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Precision medicine for long QT syndrome: patient-specific iPSCs take the lead. 长QT综合征的精准医疗:患者特异性iPSCs领先。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-01-04 DOI: 10.1017/erm.2022.43
Yang Yu, Isabelle Deschenes, Ming-Tao Zhao

Long QT syndrome (LQTS) is a detrimental arrhythmia syndrome mainly caused by dysregulated expression or aberrant function of ion channels. The major clinical symptoms of ventricular arrhythmia, palpitations and syncope vary among LQTS subtypes. Susceptibility to malignant arrhythmia is a result of delayed repolarisation of the cardiomyocyte action potential (AP). There are 17 distinct subtypes of LQTS linked to 15 autosomal dominant genes with monogenic mutations. However, due to the presence of modifier genes, the identical mutation may result in completely different clinical manifestations in different carriers. In this review, we describe the roles of various ion channels in orchestrating APs and discuss molecular aetiologies of various types of LQTS. We highlight the usage of patient-specific induced pluripotent stem cell (iPSC) models in characterising fundamental mechanisms associated with LQTS. To mitigate the outcomes of LQTS, treatment strategies are initially focused on small molecules targeting ion channel activities. Next-generation treatments will reap the benefits from development of LQTS patient-specific iPSC platform, which is bolstered by the state-of-the-art technologies including whole-genome sequencing, CRISPR genome editing and machine learning. Deep phenotyping and high-throughput drug testing using LQTS patient-specific cardiomyocytes herald the upcoming precision medicine in LQTS.

长QT综合征(Long QT syndrome, LQTS)是一种主要由离子通道表达异常或功能异常引起的有害心律失常综合征。LQTS亚型的室性心律失常、心悸和晕厥的主要临床症状各不相同。恶性心律失常的易感性是心肌细胞动作电位(AP)复极延迟的结果。LQTS有17个不同的亚型,与15个常染色体显性基因有单基因突变。然而,由于修饰基因的存在,相同的突变可能导致不同携带者的临床表现完全不同。在这篇综述中,我们描述了各种离子通道在协调APs中的作用,并讨论了各种类型LQTS的分子病因。我们强调使用患者特异性诱导多能干细胞(iPSC)模型来表征与LQTS相关的基本机制。为了减轻LQTS的后果,治疗策略最初集中在靶向离子通道活性的小分子上。利用全基因组测序、CRISPR基因组编辑、机器学习等尖端技术开发的LQTS患者特异性iPSC平台,将成为下一代治疗的优势。利用LQTS患者特异性心肌细胞进行深度表型分析和高通量药物检测,预示着LQTS精准医学的到来。
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引用次数: 2
Modelling Alzheimer's disease using human brain organoids: current progress and challenges. 用人脑类器官模拟阿尔茨海默病:目前的进展和挑战。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-12-15 DOI: 10.1017/erm.2022.40
Mario Yanakiev, Olivia Soper, Daniel A Berg, Eunchai Kang

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by gradual memory loss and declining cognitive and executive functions. AD is the most common cause of dementia, affecting more than 50 million people worldwide, and is a major health concern in society. Despite decades of research, the cause of AD is not well understood and there is no effective curative treatment so far. Therefore, there is an urgent need to increase understanding of AD pathophysiology in the hope of developing a much-needed cure. Dissecting the cellular and molecular mechanisms of AD pathogenesis has been challenging as the most commonly used model systems such as transgenic animals and two-dimensional neuronal culture do not fully recapitulate the pathological hallmarks of AD. The recent advent of three-dimensional human brain organoids confers unique opportunities to study AD in a humanised model system by encapsulating many aspects of AD pathology. In the present review, we summarise the studies of AD using human brain organoids that recapitulate the major pathological components of AD including amyloid-β and tau aggregation, neuroinflammation, mitochondrial dysfunction, oxidative stress and synaptic and circuitry dysregulation. Additionally, the current challenges and future directions of the brain organoids modelling system are discussed.

阿尔茨海默病(AD)是一种进行性神经退行性疾病,其特征是逐渐丧失记忆,认知和执行功能下降。阿尔茨海默病是痴呆症的最常见原因,影响着全世界5000多万人,是社会的一个主要健康问题。尽管经过数十年的研究,人们对阿尔茨海默病的病因仍不甚了解,迄今为止也没有有效的治疗方法。因此,迫切需要增加对阿尔茨海默病病理生理的了解,以期开发出急需的治疗方法。解剖阿尔茨海默病发病的细胞和分子机制一直具有挑战性,因为最常用的模型系统,如转基因动物和二维神经元培养,并不能完全概括阿尔茨海默病的病理特征。最近出现的三维人脑类器官通过封装阿尔茨海默病病理的许多方面,为在人性化模型系统中研究阿尔茨海默病提供了独特的机会。在本综述中,我们总结了利用人脑类器官对阿尔茨海默病的研究,这些器官概括了阿尔茨海默病的主要病理成分,包括淀粉样蛋白β和tau聚集、神经炎症、线粒体功能障碍、氧化应激以及突触和电路失调。此外,还讨论了脑类器官建模系统目前面临的挑战和未来的发展方向。
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引用次数: 1
Oral microbiota in cancer: could the bad guy turn good with application of polyphenols? 口腔微生物群在癌症中的作用:多酚的应用能让坏家伙变好吗?
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-12-13 DOI: 10.1017/erm.2022.39
Mariya Gover Antoniraj, Kasi Pandima Devi, Ioana Berindan-Neagoe, Seyed Fazel Nabavi, Hamid Reza Khayat Kashani, Safieh Aghaabdollahian, Farzaneh Afkhami, Philippe Jeandet, Zahra Lorigooini, Maryam Khayatkashani, Seyed Mohammad Nabavi

The human oral cavity is comprised of dynamic and polynomial microbes which uniquely reside in the microenvironments of oral cavities. The cumulative functions of the symbiotic microbial communities maintain normal homeostasis; however, a shifted microbiota yields a dysbiosis state, which produces local and systemic diseases including dental caries, periodontitis, cancer, obesity and diabetes. Recent research reports claim that an association occurs between oral dysbiosis and the progression of different types of cancers including oral, gastric and pancreatic ones. Different mechanisms are proposed for the development of cancer, such as induction of inflammatory reactions, production of carcinogenic materials and alteration of the immune system. Medications are available to treat these associated diseases; however, the current strategies may further worsen the disease by unwanted side effects. Natural-derived polyphenol molecules significantly inhibit a wide range of systemic diseases with fewer side effects. In this review, we have displayed the functions of the oral microbes and we have extended the report regarding the role of polyphenols in oral microbiota to maintain healthy conditions and prevention of diseases with emphasis on the treatment of oral microbiota-associated cancer.

人类口腔是由动态和多项式微生物组成的,它们独特地生活在口腔微环境中。共生微生物群落的累积功能维持正常的体内平衡;然而,转移的微生物群会产生生态失调状态,从而产生局部和全身性疾病,包括龋齿、牙周炎、癌症、肥胖和糖尿病。最近的研究报告称,口腔生态失调与包括口腔癌、胃癌和胰腺癌在内的不同类型癌症的进展之间存在关联。对于癌症的发展提出了不同的机制,例如诱导炎症反应,致癌物质的产生和免疫系统的改变。有治疗这些相关疾病的药物;然而,目前的策略可能会因不必要的副作用而进一步恶化疾病。天然衍生的多酚分子显著抑制广泛的系统性疾病,副作用少。在这篇综述中,我们展示了口腔微生物的功能,并扩展了多酚在口腔微生物群中的作用,以维持健康状况和预防疾病,重点是口腔微生物群相关癌症的治疗。
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引用次数: 0
Irisin enhances longevity by boosting SIRT1, AMPK, autophagy and telomerase. 鸢尾素通过促进SIRT1、AMPK、自噬和端粒酶来延长寿命。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-12-12 DOI: 10.1017/erm.2022.41
Begoña Sánchez, Mario F Muñoz-Pinto, Mercedes Cano

Ageing is characterised by the accumulation of molecular and cellular damage through time, leading to a decline in physical and mental abilities. Currently, society has experienced a rapid increase in life expectancy, which has led to an increase in age-associated diseases. Therefore, it is crucial to study the process of ageing to guarantee the best conditions in the final stages of life. In recent years, interest has increased in a myokine known as irisin, which is secreted during physical exercise. This polypeptide hormone is produced by various organs, mainly muscle, and once it is released into the blood, it performs a wide variety of functions that are involved in metabolic control and may be relevant during some of the diseases associated with ageing. The aim of this review is to highlight the recent studies of irisin, such as its mechanism of expression, blood release, distribution, tissue target and participation in various cellular metabolic reactions and the relationship with key anti-ageing pathways such as adenosine monophosphate-activated protein kinase, silent information regulator T 1, autophagy and telomerase. In conclusion, irisin is a key player during the ageing process and it could be a novel target molecule for the therapeutic approach to boost longevity pathways. However, more research will be necessary to use this promising hormone for this gain.

衰老的特点是随着时间的推移,分子和细胞的损伤不断累积,导致身体和精神能力的下降。目前,社会预期寿命迅速增加,这导致与年龄有关的疾病增加。因此,研究衰老过程以保证生命最后阶段的最佳状态是至关重要的。近年来,人们对一种名为鸢尾素的肌肉因子的兴趣有所增加,鸢尾素是在体育锻炼中分泌的。这种多肽激素由各种器官产生,主要是肌肉,一旦它被释放到血液中,它就会发挥各种各样的功能,这些功能涉及代谢控制,并可能与一些与衰老相关的疾病有关。本文就鸢尾素的表达机制、血液释放、分布、组织靶点、参与各种细胞代谢反应以及与单磷酸腺苷活化蛋白激酶、沉默信息调节因子t1、自噬和端粒酶等关键抗衰老途径的关系等方面的研究进展进行综述。综上所述,鸢尾素在衰老过程中起着关键作用,它可能是一种新的靶向分子,用于促进长寿途径的治疗方法。然而,要使用这种有前途的激素来获得这种好处,还需要更多的研究。
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引用次数: 4
Hepatitis B virus DNA methylation and its potential role in chronic hepatitis B. 乙型肝炎病毒DNA甲基化及其在慢性乙型肝炎中的潜在作用
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-11-16 DOI: 10.1017/erm.2022.38
Wei Feng Low, Yun Fong Ngeow, Jack Bee Chook, Kok Keng Tee, Seng-Kai Ong, Suat Cheng Peh, Jan Jin Bong, Rosmawati Mohamed

Hepatitis B virus (HBV) infection led to 66% liver deaths world-wide in year 2015. Thirty-seven per cent of these deaths were the result of chronic hepatitis B (CHB)-associated hepatocellular carcinoma (HCC). Although early diagnosis of HCC improves survival, early detection is rare. Methylation of HBV DNA including covalently closed circular DNA (cccDNA) is more often encountered in HCC cases than those in CHB and cirrhosis. Three typical CpG islands within the HBV genome are the common sites for methylation. The HBV cccDNA methylation affects the viral replication and protein expression in the course of infection and may associate with the disease pathogenesis and HCC development. We review the current findings in HBV DNA methylation that provide insights into its role in HCC diagnosis.

2015年,乙型肝炎病毒(HBV)感染导致全球66%的肝脏死亡。其中37%的死亡是慢性乙型肝炎(CHB)相关肝细胞癌(HCC)的结果。虽然肝癌的早期诊断可以提高生存率,但早期发现是罕见的。HBV DNA包括共价闭合环DNA (cccDNA)的甲基化在HCC病例中比在CHB和肝硬化病例中更常见。HBV基因组中三个典型的CpG岛是甲基化的常见位点。HBV cccDNA甲基化在感染过程中影响病毒复制和蛋白表达,可能与疾病的发病机制和HCC的发展有关。我们回顾了目前在HBV DNA甲基化方面的发现,为其在HCC诊断中的作用提供了见解。
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引用次数: 0
Effects of lifespan-extending interventions on cognitive healthspan. 延长寿命干预对认知健康的影响。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-11-15 DOI: 10.1017/erm.2022.36
Luka Culig, Burcin Duan Sahbaz, Vilhelm A Bohr

Ageing is known to be the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. They are currently incurable and worsen over time, which has broad implications in the context of lifespan and healthspan extension. Adding years to life and even to physical health is suboptimal or even insufficient, if cognitive ageing is not adequately improved. In this review, we will examine how interventions that have the potential to extend lifespan in animals affect the brain, and if they would be able to thwart or delay the development of cognitive dysfunction and/or neurodegeneration. These interventions range from lifestyle (caloric restriction, physical exercise and environmental enrichment) through pharmacological (nicotinamide adenine dinucleotide precursors, resveratrol, rapamycin, metformin, spermidine and senolytics) to epigenetic reprogramming. We argue that while many of these interventions have clear potential to improve cognitive health and resilience, large-scale and long-term randomised controlled trials are needed, along with studies utilising washout periods to determine the effects of supplementation cessation, particularly in aged individuals.

众所周知,衰老是大多数神经退行性疾病的主要风险因素,包括阿尔茨海默病、帕金森病和亨廷顿病。它们目前无法治愈并随着时间的推移而恶化,这在寿命和健康寿命延长的背景下具有广泛的意义。如果认知老化没有得到充分改善,延长寿命甚至身体健康都是不理想的,甚至是不够的。在这篇综述中,我们将研究有可能延长动物寿命的干预措施如何影响大脑,以及它们是否能够阻止或延缓认知功能障碍和/或神经退行性变的发展。这些干预措施包括生活方式(热量限制、体育锻炼和环境富集)、药理学(烟酰胺腺嘌呤二核苷酸前体、白藜芦醇、雷帕霉素、二甲双胍、亚精胺和抗衰老药物)和表观遗传重编程。我们认为,虽然这些干预措施中有许多具有改善认知健康和恢复能力的明显潜力,但需要大规模和长期随机对照试验,以及利用洗脱期来确定补充剂停止的影响的研究,特别是在老年人中。
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引用次数: 0
Roles of TGF-β in cancer hallmarks and emerging onco-therapeutic design. TGF-β在癌症标志物中的作用和新出现的肿瘤联合治疗设计。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-11-08 DOI: 10.1017/erm.2022.37
Xiaofeng Dai, Dong Hua, Xiaoxia Lu

Transforming growth factor-beta (TGF-β) is a double-edged sword in cancer treatment because of its pivotal yet complex and roles played during cancer initiation/development. Current anti-cancer strategies involving TGF-β largely view TGF-β as an onco-therapeutic target that not only substantially hinders its full utilisation for cancer control, but also considerably restricts innovations in this field. Thereby, how to take advantages of therapeutically favourable properties of TGF-β for cancer management represents an interesting and less investigated problem. Here, by categorising cancer hallmarks into four critical transition events and one enabling characteristic controlling cancer initiation and progression, and delineating TGF-β complexities according to these cancer traits, we identify the suppressive role of TGF-β in tumour initiation and early-stage progression and its promotive functionalities in cancer metastasis as well as other cancer hallmarks. We also propose the feasibility and possible scenarios of combining cold atmospheric plasma (CAP) with onco-therapeutics utilising TGF-β for cancer control given the intrinsic properties of CAP against cancer hallmarks.

转化生长因子-β (TGF-β)在癌症发生/发展过程中发挥着关键而复杂的作用,是癌症治疗中的一把双刃剑。目前涉及TGF-β的抗癌策略在很大程度上将TGF-β视为一种联合治疗的靶点,这不仅极大地阻碍了TGF-β在癌症控制中的充分利用,也极大地限制了该领域的创新。因此,如何利用TGF-β在治疗上的有利特性进行癌症治疗是一个有趣但研究较少的问题。本研究通过将癌症特征分类为控制癌症发生和进展的四个关键转变事件和一个使能特征,并根据这些癌症特征描述TGF-β的复杂性,我们确定了TGF-β在肿瘤发生和早期进展中的抑制作用,以及它在癌症转移和其他癌症特征中的促进作用。鉴于冷大气等离子体(CAP)对癌症特征的内在特性,我们还提出了将冷大气等离子体(CAP)与利用TGF-β的肿瘤治疗药物结合起来进行癌症控制的可行性和可能方案。
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引用次数: 1
Preclinical activities of Cassia tora Linn against aging-related diseases. 决明子抗衰老相关疾病的临床前研究。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-10-25 DOI: 10.1017/erm.2022.33
Sun-Young Hwang, Chang-Su Na, Byeong Cheol Moon, Jung-Hyun Shim, Mee-Hyun Lee

Globally, an aging population is increasing, and aging is a natural physiological process and a major risk factor for all age-related diseases. It seriously threatens personal health and imposes a great economic burden. Therefore, there is a growing scientific interest in strategies for well-aging with prevention and treatment of age-related diseases. The seed, root, stem or leaves of Cassia tora Linn. are useful for anti-bacteria, anti-hyperlipidemia and anti-obesity due to its pharmacological activities such as anti-inflammation and anti-oxidant both in vitro and in vivo. Nevertheless, no clinical trials have been attempted so far, therefore here we would like to understand the current preclinical activities for aging-related disease models including cataract, metabolic dysfunction and neurodegeneration, then discuss their preparation for clinical trials and perspectives.

在全球范围内,人口老龄化日益加剧,老龄化是一种自然的生理过程,也是所有与年龄有关的疾病的主要危险因素。它严重威胁个人健康,并造成巨大的经济负担。因此,越来越多的科学兴趣是如何预防和治疗与年龄有关的疾病。决明子决明子的种子、根、茎或叶在体内体外均具有抗炎、抗氧化等药理作用,具有抗菌、抗高脂血症、抗肥胖等作用。然而,到目前为止,还没有临床试验的尝试,因此,我们想了解目前的衰老相关疾病模型的临床前活动,包括白内障,代谢功能障碍和神经退行性变,然后讨论他们的临床试验准备和观点。
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引用次数: 0
Metabolic signatures of immune cells in chronic kidney disease. 慢性肾脏疾病免疫细胞的代谢特征。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-10-21 DOI: 10.1017/erm.2022.35
Jie Li, Yi Yang, Yanan Wang, Qing Li, Fan He

Immune cells play a key role in maintaining renal dynamic balance and dealing with renal injury. The physiological and pathological functions of immune cells are intricately connected to their metabolic characteristics. However, immunometabolism in chronic kidney disease (CKD) is not fully understood. Pathophysiologically, disruption of kidney immune cells homeostasis causes inflammation and tissue damage via triggering metabolic reprogramming. The diverse metabolic characteristics of immune cells at different stages of CKD are strongly associated with their different pathological effect. In this work, we reviewed the metabolic characteristics of immune cells (macrophages, natural killer cells, T cells, natural killer T cells and B cells) and several non-immune cells, as well as potential treatments targeting immunometabolism in CKD. We attempt to elaborate on the metabolic signatures of immune cells and their intimate correlation with non-immune cells in CKD.

免疫细胞在维持肾脏动态平衡和处理肾损伤中起着关键作用。免疫细胞的生理和病理功能与其代谢特性有着错综复杂的联系。然而,慢性肾脏疾病(CKD)的免疫代谢尚不完全清楚。病理生理上,肾脏免疫细胞稳态的破坏通过触发代谢重编程引起炎症和组织损伤。CKD不同阶段免疫细胞不同的代谢特性与其不同的病理作用密切相关。在这项工作中,我们综述了免疫细胞(巨噬细胞、自然杀伤细胞、T细胞、自然杀伤T细胞和B细胞)和几种非免疫细胞的代谢特征,以及针对CKD免疫代谢的潜在治疗方法。我们试图阐述CKD中免疫细胞的代谢特征及其与非免疫细胞的密切关系。
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引用次数: 6
Extracellular vesicle isolation, purification and evaluation in cancer diagnosis. 细胞外囊泡的分离纯化及其在肿瘤诊断中的评价。
IF 6.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2022-10-21 DOI: 10.1017/erm.2022.34
Keywan Mortezaee, Jamal Majidpoor, Fardin Fathi

Strategies for non-invasive biomarker discovery in early detection of cancer are an urgent need. Extracellular vesicles (EVs) have generated increasing attention from the scientific community and are under intensive investigations due to their unique biological profiles and their non-invasive nature. EVs are membrane-enclosed vesicles with variable sizes and function. Such vesicles are actively secreted from multiple cell types and are considered as key vehicles for inter-cellular communications and signalling. The stability and potential to easily cross biological barriers enable EVs for exerting durable effects on target cells. These along with easy access to such vesicles, the consistent secretion from tumour during all stages of tumorigenesis and their content providing a reservoir of molecules as well as mirroring the identity of the cell of origin are virtues that have made EVs appealing to be assessed in liquid biopsy approaches and for using as a promising resource of biomarkers in cancer diagnosis and therapy and monitoring targeted cancer therapy. Early detection of EVs will guide time-scheduled personalised therapy. Surveying reliable and sensitive methods for rapid isolation of EVs from biofluids, the purity of isolated vesicles and their molecular profiling and marker specification for clinical translation in patients with cancer are issues in the area and the hot topics of many recent studies. Here, the focus is over methods for EV isolation and stratification for digging more information about liquid biopsy-based diagnosis. Extending knowledge regarding EV-based strategies is a key to validate independent patient follow-up for cancer diagnosis at early stages and inspecting the efficacy of therapeutics.

在癌症的早期检测中,非侵入性生物标志物的发现是迫切需要的。细胞外囊泡(EVs)由于其独特的生物学特征和非侵入性,引起了科学界越来越多的关注,并正在进行深入的研究。EVs是膜封闭的囊泡,具有不同的大小和功能。这些囊泡从多种细胞类型中积极分泌,被认为是细胞间通信和信号传导的关键载体。电动汽车的稳定性和跨越生物屏障的潜力使其能够对靶细胞产生持久的作用。这些优点加上易于接近这些囊泡,在肿瘤发生的所有阶段从肿瘤中持续分泌,其内容提供了分子储存库,并反映了起源细胞的身份,这些优点使得电动汽车在液体活检方法中具有吸引力,并被用作癌症诊断和治疗以及监测靶向癌症治疗的生物标志物资源。早期发现电动汽车将指导及时安排的个性化治疗。寻找可靠、灵敏的方法从生物体液中快速分离出ev,分离出的囊泡的纯度及其分子谱和标记物规范用于癌症患者的临床转化是该领域的问题,也是近年来许多研究的热点。在此,重点介绍EV分离和分层方法,以挖掘更多基于液体活检的诊断信息。扩展关于基于ev的策略的知识是验证早期癌症诊断的独立患者随访和检查治疗效果的关键。
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引用次数: 3
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Expert Reviews in Molecular Medicine
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