Genetic control of anti-Sm autoantibody production in NOD congenic mice narrowed to the Idd9.3 region

Anti-Smith (anti-Sm) autoantibodies are directed to proteins in the small-nuclear ribonucleoprotein (snRNP) family and are considered specific for systemic lupus erythematosus (SLE) in both humans and mice. We previously established that NOD.c3c4 mice, carrying B6 and B10 congenic segments from chromosomes 3 to 4 on an nonobese diabetic (NOD) background, and NOD.Idd9R28 mice, carrying a B10 segment on c4 alone, developed significant penetrance of anti-Sm antibody production. Here we determine autoantibody incidence in additional NOD.Idd9 congenic strains and use a congenic mapping approach to narrow the interval necessary for enhanced autoantibody production to a ∼5.6-Mb region containing insulin-dependent diabetes (Idd)9.3. The Idd9.3 interval contains the candidate molecule cluster of differentiation (CD)137, which is a member of the tumor necrosis factor (TNF) receptor superfamily, functions as an inducible costimulator of T cells, and controls T–B interactions. The NOD and B10 CD137 alleles have sequence polymorphisms and different functional effects on T cells; the NOD CD137 allele mediates weaker T cell proliferative responses and decreased interleukin (IL)-2 production after CD137-mediated costimulation. Our work establishes CD137 as a candidate gene for control of autoantibody production in NOD.Idd9.3 congenic mice.     

Cannabinoid receptor 1 (CNR1) gene variant moderates neural index of cognitive disruption during nicotine withdrawal

Nicotine withdrawal‐related disruption of cognitive control may contribute to the reinforcement of tobacco use. Identification of gene variants that predict this withdrawal phenotype may lead to tailored pharmacotherapy for smoking cessation. Variation on the cannabinoid receptor 1 gene (CNR1) has been related to nicotine dependence, and CNR1 antagonists may increase attention and memory functioning. We targeted CNR1 variants as moderators of a validated neural marker of nicotine withdrawal‐related cognitive disruption. CNR1 polymorphisms comprising the ‘TAG’ haplotype (rs806379, rs1535255 and rs2023239) were tested independently, as no participants in this sample possessed this haplotype. Nicotine withdrawal‐related cognitive disruption was indexed as increased resting electroencephalogram (EEG) alpha‐1 power density across 17 electrodes. Seventy‐three Caucasian Non‐Hispanic smokers (≥15 cigarettes per day) visited the laboratory on two occasions following overnight smoking/nicotine deprivation. Either two nicotine or two placebo cigarettes were smoked prior to collecting EEG data at each session. Analyses showed that rs806379 moderated the effects of nicotine deprivation increasing slow wave EEG (P = 0.004). Smokers homozygous for the major allele exhibited greater nicotine withdrawal‐related cognitive disruption. The current findings suggest potential efficacy of cannabinoid receptor antagonism as a pharmacotherapy approach for smoking cessation among individuals who exhibit greater nicotine withdrawal‐related cognitive disruption.     

Ginsenoside Rg1 ameliorates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress‐induced apoptosis in a streptozotocin‐induced diabetes rat model

Ginsenoside Rg1 has been demonstrated to have cardiovascular protective effects. However, whether the cardioprotective effects of ginsenoside Rg1 are mediated by endoplasmic reticulum (ER) stress‐induced apoptosis remain unclear. In this study, among 80 male Wistar rats, 15 rats were randomly selected as controls; the remaining 65 rats received a diet rich in fat and sugar content for 4 weeks, followed by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg) to establish a diabetes model. Seven days after STZ injection, 10 rats were randomly selected as diabetic model (DM) controls, 45 eligible diabetic rats were randomized to three treatment groups and administered ginsenoside Rg1 in a dosage of 10, 15 or 20 mg/kg/day, respectively. After 12 weeks of treatment, rats were killed and serum samples obtained to determine cardiac troponin (cTn)‐I. Myocardial tissues were harvested for morphological analysis to detect myocardial cell apoptosis, and to analyse protein expression of glucose‐regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and Caspase‐12. Treatment with ginsenoside Rg1 (10–20 mg/kg) significantly reduced serum cTnI levels compared with DM control group (all P < 0.01). Ginsenoside Rg1 (15 and 20 mg/kg) significantly reduced the percentage of apoptotic myocardial cells and improved the parameters of cardiac function. Haematoxylin and eosin and Masson staining indicated that ginsenoside Rg1 could attenuate myocardial lesions and myocardial collagen volume fraction. Additionally, ginsenoside Rg1 significantly reduced GRP78, CHOP, and cleaved Caspase‐12 protein expression in a dose‐dependent manner. These findings suggest that ginsenoside Rg1 appeared to ameliorate diabetic cardiomyopathy by inhibiting ER stress‐induced apoptosis in diabetic rats.     

Short‐term exposure to mobile phone base station signals does not affect cognitive functioning or physiological measures in individuals who report sensitivity to electromagnetic fields and controls

Individuals who report sensitivity to electromagnetic fields often report cognitive impairments that they believe are due to exposure to mobile phone technology. Previous research in this area has revealed mixed results, however, with the majority of research only testing control individuals. Two studies using control and self‐reported sensitive participants found inconsistent effects of mobile phone base stations on cognitive functioning. The aim of the present study was to clarify whether short‐term (50 min) exposure at 10 mW/m² to typical Global System for Mobile Communication (GSM) and Universal Mobile Telecommunications System (UMTS) base station signals affects attention, memory, and physiological endpoints in sensitive and control participants. Data from 44 sensitive and 44 matched‐control participants who performed the digit symbol substitution task (DSST), digit span task (DS), and a mental arithmetic task (MA), while being exposed to GSM, UMTS, and sham signals under double‐blind conditions were analyzed. Overall, cognitive functioning was not affected by short‐term exposure to either GSM or UMTS signals in the current study. Nor did exposure affect the physiological measurements of blood volume pulse (BVP), heart rate (HR), and skin conductance (SC) that were taken while participants performed the cognitive tasks. Bioelectromagnetics 30:556–563, 2009. © 2009 Wiley‐Liss, Inc.     

帕金森病认知功能障碍的相关因素及临床特点分析

目的:探讨帕金森病(PD)伴轻度认知功能障碍(PD-MCI)的相关因素及临床特征,找出帕金森病伴轻度认知功能障碍的预测因子。方法:参照运动障碍协会工作组推荐的帕金森病伴轻度认知功能障碍的诊断标准,用蒙特利尔认知功能评估量表(Mo C A)及帕金森病统一评定量表(Ⅰ~Ⅲ)对81例PD患者进行评估。结果:81例PD患者中47例为轻度认知功能障碍,占58%,23例无认知功能障碍,占28%;14%PD-MCI病人病程小于5年。PD-MCI组与帕金森病不伴有认知功能障碍(PD-NCI)组在文化程度、HY分期、每日左旋多巴等效剂量(LEDD)上差异有统计学意义(P0.05);视空间/执行功能、延迟记忆、注意力、语言、抽象能力认知域差异有统计学意义(P0.05);UPDRSⅢ、姿势不稳步态障碍(PIGD)差异有统计学意义(P0.05);Mo CA评分与年龄(r=-0.31,P0.05)、HY分期(r=-0.44,P0.05)、UPDRS-Ⅲ分数(r=-0.32,P0.05)、UPDRS-Ⅱ(r=-0.35,P0.05)、UPDRS-Ⅰ(r=-0.40,P0.05)、迟缓(r=-0.38,P0.05)、PIGD呈负相关(r=-0.31,P0.05),与教育程度呈正相关(r=0.30,P0.05)。纳入Mo CA评分为因变量,年龄、教育程度、HY分期、UPDRS-Ⅲ分数、UPDRS-Ⅱ分数、UPDRS-Ⅰ分数为自变量行多元线性回归分析,年龄(βcoefficients-0.06,P0.05)和HY分期(βcoefficients-0.80,P0.05)为帕金森病伴轻度认知功能障碍的预测因子;为观察UPDRSⅢ中亚项评分对认知功能的独立影响,单独纳入迟缓和PIGD评分为自变量,结果迟缓为帕金森病伴轻度认知功能障碍的预测因子(βcoefficients-0.12,P0.05)。结论:MCI是PD患者中发生率较高的一种非运动症状,以视空间/执行功能、延迟记忆、注意力、语言功能障碍为主。患者的认知功能和年龄、教育程度、疾病严重程度、运动障碍密切相关,特别是迟缓与姿势不稳/步态障碍。年龄、HY分期、迟缓为PD-MCI的预测因子。     

Receptor for advanced glycation end products aggravates cognitive deficits in type 2 diabetes through binding of C‐terminal AAs 2‐5 to mitogen‐activated protein kinase kinase 3 (MKK3) and facilitation of MEKK3‐MKK3‐p38 module assembly

In this study, we explored the precise mechanisms underlying the receptor for advanced glycation end products (RAGE)‐mediated neuronal loss and behavioral dysfunction induced by hyperglycemia. We used immunoprecipitation (IP) and GST pull‐down assays to assess the interaction between RAGE and mitogen‐activated protein kinase kinase 3 (MKK3). Then, we investigated the effect of specific mutation of RAGE on plasticity at hippocampal synapses and behavioral deficits in db/db mice through electrophysiological recordings, morphological assays, and behavioral tests. We discovered that RAGE binds MKK3 and that this binding is required for assembly of the MEKK3‐MKK3‐p38 signaling module. Mechanistically, we found that activation of p38 mitogen‐activated protein kinase (MAPK)/NF‐κB signaling depends on mediation of the RAGE‐MKK3 interaction by C‐terminal RAGE (ctRAGE) amino acids (AAs) 2‐5. We found that ctRAGE R2A‐K3A‐R4A‐Q5A mutation suppressed neuronal damage, improved synaptic plasticity, and alleviated behavioral deficits in diabetic mice by disrupting the RAGE‐MKK3 conjugation. High glucose induces direct binding of RAGE and MKK3 via ctRAGE AAs 2‐5, which leads to assembly of the MEKK3‐MKK3‐p38 signaling module and subsequent activation of the p38MAPK/NF‐κB pathway, and ultimately results in diabetic encephalopathy (DE).     

Influence of 50 Hz frequency sinusoidal magnetic field on the blood-brain barrier permeability of diabetic rats

The combined effects of diabetes and a 50 Hz, 5 mT RMS flux density sinusoidal magnetic field for 8 h a day, for 21 consecutive days on the permeation of Evans-blue dye through the blood-brain barrier were studied in male Wistar albino rats. Our results suggest that magnetic field has no effect on the blood-brain barrier permeability in normoglycemic animals, but that diabetic rats are vulnerable to magnetic fields.     

Role of Ca2+,Mg2+-ATPases in Diabetes-Induced Alterations in Calcium Homeostasis in Input Neurons of the Nociceptive System

In a rat model of streptozotocin (STZ)-induced diabetes, we earlier showed that under these conditions the concentration of free cytosolic Ca²⁺ in input neurons of the nociceptive system increases, Ca²⁺ signals are prolonged, while Ca²⁺ release from intracellular calcium stores decreases. The aim of our study was to test the hypothesis that changes in the activities of Ca²⁺,Mg²⁺-ATPases of the endoplasmic reticulum (SERCA) and plasmalemma (PMCA) could be responsible for diabetes-induced disorders of calcium homeostasis in nociceptive neurons. We measured the Ca²⁺,Mg²⁺-ATPase activities in microsomal fractions obtained from tissues of the dorsal root ganglia (DRG) and spinal dorsal horn (DH) of control rats and rats with experimentally induced diabetes. The integral specific Ca²⁺,Mg²⁺-ATPase activity in microsomes from diabetic rats was lower than that in the control group. The activity of SERCA in samples of DRG and DH of diabetic rats was reduced by 50 ± 8 and 48 ± 12%, respectively, as compared with the control (P < 0.01). At the same time, the activity of PMCA decreased by 63 ± 6% in DRG and by 60 ± 9% in DH samples (P < 0.01). We conclude that diabetic polyneuropathy is associated with the reduction of the rate of recovery of the Ca²⁺ level in the cytosol of DRG and DH neurons due to down-regulation of the SERCA and PMCA activities.     

Elevation of the post-translational modification of proteins by O-linked N-acetylglucosamine leads to deterioration of the glucose-stimulated insulin secretion in the pancreas of diabetic Goto-Kakizaki rats

Many nuclear and cytoplasmic proteins are O-glycosylated on serine or threonine residues with the monosaccharide beta-N-acetylglucosamine, which is then termed O-linked N-acetylglucosamine (O-GlcNAc). It has been shown that abnormal O-GlcNAc modification (O-GlcNAcylation) of proteins is one of the causes of insulin resistance and diabetic complications. In this study, in order to examine the relationship between O-GlcNAcylation of proteins and glucose-stimulated insulin secretion in noninsulin-dependent type (type 2) diabetes, we investigated the level of O-GlcNAcylation of proteins, especially that of PDX-1, and the expression of O-GlcNAc transferase in Goto-Kakizaki (GK) rats, which are an animal model of type-2 diabetes. By immunoblot and immunohistochemical analyses, the expression of O-GlcNAc transferase protein and O-GlcNAc-modified proteins in whole pancreas and islets of Langerhans of 15-week-old diabetic GK rats and nondiabetic Wistar rats was examined. The expression of O-GlcNAc transferase at the protein level and O-GlcNAc transferase activity were increased significantly in the diabetic pancreas and islets. The diabetic pancreas and islets also showed an increase in total cellular O-GlcNAc-modified proteins. O-GlcNAcylation of PDX-1 was also increased. In the diabetic GK rats, significant increases in the immunoreactivities of both O-GlcNAc and O-GlcNAc transferase were observed. PUGNAc, an inhibitor of O-GlcNAcase, induced an elevation of O-GlcNAc level and a decrease of glucose-stimulated insulin secretion in isolated islets. These results indicate that elevation of the O-GlcNAcylation of proteins leads to deterioration of insulin secretion in the pancreas of diabetic GK rats, further providing evidence for the role of O-GlcNAc in the insulin secretion.