miR-122

MiR - 122
  • 文章类型: Journal Article
    鸡的肝脏对于维持生理活动和体内平衡至关重要。本研究旨在探讨microRNA-122(miR-122)的特异性功能及其分子调控机制。在鸡肝中高度表达。构建了慢病毒介导的miR-122过表达载体,并将其用于感染12日龄的雌性清源Partridge鸡。进行转录组测序分析以鉴定肝脏中差异表达的基因。miR-122的过表达导致776个差异表达基因(DEGs)。富集分析,包括基因本体论(GO),京都基因和基因组百科全书(KEGG),和基因集富集分析(GSEA)揭示了与脂质代谢的关联,细胞衰老,细胞粘附分子,和MAPK信号通路。miR-122的八个潜在靶基因(ARHGAP32,CTSD,LBH,PLEKHB2,SEC14L1,SLC2A1,SLC6A14和SP8)通过miRNA靶标预测平台和文献整合进行鉴定。本研究为miR-122在鸡肝中的分子调控机制提供了新的见解。强调其在关键生物过程和信号通路中的作用。这些发现增强了我们对miR-122对鸡肝脏功能影响的理解,并为改善鸡的生产性能和健康提供了有价值的信息。
    The liver of chickens is essential for maintaining physiological activities and homeostasis. This study aims to investigate the specific function and molecular regulatory mechanism of microRNA-122 (miR-122), which is highly expressed in chicken liver. A lentivirus-mediated overexpression vector of miR-122 was constructed and used to infect 12-day-old female Qingyuan Partridge chickens. Transcriptome sequencing analysis was performed to identify differentially expressed genes in the liver. Overexpression of miR-122 resulted in 776 differentially expressed genes (DEGs). Enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) revealed associations with lipid metabolism, cellular senescence, cell adhesion molecules, and the MAPK signaling pathway. Eight potential target genes of miR-122 (ARHGAP32, CTSD, LBH, PLEKHB2, SEC14L1, SLC2A1, SLC6A14, and SP8) were identified through miRNA target prediction platforms and literature integration. This study provides novel insights into the molecular regulatory mechanisms of miR-122 in chicken liver, highlighting its role in key biological processes and signaling pathways. These discoveries enhance our understanding of miR-122\'s impact on chicken liver function and offer valuable information for improving chicken production performance and health.
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  • 文章类型: Systematic Review
    酒精性肝病(ALD)包括一系列肝脏疾病,包括肝脏脂肪变性,酒精性肝炎(AH),纤维化,肝硬化,和肝细胞癌(HCC)。microRNAs(miRNAs)作为ALD的潜在生物标志物已经引起了极大的兴趣。
    我们搜索了PubMed,Embase,从开始到2024年6月,WebofScience和Cochrane中央对照试验登记册(CENTRAL)系统。根据ALD的阶段对所有提取的数据进行分层。投票计数策略对miRNA表达谱进行了荟萃分析。
    我们纳入了40项研究。在饮酒个体的血清中与不饮酒,miRNA-122和miRNA-155上调,miRNA-146a下调。在ALD患者中与健康的控制,miRNA-122和miRNA-155也上调,miRNA-146a下调。然而,AH患者与健康的个体,只有血清miRNA-122水平上调。由于诊断准确性数据不足,我们未能得出miRNA区分ALD相关肝纤维化不同阶段的能力的结论.ALD相关HCC的结果也是不足和有争议的。
    循环miRNA-122是管理ALD个体最有希望的生物标志物。miRNA在ALD中的诊断准确性需要更多的研究。
    该协议已在国际前瞻性系统审查注册(PROSPERO)上注册(www.crd.约克。AC.英国/普适诺/),注册号为CRD42023391931。
    UNASSIGNED: Alcoholic liver disease (ALD) encompasses a spectrum of liver conditions, including liver steatosis, alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). microRNAs (miRNAs) have garnered significant interest as potential biomarkers for ALD.
    UNASSIGNED: We searched PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) systemically from inception to June 2024. All extracted data was stratified according to the stages of ALD. The vote-counting strategy performed a meta-analysis on miRNA expression profiles.
    UNASSIGNED: We included 40 studies. In serum of individuals with alcohol-use vs. no alcohol-use, miRNA-122 and miRNA-155 were upregulated, and miRNA-146a was downregulated. In patients with ALD vs. healthy controls, miRNA-122 and miRNA-155 were also upregulated, and miRNA-146a was downregulated. However, in patients with AH vs. healthy individuals, only the serum miRNA-122 level was upregulated. Due to insufficient data on diagnostic accuracy, we failed to conclude the ability of miRNAs to distinguish between different stages of ALD-related liver fibrosis. The results for ALD-related HCC were also insufficient and controversial.
    UNASSIGNED: Circulating miRNA-122 was the most promising biomarker to manage individuals with ALD. More studies were needed for the diagnostic accuracy of miRNAs in ALD.
    UNASSIGNED: This protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (www.crd.york.ac.uk/prospero/) with registration number CRD42023391931.
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  • 文章类型: Journal Article
    胆道闭锁(BA)是新生儿黄疸的主要原因,具有多种病理机制。许多BA患者可能会出现进行性肝功能障碍,最终需要肝移植。因此,确定BA的潜在非侵入性生物标志物至关重要。miR-122,肝脏中最丰富的microRNA,在不同的肝脏疾病中起重要作用。本研究旨在评估BA患者的miR-122水平。从设拉子儿童肝硬化队列研究(SPLCCS)中随机选择18例胆道闭锁患者,以及18个健康对照。采集血样,和生化参数(如肝功能检查)进行测量。对来自病例组和对照组的血清样品进行定量逆转录PCR(RT-PCR)以分析miR-122水平。研究结果表明,与对照组相比,BA患者血清miR-122表达升高,虽然没有达到统计学意义。此外,在BA病例中,miR-122表达与血清肝酶水平或其他实验室检查结果无相关性.miR-122可能是诊断BA的潜在靶标;然而,需要对更大人群进行进一步研究,以确定miR-122是否可以作为诊断BA的有用生物标志物.
    Biliary atresia (BA) is the primary cause of neonatal jaundice with various pathological mechanisms. Many BA patients may experience progressive liver dysfunction and eventually need a liver transplant. Therefore, identifying potential non-invasive biomarkers for BA is crucial. miR-122, the most abundant microRNA in the liver, plays significant roles in different liver diseases. This study aimed to assess miR-122 levels in BA patients. Eighteen patients with biliary atresia were selected at random from the Shiraz Pediatric Liver Cirrhosis Cohort Study (SPLCCS), along with 18 healthy controls. Blood samples were collected, and biochemical parameters (such as liver function tests) were measured. Quantitative reverse-transcription PCR (RT-PCR) was conducted on serum samples from both the case and control groups to analyze miR-122 levels. The study results indicated that serum miR-122 expression in BA patients was elevated compared to the control group, although it did not reach statistical significance. Additionally, no correlation was found between miR-122 expression and serum levels of liver enzymes or other laboratory findings in BA cases. miR-122 could be a potential target for diagnosing BA; however, further research with a larger population is necessary to determine if miR-122 could serve as a useful biomarker for diagnosing BA.
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  • 文章类型: Journal Article
    背景:扑热息痛(对乙酰氨基酚)过量是许多西方国家急性肝衰竭的主要原因。在某些情况下,这种中毒的诊断工具可能不是最佳的,并且已经研究了新的生物标志物。我们研究了毛细血管microRNA-122(miR-122)作为肝损伤的预后生物标志物在对乙酰氨基酚过量患者的临床管理中的作用。
    方法:在对乙酰氨基酚过量患者队列中,miR-122通过定量聚合酶链反应在用N-乙酰半胱氨酸处理的解毒剂周期处理(12小时)结束时通过手指刺破获得的血滴中测量。肝损伤定义为治疗开始后10或20小时收集的血清丙氨酸氨基转移酶(ALT)活性>100IU/L。进行Pearson相关分析。
    结果:对乙酰氨基酚过量的患者,毛细血管miR-122与10h和20h时的ALT呈正相关(r=0.83,P<0.0001;r=0.96,P<0.0001)。
    结论:这项工作支持在扑热息痛过量患者的整个临床治疗中,毛细血管miR-122作为肝损伤的预后生物标志物的潜在用途。可以在通过手指刺破收集的血滴中测量毛细管miR-122,用于患者分层的微创诊断测试。
    BACKGROUND: Paracetamol (acetaminophen) overdose is a leading cause of acute liver failure in many Western countries. Diagnostic tools for this poisoning may be suboptimal in some cases and new biomarkers have been investigated. We investigated the role of capillary microRNA-122 (miR-122) as a prognostic biomarker of liver injury in the clinical management of patients with paracetamol overdose.
    METHODS: In a paracetamol overdose patient cohort, miR-122 was measured by quantitative polymerase chain reaction in a blood drop obtained by a finger prick at the end of an antidote cycle treatment with N-acetylcysteine treatment (12 h). Liver injury was defined as serum alanine aminotransferase (ALT) activity > 100 IU/L collected at 10 or 20 h after the start of treatment. Pearson\'s correlation analyses were performed.
    RESULTS: In patients with paracetamol overdose, capillary miR-122 was positively correlated with ALT measured at 10 h and at 20 h (r = 0.83, P < 0.0001; r = 0.96, P < 0.0001, respectively).
    CONCLUSIONS: This work supports the potential use of capillary miR-122 as a prognostic biomarker of liver injury throughout clinical management of patients with paracetamol overdose. Capillary miR-122 can be measured in a blood drop collected by a finger prick, a minimally invasive diagnostic test for patient stratification.
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  • 文章类型: Journal Article
    背景:血清microRNA-122(miR-122)水平已被报道为检测肝损伤的敏感诊断生物标志物,与转氨酶相当。天冬氨酸转氨酶(AST)和丙氨酸转氨酶(ALT)活性在其他条件下增加,如急性骨骼肌损伤(ASMI)。我们确定miR-122在患有ASMI的患者中是否非特异性增加。
    方法:我们测量了ALT,AST,肌酸激酶(CK),和miR-1223组:健康对照(n=24),ASMI患者(总共n=29,11例使用娱乐性药物,18例未使用娱乐性药物),和急性肝损伤患者(ALI;n=14)。
    结果:ALT水平,AST,CK增加了83%,97%,ASMI患者为100%,ALI患者所有3种酶均为100%。相比之下,miR-122在34%的ASMI患者(44.4%使用娱乐性药物和18.2%不使用娱乐性药物)和100%的ALI患者中增加。在2例药物性肝损伤病例中,miR-122在ALT和AST前约12-24小时增加。
    结论:娱乐性药物滥用与横纹肌溶解和药物性肝损伤(DILI)均相关。在大多数ASMI患者中,传统的肝功能标志物AST和ALT非特异性升高。miR-122仅在有DILI风险的患者中增加,并对肝损伤表现出优异的特异性。
    BACKGROUND: Serum level of microRNA-122 (miR-122) has been reported as a sensitive diagnostic biomarker for detecting liver injury, comparable to the aminotransferases. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities are increased in other conditions, such as acute skeletal muscle injury (ASMI). We determined whether miR-122 is nonspecifically increased in patients suffering from ASMI.
    METHODS: We measured ALT, AST, creatine kinase (CK), and miR-122 in 3 groups: healthy controls (n = 24), patients with ASMI (total n = 29, 11 with recreational drug use and 18 without recreational drug use), and patients with acute liver injury (ALI; n = 14).
    RESULTS: Levels of ALT, AST, and CK increased 83%, 97%, and 100% for patients with ASMI and 100% for all 3 enzymes in ALI patients. In contrast, miR-122 increased in 34% of patients with ASMI (44.4% with recreational drug use and 18.2% without recreational drug use) and 100% of ALI patients. In 2 drug-induced liver injury cases, miR-122 increased about 12-24 hours before ALT and AST.
    CONCLUSIONS: Recreational drug misuse is associated with both rhabdomyolysis and drug-induced liver injury (DILI). The traditional liver function markers AST and ALT were nonspecifically increased in the majority of patients with ASMI. miR-122 is only increased in patients at risk for DILI and demonstrates superior specificity for liver injury.
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  • 文章类型: Journal Article
    Afamin是一种参与葡萄糖和脂质代谢的肝细胞因子。miR-122主要在肝脏中表达,参与脂质和碳水化合物代谢。本研究旨在调查循环中的阿法明,2型糖尿病(T2DM)患者和健康对照组中miR-122基因表达与糖尿病病程的相关性。
    这项病例对照研究包括220名参与者,100名个体作为对照,120名个体被诊断为2型糖尿病(T2DM)。使用实时PCR评估miR-122基因表达。血清生化参数的浓度,如葡萄糖水平,血脂谱,使用比色试剂盒测量低密度脂蛋白(sdLDL)。使用ELISA试剂盒测定循环阿法明和胰岛素水平。使用毛细管电泳测量糖化血红蛋白(HbA1c)。
    2型糖尿病患者的循环阿法明水平明显高于对照组,(73.8±10.8vs.分别为65.9±8.7;P<0.001)。同样,与健康对照组相比,T2DM患者的miR122表达显着增加(4.24±2.01vs.分别为1.00±0.85;P<0.001)。在诊断为T2DM的患者中,与糖尿病病程较短(≤5年)的患者相比,长期糖尿病(>5年)患者的循环afamin和miR-122表达水平显著较高(P<0.05).循环阿法明水平与腰围显著相关,低密度脂蛋白(sdLDL),空腹血糖(FBS),胰岛素,胰岛素抵抗,和miR-122表达,取决于疾病的持续时间(P<0.05)。此外,通过受试者工作特征(ROC)分析证实了阿法明作为T2DM诊断标志物的性能,曲线下面积(AUC)为0.7(P<0.001)。
    参与T2DM相关并发症的循环阿法明及其浓度与miR-122表达呈正相关,尤其是长期糖尿病患者。
    UNASSIGNED: Afamin is a hepatokine that involves in glucose and lipids metabolism. miR-122 is mainly expressed in liver and involves in lipid and carbohydrate metabolism. This study aimed at investigating the circulating afamin, its correlation with type 2 diabetes mellitus (T2DM) and miR-122 gene expression in T2DM patients and healthy control subjects according to the duration of diabetes.
    UNASSIGNED: This case-control study included 220 participants, with 100 individuals serving as controls and 120 individuals diagnosed with type 2 diabetes mellitus (T2DM). The miR-122 gene expression was assessed using real-time PCR. The serum concentration of biochemical parameters such as glucose levels, lipid profile, and small-dense low-density lipoprotein (sdLDL) were measured using colorimetric kits. Circulating afamin and insulin levels were assayed using an ELISA kit. Glycated hemoglobin (HbA1c) was measured using capillary electrophoresis.
    UNASSIGNED: Circulating afamin level was significantly higher in T2DM patients compared to the control group, (73.8 ± 10.8 vs. 65.9 ± 8.7, respectively; P < 0.001). Similarly, miR122 expression was significantly increased in T2DM patients compared to healthy control subjects (4.24 ± 2.01 vs. 1.00 ± 0.85, respectively; P < 0.001). Among patients diagnosed with T2DM, those with longstanding diabetes (>5 years) exhibited significantly higher levels of circulating afamin and miR-122 expression compared to individuals with a shorter duration of diabetes (≤5 years) (P < 0.05). Circulating afamin levels were significantly correlated with waist circumference, small-dense low-density lipoprotein (sdLDL), fasting blood sugar (FBS), insulin, resistance to insulin, and miR-122 expression, depending on the duration of the disease (P < 0.05). Furthermore, the performance of afamin as a diagnostic marker for T2DM was confirmed through receiver operating characteristic (ROC) analysis, yielding an area under the curve (AUC) of 0.7 (P < 0.001).
    UNASSIGNED: Circulating afamin involved in the T2DM-related complications and its concentration is positively correlated to the miR-122 expression, especially in patient with longstanding diabetes.
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  • 文章类型: Journal Article
    低氧运动是肥胖的有效干预措施,因为它通过调节脂肪酸(FA)代谢来促进体重减轻。miR-122对过氧化物酶体增殖物激活受体β(PPARβ)的调控可能参与了这一过程,但具体机制尚不清楚.为了解决这个问题,我们探讨了miR-122如何影响低氧训练肥胖大鼠骨骼肌FA代谢相关因子的表达。通过4周低氧运动给大鼠骨骼肌注射含有miR-122过表达载体或miR-122抑制剂的腺相关病毒9,可以调节miR-122的表达水平。身体成分和血脂水平进行了分析,和PPARβ,肉碱棕榈酰转移酶1b(CPT1b),乙酰辅酶A羧化酶2(ACC2),使用定量逆转录定量PCR(RT-qPCR)和Westernblot分析评估FA合酶(FAS)的mRNA和蛋白质水平。我们发现miR-122过表达会增加低密度脂蛋白胆固醇(LDL-C)和甘油三酯(TG)水平,降低PPARβ。ACC2和FAS表达式。相反,miR-122抑制降低TG水平,高密度脂蛋白胆固醇(HDL-C)水平升高,和上调的PPARβ,ACC2、FAS、CPT1b这些数据表明,miR-122对PPARβ的负调节通过改变低氧训练下肥胖大鼠骨骼肌中FA代谢相关因子的水平来促进FA代谢,从而提供对这种干预的有益效果的分子水平洞察。
    Hypoxic exercise is an effective intervention for obesity, because it promotes weight loss by regulating fatty acid (FA) metabolism. The regulation of peroxisome proliferator-activated receptor β (PPARβ) by miR-122 may be involved in this process, but the detailed mechanisms are unknown. In order to address this issue, we probed how miR-122 affected the expression of factors associated with FA metabolism in skeletal muscle of obese rats undergoing hypoxic training. By injecting adeno-associated virus 9 containing miR-122 overexpression vector or miR-122 inhibitor into skeletal muscles of rats with a 4-week hypoxic exercise regimen, the miR-122 expression level can be regulated. Body composition and blood lipid levels were analyzed, and PPARβ, carnitine palmitoyltransferase 1b (CPT1b), acetylCoA carboxylase 2 (ACC2), and FA synthase (FAS) mRNA and protein levels were evaluated using quantitative reverse transcription quantitative PCR(RT-qPCR) and Western blot analysis. We found that miR-122 overexpression increased low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and decreased PPARβ, ACC2, and FAS expression. Conversely, miR-122 inhibition decreased TG level, increased high-density lipoprotein cholesterol (HDL-C) level, and upregulated PPARβ, ACC2, FAS, and CPT1b. These data indicated that the negative regulation of PPARβ by miR-122 promotes FA metabolism by altering the levels of the factors related to FA metabolism in skeletal muscle of obese rat under hypoxic training, thus providing molecular-level insight into the beneficial effects of this intervention.
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  • 文章类型: Journal Article
    妊娠期糖尿病(GDM)严重影响母亲和婴儿的健康,仍然没有有效的早期诊断标志物。因此,本研究旨在探讨GDM患者血清microRNA-122和VEGF表达与妊娠结局的相关性。
    这是一项GDM患者血清microRNA-122和血管内皮生长因子(VEGF)表达与妊娠结局相关性的回顾性研究。将2021年1月至2022年10月石家庄市第四医院收治的60例GDM患者纳入研究组(RG),另外60名健康孕妇被纳入对照组(CG)。使用定量实时聚合酶链反应定量血清miR-122和VEGF水平。采用受试者工作特征曲线分析miR-122和VEGF对不良妊娠结局的预测价值。
    RG中的血清miR-122和VEGF水平相对于CG更高。RG组不良妊娠结局总发生率高于CG组(P<0.05)。预后不良组血清miR-122和VEGF水平高于预后良好组(P<0.05)。ROC分析显示miR-122和VEGF可用于预测不良妊娠结局(P<0.0001)。miR-122的曲线下面积为0.860,95%可信区间(CI)=0.793-0.926,VEGF的曲线下面积为0.780,95%CI=0.694-0.866。血清miR-122、VEGF水平与流产呈正相关,早产,低出生体重儿,宏观发生婴儿,和胎儿发育异常(P<0.001)。
    血糖控制满意的GDM患者血清miR-122和VEGF水平较高,不良妊娠结局的可能性越大,应引起临床医生的重视。
    UNASSIGNED: Gestational diabetes mellitus (GDM) seriously influences the health of mothers and babies, and there are still no effective early diagnostic markers. Therefore, our study planned to probe the correlation between serum microRNA-122 and VEGF expression and pregnancy outcome in GDM patients.
    UNASSIGNED: This was a retrospective study of the correlation between serum microRNA-122 and vascular endothelial growth factor (VEGF) expression and pregnancy outcome in GDM patients. Sixty GDM patients admitted to the Fourth Hospital of Shijiazhuang from January 2021 to October 2022 were included in the research group (RG), and another 60 healthy pregnant women were included in the control group (CG). Serum miR-122 and VEGF levels were quantified using quantitative real-time polymerase chain reaction. The value of miR-122 and VEGF in predicting adverse pregnancy outcomes was analyzed by receiver operating characteristic curve.
    UNASSIGNED: Serum miR-122 and VEGF levels in the RG were higher relative to the CG. The total occurrence of adverse pregnancy outcomes in the RG was higher relative to the CG (P<0.05). Serum miR-122 together with VEGF levels in the poor outcome group was higher relative to the good outcome group (P<0.05). ROC analysis revealed that miR-122 and VEGF could be used to predict adverse pregnancy outcome (P<0.0001). The area under the curve of miR-122 was 0.860, 95% confidence interval (CI) =0.793-0.926, and the area under the curve of VEGF was 0.780, 95% CI =0.694-0.866. Serum levels of miR-122, VEGF were positively related with abortion, preterm delivery, low birth weight infants, macrogenesis infants, and fetal development abnormalities (P<0.001).
    UNASSIGNED: The higher serum miR-122 and VEGF levels in GDM patients with satisfactory blood glucose control, the greater the probability of adverse pregnancy outcome, which should be paid attention to by clinicians.
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  • 文章类型: Journal Article
    miRNA被证实是一种短且非常保守的非编码RNA,通过与靶向多个靶信使RNA的3'-非翻译区(3'-UTR)结合在转录后水平上调节基因表达。最近,越来越多的证据强调它们在各种病理过程中起着至关重要的作用,包括人类癌症。失调的miRNA在许多癌症类型中充当癌基因或肿瘤抑制基因。其中,我们注意到miR-122已被广泛报道通过调节靶基因和信号通路显著影响多种肿瘤的致癌性。这里,我们关注miR-122在调控机制和肿瘤生物学过程中的表达。我们还讨论了miR-122失调在各种类型的人类恶性肿瘤中的作用以及开发新的分子miR-122靶向疗法的潜力。本综述提示miR-122可能是潜在有用的癌症诊断和治疗生物标志物。未来需要进一步开展更多的临床诊断。改善癌症患者预后的有希望的方向可能将miR-122与其他传统肿瘤生物标志物相结合。
    MiRNAs are confirmed to be a kind of short and eminently conserved noncoding RNAs, which regulate gene expression at the post-transcriptional level via binding to the 3\'- untranslated region (3\'-UTR) of targeting multiple target messenger RNAs. Recently, growing evidence stresses the point that they play a crucial role in a variety of pathological processes, including human cancers. Dysregulated miRNAs act as oncogenes or tumor suppressor genes in many cancer types. Among them, we noticed that miR-122 has been widely reported to significantly influence carcinogenicity in a variety of tumors by regulating target genes and signaling pathways. Here, we focused on the expression of miR-122 in regulatory mechanisms and tumor biological processes. We also discussed the effects of miR-122 dysregulation in various types of human malignancies and the potential to develop new molecular miR-122-targeted therapies. The present review suggests that miR-122 may be a potentially useful cancer diagnosis and treatment biomarker. More clinical diagnoses need to be further launched in the future. A promising direction to improve the outcomes for cancer patients will likely combine miR-122 with other traditional tumor biomarkers.
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  • 文章类型: Journal Article
    乙型肝炎病毒(HBV)劫持自噬的复制。Nucleos(t)ide类似物(NUCs)治疗抑制HBV复制并降低肝细胞癌(HCC)发病率。然而,在血清丙氨酸转氨酶(ALT)水平正常或最低限度升高的慢性乙型肝炎(CHB)患者中使用NUCs仍存在争议。动物模型对于研究未解决的问题和评估新疗法至关重要。微小RNA-122(miR-122),调节脂肪酸和胆固醇的代谢,在肝炎和HCC进展期间下调。miR-122与HBV的相互抑制突出了其在HCC发展中作为肿瘤抑制因子的作用。通过杂交HBV转基因小鼠与miR-122敲除小鼠,我们建立了一个混合小鼠模型,HCC的发病率高达89%,并且在HCC之前ALT水平正常。该模型表现出早发性肝脂肪变性,进行性肝纤维化,晚期自噬受损。代谢组学和微阵列分析确定了代谢特征,包括脂质代谢失调,炎症,基因组不稳定性,Warburg效应,降低TCA循环通量,能量不足,和自由基清除受损。与未经处理的小鼠相比,抗病毒治疗可将杂种小鼠中的HCC发病率降低约30-35%。这种作用与ER应激反应性转录因子ATF4的激活,自噬体货物p62的清除以及CHOP介导的凋亡途径的抑制有关。总之,这项研究表明,尽管ALT升高最小,HBV复制可导致肝损伤。内质网应激,降低miR-122水平,线粒体和代谢功能障碍,阻断保护性自噬导致p62积累,凋亡,纤维化,和HCC。抗病毒可能通过抑制HBV改善上述发病机制。
    Hepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA-122 (miR-122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR-122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV-transgenic mice with miR-122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early-onset hepatic steatosis, progressive liver fibrosis, and impaired late-phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30-35% compared to untreated mice. This effect was linked to the activation of ER stress-responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP-mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR-122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above-mentioned pathogenesis through HBV suppression.
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