m6A甲基化修饰在动脉粥样硬化中的作用

N6-甲基嘌呤(m⁶A)是真核生物中最常见的转录后RNA修饰类型,涉及多种类型RNA。m⁶A甲基化修饰是动态可逆的,主要由多种酶和蛋白进行调控,包括甲基转移酶、去甲基化酶和m⁶A相关结合蛋白。动脉粥样硬化是心脑血管疾病的主要原因。近期研究发现m⁶A甲基化修饰与动脉粥样硬化密切相关。该文总结了目前对m⁶A甲基化修饰机制的认识,并阐述了与动脉粥样硬化相关细胞中m⁶A甲基化修饰的机制及最新进展,为动脉粥样硬化的诊断和防治提供新靶点。     

m6A甲基化在心肌缺血再灌注与心肌再生中的研究进展

N6-甲基腺嘌呤(N6-methyladenosine, m⁶A)RNA甲基化是最常见的、动态的、可逆的表观遗传RNA修饰，参与了包括心血管疾病在内的多种人类疾病的发病机制。最近的研究表明，m⁶A RNA甲基化在心肌缺血再灌注及心脏再生中发挥重要调控作用。重要的是，这些新发现表明，通过改变m⁶A的调节因子来控制m⁶A的水平，可能是防止心脏功能恶化促进心脏修复的一种新颖而有力的策略。     

N6-甲基腺苷修饰在HBV感染中的作用

N⁶-甲基腺苷（m⁶A）甲基化修饰现象普遍存在于人体各个组织和细胞中,是真核生物mRNA普遍的内部修饰。m⁶A修饰是动态可逆的,多种甲基转移酶、去甲基化酶及m⁶A结合蛋白参与此过程的调控。最近的研究结果表明,m⁶A修饰可影响病毒基因的表达,尤其在HBV感染过程中发挥着重要的作用。本文简要概括了m⁶A修饰的研究现状及机制,并重点关注其与HBV感染的关系。阐述了HBV转录物的m⁶A修饰作用,回顾了m⁶A参与HBV感染免疫应答的相关研究结果,归纳了HBV感染对宿主细胞m⁶A修饰及HBV相关肝细胞癌的影响,以期探讨其在HBV感染研究中的发展方向和潜在价值。     

m6A甲基化修饰在消化系统恶性肿瘤免疫治疗中的研究进展

N⁶-甲基腺苷(m⁶A)作为转录表达的关键调节剂,是真核细胞中最为常见的表观转录组学修饰。通过三大调节因子甲基转移酶、去甲基化酶和结合蛋白的共同调节,m⁶A在肿瘤的发生、发展中起有重要作用。免疫治疗作为多种晚期恶性肿瘤的一线治疗方案,在许多消化系统恶性肿瘤患者中表现出明显的耐药性。最近的研究证实,m⁶A甲基化修饰对肿瘤免疫起有重要的调节作用,从而影响肿瘤患者免疫治疗的疗效。本文就m⁶A甲基化修饰在消化系统恶性肿瘤免疫治疗中的研究进展作一综述。     

RNA甲基化修饰在肺动脉高压中作用机制研究进展

肺动脉高压(PAH)是一类多病因引起的以肺血管重构为主要特征，并最终引起右心衰竭和过早死亡的临床综合征。尽管PAH临床诊治取得明显进展，但疗效仍不能令人满意，患者5年生存率较低，且其发病机制复杂，目前仍未完全阐明。RNA甲基化修饰作为表观遗传学修饰中的第三大研究领域，其主要通过甲基转移酶(Writers)、去甲基化酶(Erasers)和甲基识别蛋白(Readers)三类蛋白可逆地写入、移除和读取甲基，在不改变基因序列的情况下对细胞增殖、凋亡、代谢等细胞生物学行为发挥重要作用。RNA甲基化修饰在肿瘤、心血管疾病、免疫与代谢性疾病等的发生发展中起着关键的调节作用，此外，其也参与了PAH的发生发展，并给PAH的治疗带来了新的希望。本研究综述了RNA甲基化修饰的种类及作用，N⁶-甲基腺嘌呤(m⁶A)、5-甲基胞嘧啶(m⁵C)和7-甲基鸟苷(m⁷G)修饰在PAH中的作用机制，以期为研究者提供新思路。     

RNA m6A修饰与心血管疾病研究进展

心血管疾病已成为我国成年人群的首位死亡原因。但其病因多样,发生机制至今仍未完全阐明。大量研究表明表观遗传修饰在心血管疾病发生发展中起重要作用。N⁶-甲基腺苷(m⁶)修饰是RNA最普遍的一种表观遗传修饰。研究提示m⁶修饰可能在心血管疾病中发挥重要功能。本文就RNA m⁶修饰在心血管疾病中的调控作用的相关研究进行综述。     

RNA N6-甲基腺苷甲基化对老年患者阿司匹林反应性的影响

目的 探讨RNA N⁶-甲基腺苷(m⁶A)甲基化水平及相关基因对老年患者阿司匹林反应性的影响。方法 纳入规律服用阿司匹林100 mg/d的老年患者34例，根据光比浊法检测花生四烯酸诱导的血小板聚集率分为低反应组14例(血小板聚集率>12%),高反应组20例(血小板聚集率<7%)。检测全血RNA m⁶A甲基化水平及相关基因(YTHDF1、METTL3等)表达，血浆前列腺素H₂和血栓素B₂水平。结果 低反应组全血RNA m⁶A甲基化水平明显高于高反应组，差异有统计学意义(P<0.05)。低反应组YTHDF1和METTL3 mRNA表达明显高于高反应组[2.77(1.25,4.61)vs 1.32(0.75,1.84),P<0.05;1.64(1.01,2.92)vs 0.80(0.57,1.26),P<0.01]。低反应组血浆前列腺素H₂和血栓素B₂水平明显高于高反应组[(180.21±...     

N6-甲基腺苷甲基化在射血分数保留性心力衰竭中的作用的研究进展

表观遗传学参与心血管疾病进展的过程。近年研究表明,射血分数保留性心力衰竭(HFpEF)患者的多个基因转录本存在N⁶-甲基腺苷(m⁶A)水平的改变。现介绍m⁶A及其调节因子(甲基化酶、去甲基化酶和甲基化阅读蛋白)与HFpEF的关系,说明m⁶A可能通过影响心肌肥厚与纤维化、细胞自噬、炎症与氧化应激、糖脂代谢参与HFpEF的发生和发展,以期为HFpEF的治疗靶点提供新的研究方向。     

缺血性脑卒中m6A修饰与免疫微环境相关性分析

目的 初步探究N⁶-甲基腺苷(m⁶A)调节因子在缺血性脑卒中(IS)免疫微环境中的潜在作用与机制。方法 基于基因表达综合数据库(GEO),应用单样本基因集富集分析(ssGSEA)、一致性聚类分析和基因集富集分析(GSEA)等生物信息学方法综合分析m⁶A调节因子与IS免疫微环境的相关性。结果 Spearman相关分析结果显示,IGF2BP2 mRNA的表达与CD56亮自然杀伤细胞富集分数的正相关关系最强(r_s=0.66),IGF2BP2 mRNA的表达与2型T辅助细胞富集分数的负相关关系最强(r_s=-0.64);ELF3 mRNA的表达与TGFb家族成员富集分数的正相关关系最强(r_s=0.56),ELAVL1 mRNA的表达与趋化因子富集分数的负相关关系最强(r_s=-0.66)(均P<0.05)。一致性聚类分析确定了两种具有不同m⁶A修饰模式的IS亚型,亚型1中活化B细胞、活化CD4 T细胞、活化CD8 T细...     

刚地弓形虫感染对小鼠脑组织转录本m6A甲基化修饰的影响

目的 分析刚地弓形虫感染对小鼠脑组织转录本的N6-甲基腺苷(m⁶A)甲基化修饰水平的影响。方法 20只雌性C57BL/6J小鼠随机分为TgCtwh6感染组(7只)、LHG感染组(7只)和对照组(TgCtwh6感染组、LHG感染组的对照各3只)。TgCtwh6感染组、LHG感染组分别灌胃接种中国Ⅰ型wh6株(TgCtwh6)和中国Ⅲ型LHG株刚地弓形虫感染小鼠脑组织悬液0.2ml (20个包囊/鼠),对照组灌胃等量的生理盐水。分别在接种后15、30和45 d,用抽签法随机抽取感染组小鼠各1只,麻醉后处死,取脑组织,于显微镜下分别记录大脑皮层区、海马区和嗅球区的包囊数。感染后45 d每组分别取3只小鼠的全脑组织,提取总RNA,制备基因组文库,进行转录组测序,筛选差异甲基化位点(DML),统计感染组和对照组的mRNA的差异m⁶A甲基化位点及其所在转录本;对甲基化位点所在转录本进行基因本体功能注释(GO)分析,京都基因与基因组百科全书(KEGG)富集分析,对甲基化差异转录本进行基因集富集分析(GSEA)。选取甲基转移酶样3 (METTL3)、肥胖相关...     

Decreased protein synthesis by microsomes from aging Drosophila melanogaster.

A microsomal preparation from larvae of Drosophila melanogaster readily incorporated a ¹⁴C-amino acid mixture into its protein. Amino acid incorporation by microsomes from adult organisms, however, declined markedly with age. The decline in amino acid incorporation did not appear to be due to decreases in ribosomes or messenger RNA, since ribosome levels decreased only 6%, while incorporation decreased more than 70%, and only a 23% decrease in polysome-bound RNA could be detected. However, the ppolyuridylate-promoted incorporation of ¹⁴C-phenylalanine into polypeptide exhibited a sharp, age-related decline, indicating that some component of the translation system, other than messenger RNA, is responsible for the observed decline in protein synthesis     

Melatonin restores the pluripotency of long-term-cultured embryonic stem cells through melatonin receptor-dependent m6A RNA regulation

N6-methyladenosine (m6A) methylation is the most common and abundant modification on mammalian messenger RNA (mRNA) and regulates the pluripotency of embryonic stem cells (ESCs). Research has shown that melatonin plays a fundamental role in DNA and histone modifications. However, the effect of melatonin on RNA modification is unknown. Here, for the first time, we investigated the effect of melatonin on m6A modifications in long-term-cultured ESCs. Pluripotency studies indicated that 10 μmol/L melatonin sufficiently maintained ESCs with stemness features over 45 passages (more than 90 days). Notably, treatment of ESCs with melatonin led to a significant decrease in the nuclear presence of m6A methyltransferase complex and decreased global m6A modification. Depletion of melatonin receptor 1 (MT1) by CRISPR/Cas9 significantly reduced the effects of melatonin on ESC pluripotency and m6A modification. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) revealed that melatonin promotes stabilization of core pluripotency factors, such as Nanog, Sox2, Klf4, and c-Myc, by preventing m6A-dependent mRNA decay. Using cell signaling pathway profiling systems, melatonin was shown to regulate m6A modification predominantly through the MT1-JAK2/STAT3-Zfp217 signal axis. This study reveals a new dimension regarding melatonin regulation of gene expression at the RNA level.     

m6A甲基化与代谢性疾病的研究进展

N6-甲基腺嘌呤(N6-methyladenosine,m⁶A)是腺嘌呤(A)第6位氮原子被甲基转移酶催化形成的一种RNA甲基化修饰,是真核生物信使RNA(mRNA)上最多的化学修饰形式。近年来研究发现m⁶A对RNA在脂肪组织生成、细胞分化和免疫/炎症反应等过程中发挥重要的调控作用。代谢性疾病是由体内蛋白质、葡萄糖和脂质代谢紊乱引起的一类慢性炎症疾病。在肥胖、2型糖尿病和心血管疾病等代谢性疾病的发生发展中,m⁶A甲基化修饰通过调控糖脂代谢和免疫/炎症发挥着重要角色。文章拟对m⁶A甲基化在代谢性疾病中的作用做一综述,并从表观转录组学的角度为代谢性疾病的防治提供新的思路。     

Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure

OBJECTIVES

The purpose of the study was to investigate the effects of beta₁-blockade on left ventricular (LV) size and function for patients with chronic heart failure.

BACKGROUND

Large-scale trials have shown that a marked decrease in mortality can be obtained by treatment of chronic heart failure with beta-adrenergic blocking agents. Possible mechanisms behind this effect remain yet to be fully elucidated, and previous studies have presented insignificant results regarding suspected LV antiremodeling effects.

METHODS

In this randomized, placebo-controlled and double-blind substudy to the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF), 41 patients were examined with magnetic resonance imaging three times in a six-month period, assessing LV dimensions and function.

RESULTS

Decreases in both LV end-diastolic volume index (150 ml/m² at baseline to 126 ml/m² after six months, P = 0.007) and LV end-systolic volume index (107 ml/m² to 81 ml/m², P = 0.001) were found, whereas LV ejection fraction increased in the metoprolol CR/XL group (29% to 37%, P = 0.005). No significant changes were seen in the placebo group regarding these variables. Left ventricular stroke volume index remained unchanged, whereas LV mass index decreased in both groups (175 g/m² to 160 g/m² in the placebo group [p = 0.005] and 179 g/m² to 164 g/m² in the metoprolol CR/XL group [p = 0.01]).

CONCLUSIONS

This study is the first randomized study to demonstrate that the beta₁-blocker metoprolol CR/XL has antiremodeling effects on the LV in patients with chronic heart failure and consequently provides an explanation for the highly significant decrease in mortality from worsening heart failure found in the MERIT-HF trial.     

青中年时期体重状态变化与中老年时期高血压的关系

目的:探讨青年及中年时期超重后的体重状态变化及减重比与中老年高血压患病风险的关系。方法:选取中国糖尿病和代谢紊乱研究中年龄40～79岁的人群。减重比定义为(最大体重-目前体重)/最大体重。采用多因素 logistic回归分析,分别探讨青年及中年超重后的体重状态变化及减重比与高血压的关系。 结果:共...     

Comparison of time of reperfusion during anterior wall acute myocardial infarction to left ventricular volume one month and 20 months later

We studied 95 patients with a first anterior wall acute myocardial infarction who received successful reperfusion within 72 hours after the onset. The patients were divided into 4 groups based on the time required to achieve reperfusion; <3 hours (n = 23), 3 to 6 hours (n = 42), 6 to 24 hours (n = 17), and >24 to 72 hours (n = 13). The infarct size, as evaluated by thallium-201 single-photon emission computed tomography, at 1 month after the infarct was significantly larger (p <0.05) in >24 to 72 hours (1,593 ± 652 U) than that in <3 hours (749 ± 650 U), but was not significantly different from that at 3 to 6 hours (1,353 ± 770 U) or 6 to 24 hours (1,371 ± 561 U). The end-diastolic volume index at 1 month did not differ among the 4 groups. However, the end-diastolic volume index during the follow-up period (20 ± 8 months) in >24 to 72 hours (93 ± 23 ml/m²) was significantly larger than that in the other 3 groups (<3 hours [65 ± 21 ml/m²], 3 to 6 hours [65 ± 22 ml/m²], and 6 to 24 hours [70 ± 25 ml/m²]). Similar findings were observed in end-systolic volume index. In conclusion, although infarct size reduction was not observed by late reperfusion, left ventricular volumes at 1 month were comparable among patients with successful reperfusion within 3 and up to >24 hours. Left ventricular volumes 2 years after acute myocardial infarction were significantly larger in patients who did not under reperfusion for >24 hours.     

Functional Modification of 16S Ribosomal RNA by Kethoxal

Kethoxal reacts with 30S ribosomal subunits to give totally inactive particles, as measured by in vitro protein synthesis. It is postulated that functional modification occurs at the binding site for transfer RNA since (a) loss of specific binding of transfer RNA, but not binding of messenger RNA, is simultaneous with loss of protein synthesis, and (b) loss of activity is inhibited by bound transfer RNA. By means of in vitro reconstitution and labeling techniques, it is found that loss of transfer RNA-binding activity is correlated with the modification of six or seven guanine residues in 16S RNA.