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Mechanism and application of immune interventions in intracerebral haemorrhage. 免疫干预在脑出血中的机制和应用。
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-08 DOI: 10.1017/erm.2024.22
Xiaoxiao Xu, Yuanwei Li, Shiling Chen, Xuan Wu, Jiarui Li, Gaigai Li, Zhouping Tang

Despite stroke being one of the major and increasing burdens to global health, therapeutic interventions in intracerebral haemorrhage (ICH) continue to be a challenge. Existing treatment methods, such as surgery and conservative treatment have shown limited efficacy in improving the prognosis of ICH. However, more and more studies show that exploring the specific process of immune response after ICH and taking corresponding immunotherapy may have a definite significance to improve the prognosis of cerebral haemorrhage. Therefore, immune interventions are currently under consideration as therapeutic interventions in the ICH. In this review, we aim to clarify unique immunological features of stroke, and consider the evidence for immune interventions. In acute ICH, activation of glial cells and cell death products trigger an inflammatory cascade that damages vessels and the parenchyma within minutes to hours of the haemorrhage. Immune interventions that ameliorate brain inflammation, vascular permeability and tissue oedema should be administered promptly to reduce acute immune destruction and avoid subsequent immunosuppression. A deeper understanding of the immune mechanisms involved in ICH is likely to lead to successful immune interventions.

尽管中风是全球健康的主要负担之一,而且这一负担还在不断增加,但脑出血(ICH)的治疗干预仍是一项挑战。现有的治疗方法,如手术和保守治疗,对改善 ICH 的预后效果有限。然而,越来越多的研究表明,探索 ICH 后免疫反应的特殊过程并采取相应的免疫疗法,对于改善脑出血的预后可能具有一定的意义。因此,目前正在考虑将免疫干预作为 ICH 的治疗干预手段。在本综述中,我们旨在阐明脑卒中独特的免疫学特征,并考虑免疫干预的证据。在急性 ICH 中,神经胶质细胞的激活和细胞死亡产物引发炎症级联反应,在出血后数分钟至数小时内破坏血管和实质。应及时采取能改善脑部炎症、血管通透性和组织水肿的免疫干预措施,以减少急性免疫破坏,避免后续免疫抑制。更深入地了解 ICH 所涉及的免疫机制很可能会成功地进行免疫干预。
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引用次数: 0
ATXN3: a multifunctional protein involved in the polyglutamine disease spinocerebellar ataxia type 3. ATXN3:一种与多聚谷氨酰胺病脊髓小脑共济失调 3 型有关的多功能蛋白质。
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1017/erm.2024.10
Esperanza Hernández-Carralero, Grégoire Quinet, Raimundo Freire

ATXN3 is a ubiquitin hydrolase (or deubiquitinase, DUB), product of the ATXN3 gene, ubiquitously expressed in various cell types including peripheral and neuronal tissues and involved in several cellular pathways. Importantly, the expansion of the CAG trinucleotides within the ATXN3 gene leads to an expanded polyglutamine domain in the encoded protein, which has been associated with the onset of the spinocerebellar ataxia type 3, also known as Machado-Joseph disease, the most common dominantly inherited ataxia worldwide. ATXN3 has therefore been under intensive investigation for decades. In this review, we summarize the main functions of ATXN3 in proteostasis, DNA repair and transcriptional regulation, as well as the emerging role in regulating chromatin structure. The mentioned molecular functions of ATXN3 are also reviewed in the context of the pathological expanded form of ATXN3.

ATXN3 是一种泛素水解酶(或去泛素化酶,DUB),是 ATXN3 基因的产物,在包括外周组织和神经元组织在内的各种细胞类型中普遍表达,并参与多种细胞通路。重要的是,ATXN3 基因中 CAG 三核苷酸的扩增导致编码蛋白中多谷氨酰胺结构域的扩增,这与脊髓小脑共济失调 3 型(又称马查多-约瑟夫病)的发病有关,该病是全球最常见的显性遗传共济失调。因此,几十年来,ATXN3 一直在接受深入研究。在这篇综述中,我们总结了 ATXN3 在蛋白稳态、DNA 修复和转录调控方面的主要功能,以及在调控染色质结构方面的新作用。我们还结合 ATXN3 的病理扩展形式,对上述 ATXN3 的分子功能进行了综述。
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引用次数: 0
Epigenetic tuning of tumour-associated macrophages (TAMs): a potential approach in hepatocellular carcinoma (HCC) immunotherapy. 肿瘤相关巨噬细胞(TAMs)的表观遗传学调整:肝细胞癌(HCC)免疫疗法的一种潜在方法。
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1017/erm.2024.9
Israa M Helal, Monica A Kamal, Mostafa K Abd El-Aziz, Hend M El Tayebi

Recent development in immunotherapy for cancer treatment has substantiated to be more effective than most of the other treatments. Immunity is the first line of defence of the body; nevertheless, cancerous cells can manipulate immunity compartments to play several roles in tumour progression. Tumour-associated macrophages (TAMs), one of the most dominant components in the tumour microenvironment, are recognized as anti-tumour suppressors. Unfortunately, the complete behaviour of TAMs is still unclear and understudied. TAM density is directly correlated with the progression and poor prognosis of hepatocellular carcinoma (HCC), therefore studying TAMs from different points of view passing by all the factors that may affect its existence, polarization, functions and repolarization are of great importance. Different epigenetic regulations were reported to have a direct relation with both HCC and TAMs. Here, this review discusses different epigenetic regulations that can affect TAMs in HCC whether positively or negatively.

免疫疗法在癌症治疗领域的最新发展证明,它比大多数其他疗法都更为有效。免疫是人体的第一道防线;然而,癌细胞可以操纵免疫系统,在肿瘤进展过程中发挥多种作用。肿瘤相关巨噬细胞(TAMs)是肿瘤微环境中最主要的组成部分之一,被认为是抗肿瘤抑制因子。遗憾的是,TAMs 的全部行为仍不清楚,研究也不足。TAM的密度与肝细胞癌(HCC)的进展和不良预后直接相关,因此从不同角度研究TAM,包括可能影响其存在、极化、功能和再极化的所有因素,具有重要意义。据报道,不同的表观遗传调控与 HCC 和 TAMs 都有直接关系。本综述将讨论不同的表观遗传调控对 HCC 中的 TAMs 产生的积极或消极影响。
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引用次数: 0
PARP enzymes and mono-ADP-ribosylation: advancing the connection from interferon-signalling to cancer biology. PARP酶和单ADP-核糖基化:推进从干扰素信号到癌症生物学的联系。
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-27 DOI: 10.1017/erm.2024.13
Barbara Morone, Giovanna Grimaldi

ADP-ribosyltransferases of the PARP family encompass a group of enzymes with variegated regulatory functions in cells, ranging from DNA damage repair to the control of cell-cycle progression and immune response. Over the years, this knowledge has led to the use of PARP1/2 inhibitors as mainstay pharmaceutical strategies for the treatment of ovarian, pancreatic, prostate and breast cancers, holding mutations in genes encoding for proteins involved in the DNA repair mechanisms (synthetic lethality). Meanwhile, the last decade has witnessed significant progress in comprehending cellular pathways regulated by mono-ADP-ribosylation, with a huge effort in the development of novel selective compounds to inhibit those PARPs endowed with mono-ADP-ribosylation activity. This review focuses on the progress achieved in the cancer field, delving into most recent findings regarding the role of a subset of enzymes - the interferon-stimulated PARPs - in cancer progression.

PARP 家族的 ADP 核糖转移酶包括一组在细胞中具有各种调节功能的酶,从 DNA 损伤修复到控制细胞周期进展和免疫反应。多年来,这些知识促使人们将 PARP1/2 抑制剂作为治疗卵巢癌、胰腺癌、前列腺癌和乳腺癌的主要药物策略,因为 DNA 修复机制(合成致死)涉及的蛋白质编码基因发生了突变。与此同时,在过去十年中,人们在理解受单 ADP 核糖基化调控的细胞通路方面取得了重大进展,并在开发新型选择性化合物以抑制具有单 ADP 核糖基化活性的 PARPs 方面做出了巨大努力。本综述将重点关注癌症领域取得的进展,深入探讨有关干扰素刺激的 PARPs 这一类酶在癌症进展中所起作用的最新发现。
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引用次数: 0
Specific and shared biological functions of PARP2 – is PARP2 really a lil’ brother of PARP1? PARP2 的特定和共享生物功能--PARP2 真的是 PARP1 的小弟弟吗?
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-03 DOI: 10.1017/erm.2024.14
Magdolna Szántó, José Yélamos, Péter Bai
PARP2, that belongs to the family of ADP-ribosyl transferase enzymes (ART), is a discovery of the millennium, as it was identified in 1999. Although PARP2 was described initially as a DNA repair factor, it is now evident that PARP2 partakes in the regulation or execution of multiple biological processes as inflammation, carcinogenesis and cancer progression, metabolism or oxidative stress-related diseases. Hereby, we review the involvement of PARP2 in these processes with the aim of understanding which processes are specific for PARP2, but not for other members of the ART family. A better understanding of the specific functions of PARP2 in all of these biological processes is crucial for the development of new PARP-centred selective therapies.
PARP2 属于 ADP 核糖基转移酶(ART)家族,于 1999 年被发现,是一项千年发现。尽管 PARP2 最初被描述为一种 DNA 修复因子,但现在人们发现,PARP2 参与了多种生物过程的调节或执行,如炎症、致癌和癌症进展、新陈代谢或氧化应激相关疾病。在此,我们回顾了 PARP2 参与这些过程的情况,目的是了解哪些过程是 PARP2 所特有的,而 ART 家族的其他成员则没有。更好地了解 PARP2 在所有这些生物过程中的特定功能对于开发以 PARP 为中心的新型选择性疗法至关重要。
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引用次数: 0
The multifaceted functions of long non-coding RNA HOTAIR in neuropathologies and its potential as a prognostic marker and therapeutic biotarget 长非编码 RNA HOTAIR 在神经病变中的多方面功能及其作为预后标记和治疗生物靶点的潜力
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-29 DOI: 10.1017/erm.2024.11
Faraz Ahmad, Ravi Sudesh, Atheeq Toufeeq Ahmed, Mohanapriya Arumugam, Darin Mansor Mathkor, Shafiul Haque

Long non-coding RNAs (lncRNAs) are progressively being perceived as prominent molecular agents controlling multiple aspects of neuronal (patho)physiology. Amongst these is the HOX transcript antisense intergenic RNA, often abbreviated as HOTAIR. HOTAIR epigenetically regulates its target genes via its interaction with two different chromatin-modifying agents; histone methyltransferase polycomb-repressive complex 2 and histone demethylase lysine-specific demethylase 1. Parenthetically, HOTAIR elicits trans-acting sponging function against multiple micro-RNA species. Oncological research studies have confirmed the pathogenic functions of HOTAIR in multiple cancer types, such as gliomas and proposed it as a pro-oncological lncRNA. In fact, its expression has been suggested to be a predictor of the severity/grade of gliomas, and as a prognostic biomarker. Moreover, a propound influence of HOTAIR in other aspects of brain heath and disease states is just beginning to be unravelled. The objective of this review is to recapitulate all the relevant data pertaining to the regulatory roles of HOTAIR in neuronal (patho)physiology. To this end, we discuss the pathogenic mechanisms of HOTAIR in multiple neuronal diseases, such as neurodegeneration, traumatic brain injury and neuropsychiatric disorders. Finally, we also summarize the results from the studies incriminating HOTAIR in the pathogeneses of gliomas and other brain cancers. Implications of HOTAIR serving as a suitable therapeutic target in neuropathologies are also discussed.

长非编码 RNA(lncRNA)逐渐被认为是控制神经元(病理)生理学多个方面的重要分子介质。其中包括 HOX 转录本反义基因间 RNA,通常缩写为 HOTAIR。HOTAIR 通过与两种不同的染色质修饰因子(组蛋白甲基转移酶多聚酶抑制复合体 2 和组蛋白去甲基化酶赖氨酸特异性去甲基化酶 1)相互作用,对其目标基因进行表观遗传调控。此外,HOTAIR 对多种微 RNA 具有反式作用海绵功能。肿瘤学研究证实了 HOTAIR 在神经胶质瘤等多种癌症类型中的致病功能,并提出它是一种促肿瘤的 lncRNA。事实上,它的表达被认为是胶质瘤严重程度/分级的预测因子,也是一种预后生物标志物。此外,HOTAIR 对大脑健康和疾病状态其他方面的影响也刚刚开始揭示。本综述旨在概述与 HOTAIR 在神经元(病理)生理学中的调控作用有关的所有相关数据。为此,我们讨论了 HOTAIR 在神经变性、脑外伤和神经精神疾病等多种神经元疾病中的致病机制。最后,我们还总结了将 HOTAIR 与神经胶质瘤和其他脑癌的发病机制联系起来的研究结果。此外,我们还讨论了将 HOTAIR 作为神经病理学治疗靶点的意义。
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引用次数: 0
Decoding bioactive signals of the RNA secretome: the cell-free messenger RNA catalogue 解码 RNA 分泌组的生物活性信号:无细胞信使 RNA 目录
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-29 DOI: 10.1017/erm.2024.12
Rhys E. De Sota, Stephen R. Quake, John J. Sninsky, Shusuke Toden

Despite gene-expression profiling being one of the most common methods to evaluate molecular dysregulation in tissues, the utilization of cell-free messenger RNA (cf-mRNA) as a blood-based non-invasive biomarker analyte has been limited compared to other RNA classes. Recent advancements in low-input RNA-sequencing and normalization techniques, however, have enabled characterization as well as accurate quantification of cf-mRNAs allowing direct pathological insights. The molecular profile of the cell-free transcriptome in multiple diseases has subsequently been characterized including, prenatal diseases, neurological disorders, liver diseases and cancers suggesting this biological compartment may serve as a disease agnostic platform. With mRNAs packaged in a myriad of extracellular vesicles and particles, these signals may be used to develop clinically actionable, non-invasive disease biomarkers. Here, we summarize the recent scientific developments of extracellular mRNA, biology of extracellular mRNA carriers, clinical utility of cf-mRNA as disease biomarkers, as well as proposed functions in cell and tissue pathophysiology.

尽管基因表达谱分析是评估组织中分子失调的最常用方法之一,但与其他 RNA 类别相比,利用无细胞信使 RNA(cf-mRNA)作为基于血液的非侵入性生物标记分析物一直受到限制。然而,最近在低输入 RNA 测序和归一化技术方面取得的进展,使 cf-mRNA 的特征描述和精确定量成为可能,从而能直接揭示病理。无细胞转录组在多种疾病中的分子特征随后得到了表征,包括产前疾病、神经系统疾病、肝脏疾病和癌症,这表明这一生物区划可作为一个与疾病无关的平台。由于 mRNA 包装在无数细胞外囊泡和颗粒中,这些信号可用于开发临床可操作的非侵入性疾病生物标记物。在此,我们总结了细胞外 mRNA 的最新科学发展、细胞外 mRNA 载体的生物学特性、cf-mRNA 作为疾病生物标记物的临床用途,以及在细胞和组织病理生理学中的拟议功能。
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引用次数: 0
AAV-mediated gene therapies for glaucoma and uveitis: are we there yet? AAV 介导的青光眼和葡萄膜炎基因疗法:我们成功了吗?
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-15 DOI: 10.1017/erm.2024.4
Brenda Castro, Jason C. Steel, Christopher J. Layton
Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.
青光眼和葡萄膜炎属于非血管性眼病,是导致失明和视力丧失的主要原因之一。这两种疾病的特点和机制各不相同,但都具有多因素和复杂性的特点,因此对患者和临床医生来说,这两种疾病的治疗充满挑战和负担。此外,青光眼早期症状不明显,葡萄膜炎病因多样,这些都阻碍了及时准确的诊断,是导致这两种疾病视力低下的原因之一。虽然目前的治疗方法在大多数情况下是有效的,但往往与患者依从性低和不良事件有关,这直接影响了整体治疗的成功率。因此,我们需要安全性更高、疗效更好的长效替代疗法。基因疗法,尤其是利用腺相关病毒(AAV)载体的疗法,已成为解决这些疾病未得到满足的需求的一种前景广阔的方法。人们提出了具有更强趋向性和更低免疫原性的工程化囊壳,以及设计用于靶向和可控表达的构建体。此外,单基因或多基因表达盒、基因编辑和沉默方法也已针对与这些疾病的发病机制有关的几种途径进行了研究。本综述讨论了基于 AAV 的青光眼和非感染性葡萄膜炎基因疗法所采用的策略,并概述了当前的进展和未来的方向。
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引用次数: 0
Impact of diabetes mellitus on osteoarthritis: a scoping review on biomarkers 糖尿病对骨关节炎的影响:生物标志物范围综述
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-12 DOI: 10.1017/erm.2024.7
Shi Rui Seow, Sumaiyah Mat, Amalina Ahmad Azam, Nor Fadilah Rajab, Intan Safinar Ismail, Devinder Kaur Ajit Singh, Suzana Shahar, Maw Pin Tan, Francis Berenbaum
Osteoarthritis (OA) commonly affects the knee and hip joints and accounts for 19.3% of disability-adjusted life years and years lived with disability worldwide (Refs 1, 2). Early management is important in order to avoid disability uphold quality of life (Ref. 3). However, a lack of awareness of subclinical and early symptomatic stages of OA often hampers early management (Ref. 4). Moreover, late diagnosis of OA among those with severe disease, at a stage when OA management becomes more complicated is common (Refs 5, 6, 7, 8). Established risk factors for the development and progression of OA include increasing age, female, history of trauma and obesity (Ref. 9). Recent studies have also drawn a link between OA and metabolic syndrome, which is characterized by insulin resistance, dyslipidaemia and hypertension (Refs 10, 11).
骨关节炎(OA)通常影响膝关节和髋关节,占全球残疾调整寿命年数和残疾生活年数的19.3%(参考文献1、2)。为了避免残疾,提高生活质量,早期治疗非常重要(参考文献 3)。然而,由于缺乏对OA亚临床和早期症状阶段的认识,往往阻碍了早期治疗(参考文献4)。此外,在病情严重的患者中,OA诊断较晚的情况也很常见,因为此时OA的治疗变得更加复杂(参考文献5、6、7、8)。导致 OA 发生和恶化的既定风险因素包括年龄增长、女性、外伤史和肥胖(参考文献 9)。最近的研究还发现,OA 与代谢综合征之间存在联系,代谢综合征的特征是胰岛素抵抗、血脂异常和高血压(参考文献 10、11)。
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引用次数: 0
Stability-based approaches in chemoproteomics 基于稳定性的化学蛋白质组学方法
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-04-12 DOI: 10.1017/erm.2024.6
Amy L. George, Maria Emilia Dueñas, José Luis Marín-Rubio, Matthias Trost

Target deconvolution can help understand how compounds exert therapeutic effects and can accelerate drug discovery by helping optimise safety and efficacy, revealing mechanisms of action, anticipate off-target effects and identifying opportunities for therapeutic expansion. Chemoproteomics, a combination of chemical biology with mass spectrometry has transformed target deconvolution. This review discusses modification-free chemoproteomic approaches that leverage the change in protein thermodynamics induced by small molecule ligand binding. Unlike modification-based methods relying on enriching specific protein targets, these approaches offer proteome-wide evaluations, driven by advancements in mass spectrometry sensitivity, increasing proteome coverage and quantitation methods. Advances in methods based on denaturation/precipitation by thermal or chemical denaturation, or by protease degradation are evaluated, emphasising the evolving landscape of chemoproteomics and its potential impact on future drug-development strategies.

靶点解旋有助于了解化合物如何发挥治疗效果,并通过帮助优化安全性和有效性、揭示作用机制、预测脱靶效应以及确定扩大治疗范围的机会,加速药物发现。化学蛋白质组学是化学生物学与质谱技术的结合,它改变了靶标解旋。本综述讨论了利用小分子配体结合引起的蛋白质热力学变化的无修饰化学蛋白质组学方法。与基于修饰的方法不同,这些方法依赖于富集特定的蛋白质目标,在质谱灵敏度、蛋白质组覆盖率和定量方法不断提高的推动下,这些方法提供了全蛋白质组的评估。本文评估了基于热变性或化学变性或蛋白酶降解的变性/沉淀方法的进展,强调了化学蛋白质组学不断发展的前景及其对未来药物开发战略的潜在影响。
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引用次数: 0
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