Micro RNAs与急性心肌梗死关系的研究进展

急性心肌梗死(acute myocardial infarction,AMI)是冠状动脉疾病最严重的表现,其引起的心肌组织损伤可促进心力衰竭的发展。尽管近些年由于生活方式的改变、治疗方式(如经皮冠状动脉介入治疗)的发展使AMI的预后得到了改善,但是AMI依旧每年危害着全球700多万人的身心健康,AMI仍然是世界范围内高发病率和高死亡率的主要疾病之一[1]。微小RNA(micro RNAs,miRNAs)是在20世纪90年代被发现的,mi RNAs的研究已经迅速发展成为一个成熟而广阔的领域。mi RNAs存在于几乎所有类型的细胞和细胞的病理生理活动中,包括与心血管系统相关的细胞。本文将mi RNAs对AMI病理生理进程的影响进行综述,希望为临床治疗提供新思路。

脑梗死患者血micro RNA表达水平对预后的影响

目的探讨脑梗死患者血micro RNA(miRNA)表达水平对预后的影响。方法选取邯郸市中心医院和安国市医院收治的63例急性脑梗死患者临床资料,分为两组,预后良好组31例,预后不良组32例。收集患者的一般资料,采集患者治疗前外周静脉血予以实时荧光定量-聚合酶链式反应(qPCR)检测miR-124、miR-125b、miR-126、miR-223、miR-422、miR-221、miR-335等miRNA的表达水平,进行多因素Logistic回归分析预后的影响因素。结果两组患者吸烟、NIHSS评分之间差异有统计学意义(χ^(2)/t=7.746、16.387,P<0.05)。预后良好组的miR-124、miR-125b、miR-126、miR-422、miR-221、miR-335水平显著低于预后不良组,而miR-223显著高于预后不良组,差异有统计学意义(t=8.421、6.348、5.434、9.847、7.987、10.346、7.652,P<0.05);miR-124、miR-125b、miR-126、miR-422、miR-221、miR-335、NIHSS评分均是影响不同预后的因素[OR(95%CI)=8.303(1.226~2.375)、4.241(1.119~6.890)、4.953(1.106~2.421)、4.860(0.316~5.900)、4.746(1.110~7.033)、6.677(0.266~8.219)、1.496(1.009~2.219),P<0.05]。结论不同预后的脑梗死患者外周血miRNA表达水平存在差异,对患者miR-124、miR-125b、miR-126、miR-422、miR-221、miR-335等指标进行监测,有助于观察患者的临床疗效及预后。

Micro RNA在缺血性卒中后炎症反应中的研究进展

Micro RNA(miRNA)是一类小型非编码RNA,是控制正常和患病大脑各种功能所必需的基因调节因子,其正常表达对于维持大脑的正常功能是必不可少的。脑缺血后,多种miRNAs的表达水平发生了显著变化,并在脑卒中的病理生理过程中发挥了重要作用。近年来,miRNAs在脑缺血后炎症反应中的重要调控作用逐渐受到重视,其对神经元、小胶质细胞、星形胶质细胞、少突胶质细胞等的调控作用也逐渐清晰。

红景天苷通过micro RNA-370改善2型糖尿病小鼠糖代谢的作用机制

目的观察红景天苷改善2型糖尿病小鼠血糖作用,探讨红景天苷改善2型糖尿病小鼠糖代谢紊乱的分子机制。方法采用高脂饮食联合腹腔注射链脲佐菌素(STZ)建立2型糖尿病小鼠模型,检测血糖相关指标、血清和肝脏micro RNA-370表达,以及肝组织糖异生关键酶(PEPCK/G6Pase)蛋白表达水平,观察红景天苷对2型糖尿病小鼠糖代谢紊乱的改善作用。分离培养小鼠原代肝细胞,采用瞬时转染技术将micro RNA-370沉默或过表达,观察micro RNA-370对糖代谢的影响及红景天苷调节糖代谢的分子机制。结果与模型对照组比较,红景天苷各剂量组小鼠血糖相关指标均明显改善(P<0.05);血清和肝组织micro RNA-370表达水平以及肝组织PEPCK/G6Pase蛋白相对表达水平均不同程度降低,且呈剂量依赖性,中、大剂量组降低较明显(P<0.05),小剂量组有降低趋势,但差异无统计学意义。细胞实验中,与空白对照组比较,红景天苷组和micro RNA抑制剂组PEPCK/G6Pase表达均被抑制(P<0.05),micro RNA-370激动剂组PEPCK/G6Pase表达明显促进(P<0.05),红景天苷与micro RNA-370激动剂联用能逆转micro RNA-370激动剂所致PEPCK/G6Pase蛋白表达增高(P<0.05)。结论红景天苷能明显改善2型糖尿病小鼠糖代谢紊乱,且该作用至少部分通过抑制micro RNA-370实现。

胃癌组织中micro RNA-375基因DNA甲基化及临床意义

目的探讨胃癌组织中microRNA－375基因DNA甲基化状态及其与胃癌相关临床病理因素的关系。方法收集2012年2～8月济南军区总医院20对新鲜胃癌组织和癌旁正常组织，应用甲基化特异性聚合酶链反应（MSP）技术检测组织中microRNA－375基因启动子区DNA甲基化水平，并分析其与胃癌相关临床病理因素的关系。结果microRNA－375基因启动子区甲基化阳性率在胃癌组及癌旁正常组分别为80％（16／20）和25％（5／20），差异有统计学意义（P〈O．05）。其DNA甲基化阳性率与胃癌的临床病理因素（性别、年龄、大体类型、组织学分型、TNM分期、淋巴结转移、远处转移、CEA）无显著性关系。结论胃癌组织中存在microRNA-375基因启动子区DNA甲基化．表明其可能参与了胃癌的发生和发展过程。

micro RNA-98干扰肺癌患者外周血B细胞IL-10的表达

目的验证miR-98可抑制肺癌患者B10细胞IL-10的表达。方法收集肺癌组和对照组外周血各10例,分离培养CD19B淋巴细胞,流式细胞检测B10细胞数,RT-PCR检测B10细胞miR-98和IL-10mRNA的表达,制备miR-98脂质体及建立肺癌小鼠模型,观察miR-98脂质体对小鼠瘤体生长的抑制作用。结果肺癌组外周血B10细胞miR-98显著低于对照组,IL-10 m RNA水平显著高于对照组,B10细胞miR-98与IL-10 mRNA间存在负相关。结论在miR-98高表达的环境下,B淋巴细胞IL-10表达降低,对荷瘤小鼠应用脂质体包埋miR-98能减慢肺癌生长。

Inhibition of Micro RNA 219 Expression Protects Synaptic Plasticity via Activating NMDAR1, Ca MKIIγ,and p-CREB after Microwave Radiation

In recent decades,the potential health hazards of microwave exposure have been attracting increasing attention.Our previous studies have demonstrated that microwave exposure impaired learning and memory in experimental animal models[1,2].

Loss of micro RNA-124 expression in neurons in the peri-lesion area in mice with spinal cord injury

Micro RNA-124（mi R-124） is abundantly expressed in neurons in the mammalian central nervous system, and plays critical roles in the regulation of gene expression during embryonic neurogenesis and postnatal neural differentiation. However, the expression profile of mi R-124 after spinal cord injury and the underlying regulatory mechanisms are not well understood. In the present study, we examined the expression of mi R-124 in mouse brain and spinal cord after spinal cord injury using in situ hybridization. Furthermore, the expression of mi R-124 was examined with quantitative RT-PCR at 1, 3 and 7 days after spinal cord injury. The mi R-124 expression in neurons at the site of injury was evaluated by in situ hybridization combined with Neu N immunohistochemical staining. The mi R-124 was mainly expressed in neurons throughout the brain and spinal cord. The expression of mi R-124 in neurons significantly decreased within 7 days after spinal cord injury. Some of the neurons in the peri-lesion area were Neu N＋/mi R-124-. Moreover, the neurons distal to the peri-lesion site were Neu N＋/mi R-124＋. These findings indicate that mi R-124 expression in neurons is reduced after spinal cord injury, and may reflect the severity of spinal cord injury.

Role of mitochondria in regulating micro RNA activity and its relevance to the central nervous system

Mitochondria serve as the powerhouse of cells,respond to cellular demands and stressors,and play an essential role in cell signaling,differentiation,and survival.Aberrant mitochondria function has been linked to diverse and complex human diseases such as neurodegenerative diseases,cancers,myopathies,premature aging,and metabolic syndromes（Nunnari and Suomalainen,2012）.

Valproic acid as a micro RNA modulator to promote neurite outgrowth

Valproic acid （VPA） has been a first-choice drug for clinical treatment of epilepsy and manic disorder. For decades, its phar- macological action was believed to act on inhibition of gam- ma-aminobutyric acid （GABA） transaminase, in turn, increas- ing GABA in inhibitory synapses. However, in recent years, VPA has been investigated on other therapeutic actions. Those investigations demonstrate that VPA shows neuroprotective ef- fects by promoting neurogenesis, neuronal differentiation, and neuroregeneration （Foti et al., 2013）.

Micro RNAs potential utility in colon cancer: Early detection, prognosis, and chemosensitivity

Over the past decade, research has shown that aberrant expression of micro RNA(mi RNA) is involved in colorectal cancer development and progression. Micro RNAs are small sequences of non-coding RNA that regulate expression of genes involved in important cellular functions, such as cell differentiation, multiplication, and apoptosis. A specific mi RNA may display the effects of a tumor suppressor or oncogene. Altered mi RNA expression is found in colorectal cancer(CRC) and patterns of mi RNA expression correlate with CRC detection and outcome. Studies also have examined the use of circulating serum mi RNA and fecal mi RNA expression as non-invasive markers for early detection. Here, we review recent evidence demonstrating the potential role of mi RNA in CRC and the implications of its use in the diagnosis, prognosis, and management of CRC.

Circulating micro RNAs as diagnostic and prognostic tools for hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is an aggressive malignancy and the second leading cause of cancerrelated deaths worldwide. Conventional biomarkers exhibit poor performance in the surveillance,diagnosis,and prognosis of HCC. Micro RNAs(mi RNAs) are a class of evolutionarily conserved small non-coding RNAs that are involved in the regulation of gene expression and protein translation,and they play critical roles in cell growth,differentiation,and the development of various types of cancers,including HCC. Recent evidence revealed the role of mi RNAs as potential novel and ideal biomarkers for HCC. mi RNAs are released to extracellular spaces,and they are extremely stable in bodily fluids,including serum or plasma,where they are packaged into various microparticles or associated with RNA-binding proteins. Numerous studies have demonstrated that circulating mi RNAs have potential applications as minimally invasive biomarkers for HCC diagnosis and prognosis. The present review highlights current understanding of mi RNA biogenesis and the origins and types of circulating mi RNAs. We summarize recent progress in the use of circulating mi RNAs as diagnostic and prognostic biomarkers for HCC. We also discuss the challenges and perspectives of the clinical utility of circulating mi RNAs in HCC.

Circulating micro RNAs and long non-coding RNAs in gastric cancer diagnosis:An update and review

Gastric cancer(GC) is the fourth most common cancer and the third leading cause of cancer mortality worldwide. Micro RNAs(mi RNAs) and long non-coding RNAs(lnc RNAs) are the most popular non-coding RNAs in cancer research. To date,the roles of mi RNAs and lnc RNAs have been extensively studied in GC,suggesting that mi RNAs and lnc RNAs represent a vital component of tumor biology. Furthermore,circulating mi RNAs and lnc RNAs are found to be dysregulated in patients with GC compared with healthy individuals. Circulating mi RNAs and lnc RNAs may function as promising biomarkers to improve the early detection of GC. Multiple possibilities for mi RNA secretion have been elucidated,including active secretion by microvesicles,exosomes,apoptotic bodies,highdensity lipoproteins and protein complexes as well as passive leakage from cells. However,the mechanism underlying lnc RNA secretion and the functions of circulating mi RNAs and lnc RNAs have not been fully illuminated. Concurrently,to standardize results of global investigations of circulating mi RNAs and lnc RNAs biomarker studies,several recommendations for preanalytic considerations are put forward. In this review,we summarize the known circulating mi RNAs and lnc RNAs for GC diagnosis. The possible mechanism of mi RNA and lnc RNA secretion as well as methodologies for identification of circulating mi RNAs and lnc RNAs are also discussed. The topics covered here highlight new insights into GC diagnosis and screening.

Micro RNA-1290 promotes esophageal squamous cell carcinoma cell proliferation and metastasis

AIM:To investigate the biological role of mi R-1290 in esophageal squamous cell carcinoma(ESCC) progression and invasion and the underlying mechanism.METHODS:Quantitative real-time polymerase chain reaction(q RT-PCR) was performed to evaluate mi R-1290 expression in ESCC tissue samples.The roles of mi R-1290 in cell proliferation,migration and invasion were identified using mi R-1290 mimic-transfected cells.In addition,the regulatory effect of mi R-1290 on suppressor of cancer cell invasion(SCAI) was evaluated using q RT-PCR,Western blot analysis and a dual luciferase reporter assay.RESULTS:mi R-1290 was significantly upregulated in ESCC tissue samples compared with normal adjacent tissues(9.213 ± 1.150 vs 1.000 ± 0.0),(P < 0.01).Upregulation of mi R-1290 was associated with tumor differentiation(P = 0.021),N classification(P = 0.006) and tumor-node-metastasis stage(P = 0.021) in ESCC patients.Moreover,ectopic mi R-1290 expression potently promoted ESCC cell growth(P < 0.01),migration(P < 0.01) and invasion(P < 0.01) in vitro.mi R-1290 overexpression in ESCC cell lines decreased SCAI expression at the translational level and reduced SCAI-driven luciferase-reporter activity(P < 0.01).CONCLUSION:Our findings suggested that mi R-1290 may play an oncogenic role in cellular processes of ESCC.

Hepatitis B virus and micro RNAs:Complex interactions affecting hepatitis B virus replication and hepatitis B virusassociated diseases

Chronic infection with the hepatitis B virus(HBV) is the leading risk factor for the development of hepatocellular carcinoma(HCC). With nearly 750000 deaths yearly, hepatocellular carcinoma is the second highest cause of cancer-related death in the world. Unfortunately, the molecular mechanisms that contribute to the development of HBV-associated HCC remain incompletely understood. Recently, micro RNAs(mi RNAs), a family of small non-coding RNAs that play a role primarily in post-transcriptional gene regulation, have been recognized as important regulators of cellular homeostasis, and altered regulation of mi RNA expression has been suggested to play a significant role in virus-associated diseases and the development of many cancers. With this in mind, many groups have begun to investigate the relationship between mi RNAs and HBV replication and HBV-associated disease. Multiple findings suggest that some mi RNAs, such as mi R-122, and mi R-125 and mi R-199 family members, are playing a role in HBV replication and HBV-associated disease, including the development of HBV-associated HCC. In this review, we discuss the current state of our understanding of the relationship between HBV and mi RNAs, including how HBV affects cellular mi RNAs, how these mi RNAs impact HBV replication, and the relationship between HBV-mediated mi RNA regulation and HCC development. We also address the impact of challenges in studying HBV, such as the lack of an effective model system for infectivity and a reliance on transformed cell lines, on our understanding of the relationship between HBV and mi RNAs, and proposepotential applications of mi RNA-related techniques that could enhance our understanding of the role mi RNAs play in HBV replication and HBV-associated disease, ultimately leading to new therapeutic options and improved patient outcomes.

血浆中micro RNA-122表达量与肝癌手术前后肝损伤的相关性

目的研究血浆中micro RNA-122（miR-122）的表达量与肝癌手术前后肝损伤的相关性。方法利用荧光定量检测30名健康人与30例肝癌患者的术前miR-122及丙氨酸氨基转移酶（ALT）的表达量,并进行比较,且检测30例肝癌患者的术前,术后第1、3、7天的血浆中miR-122及ALT,探讨miR-122与ALT的相关性。结果术前肝癌患者血浆中miR-122以及ALT的表达量均显著高于健康人群（P〈0.05）。患者术前,术后第1、3、7天血浆中的miR-122均与ALT呈正相关。结论血浆miR-122与肝切除术肝功能损伤相关,有望成为肝癌肝切除术前后肝功能损伤的检测指标。

Studied microRNA gene expression in human hepatocellular carcinoma by micro RNA microarray techniques

AIM: To achieve a better understanding of the molecular mechanisms of micro RNA expression changes involved in hepatocellular carcinoma.METHODS: In this research process, patients were not treated with antivirals, immunosuppressants or immunomodulators for at least 6 mo before collecting serum. The study population was composed of 35 outpatient hepatitis B virus(HBV) cases and 12 healthy control cases from the Affiliated Hospital of Inner Mongolia Medical University(Inner Mongolia, China) from July 2013 to April 2014. The 35 HBV cases were divided into two groups: a hepatocirrhosis group with 20 cases and a liver cancer group with 15 cases. All 35 cases carried HBs Ag. The diagnostic criteria followed the European Association for the Study of the Liver 2012(EASL2012) standards. Micro RNA(mi RNA) was extracted from a control group of patients, a group with hepatocirrhosis and a group with liver cancer and its quality was analyzed using the human V2 micro RNA expression beadchip. Cluster analysis and a radar chart were then applied to the mi RNA changes.RESULTS: The mi RNA-qualified rate of human serum samples was 93%. The concentration of a single sample was > 200 ng/μL and the volume was > 5 μL.All mi RNA serum samples were uncontaminated by the genome. The Mann-Whitney test showed significant differences in mi RNA between each group, with a detection P-value of < 0.05. Illumina software was set up with Diff Score set to ± 13, meaning that P = 0.001.There were significant changes in mi RNA expression between the three groups. mi RNA-183 was the most up-regulated, followed by mi RNA-373. mi RNA-129 and mi RNA-188 were both strongly down-regulated and mi RNA-378 was down-regulated a small amount. The liver cancer group had greater changes, which indicated that changes in mi RNA expression levels were caused by hepatocirrhosis. The liver cancer disease course then further increased these changes. In the pentagon created by these five mi RNAs, three groups showed significant deviation. The liver cancer group had a bigger deviation trend. The chart indicated that mi RNA expression changes occurred in the hepatocirrhosis group, which increased in the liver cancer disease course and were irreversible.CONCLUSION: There was a significant relationship between the irreversible up-regulation of mi RNA-183/373 and down-regulation of mi RNA-129/188/378 and incidences of hepatocirrhosis and liver cancer.

Host cellular micro RNA involvement in the control of hepatitis B virus gene expression and replication

A large number of studies have demonstrated that the synergistic collaboration of a number of micro RNAs(mi RNAs), their growth factors and their downstream agents is required for the initiation and completion of pathogenesis in the liver. mi RNAs are thought to exert a profound effect on almost every aspect of liver biology and pathology. Accumulating evidence indicates that several mi RNAs are involved in the hepatitis B virus(HBV) life cycle and infectivity, in addition to HBVassociated liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma(HCC). In turn, HBV can modulate the expression of several cellular mi RNAs, thus promoting a favorable environment for its replication and survival. In this review, we focused on the involvement of host cellular mi RNAs that are directly and indirectly associated with HBV RNA or HBV associated transcription factors. Exploring different facets of the interactions among mi RNA, HBV and HCV infections, and the carcinogenesis and progress of HCC, could facilitate the development of novel and effective treatment approaches for liver disease.

Micro RNAs in cancer therapeutic response: Friend and foe

Cancer initiation and development engage extremely complicated pathological processes which involve alterations of a large number of cell signaling cascades and functional networks in temporal and spatial orders. During last decades, microR NAs(miR NAs), a class of noncoding RNAs, have emerged as critical players in cancer pathogenesis and progression by modulating many pathological aspects related to tumor development, growth, metastasis, and drug resistance. The major function of miR NAs is to post-transcriptionally regulate gene expression depending on recognition of complementary sequence residing in target mR NAs. Commonly, a particular mi RNA recognition sequence could be found in a number of genes, which allows a single miR-NA to regulate multiple functionally connected genes simultaneously and/or chronologically. Furthermore, a single gene can be targeted and regulated by multiple miR NAs. However, previous studies have demonstrated that mi RNA functions are highly context-dependent,which leads to distinct pathological outcomes in different types of cancer as well as at different stages by alteration of the same miR NA. Here we summarize recent progress in studies on miR NA function in cancer initiation, metastasis and therapeutic response, focusing on breast cancer. The varying functions of mi RNAs and potential application of using miR NAs as biomarkers as well as therapeutic approaches are further discussed in the context of different cancers.

Up-regulation of micro RNA-210 inhibits proliferation of hepatocellular carcinoma cells by targeting YES1

AIM: To determine the expression of micro RNA-210(mi R-210) in hepatocellular carcinoma(HCC) and to examine its role using HCC cells.METHODS: The expression of mi R-210 was determined in 21 pairs of HCC samples and the corresponding surrounding non-tumor tissues. The effects of mi R-210 on proliferation and cell cycle progression were examined using Hep G2 and Hu H7 cells. Overexpression and inhibition of mi R-210 was achieved by transfection of the cells with mi R-210 mimic or inhibitor. Luciferase reporter constructs were used to identify the mi R-210 interacting site on Yes1. Yes1 expression was examined after mi R-210 transfection,as well as in the HCC samples.RESULTS: mi R-210 was significantly up-regulated by 3.4 fold(P < 0.01) in the tumor samples. The over-expression of mi R-210 significantly reduced cell proliferation compared to the mock-treated cells(68.9% ± 7.4% and 53.6% ± 5.0%,P < 0.05 for the Hep G2 and Hu H7 cells respectively). Analysis of the Hu H7 cells transfected with mi R-210 mimic by flow cytometry showed that the cells took a longer time to reach the G2/M phase. The interaction between mi R-210 and the 3'UTR of the Yes1 transcript was confirmed using a luciferase reporter assay. Over-expression of mi R-210 reduced the expression of Yes1 protein in both Hu H7 and Hep G2 cells. Tumors with a greater than fourfold increase in the expression of mi R-210 showed consistently lower expressions of Yes1 in the tumors.In nocodazole-treated cells with a significant G2/M cell population,Yes1 protein was significantly reduced and pre-inhibition of mi R-210 in Hu H7 cells was able to prevent the reduction of Yes1 protein expression. Knock-down of Yes1 by si RNA also led to reduced cell proliferation(70.8% ± 7.5%,P < 0.05 in the Hu H7 cells).CONCLUSION: Up-regulation of mi R-210 inhibits cell proliferation. Yes1 is a target of mi R-210 and affects cell proliferation in HCC.