Identification of new potent inhibitor of aldose reductase from Ocimum basilicum

Recent efforts to develop cure for chronic diabetic complications have led to the discovery of potent inhibitors against aldose reductase (AKR1B1, EC 1.1.1.21) whose role in diabetes is well-evident. In the present work, two new natural products were isolated from the ariel part of Ocimum basilicum; 7-(3-hydroxypropyl)-3-methyl-8-β-O-d-glucoside-2H-chromen-2-one (1) and E-4-(6′-hydroxyhex-3′-en-1-yl)phenyl propionate (2) and confirmed their structures with different spectroscopic techniques including NMR spectroscopy etc. The isolated compounds (1, 2) were evaluated for in vitro inhibitory activity against aldose reductase (AKR1B1) and aldehyde reductase (AKR1A1). The natural product (1) showed better inhibitory activity for AKR1B1 with IC₅₀ value of 2.095 ± 0.77 µM compare to standard sorbinil (IC₅₀ = 3.14 ± 0.02 µM). Moreover, the compound (1) also showed multifolds higher activity (IC₅₀ = 0.783 ± 0.07 µM) against AKR1A1 as compared to standard valproic acid (IC₅₀ = 57.4 ± 0.89 µM). However, the natural product (2) showed slightly lower activity for AKR1B1 (IC₅₀ = 4.324 ± 1.25 µM). Moreover, the molecular docking studies of the potent inhibitors were also performed to identify the putative binding modes within the active site of aldose/aldehyde reductases.     

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。     

西格列汀通过增加肾组织中SOCS 1和Podocalyxin的表达改善糖尿病肾病大鼠肾功能

目的:探讨西格列汀对糖尿病肾病大鼠肾功能及肾组织中细胞因子信号传导负调控因子1(Suppressors of cytockine signaling,SOCS 1)和足细胞特异蛋白抗体(Podocalyxin)表达的影响。方法:将大鼠随机分为4组:对照组,模型组,西格列汀组和贝那普利组。模型组、西格列汀组和贝那普利组采用腹腔注射链脲佐菌素建立模型,对照组给予腹腔注射等量生理盐水。造模成功后,西格列汀组(n=8)和贝那普利组(n=8)分别灌胃给予7 mg/kg/d的西格列汀和贝那普利。模型组(n=8)和对照组(n=10)均给予等体积的蒸馏水灌胃,连续8周。检测并对比各组大鼠代谢相关指标,肾组织纤维化程度指标,肾组织中炎症因子水平以及Podocalyxin、SOCS 1和结蛋白(Desmin)表达。结果:干预8周后,与对照组对比,模型组空腹血糖、糖化血红蛋白、甘油三酯、总胆固醇、24 h尿蛋白排泄率、肌酐、体重、肾组织转化生长因子-β1(Transforming growth factor,TGF-β1)、白介素(Interleukin,IL)-6、IL-1β、SOCS 1和Desmin水平均显著增加,Ⅳ型胶原蛋白(Collagen-Ⅳ,C-Ⅳ)、纤维连接蛋白(Fibronectin,FN)、层黏连蛋白(Laminin,LN)和Podocalyxin水平显著降低(P0.05);与模型组对比,西格列汀组和厄贝沙坦组空腹血糖、糖化血红蛋白、甘油三酯、总胆固醇、24 h尿蛋白排泄率、肌酐、体重、肾组织TGF-β1、IL-6、IL-1β和Desmin水平均显著降低,Podocalyxin和SOCS 1蛋白表达增加(P0.05)。但厄贝沙坦组与西格列汀组以上各指标对比差异无统计学意义(P0.05)。结论:西格列汀可能通过增加Podocalyxin和SOCS 1蛋白表达,降低肾组织中炎症因子和Desmin蛋白表达,进而改善糖尿病肾病大鼠肾纤维化和肾功能。     

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。     

NLRP3 inflammasome negatively regulates podocyte autophagy in diabetic nephropathy

Inflammasome mechanisms are recognized as a key pathophysiology of diabetic nephropathy (DN). The nucleotide-oligomerization domain-like receptor 3 (NLRP3) inflammasome has attracted the most attention. Autophagy as a conserved intracellular catabolic pathway plays essential roles in the maintenance of podocytes. Although autophagy was involved in preventing excessive inflammatory responses in kidney diseases, a clear understanding of the regulation of NLRP3 inflammasome on autophagy in glomerular damage in DN is still lacking. In this study, we focused on the effect of the activation of NLRP3 inflammasome on the suppression of podocyte autophagy and aimed to investigate the role of autophagy in podocyte injury in DN. Podocyte autophagy has been confirmed to be inhibited in high-fat diet/streptozotocin (HFD/STZ)-induced DN mice, and NLRP3 has been found to be upregulated in both mice and human DN biopsies and in vitro. Activation of NLRP3 inflammasome exacerbated podocyte autophagy and reduced podocyte nephrin expression, while silencing of NLRP3 efficiently restored podocyte autophagy and ameliorated podocyte injury induced by high glucose. The results showed that NLRP3 was a negative regulator of autophagy and suggested that restoration of podocyte autophagy by inactivation of NLRP3 under high glucose could reduce podocyte injury. Proper modification of autophagy and inflammasome has the potential to benefit the kidney in DN.     

Exenatide prevents high-glucose-induced damage of retinal ganglion cells through a mitochondrial mechanism

Exenatide (exendin-4 analogue) is widely used in clinics and shows a neuroprotective effect. The main objectives of the present study were to prove that retinal ganglion cells (RGC-5) express GLP-1R, to ascertain whether exenatide prevents a high-glucose-induced RGC-5 impairment, to determine the appropriate concentration of exenatide to protect RGC-5 cells, and to explore the neuroprotective mechanisms of exenatide. Immunofluorescence and Western blot analyses demonstrated that RGC-5 cells express GLP-1R. We incubated RGC-5 cells with 25 mM glucose prior to incubation with either 25 mM glucose, 55 mM glucose (high), high glucose plus exenatide or high glucose plus a GLP-1R antagonist. The survival rates of the cells were measured by CCK-8, and cellular injury was detected by electron microscopy. There were statistical differences between the high-glucose group and the control group (P<0.05). Exenatide improved the survival rate of the cells and suppressed changes in the mitochondrial morphology. The optimum concentration of exenatide to protect the RGC-5 cells from high-glucose-induced RGC injury was 0.5 μg/ml, and this protective effect could be inhibited by exendin (9-39). To further study the mechanism underlying the beneficial effects of exenatide, the expression levels of cytochrome c, Bcl-2, Bax and caspase-3 were analysed by Western blot. The present study showed that treatment with exenatide significantly inhibited cytochrome c release and decreased the intracellular expression levels of Bax and caspase-3, whereas Bcl-2 was increased (P<0.05). These results suggested that GLP-1R activation can inhibit the cellular damage that is induced by high glucose. A mitochondrial mechanism might play a key role in the protective effect of exenatide on the RGC-5 cells, and exenatide might be beneficial for patients with diabetic retinopathy.     

Novel triazine-based pyrimidines suppress glomerular mesangial cells proliferation and matrix protein accumulation through a ROS-dependent mechanism in the diabetic milieu

Diabetic nephropathy (DN) is one of the most serious complications of diabetes worldwide. It is depicted as the leading cause of end-stage renal disease. Oxidative stress plays a key role in hyperglycemia-induced DN. The preparation and characterization of novel mono-, di-, and trisubstituted-s-triazines endowed with uracil and/or thymine are described in this paper. The synthesis of the title compounds was realized through selective nucleophilic substitution reactions of cyanuric chloride with the corresponding hydrazide nucleobases. In this study, we assessed the effects of these derivatives on the progression of diabetic nephropathy. Our results show that trisubstituted-s-triazines endowed with acylhydrazides attenuate high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. Notably, these derivatives also display anti-oxidative properties. This suggests that the novel trisubstituted-s-triazine derivatives provide renal protection through a reactive oxygen species (ROS)-dependent mechanism. Our data provide evidence that these derivatives may serve as potential therapeutic candidates in the treatment of DN.