过氧化物酶体增殖物激活受体γ配体噻唑烷二酮类在脑缺血中的神经保护作用

噻唑烷二酮类物质为过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptorγ,PPARγ)的合成配体.PPARγ对多种类型组织均有一定的保护作用,研究涉及的领域包括糖及脂类代谢、癌症、动脉粥样硬化等.目前,噻唑烷二酮类物质在中枢神经系统疾病中的作用备受关注,如脑梗死、多发性硬化、阿尔茨海默病等.文章综述了脑缺血后PPARγ配体噻唑烷二酮类对抑制神经胶质细胞增殖、促进血管生成以及对抗神经元凋亡的作用.     

急性肺损伤中过氧化物酶体增殖物激活受体γ通路参与保护作用的阶段性研究

背景 急性肺损伤(acute lung injury,ALI)在临床上主要表现为严重的低氧血症、弥漫性肺浸润和肺微血管通透性增高所致的肺水肿.目前认为,ALI的主要发病机制为炎症反应失衡,促炎因子大量释放.过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptorγ,PPARγ)是调节目的基因表达的核内受体转录因子超家族成员,主要表达于脂肪组织以及巨噬细胞和其他脂肪贮存细胞. 目的 介绍PPARγ在ALI中的保护作用. 内容 PPARγ具有广泛的抗炎作用,近年来的研究发现其在ALI的保护方面具有重要作用. 趋向 为预防和治疗ALI提供新思路.     

清金化痰汤对慢性阻塞性肺疾病急性加重期模型大鼠肺组织 Foxp3和 RORγt 表达的影响

目的探讨清金化痰汤对慢性阻塞性肺疾病急性加重期(AECOPD)模型大鼠肺组织叉头翼状螺旋转录因子P3(Foxp3)、维甲酸相关孤核受体γt(RORγt)表达的影响。方法 40只SPF Wistar雄性大鼠随机分为正常组、模型组、清金化痰汤组、克拉霉素组。除正常组外,其余组采取气道滴注脂多糖(LPS)联合烟熏的方法建立AECOPD气道黏液高分泌模型,并同时连续30 d分别给予生理盐水、清金化痰汤(8.4 g/kg)、克拉霉素(50 mg/kg)灌胃。实验第31天,提取大鼠肺组织,制作病理切片,并采用免疫组化法检测肺组织中黏蛋白5AC(Muc5AC)、中性粒细胞弹性蛋白酶(NE)的表达,观察Foxp3和RORγt的表达,免疫印迹法检测肺组织中Foxp3和RORγt的蛋白表达。结果与正常组比较,模型组Foxp3表达量无明显差异(P0.05),RORγt、Muc5AC、NE表达显著升高,Foxp3/RORγt显著下降(P0.01);清金化痰汤组与模型组比较,Foxp3表达量无明显差异(P0.05),RORγt、Muc5AC、NE表达显著降低,Foxp3/RORγt显著升高(P0.01或P0.05)。清金化痰汤组与克拉霉素组比较,Muc5AC显著降低(P0.05)。结论清金化痰汤可显著下调模型大鼠肺组织中RORγt蛋白表达,上调Foxp3/RORγt,这可能是清金化痰汤调节AECOPD黏液高分泌的机制之一。     

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain

Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of l-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A)receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.     

Ceramides are associated with inflammatory processes in human mediastinal adipose tissue

Background and AimCeramides are poorly characterized in human adipose tissue. The aim of this study was to investigate concentrations of different ceramide species in human subcutaneous and visceral adipose tissue depots and to determine associations between ceramides and global gene expression profiles.Methods and ResultsConcentrations of six ceramide species were determined in plasma and in subcutaneous and mediastinal adipose tissue from 10 overweight subjects (BMI 29.4 ± 4.9 kg/m²). In the adipose tissue biopsies gene expression arrays were performed and relationships between ceramides and gene expression analyzed. Immunostaining of the two adipose tissue depots was performed in an independent group of 10 patients. Mediastinal adipose tissue contained significantly higher concentrations (p < 0.05) of all six ceramide species than the subcutaneous depot. Of the six ceramides in plasma, concentrations of only two (Cer d18:1/18:0 and Cer d18:1/22:0) correlated significantly (p < 0.05) with the corresponding species in mediastinal adipose tissue, but there were no significant correlations between ceramides in plasma and subcutaneous adipose tissue. Multivariate analysis identified significant correlations between the total ceramide concentration and global gene expression within mediastinal, but not subcutaneous adipose tissue, according to cross-validation. Gene ontology analysis of genes related to ceramides in the mediastinal depot revealed that genes positively correlated with ceramides were associated mainly with immune and inflammatory categories, while genes negatively correlated with ceramides were associated mainly with lipid and carbohydrate metabolism.ConclusionsCeramides in human mediastinal adipose tissue may be involved in inflammation and lipid and carbohydrate metabolism.     

Bariatric surgery in severely obese adolescents improves major comorbidities including hyperuricemia

Objective

Serum uric acid (sUA) is believed to contribute to the pathogenesis of metabolic comorbidities like hypertension, insulin-resistance (IR) and endothelial dysfunction (EDF) in obese children. The present pilot study investigated the association between sUA concentrations and loss of body weight following laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y-gastric bypass (RYGB) in severely obese adolescents.

Materials/Methods

10 severely obese adolescents underwent either LSG (n = 5) or RYGB (n = 5). 17 normal weight, healthy, age- and gender-matched adolescents served as a normal weight peer group (NWPG). Pre- and 12 months postoperatively, sUA and relevant metabolic parameters (glucose homeostasis, transaminases, lipids) were compared.

Results

Preoperatively, sUA was significantly elevated in patients with severe obesity compared to NWPG. Twelve months after LSG and RYGB, a significant decrease in sUA, BMI, CVD risk factors, hepatic transaminases, and HOMA-IR was observed. Reduction in SDS-BMI significantly correlated with changes in sUA.

Conclusions

sUA levels and metabolic comorbidities improved following bariatric surgery in severely obese adolescents. The impact of changes in sUA on long-term clinical complications of childhood obesity deserves further study.     

Serum γ-glutamyltransferase as an independent predictor for incident type 2 diabetes in middle-aged and older adults: Findings from the KoGES over 12 years of follow-up

Backgrounds and aimsLimited evidence is available on whether serum γ-glutamyltransferase (GGT) has value as a predictor of type 2 diabetes in East Asian populations. We investigated the causal relationship between serum GGT level and incident type 2 diabetes in Korean adults.Methods and resultsA total of 7739 nondiabetic adults aged 40–69 years from the Korean Genome and Epidemiology Study were studied. We divided the population into four groups according to sex-specific quartiles by serum GGT levels. Hazard ratios (HRs) with 95% Confidence intervals (CIs) for incident type 2 diabetes were prospectively analyzed using multivariate Cox proportional hazards regression models. A total of 1432 (18.5%) participants developed type 2 diabetes over 12 years of follow-up. The higher the serum GGT group quartile, the higher the cumulative type 2 diabetes incidence over 12 years with significance in both sexes (log-rank test P < 0.001). HRs (95% CIs) for incident type 2 diabetes for the highest quartile versus referent lowest quartile for serum GGT levels were 2.55 (1.86–3.51) for men and 1.90 (1.40–2.58) for women after adjusting for confounding variables.ConclusionsHigher serum GGT levels preceded and positively associated with incident type 2 diabetes among community-dwelling middle-aged and older Korean adults.