed, Homo sapiens is exposed to an overwhelming number of chemical contaminants circulating every day in the air, water, food, and general environment. The body is a well-equipped entity with capabilities to excrete water-soluble pollutants, but not as well-equipped to excrete some of the lipid-soluble xenobiotics. Here we present data that adipose tissue may be an important participant in the environmental molecular toxicology. Numerous evidence demonstrates that the exposure to persistent organic pollutants may contribute to the pathogenesis of obesity and its related diseases. Noteworthy, these pollutants accumulate mainly in the adipose tissue. And xenobiotic-metabolizing cytochromes p450 (CYP) are expressed in adipose tissue, where CYP1A1 and CYP1B1 can bioactivate carcinogenic polycyclic aromatic hydrocarbons and xenoestrogens. Altogether, the present review highlights an adipocentric approach in molecular toxicology. It is conceptualized as adipotoxicology, that is, the study of accumulation, metabolism, and release of xenobiotics in adipose tissue in health and disease. Biomedical Reviews 2012; 23: 53-60.
人类基因组计划的巨大希望在于,它可以提高我们对疾病发病机制和治疗方法的理解。然而,已发现基因仅占疾病的10%左右,其余原因似乎来自环境暴露,因此出现了暴露科学(暴露概念)。事实上,智人每天都暴露在空气、水、食物和一般环境中大量循环的化学污染物中。身体是一个装备齐全的实体,具有排泄水溶性污染物的能力,但不具备排泄一些脂溶性异体的能力。在这里,我们提出的数据,脂肪组织可能是一个重要的参与者在环境分子毒理学。大量证据表明,接触持久性有机污染物可能与肥胖及其相关疾病的发病机制有关。值得注意的是,这些污染物主要在脂肪组织中积累。异种代谢细胞色素p450 (CYP)在脂肪组织中表达,其中CYP1A1和CYP1B1可以生物激活致癌的多环芳烃和异种雌激素。总之,本综述强调了分子毒理学中以脂肪为中心的方法。它被定义为脂肪毒理学,即研究健康和疾病时脂肪组织中异种生物的积累、代谢和释放。生物医学评论2012;23: 53-60。
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引用次数: 2
Postnatal development of the afferent innervation of the mammalian cochlea 哺乳动物耳蜗传入神经的产后发育
Pub Date : 2012-12-31 DOI: 10.14748/BMR.V23.27
E. Ivanov, N. Lazarov
The adult mammalian cochlea receives dual afferent innervation: the inner hair cells (IHCs) are innervated exclusively by type I spiral ganglion neurons (SGNs), whereas the outer hair cells (OHCs) are innervated by type II SGNs. We have characterized the reorganization and morphology of this dual afferent innervation pattern as it is established in the developing rat cochlea. Before the cochlear afferent innervation reaches a mature configuration, there is an initial mismatch, where both populations of SGNs innervate both types of sensory hair cells: during the first postnatal week in the rat cochlea, type I SGN innervation is eliminated from the OHC and type II SGN innervation is eliminated from the IHC. This reorganization occurs during the first two postnatal weeks just before the onset of hearing. Our data reveal distinct phases in the development of the afferent innervation of the organ of Corti: neurite refinement, with a formation of the outer spiral bundles innervating outer hair cells; neurite retraction and synaptic pruning to eliminate type I SGN innervation of OHCs, while retaining their supply to IHCs. Such a reorganization also makes the cochlea a model system for studying CNS synapse development, plasticity and elimination. The present article summarizes the recent progress in our understanding of the afferent innervation of the cochlea. Biomedical Reviews 2012; 23: 37-52.
成年哺乳动物耳蜗接受双重传入神经支配:内毛细胞(IHCs)仅受I型螺旋神经节神经元(sgn)的支配,而外毛细胞(OHCs)则受II型螺旋神经节神经元的支配。我们已经描述了这种双重传入神经支配模式的重组和形态,因为它是在发育中的大鼠耳蜗中建立的。在耳蜗传入神经支配达到成熟配置之前,存在一种初始错配,即两种SGN群支配两种感觉毛细胞:在大鼠耳蜗出生后的第一周,I型SGN支配从OHC中消除,II型SGN支配从IHC中消除。这种重组发生在出生后的头两周,就在听力开始之前。我们的数据揭示了Corti器官传入神经支配发育的不同阶段:神经突细化,形成支配外毛细胞的外螺旋束;神经突缩回和突触剪枝可消除OHCs的I型SGN神经支配,同时保留其对ihc的供应。这种重组也使耳蜗成为研究中枢神经系统突触发育、可塑性和消除的模型系统。本文综述了近年来对耳蜗传入神经支配的研究进展。生物医学评论2012;23: 37-52。
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引用次数: 11
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