Early reduction of circulating homocysteine levels in Goto-Kakizaki rat, a spontaneous nonobese model of type 2 diabetes

Diabetes mellitus is associated with increased risk for cardiovascular disorders, which are major causes of mortality in this disease. Hyperhomocysteinemia, defined by high plasma homocysteine levels, is an independent risk factor for the development of cardiovascular diseases. Type 2 diabetic patients have higher circulating homocysteine levels than healthy subjects and these levels are even higher in plasma of obese than nonobese diabetic patients. Homocysteine metabolism that has been studied in 2 animal models of type 2 diabetes with obesity led to conflicting data. The aim of the present study was to analyze homocysteine metabolism in a spontaneous nonobese model of type 2 diabetes, the Goto-Kakizaki rats at various successive and well characterized stages of the disease: during early postnatal normoglycemia, at the onset of hyperglycemia (around weaning), and during chronic mild hyperglycemia with progressive insulin resistance. Compared to age-matched Wistar controls, Goto-Kakizaki rats showed lower plasma levels of homocysteine and a falling trend in its major byproduct antioxidant, glutathione, from the prediabetic stage onwards. Concomitantly, Goto-Kakizaki rats exhibited increased liver activity of cystathionine beta synthase, which catalyzes the condensation of homocysteine with serine in the first step of the transsulfuration pathway. These results emphasize a strong association between homocysteine metabolism and insulin via the first step of the hepatic transsulfuration pathway in Goto-Kakizaki rats.     

Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress

Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and initiating tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB₁ and CB₂ G-protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types 1 and 2 diabetes, atherosclerosis, Alzheimer disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain.     

两种自发性2型糖尿病小鼠生物学特性比较

目的分别以C57BL/6JSlac和C57BL/KsJ-db/＋表型正常小鼠为对照组,比较自发性2型糖尿病KK-Ay/Ta和C57BL/KsJ-db/db小鼠的体生长曲线、糖代谢曲线、血清胰岛素水平、主要脏器重量、脏器系数等生物学特性的差异,并探讨其肾脏、肝脏和胰腺等组织病理学变化。方法在各自实验周期内,每2周测定实验组和对照组小鼠的体重、血糖以及血清胰岛素水平,实验结束后处死,脏器、脂肪称重,部分组织制作病理切片。结果 （1）KK小鼠体重远高于db/db小鼠,且同品系间雄性小鼠重于雌性小鼠（P〈0.05）;（2）同品系间雄性小鼠的血糖值明显大于雌性小鼠（P〈0.05）,db/db小鼠出现血糖异常症状比KK小鼠早,且血糖值大于KK小鼠（P〈0.05）,而KK小鼠血糖异常持续时间则较db/db小鼠长;（3）KK小鼠的血清胰岛素水平明显高于db/db小鼠（P〈0.05）,同品系雌雄小鼠间没有明显差异（P〉0.05）;（4）雄性KK小鼠脂肪系数及部分脏器萎缩程度大于雌性,而db/db小鼠雌雄间则无明显差异（P〉0.05）,同时db/db小鼠脾脏和胰腺的萎缩程度及脂肪系数大于KK小鼠（P〈0.05）,而KK小鼠肝脏的萎缩程度则大于db/db小鼠;（5）糖尿病模型小鼠肾脏、肝脏以及胰腺组织均出现明显病变。结论 KK-Ay/Ta和C57BL/KsJ-db/db小鼠均是肥胖的,伴有高血糖、高度胰岛素抵抗,肝脏、肾脏病变和胰岛功能不足的适用性2型糖尿病动物模型,且db/db小鼠血糖出现异常比KK小鼠早、脂肪系数大,而KK小鼠血糖异常持续时间较db/db小鼠长,同时血清胰岛素水平远大于db/db小鼠。     

EB病毒抗体和DNA联合检测可提高儿童传染性单核细胞增多症的诊断灵敏度

目的评估EB病毒抗体VCA-IgM、VCA-IgG、EA-IgG、EBNA-1-IgG及EBV-DNA载量检测在儿童传染性单核细胞增多症(传单)中的诊断意义。方法用ELISA方法检测70例传单患儿和25例健康儿童血清中EBV四种抗体及PCR荧光定量法检测外周血单个核细胞EBV-DNA载量。结果传单患儿组EBV-DNA的阳性率为87.14%(61/70),对照组阳性率为8.00%(2/25),传单组与对照组EBV-DNA的阳性率比较差异有统计学意义(P<0.01)。EBV抗体检测中,传单组的VCA-IgM阳性率最高,达91.43%(64/70),对照组VCA-IgM全部阴性。传单组EB病毒VCA-IgM和EBV-DNA联合检测的阳性率97.1%。结论 EBV抗体和EBV-DNA载量检测对儿童传单的诊断有极高的价值,尤其是VCA-IgM抗体和EBV-DNA联合检测,可提高儿童传单的临床诊断的敏感性。     

糖尿病肾病动物模型的研究进展

糖尿病肾病是糖尿病的主要并发症之一,也是终末期肾衰的元凶,其发病机制至今尚未阐明。因此,建立理想的实验动物模型是研究糖尿病肾病发病机制、疾病防治、新药开发的关键环节。本文回顾并分析了有关该疾病模型的国内外文献,从造模方法、发病机制、病理改变、适用条件、模型的优缺点等方面进行比较分析,为选择合适的动物模型应用于糖尿病肾病的研究提供参考。     

Cardiopulmonary bypass reduces atrial Na+-K+-ATPase expression in children

Cardiopulmonary bypass (CPB) may induce serious side effects, potentially leading to myocardial failure. The Na(+)-K(+)-ATPase is a key component for myocardial function. Due to its developmental regulation, results from adult studies cannot be adopted to the situation in childhood. Right atrial myocardium from patients with left-to-right shunts at atrial level (VO, n=8) and those without (NO, n=8) was excised during heart surgery before and after CPB. Na(+)-K(+)-ATPase isoforms ATP1A1 (p=0.008) and ATP1A3 (p=0.038) decreased during CPB, which decrease was restricted to the VO group. This study highlights the importance of the underlying heart defect for susceptibility to the effects of CPB, showing a reduced Na(+)-K(+)-ATPase mRNA expression only in patients with left-to-right shunts on the atrial level. This seemed to be an early molecular event, as apart from one, none of the patients showed heart failure before or after surgery.     

The specific p38 mitogen-activated protein kinase pathway inhibitor FR167653 keeps insulitis benign in nonobese diabetic mice

The p38 mitogen-activated protein kinase (MAPK) pathway is important in Th1 immunity, macrophage activation, and apoptosis. Since they may be associated with beta-cell destruction during the development of type 1 diabetes, we investigated the role of the p38 MAPK pathway in female nonobese diabetic (NOD) mice. Phosphorylated p38 MAPK was observed immunohistochemically in CD4+ cells that had infiltrated into the islets and part of beta-cells, increasing in proportion to the severity of insulitis. Continuous oral administration of 0.08% FR167653, a specific p38 MAPK pathway inhibitor, significantly reduced the ex vivo production of interferon-gamma by splenic Th1 cells without affecting interleukin-4 production by Th2 cells. FR167653 administration from 4-30 weeks of age prevented NOD mice from developing diabetes without affecting the severity of insulitis. Treatment with FR167653 after insulitis had developed (i.e. from 10-30 weeks of age) also prevented diabetes, further suggesting that treatment with the p38 MAPK pathway inhibitor keeps insulitis benign in NOD mice, partly by inhibiting Th1 immunity. These findings suggest that p38 MAPK is a key mediator that switches insulitis from benign to destructive in the development of type 1 diabetes.     

The MEK inhibitor U0126 ameliorates diabetic cardiomyopathy by restricting XBP1's phosphorylation dependent SUMOylation

Background: Chronic diabetes accelerates vascular dysfunction often resulting in cardiomyopathy but underlying mechanisms remain unclear. Recent studies have shown that the deregulated unfolded protein response (UPR) dependent on highly conserved IRE1α-spliced X-box- binding protein (XBP1s) and the resulting endoplasmic reticulum stress (ER-Stress) plays a crucial role in the occurrence and development of diabetic cardiomyopathy (DCM). In the present study, we determined whether targeting MAPK/ERK pathway using MEK inhibitor U0126 could ameliorate DCM by regulating IRE1α-XBP1s pathway.Method: Three groups of 8-week-old C57/BL6J mice were studied: one group received saline injection as control (n=8) and two groups were made diabetic by streptozotocin (STZ) (n=10 each). 18 weeks after STZ injection and stable hyperglycemia, one group had saline treatment while the second group was treated with U0126 (1mg/kg/day), 8 weeks later, all groups were sacrificed. Cardiac function/histopathological changes were determined by echocardiogram examination, Millar catheter system, hematoxylin-eosin staining and western blot analysis. H9C2 cardiomyocytes were employed for in vitro studies.Results: Echocardiographic, hemodynamic and histological data showed overt myocardial hypertrophy and worsened cardiac function in diabetic mice. Chronic diabetic milieu enhanced SUMOylation and impaired nuclear translocation of XBP1s. Intriguingly, U0126 treatment significantly ameliorated progression of DCM, and this protective effect was achieved through enriching XBP1s'' nuclear accumulation. Mechanistically, U0126 inhibited XBP1s'' phosphorylation on S348 and SUMOylation on K276 promoting XBP1s'' nuclear translocation. Collectively, these results identify that MEK inhibition restores XBP1s-dependent UPR and protects against diabetes-induced cardiac remodeling.Conclusion: The current study identifies previously unknown function of MEK/ERK pathway in regulation of ER-stress in DCM. U0126 could be a therapeutic target for the treatment of DCM.     

糖尿病心肌病发病机制的研究进展

糖尿病心肌病是一种特异性心肌病,病理表现为心肌肥厚和心肌纤维化。其发病机制复杂,可能涉及代谢紊乱(如葡萄糖转运子活性下降、游离脂肪酸增加、钙平衡调节异常、铜代谢紊乱、胰岛素抵抗)、心肌纤维化(与高血糖、心肌细胞凋亡、血管紧张素Ⅱ、胰岛素样生长因子-1、炎性细胞因子和基质金属蛋白酶等有关)、心脏自主神经病变和干细胞等多种因素。本文对近年来国内外有关糖尿病心肌病机制研究的进展予以综述,以期为临床有效防治提供依据。