Translocation of H-Ras and its implications in the development of diabetic retinopathy

H-Ras, a small molecular weight G-protein, undergoes post-translational modifications enabling its translocation from cytosol to the membrane. Hyperglycemia increases apoptosis of retinal capillary cells via activation of H-Ras, which can be ameliorated by farnesylation inhibitors. Our aim is to investigate the mechanism of retinal H-Ras activation in diabetes. H-Ras and Raf-1 were quantified in the retinal membrane and cytosol fractions obtained from streptozotocin-induced diabetes rats, and the role of post-translation modification was determined by investigating the effect of simvastatin on diabetes-induced alterations. The effect of H-Ras-siRNA on membrane translocation and apoptosis was also determined in bovine retinal endothelial cells (BRECs). Diabetes increased expressions of H-Ras and Raf-1 in the retinal membranes, and simvastatin prevented such translocation. Glucose-exposure of BRECs increased membrane H-Ras expression and H-Ras-siRNA prevented this translocation, and also decreased their apoptosis. Thus, membrane translocation of H-Ras is a plausible mechanism responsible for accelerated apoptosis of retinal capillary cells in diabetes.     

延长糖尿病模型大鼠生存期对糖尿病视网膜病变的影响

目的延长糖尿病模型大鼠生存期,动态观察糖尿病视网膜病变(DR)的形成和发展过程。方法雄性SD大鼠70只,随机分成对照组(20只)和模型组(50只),采用链脲佐菌素(STZ)60 mg/(kg.bw)体重腹腔1次注射造模,分别于69、、12月时处死取眼球,采用视网膜微血管消化铺片技术观察糖尿病视网膜病变的微血管形态学改变。结果糖尿病大鼠DR样病变随着病程的延长病变呈多样性改变,以12月DR出现的小动脉硬化尤为严重。结论糖尿病大鼠生存期的延长对糖尿病视网膜病变的研究有着积极的意义。     

A computational modeling for the detection of diabetic retinopathy severity

Prolonged diabetes ultimately leads to Diabetic Retinopathy (DR) which is one of the leading causes of preventable blindness in theworld. Through advanced image analysis techniques are used for abnormalities detection in retina that define and correlate theseverity of DR. A thorough study is done in this area in recent past years and on the basis of these studies we have developed acomputer based prediction model that is used to determine the severity of DR. To identify severity DR, we have analyzed thehuman eye image. We have extracted some important features from human eye image i.e. Blood Artery, Optical disc, Exudates.Based on these image and data we have designed an automated system for the determination of DR severity. This automated DRseverity assessment methods can be used to predict the clinical case and conditions when young clinicians would agree or disagreewith their more experienced fellow members. The algorithms described in this study may be used in clinical practice to validate orinvalidate the diagnoses. Algorithms or method developed here may also be used for pooling diagnostic knowledge for servingmankind. Here we have described a computational based low cost retinal diagnostic approach which can aid an ophthalmologist toquickly diagnose the various stages of DR. This system can accept retinal images and can successfully detect any pathologicalcondition associated with DR.     

Mechanisms involved in the development of diabetic retinopathy induced by oxidative stress

Background: Diabetic retinopathy (DR) is one of the main complications in patients with diabetes and has been the leading cause of visual loss since 1990. Oxidative stress is a biological process resulting from excessive production of reactive oxygen species (ROS). This process contributes to the development of many diseases and disease complications. ROS interact with various cellular components to induce cell injury. Fortunately, there is an antioxidan t system that protects organisms against ROS. Indeed, when ROS exceed antioxidant capacity, the resulting cell injury can cause diverse physiological and pathological changes that could lead to a disease like DR.

Objective: This paper reviews the possible mechanisms of common and novel biomarkers involved in the development of DR and explores how these biomarkers could be used to monitor the damage induced by oxidative stress in DR, which is a significant complication in people with diabetes.

Conclusion: The poor control of glucemy in pacients with DB has been shown contribute to the development of complications in eyes as DR.     

前列地尔联合尿激酶治疗糖尿病肾病尿蛋白的临床观察

目的:观察短期应用注前列地尔注射液、前列地尔注射液联合小剂量尿激酶对Ⅳ期糖尿病肾病患者尿蛋白的影响。方法:选取我院2005年1月～2009年12月的Ⅳ期糖尿病肾病住院患者548例,均采取强化控制血糖、血压,低蛋白饮食等基础治疗,分为前列地尔治疗组216例、前列地尔联合尿激酶治疗组332例,给予14天短期输液治疗,测定治疗前后24小时尿蛋白。结果:两组患者治疗前年龄、性别组成、糖尿病病程、血糖、血压、血脂、尿蛋白、肾功能等各项指标无显著差异。两组治疗前后各自比较,单独应用注前列地尔注射液、前列地尔注射液联合小剂量尿激酶,均可有效减少糖尿病肾病24小时尿蛋白排泄,但前列地尔注射液联合小剂量尿激酶改善尿蛋白排泄的效果较单独应用注前列地尔更显著(p<0.05),有效率更高(88.2%vs.75.4%,p<0.05);应用小剂量尿激酶未见眼底、皮肤、黏膜出血等不良反应,无凝血功能异常发生。结论:短期静脉应用前列地尔联合小剂量尿激酶治疗Ⅳ期糖尿病肾病,较单独使用前列地尔可更有效减少尿蛋白排泄,不增加眼底出血、皮肤出血、黏膜出血的风险,是一种降低糖尿病肾病尿蛋白水平的安全有效的治疗方法。     

Role of matrix metalloproteinase-2 and -9 in the development of diabetic retinopathy

Diabetic retinopathy represents the most common causes of vision loss in patients affected by diabetes mellitus. The cause of vision loss in diabetic retinopathy is complex and remains incompletely understood. One of the earliest changes in the development of retinopathy is the accelerated apoptosis of retinal microvascular cells and the formation of acellular capillaries by unknown mechanism. Results of a recent research suggest an important role of matrix metalloproteinases (MMPs) in the development of diabetic retinopathy. MMPs are a large family of proteinases that remodel extracellular matrix components, and under pathological condition, its induction is considered as a negative regulator of cell survival; and in diabetes, latent MMPs are activated in the retina and its capillary cells, and activation of MMP-2 and -9 induces apoptosis of retinal capillary cells. This review will focus on the MMP-2 and MMP-9 in the diabetic retina with special reference to oxidative stress, mitochondria dysfunction, inflammation and angiogenesis, as well as summarizing the current information linking these proteins to pathogenesis of diabetic retinopathy.     

Catalogue of soluble proteins in the human vitreous humor: comparison between diabetic retinopathy and macular hole

Two-dimensional gel electrophoresis and mass spectrometry were used to make a catalogue of soluble proteins in the human vitreous humor (VH). Fifty-one different proteins were identified on silver-stained two-dimensional (2D) gel patterns with VH proteins obtained from diabetic retinopathy and macular hole. Thirty of these have not been listed in the reported 2D profiles of plasma. Immunoglobulin (Ig), alpha1-antitrypsin, alpha2-HS glycoprotein,and complement C(4) fragment showed stronger spots in VH with diabetic retinopathy patient samples than those with macular hole. Pigment epithelium-derived factor, a potent inhibitor of angiogenesis in the cornea and vitreous, was clearly detected in VH with diabetes. It is impressive that the inhibitor increases in the vitreous with proliferative angiogenesis.     

A C597-->A polymorphism in the Norrie disease gene is associated with advanced retinopathy of prematurity in premature Kuwaiti infants

Retinopathy of prematurity (ROP) is a retinal vascular disease which occurs in infants with a short gestational age and low birth weight and may lead to retinal detachment and blindness. In some premature infants, ROP progresses to advanced stages despite rigorous intervention, but in the majority, it spontaneously regresses before the threshold stage. Genetic factors, e.g. mutations in the Norrie disease (ND) gene, have been implicated in determining the progression of ROP to advanced stages. We have identified a novel C597A polymorphism of the ND gene; we screened this and another mutation in the ND gene, C110G, in 210 premature Kuwaiti infants using PCR-RFLP, DNA sequence analysis and DNA enzyme immunoassay hybridization to investigate their association with advanced-stage ROP. In this cohort of premature Kuwaiti newborns, 115 of 210 babies had no eye problems and served as controls, while 95 were found to have ROP. In 71 of the 95 ROP cases, the disease spontaneously regressed at or before stage 3, while in 24 of 95 ROP cases, the disease progressed to advanced stages 4 or 5. The incidence of the AA genotype of the C597A polymorphism was considerably higher in advanced-stage ROP cases (83.3%) compared to spontaneously regressing ROP cases (0%) and the normal controls (10.4%) (p < 0.0001). For the other genotypes, no significant difference was detected between the controls and ROP cases. In the case of the C110G mutation in the ND gene, no significant differences were detected between the controls and ROP cases, and the majority of subjects had a CC genotype in all three groups.     

Ginseng modifies the diabetic phenotype and genes associated with diabetes in the male ZDF rat

Asian ginseng (Panax ginseng) and its close relative North American ginseng (Panax quinquefolius) are perennial aromatic herbs that are widely used in Oriental medicine and have been acclaimed to have various health benefits including diabetes treatment. In this study, we compared the effects of a diet containing rosiglitazone to a diet containing ginseng (Panax quinquefolius) in male Zucker diabetic fatty (ZDF) rats. Animals were assigned to one of three diets: control, rosiglitazone (0.1 g/1 kg diet), or ginseng (10 g/1 kg diet). During the 11-week study, body weight, food intake, organ weight, blood glucose, plasma cholesterol, and plasma triglyceride levels were evaluated. Animals treated with rosiglitazone or ginseng exhibited increased body weight (p<0.05) and decreased kidney weight (p<0.05) compared to control animals. The rosiglitazone group demonstrated decreased food intake and plasma triglyceride levels versus the other groups (p<0.05). The ginseng group revealed decreased cholesterol levels relative to the control group (p<0.05). Furthermore, ginseng and rosiglitazone had marked effects on the expression of genes involved in PPAR actions and triglyceride metabolism compared to controls. In conclusion, ginseng modified the diabetic phenotype and genes associated with diabetes in the male ZDF rat. These data are encouraging, and warrant further research to determine the therapeutic value of this medicinal herb in treating human diabetes.     

A critical role of STAT1 in streptozotocin-induced diabetic liver injury in mice: Controlled by ATF3

It is well-established that the administration of streptozotocin accelerates diabetic liver injury as well as type-I diabetes, however the underlying mechanisms are poorly understood. Here we investigated the molecular mechanisms of diabetic liver injury in a model of streptozotocin (STZ)-induced type-I diabetes. STZ administration induced type-1 diabetes and chronic liver injury was associated with increased STAT1, which is implicated in diabetic liver injury by virtue of its ability to promote hepatocyte apoptosis, in the liver and pancreas, which were all strongly inhibited in STAT1^−/– mice. Similarly, STZ-induced ATF3, a stress-inducible gene, was completely abolished in the liver of IFN-γ^−/− mice, but not in STAT1^−/− mice. Inhibition of STAT1 by siRNA or dominant-negative DNA did not affect ATF3 protein expression but blocked IFN-γ-induced ATF3 translocation from the cytosol into the nucleus. In contrast, inhibition of ATF3 by using siRNA diminished STAT1 protein expression and IFN-γ/STZ-induced hepatocyte apoptosis. Furthermore, GST pull-down and co-IP assay showed that STAT1 bound to C-terminal domain of ATF3. Such direct interaction increased the stability of STAT1 by inhibiting its ubiquitination as well as proteasome activity. Our results suggest that STAT1 is a common signaling pathway contributing to STZ-induced diabetes and diabetic liver injury. ATF3 functions as a potent regulator of STAT1 stability, accelerating STZ-induced diabetes and diabetic liver injury.     

Effects of trientine,a metal chelator,on defective endothelium-dependent relaxation in the mesenteric vasculature of diabetic rats

Diabetes mellitus compromises endothelium-dependent relaxation of blood vessels. This has been linked to the generation of reactive oxygen species (ROS), which neutralise nitric oxide (NO) and interfere with vasodilator function. Experiments using chelators have emphasised the importance of ROS produced by transition metal catalysed reactions. However, particularly for the small arteries and arterioles that control microcirculatory blood flow, NO is not the only endothelium-derived mediator; endothelium-derived hyperpolarizing factor (EDHF) has a major role. EDHF-mediated vasodilation is severely curtailed by diabetes; however, little information exists on the underlying pathophysiology. Deficits in the EDHF system, alone or in combination with the NO system, are crucial for the development of diabetic microvascular complications. To further elucidate the mechanisms involved, the aim was to examine the effects of diabetes and preventive and intervention chelator therapy with trientine on a preparation that has well-defined NO and EDHF-mediated responses, the rat mesenteric vascular bed. In phenylephrine-preconstricted preparations, maximum vasodilation to acetylcholine was reduced by 35 and 44% after 4 and 8 weeks of streptozotocin-induced diabetes, respectively. Trientine treatment over the first 4 weeks gave 72% protection; intervention therapy over the final 4 weeks prevented deterioration and corrected the initial deficit by 68%. These responses depend on both NO and EDHF. When the latter mechanism was isolated by NO synthase inhibition, diabetic deficits of 53.4 (4 weeks) and 65.4% (8 weeks) were revealed, that were 65% prevented and 50% corrected by trientine treatment. Neither diabetes nor trientine altered vascular smooth muscle responses to the NO donor, sodium nitroprusside (SNP). Thus, the data suggest that metal catalysed ROS production makes a substantial contribution to defects in both the EDHF and NO endothelial mechanisms in diabetes, which has therapeutic implications for microvascular complications.     

Trypanosoma cruzi: The effects of zinc supplementation in the immune response during the course of experimental disease

Zinc is an essential nutritional component required for normal development and maintenance of immune functions. The possible effects of zinc in upregulating the host immune response during the acute and chronic phases of experimental Chagas’ disease were evaluated. In young, infected and Zn-supplemented animals, higher concentrations of IFN-γ and NO were observed. During the chronic phase, decreased concentrations of NO and IFN-γ were found for older infected animals that received Zn supplementation. For young animals, hearts from Zn-supplemented groups displayed reduced inflammatory infiltrate, heart weight and number of amastigote burdens. For older, infected and Zn-supplemented animals amastigote nests were absent with reduced inflammatory cell infiltrate. This study identifies a potentially novel therapeutic approach that could control the parasite load during acute phase of disease, consequently preventing the deleterious, parasite-elicited responses observed during chronic phase.     

Multichannel surface electrodes increase the sensitivity of diagnosis of neuropathy in diabetic patients

This prospective study investigated the diagnostic sensitivity of a novel multichannel surface electrode for detecting electrophysiologic changes in symptomatic diabetic neuropathy. We recruited healthy subjects without neuropathic complaints and diabetic patients with distal symmetric sensory symptoms who had normal nerve conduction studies (NCS). Eight compound muscle action potentials (CMAPs) were recorded using a multichannel electrode from each subject’s abductor pollicis brevis muscle by stimulating the median nerve at the wrist. Latency- and amplitude-related variables were obtained and analyzed to compare the two groups. We used the Classification and Regression Tree (CART) algorithm to determine the cut-off values for selected predictors of diabetic neuropathy. All of the variables related to CMAP latency showed statistically significant differences between the median values for the diabetic group and the healthy control group. For example, the median value of the maximum latency and standard deviation of the eight CMAP onset latencies in diabetic patients (3.82 ms and 0.15 ms, respectively) were significantly larger than those in controls (3.26 ms and p < 0.001; 0.09 ms and p < 0.001, respectively). The CART analysis revealed that these variables were the most sensitive and specific variables for discriminating between patients with diabetic neuropathy and normal subjects. The multichannel surface electrode demonstrated both high sensitivity and specificity in detecting neurophysiologic abnormality of diabetic neuropathy, even when conventional NCS did not detect the abnormality.     

棉籽蛋白质和油分含量预测的生态模型

为研究棉籽蛋白质和油分含量与环境因子间的定量关系,选择不同熟性棉花品种在长江流域下游棉区和黄河流域黄淮棉区各2个地点进行分期播种和施氮量试验,分析了品种、主要气象条件和施氮量对棉籽蛋白质和油分含量的影响.结果表明:棉籽蛋白质和油分含量的主要影响因子除品种外依次为铃期平均温度、太阳辐射量和施氮量;棉籽蛋白质和油分形成的最适宜铃期日均温分别为26.1℃和25.7℃;充足的光照不利于棉籽蛋白质和油分含量的提高;增加施氮量提高了棉籽蛋白质含量,降低了油分含量.建立了棉籽蛋白质含量与油分含量的生态模型,模型以品种、铃期平均温度、铃期日均太阳辐射量和施氮量为模型输入,简便易行.模型对棉籽蛋白质含量和油分含量预测的根均方差(RMSE)分别为2.03％和2.54％,具有较好的预测性.     

Improving the simultaneous removal efficiency of COD and color in a combined HABMR-CFASR system based MPDW. Part 1: optimization of operational parameters for HABMR by using response surface methodology

The aim of this study was to implement central-composite design (CCD) and response surface methodology (RSM) to optimize the operational parameters for hybrid anaerobic baffled microbial reactor (HABMR) remedying mixed printing and dyeing wastewater (MPDW). The individual and interactive effects of three variables, hydraulic retention time (HRT), pH, sludge loading rate (SLR) on the COD and color removal rates were evaluated. In the area of HRT: 12.5-13.9 h, pH: 9.0-9.5 and SLR: 0.27-0.33 kg COD/(kg MLVSSd), COD and color removal rates of HABMR exceeded 40% and 60%, simultaneously. The check experiment revealed that the amount of COD and color in the effluent could be decreased by 9.97% and 10.12% compared to the usual operating conditions, respectively. The results verified that the RSM was useful for optimizing the operational parameters of HABMR in treating MPDW.     

Niche-based modelling as a tool for predicting the risk of alien plant invasions at a global scale

Predicting the probability of successful establishment of plant species by matching climatic variables has considerable potential for incorporation in early warning systems for the management of biological invasions. We select South Africa as a model source area of invasions worldwide because it is an important exporter of plant species to other parts of the world because of the huge international demand for indigenous flora from this biodiversity hotspot. We first mapped the five ecoregions that occur both in South Africa and other parts of the world, but the very coarse definition of the ecoregions led to unreliable results in terms of predicting invasible areas. We then determined the bioclimatic features of South Africa's major terrestrial biomes and projected the potential distribution of analogous areas throughout the world. This approach is much more powerful, but depends strongly on how particular biomes are defined in donor countries. Finally, we developed bioclimatic niche models for 96 plant taxa (species and subspecies) endemic to South Africa and invasive elsewhere, and projected these globally after successfully evaluating model projections specifically for three well‐known invasive species (Carpobrotus edulis, Senecio glastifolius, Vellereophyton dealbatum) in different target areas. Cumulative probabilities of climatic suitability show that high‐risk regions are spatially limited globally but that these closely match hotspots of plant biodiversity. These probabilities are significantly correlated with the number of recorded invasive species from South Africa in natural areas, emphasizing the pivotal role of climate in defining invasion potential. Accounting for potential transfer vectors (trade and tourism) significantly adds to the explanatory power of climate suitability as an index of invasibility. The close match that we found between the climatic component of the ecological habitat suitability and the current pattern of occurrence of South Africa alien species in other parts of the world is encouraging. If species' distribution data in the donor country are available, climatic niche modelling offers a powerful tool for efficient and unbiased first‐step screening. Given that eradication of an established invasive species is extremely difficult and expensive, areas identified as potential new sites should be monitored and quarantine measures should be adopted.