间充质干细胞治疗糖尿病心脏病研究进展及其机制

糖尿病心脏病(diabetic cardiomyopathy,DCM)患者心脏病变弥漫、病变程度严重,患病率与死亡率逐年上升,缺乏有效的治疗手段,找到其他的治疗途径已成为一项重要内容。有研究发现,间充质干细胞(mesenchymal stem cells,MSCs)作为一种具有多分化潜能的细胞,能够通过多种机制作用于DCM的病理改变,提高心脏射血分数、改善心室重塑,是一种富有前景的治疗手段,本文着重就DCM的发病机制、MSCs对DCM的治疗机制及效果做一综述,为MSCs在DCM治疗中的应用提供重要的临床前实验依据。     

FBXL10 regulates cardiac dysfunction in diabetic cardiomyopathy via the PKC β2 pathway

Diabetic cardiomyopathy (DCM) is a condition associated with significant structural changes including cardiac tissue necrosis, localized fibrosis, and cardiomyocyte hypertrophy. This study sought to assess whether and how FBXL10 can attenuate DCM using a rat streptozotocin (STZ)‐induced DCM model system. In the current study, we found that FBXL10 expression was significantly decreased in diabetic rat hearts. FBXL10 protected cells from high glucose (HG)‐induced inflammation, oxidative stress, and apoptosis in vitro. In addition, FBXL10 significantly activated PKC β2 signaling pathway in H9c2 cells and rat model. The cardiomyocyte‐specific overexpression of FBXL10 at 12 weeks after the initial STZ administration attenuated oxidative stress and inflammation, thereby reducing cardiomyocyte death and preserving cardiac function in these animals. Moreover, FBXL10 protected against DCM via activation of the PKC β2 pathway. In conclusion, FBXL has the therapeutic potential for the treatment of DCM.     

Nerve growth factor regulates endothelial cell survival and pathological retinal angiogenesis

The mechanism underlying vasoproliferative retinopathies like retinopathy of prematurity (ROP) is hypoxia‐triggered neovascularisation. Nerve growth factor (NGF), a neurotrophin supporting survival and differentiation of neuronal cells may also regulate endothelial cell functions. Here we studied the role of NGF in pathological retinal angiogenesis in the course of the ROP mouse model. Topical application of NGF enhanced while intraocular injections of anti‐NGF neutralizing antibody reduced pathological retinal vascularization in mice subjected to the ROP model. The pro‐angiogenic effect of NGF in the retina was mediated by inhibition of retinal endothelial cell apoptosis. In vitro, NGF decreased the intrinsic (mitochondria‐dependent) apoptosis in hypoxia‐treated human retinal microvascular endothelial cells and preserved the mitochondrial membrane potential. The anti‐apoptotic effect of NGF was associated with increased BCL2 and reduced BAX, as well as with enhanced ERK and AKT phosphorylation, and was abolished by inhibition of the AKT pathway. Our findings reveal an anti‐apoptotic role of NGF in the hypoxic retinal endothelium, which is involved in promoting pathological retinal vascularization, thereby pointing to NGF as a potential target for proliferative retinopathies.     

超声对早期糖尿病肾病的诊断价值及肾动脉血流阻力指数与血清hs-CRP、VEGF的关系分析

目的:研究彩色多普勒超声对早期糖尿病肾病的诊断价值及肾动脉血流阻力指数与血清超敏C反应蛋白(hs-CRP)、血管内皮生长因子(VEGF)的关系。方法:选取从2017年2月～2018年2月兰州大学第二医院收治的早期糖尿病肾病患者50例记为病变组,另取同期于该院进行体检的健康人员50例记为对照组。分别对两组人员进行彩色多普勒超声检查,比较肾血流参数。采用酶联免疫吸附法检测两组人员血清hs-CRP、VEGF水平,并作指标间的相关性分析。结果:病变组肾主动脉、肾锥体两侧叶间动脉、肾段动脉的收缩期峰值速度、舒张期最低速度较对照组降低,病变组肾主动脉、肾锥体两侧叶间动脉、肾段动脉的阻力指数较对照组升高(均P0.05)。病变组血清hs-CRP、VEGF水平较对照组升高(均P0.05)。经Pearson相关性分析显示:早期糖尿病肾病患者肾主动脉、肾锥体两侧叶间动脉、肾段动脉的血流阻力指数与血清hs-CRP、VEGF均呈正相关关系(均P0.05)。结论:彩色多普勒超声应用于早期糖尿病肾病的诊断价值较高,且肾动脉血流阻力指数与血清hs-CRP、VEGF密切相关,临床工作中通过联合检测血清hs-CRP、VEGF,从而有助于早期糖尿病肾病的诊断。     

Synthesis of quinoline derivatives as diabetic II inhibitors and molecular docking studies

In searchof the potenttherapeutic agent as an α-glucosidase inhibitor, we have synthesized twenty-five analogs (1–25) of quinoline-based Schiff bases as an inhibitoragainst α-glucosidase enzyme under positive control acarbose (IC₅₀ = 38.45 ± 0.80 µM). From the activity profile it was foundthat analogs 1, 2, 3, 4, 11, 12 and 20with IC₅₀values 12.40 ± 0.40, 9.40 ± 0.30, 14.10 ± 0.40, 6.20 ± 0.30, 14.40 ± 0.40, 7.40 ± 0.20 and 13.20 ± 0.40 µMrespectively showed most potent inhibition among the series even than standard drug acarbose (IC₅₀ = 38.45 ± 0.80 µM). Here in the present study analog 4 (IC₅₀ = 6.20 ± 0.30 µM) was found with many folds better α-glucosidase inhibitory activity than the reference drug. Eight analogs like 5, 7, 8, 16, 17, 22, 24 and 25 among the whole series displayed less than 50% inhibition. The substituents effects on phenyl ring thereby superficially established through SAR study. Binding interactions of analogs and the active site of ligands proteins were confirmed through molecular docking study. Spectroscopic techniques like ¹H NMR, ¹³C NMR and ESIMS were used for characterization.     

糖尿病性视网膜病变早期mfERG的研究

目的:探讨糖尿病患者糖尿病性视网膜病变早期多焦视网膜电图(multifocal electroretinogram,mfERG)的特点。方法:应用德国ROLAND公司RETIscan系统对24例40眼糖尿病患者,同时对27例40眼正常对照眼记录mfERG。按机器的默认值一阶反应进行记录。整个记录过程中可以分为12个时段,每个时段记录为时间47秒。结果:mERG测得的糖尿病患者组1～5环所在位置的P1波的振幅密度随离心度的增加而降低,P1波和N1波幅值降低和潜伏时延迟。各象限的P1、N1波振幅密度、波幅值降低,潜伏时延迟。结论:糖尿病性视网膜病变受累的区域多发生在黄斑部,功能上的改变早于形态学的变化;病变的早期功能改变最先出现于视网膜的后极偏颞上方;糖尿病患者在未出现眼底改变时各个象限视网膜的外层已经严重受累。     

C肽对糖尿病大鼠肾脏的影响

比较C肽和胰岛素对大鼠糖尿病肾病的治疗作用。方法:选取Wistar大鼠40只,分为正常对照组(NG组)和糖尿病组(DM组),糖尿病组链脲佐菌素诱发大鼠成模后,随机分为三组:糖尿病组(DM组)、胰岛素组(IG组)和C肽组(ICG组)。治疗8周后测定各组大鼠24小时尿白蛋白排泄率(UAER)、肾重/体重,并观察糖尿病大鼠肾脏超微结构变化。结果:24小时尿白蛋白排泄率:糖尿病组明显增加,C肽组明显低于糖尿病组和胰岛素组,差异具有显著性。大鼠肾脏超微结构变化:各组大鼠肾小球截面积、肾小球平均体积(MGV)、细胞外基质/肾小球截面积比值、细胞外基质截面积、肾小球基底膜厚度相比,糖尿病组明显升高,C肽组较胰岛素组和糖尿病组明显下降,差异具有显著性。结论:C肽治疗可以降低24小时尿白蛋白排泄率,改善糖尿病大鼠肾脏超微结构病变。     

Proteome map of normal rat retina and comparison with the proteome of diabetic rat retina: new insight in the pathogenesis of diabetic retinopathy

We have employed proteomics to establish a proteome map of the normal rat retina. This baseline map was then used for comparison with the early diabetic rat retinal proteome. Diabetic rat retinae were obtained from Dark Agouti rats after 10 wk of streptozotocin-induced hyperglycaemia. Extracted proteins from normal and diabetic rat retinae were separated and compared using 2-DE. A total of 145 protein spots were identified in the normal rat retina using MALDI-MS and database matching. LC-coupled ESI-MS increased the repertoire of identified proteins by 23 from 145 to 168. Comparison with early diabetic rat retinae revealed 24 proteins unique to the diabetic gels, and 37 proteins absent from diabetic gels. Uniquely expressed proteins identified included the HSPs 70.1A and 8, and platelet activating factor. There were eight spots with increased expression and 27 with decreased expression on diabetic gels. Beta catenin, phosducin and aldehyde reductase were increased in expression in diabetes whilst succinyl coA ligase and dihydropyrimidase-related protein were decreased. Identification of such changes in protein expression has given new insights and a more comprehensive understanding of the pathogenesis of diabetic retinopathy, widening the scope of potential avenues for new therapies for this common cause of blindness.     

纳布啡鞘内注射对糖尿病神经痛模型大鼠行为能力及背根神经节TRPV1表达的影响

摘要 目的：探讨纳布啡鞘内注射对糖尿病神经痛（diabetic neuropathic pain, DNP）模型大鼠行为能力及背根神经节瞬时受体电位V1（transient receptor potential V1,TRPV1）表达的影响。方法：将糖尿病神经痛模型大鼠（n=48）随机平方为三组-模型组、纳布啡1组与纳布啡2组,每组16只。纳布啡1组与纳布啡2组分别给予纳布啡鞘内注射0.5 μg/10 μL与1.0 μg/10 μL,模型组给予注射等剂量的0.9 %氯化钠溶液,每天1次。分别于治疗第7 d、第14 d,采用血糖仪测定与记录空腹血糖（fasting blood glucose,FBG）水平并进行机械痛阈检测;治疗第14 d、第28 d,采用酶联免疫法检测血清IL-6与TNF-α含量,采用免疫印迹法检测背根神经节TRPV1蛋白的相对表达。结果：模型组、纳布啡1组与纳布啡2组治疗第7 d、第14 d的空腹血糖水平都高于20.00 mmol/L,组内与组间对比差异不具有统计学意义（P>0.05）。纳布啡1组与纳布啡2组治疗第7 d、第14 d的机械痛阈高于模型组（P<0.05）,也高于治疗前（P<0.05）,纳布啡2组与纳布啡1组差异具有统计学意义（P<0.05）。纳布啡1组与纳布啡2组治疗第14 d、第28 d的血清白细胞介素（Interleukin,IL）-6与肿瘤坏死因子（Tumor necrosis factor,TNF）-α含量明显低于模型组（P<0.05）,纳布啡2组明显低于纳布啡1组（P<0.05）。纳布啡1组与纳布啡2组治疗第14 d、第28 d的背根神经节TRPV1相对表达水平明显低于模型组（P<0.05）,纳布啡2组明显低于纳布啡1组（P<0.05）。结论：纳布啡鞘内注射在糖尿病神经痛模型大鼠的应用能改善行为能力,抑制背根神经节TRPV1的表达,还可抑制血清IL-6与TNF-α的释放,从而发挥镇痛治疗效用。