The protective effects of HMGA2 in the senescence process of bone marrow‐derived mesenchymal stromal cells

Bone marrow‐derived mesenchymal stromal cells (MSCs) have been wildly applied to cell‐based strategies for tissue engineering and regenerative medicine; however, they have to undergo the senescence process and thus appeared to be less therapeutic effective. HMGA2, a protein belonged to high mobility group A (HMGA) family, exhibits an inverse expression level related to embryonic development and acts as a developmental regulator in stem cell self‐renewal progression. Therefore, we performed senescence‐associated β‐galactosidase (SA‐β‐gal) staining, transwell assay, to examine the changes of MSCs in different stages and then over‐expressed HMGA2 in MSCs by lentivirus transfection. We found the percentage of SA‐β‐gal staining positive cells in MSCs from 24‐month‐old Sprague–Dawley (SD) rats (O‐MSCs) was significantly higher compared with MSCs from 2‐week‐old SD rats (Y‐MSCs), and the expression levels of P21 and P53, two senescence‐related molecules, were also significantly up‐regulated in O‐MSCs than in Y‐MSCs. In contrast, the HMGA2 expression level in O‐MSCs was dramatically down‐regulated in contrast to Y‐MSCs. In additional, the migration ability in O‐MSCs was significantly attenuated than in Y‐MSCs. After successfully over‐expressed HMGA2 in O‐MSCs, the percentage of SA‐β‐gal staining positive cells and the expression levels of P21 and P53 were reduced, and the migration ability was improved compared with O‐MSCs without treatment. Further, mRNA sequencing analysis revealed that overexpression of HMGA2 changed the expression of genes related to cell proliferation and senescence, such as Lyz2, Pf4, Rgs2, and Mstn. Knockdown of Rgs2 in HMGA2 overexpression O‐MSCs could antagonize the protective effect of HMGA2 in the senescence process of O‐MSCs.     

反义血管紧张素Ⅱ受体Ⅰ_B基因转移对大鼠颈动脉损伤后新生内膜的影响

目的　探讨腺病毒载体介导的大鼠反义血管紧张素Ⅱ受体ⅠB(AT1B)RNA转移对大鼠颈动脉损伤后新生内膜的影响。方法　利用重组腺病毒载体将大鼠反义AT1B RNA转移至大鼠颈动脉球囊损伤模型中 ,2 1天后观察其对新生内膜形成的影响。结果　用腺病毒载体转导大鼠反义AT1BRNA至大鼠球囊损伤的颈动脉 ,与对照组相比 ,2 1天后损伤血管新生内膜 /中层面积比降低了 4 7%(P <0 0 0 1)。结论　反义AT1BRNA对血管成形术后再狭窄可能有一定的预防作用。     

Haemodynamic, neurohumoral and exercise effects of losartan vs. captopril in chronic heart failure: results of an ELITE trial substudy. Evaluation of Losartan in the Elderly

BACKGROUND: The AT1 receptor antagonists differ from the angiotensin converting enzyme inhibitors by achieving a more complete blockade of angiotensin II's actions and by not affecting bradykinin metabolism. There is little information on whether this causes clinically significant differences in haemodynamics, neurohormones and exercise tolerance in heart failure. AIMS: To compare the effects of losartan and captopril upon central and regional haemodynamics, neurohormones and exercise capacity in heart failure. METHODS: In a double-blind, randomised trial 18 patients aged > or =65 years with symptomatic heart failure were allocated to treatment with losartan (10 patients) or captopril (eight patients). Patients underwent assessment at baseline, after the first dose, at 12 weeks and at 24 weeks. RESULTS: Systolic blood pressure fell by - 10.7% 1 h after captopril 6.25 mg (P = 0.007) and by - 4.8% 3 h after losartan 12.5 mg (P = 0.02). The blood pressure reduction was sustained with losartan at 12 and 24 weeks. Systemic vascular resistance fell acutely after captopril (-16.4%, P = 0.01). Captopril caused an acute and sustained rise in superior mesenteric artery blood flow (+ 22.9%, P = 0.04), and a slower rise in renal artery blood flow (+31.7%, P = 0.01). Losartan had no acute effects on regional haemodynamics but had increased superior mesenteric artery blood flow by 38.1% at 12 weeks (P = 0.02). There were no substantial differences between losartan and captopril, and no changes occurred in neurohormones or exercise capacity. CONCLUSION: No substantial differences were observed between losartan and captopril on central or regional haemodynamics, neurohormones or exercise capacity in elderly patients with stable symptomatic heart failure.     

AT1受体拮抗剂和ACEI对MI后心室重构作用的比较

心肌梗死 ( myocardial infarction,MI)后心室重构对 MI患者的预后具有深远的影响。 MI后循环和心脏局部组织中的肾素 -血管紧张素系统 ( renin-angiotensin system ,RAS)被激活 ,在刺激全身和心脏局部产生代偿反应的同时 ,也带来危害——心肌肥厚和间质纤维化。应用血管紧张素转换酶抑制剂 ( angiotensin converting enzyme inhibitor,ACEI)阻断这一系统 ,已显示出具有防止心脏重构、延长患者生存时间的作用。其作用主要归因于抑制循环及局部血管紧张素 ( angiotensin ,Ang )的生成 ,以及减少缓激肽 ( bradykinin,BK)的降解。与 ACEI相比 ,选择性 1型血管紧张素 受体 (简称 AT1受体 )拮抗剂在理论上能够更加长期、有效地阻断血管紧张素 通过其 1型受体发挥的作用 ,且其作用并不仅限于此。     

AT1 receptor downregulation: A mechanism for improving glucose homeostasis

There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-Ⅱ enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a m...     

ABCB1 C3435T、G2677AT基因形态与癌痛患者疼痛感知的相关性研究

目的:研究ABCB1 C3435T、G2677AT基因形态与癌痛患者疼痛感知的关系。方法:临床纳入2016年9月至2018年9月期间我院收治的185例恶性肿瘤患者组织病理学标本,将其中有癌痛的患者116例作为癌痛组,无癌痛的患者69例作为无痛组。应用三维聚丙烯酰胺凝胶DNA芯片技术检验患者ABCB1 C3435T、G2677AT基因分型情况,并分析ABCB1 C3435T、G2677AT基因形态与癌症患者癌痛的关系。结果:两组患者C3435T基因野生型、杂合子及突变型分布频率对比差异无统计学意义（P>0.05）。两组患者G2677AT基因野生型、杂合子及突变型分布频率对比差异无统计学意义（P>0.05）。疼痛程度不同的患者C3435T和G2677AT基因型分布频率无差异（P>0.05）。癌痛组患者C3435T与G2677AT不同基因型间组内对比NRS评分差异无统计学意义（P>0.05）;C3435T与G2677AT相同基因型对比NRS评分差异无统计学意义（P>0.05）。结论:ABCB1 C3435T与G2677AT基因形态与癌痛患者疼痛感知并无直接关联,尚需进一步进行深入研究。     

运用BiFC技术检测LOX-1与AT1受体的相互作用

目的运用双分子荧光互补(bimolecular fluorescence complementation,BiFC)技术探讨氧化低密度脂蛋白(ox-LDL)介导血凝素样氧化低密度脂蛋白受体-1(LOX-1)和血管紧张素Ⅱ1型受体(AT1)之间的相互作用,推测其可能是参加动脉粥样硬化等心血管疾病过程的重要机制之一。方法将LOX-1与AT1受体质粒共转染COS7细胞,给予ox-LDL(50ug/ml)刺激后,检测细胞中p-ERK表达水平。根据BiFC载体和AT1、LOX-1基因序列设计引物,将AT1、LOX-1基因克隆到BiFC特异性的荧光载体上,得到重组BiFC质粒:phmKGN-MN-AT1,phmKGC-MN-AT和phmKGC-MC-LOX-1,phmKGN-MC-LOX-1,配对共转染HEK293细胞,用ox-LDL(50ug/ml)刺激,研究AT1受体和LOX-1的相互作用;构建G蛋白偶联受体家族中另一蛋白肾上腺素受体β2(β2-adrenergi creceptor,β2AR)的BiFC重组质粒:phmKGN-MN-β2AR和phmKGC-MN-β2AR,分别与LOX-1对应的BiFC质粒转染HEK...     

Anti‐fibrotic mechanisms of angiotensin AT2‐receptor stimulation

The angiotensin AT₂‐receptor is a main receptor of the protective arm of the renin‐angiotensin system. Understanding of this unconventional G‐protein coupled receptor has significantly advanced during the past decade, largely because of the availability of a selective non‐peptide AT₂‐receptor agonist, which allowed the conduct of a multitude of studies in animal disease models. This article reviews such preclinical studies that in their entirety provide strong evidence for an anti‐fibrotic effect mediated by activation of the AT₂‐receptor. Prevention of the development of fibrosis by AT₂‐receptor stimulation has been demonstrated in lungs, heart, blood vessels, kidney, pancreas and skin. In lungs, AT₂‐receptor stimulation was even able to reverse existing fibrosis. The article further discusses intracellular signalling mechanisms mediating the AT₂‐receptor‐coupled anti‐fibrotic effect, including activation of phosphatases and subsequent interference with pro‐fibrotic signalling pathways, induction of matrix‐metalloproteinases and hetero‐dimerization with the AT₁‐receptor, the TGF‐βRII‐receptor or the RXFP1‐receptor for relaxin. Knowledge of the anti‐fibrotic effects of the AT₂‐receptor is of particular relevance because drugs targeting this receptor have entered clinical development for indications involving fibrotic diseases.