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1.
目的:探讨沉默长链非编码RNA(long non-coding RNA,lncRNA)INHBA反义RNA1(INHBA antisense RNA1,INHBA-AS1)对外阴鳞状细胞癌细胞SW954生物学行为的影响及机制。方法:37例外阴鳞状细胞癌组织中INHBA-AS1、miR-335-3p表达运用qRT-PCR检测,高迁移率族蛋白2(high mobility group AT-hook 2,HMGA2)蛋白的表达运用Western blotting检测。实验分为con组、si-NC组、si-INHBA-AS1组、miR-NC组、miR-335-3p mimic组、si-INHBA-AS1+miR-335-3p inhibitor组。应用CCK-8实验检测SW954细胞增殖抑制率,克隆形成实验检测SW954细胞克隆形成,Transwell实验和划痕实验检测SW954细胞迁移,流式细胞术检测SW954细胞凋亡。双荧光素酶报告实验鉴定INHBA-AS1与miR-335-3p、miR-335-3p与HMGA2的靶向关系。结果:外阴鳞状细胞癌组织中INHBA-AS1、HMGA2蛋白的表达水平远高于癌旁组织,miR-335-3p的表达水平低于癌旁组织(P<0.05)。转染si-INHBA-AS1沉默INHBA-AS1或转染miR-335-3p mimic过表达miR-335-3p后,miR-335-3p表达水平、SW954细胞抑制率及凋亡率升高,HMGA2蛋白的表达水平、SW954细胞克隆形成数、迁移细胞数及划痕愈合率降低(P<0.05)。INHBA-AS1靶向miR-335-3p,miR-335-3p靶向HMGA2。沉默INHBA-AS1处理的SW954细胞增殖、迁移、凋亡的影响被抑制miR-335-3p所逆转。结论:沉默外阴鳞状细胞癌细胞SW954中的INHBA-AS1通过miR-335-3p靶向HMGA2,抑制SW954细胞增殖、迁移,并诱导其凋亡。  相似文献   
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Spinal muscular atrophy (SMA) is a rare neuromuscular condition, characterized by loss of motor neurons as a result of a mutation in the survival motor neuron gene. This results in muscle wasting and in the most common and severe type, death before 24 months. Over the recent years there has been a dynamic shift in the therapeutic options for these patients involving both clinical trials in genetic modifying therapies to indirectly improve the survival motor neuron protein level and hence strength, muscle promotor therapies, up/down regulation of modifier genes and more recently gene therapy to replace the mutated survival motor neuron gene. This review addresses the pathogenesis of SMA and the resultant therapeutic approaches as well as the current state in clinical trials and future development.  相似文献   
4.
陈明武  王开宇  杨波  郑诗豪 《天津医药》2022,50(12):1246-1253
目的 探讨长链非编码RNA(lncRNA)OPA相互作用蛋白5反义转录本1(OIP5-AS1)对脑胶质瘤细胞增殖、凋亡、迁移和侵袭的影响机制。方法 收集33例胶质瘤患者(低级别胶质瘤14例、高级别胶质瘤19例)和33例颅脑损伤患者的组织标本。实时荧光定量PCR(qPCR)检测组织和细胞中OIP5-AS1、微小RNA-942-5p(miR-942-5p)和检查点激酶1(CHEK1)mRNA表达,分析胶质瘤组织中OIP5-AS1、miR-942-5p和CHEK1 mRNA表达水平的相关性。体外培养人脑胶质瘤细胞系U87、SHG-44、U251、H4和正常人星形胶质细胞NHA,Western blot检测细胞中CHEK1蛋白表达。将U87细胞分为对照(NC)组、siRNA阴性对照(si-NC)组、OIP5-AS1 siRNA(si-OIP5-AS1)组、si-OIP5-AS1+inhibitor阴性对照(si-OIP5-AS1+anti-NC)组、si-OIP5-AS1+miR-942-5p抑制剂(si-OIP5-AS1+anti-miR-942-5p)组,采用Lipofectamine 3000试剂进行转染。转染后,qPCR和Western blot检测细胞中OIP5-AS1、miR-942-5p和CHEK1 mRNA和蛋白表达水平;MTT法测定细胞增殖活性;流式细胞术检测细胞凋亡;Transwell实验检测细胞迁移和侵袭能力。最后通过双荧光素酶和RNA免疫沉淀(RIP)实验验证OIP5-AS1和miR-942-5p以及CHEK1和miR-942-5p的相互作用。结果 OIP5-AS1和CHEK1在脑胶质瘤组织和细胞中过表达,miR-942-5p呈低表达(均P<0.05);相关分析显示,脑胶质瘤组织中OIP5-AS1与miR-942-5p的表达水平呈负相关,miR-942-5p与CHEK1 mRNA的表达水平呈负相关,CHEK1与OIP5-AS1 mRNA的表达水平呈正相关;且OIP5-AS1、CHEK1 mRNA在高级别胶质瘤组织中的表达明显高于低级别组织,而高级别胶质瘤中的miR-942-5p水平明显低于低级别组织(P<0.01)。沉默OIP5-AS1可显著上调miR-942-5p,抑制CHEK1的mRNA和蛋白表达(均P<0.05);沉默OIP5-AS1可显著抑制U87细胞增殖、迁移和侵袭,促进U87细胞凋亡(均P<0.05);下调miR-942-5p可上调CHEK1表达,阻断OIP5-AS1沉默对脑胶质瘤细胞生物学行为的影响(均P<0.05)。双荧光素酶和RIP实验证实miR-942-5p是OIP5-AS1的靶基因,CHEK1是miR-942-5p的下游靶基因。结论 沉默OIP5-AS1可能通过上调miR-942-5p抑制CHEK1表达,抑制脑胶质瘤细胞的侵袭和迁移,并促进细胞凋亡。  相似文献   
5.
Central Illustration. Pathophysiological pathways providing a causal link between high plasma concentrations of lipoprotein(a) (Lp(a)) and atherosclerotic vascular disease and aortic valve stenosis (AVS). Clinical outcomes are related to accelerated atherosclerosis complicated by atherothrombosis (myocardial infarction, stroke), peripheral artery disease (PAD) or aortic valve replacement (AVR) caused by valve calcification and aortic stenosis. Apo(a): apolipoprotein(a); LDL: low-density lipoprotein; OxPL: oxidized phospholipids; NSFA: Nouvelle Société Francophone d’Athérosclérose; SP: serine-protease domain; V: plasminogen kringle V (reproduced with permission).
  相似文献   
6.

Background and aims

Heparin-binding EGF-like growth factor (HB-EGF) is a representative EGF family member that interacts with EGFR under diverse stress environment. Previously, we reported that the HB-EGF-targeting using antisense oligonucleotide (ASO) effectively suppressed an aortic aneurysm in the vessel wall and circulatory lipid levels. In this study, we further examined the effects of the HB-EGF ASO administration on the development of hyperlipidemia-associated atherosclerosis using an atherogenic mouse model.

Methods and results

The male and female LDLR deficient mice under Western diet containing 21% fat and 0.2% cholesterol content were cotreated with control and HB-EGF ASOs for 12 weeks. We observed that the HB-EGF ASO administration effectively downregulated circulatory VLDL- and LDL-associated lipid levels in circulation; concordantly, the HB-EGF targeting effectively suppressed the development of atherosclerosis in the aorta. An EGFR blocker BIBX1382 administration suppressed the hepatic TG secretion rate, suggesting a positive role of the HB-EGF signaling for the hepatic VLDL production. We newly observed that there was a significant improvement of the insulin sensitivity by the HB-EGF ASO administration in a mouse model under the Western diet as demonstrated by the improvement of the glucose and insulin tolerances.

Conclusion

The HB-EGF ASO administration effectively downregulated circulatory lipid levels by suppressing hepatic VLDL production rate, which leads to effective protection against atherosclerosis in the vascular wall.  相似文献   
7.
Introduction: Oligonucleotide therapeutics such as antisense oligonucleotides and siRNA requires chemical modifications and nano-sized carriers to circumvent stability problems in vivo, to reach target tissues, and to overcome tissue and cellular barriers. Hyaluronic acid (HA), already utilized in drug delivery and tissue engineering, possess properties that are useful to solve these problems and achieve full potential of oligonucleotide therapeutics.

Areas covered: Complexes of oligonucleotide therapeutics with HA are discussed in terms of interactions providing the complexes formation and genes targeted by the therapeutics to cure diseases such as cancer, atherosclerosis, liver cirrhosis, and inflammation. The achieved therapeutic effects are rationalized as consequences of biodistribution, cell internalization and endosomal escape provided by HA.

Expert opinion: Design of electrostatic, coordination, and hydrophobic interactions as well as covalent conjugation between oligonucleotide drugs, HA macromolecules and intermediate ligands are crucial for carrier–cargo association and dissociation under different conditions to impart oligonucleotides stability in vivo, their accumulation in diseased organs, cellular uptake, and dissociation in cytoplasm intact. These are the delivery factors that provides eventual complex formation of oligonucleotide therapeutics with their mRNA, microRNA, or protein targets. Elucidation of the impact of structural parameters of oligonucleotide/HA complexes on their therapeutic effect in vivo is important for the future rational design of the delivery agents.  相似文献   

8.
9.

Aims

Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects.

Methods

Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated.

Results

AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration–effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience.

Conclusion

Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen.  相似文献   
10.
血栓相关性疾病在人群中广泛发生,而其主要治疗药物存在一定比例的出血风险,华法林等药物尚存在需要长期监测凝血功能等不足。是否存在一种抗凝效果好、出血风险小且方便应用的药物是目前研究的重点。临床发现在凝血因子Ⅺ缺乏人群中,其血栓栓塞性疾病发生率低,且多项动物模型实验均提示Ⅺ因子缺乏模型血栓形成比例降低,且出血比例较低,近期临床试验也得到了类似结果,降低Ⅺ因子水平可能成为抗血栓治疗新的重要靶点。  相似文献   
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