大黄酸改善胰岛素敏感性的作用及其机制研究

改善胰岛素敏感性对防治2型糖尿病(T2DM)有重要意义.我国中医药治疗糖尿病效果显著但机制尚不甚清楚,本课题组从改善胰岛素敏感性的角度入手,先后通过药物筛选、细胞和动物实验3个部分研究中药大黄单体成分--大黄酸对糖尿病的治疗作用,其机制可能与上调机体外周组织的过氧化物酶体增殖物活化受体(PPAR)-慵捌咸烟亲说鞍?GLUT)表达,从而促进外周组织葡萄糖摄取并改善机体胰岛素敏感性有关.本文将分别对这3部分实验内容进行介绍并就大黄酸改善胰岛素敏感性的作用机制展开讨论.     

The synaptically evoked late hyperpolarisation in hippocampal CA1 pyramidal cells is resistant to intracellular EGTA

It has been suggested that the late hyperpolarisation following synaptic activation of hippocampal CA1 pyramidal neurons is activated by calcium influx. This hypothesis was examined using microelectrodes containing EGTA. Intracellular injection of EGTA blocked the afterhyperpolarisation which normally followed cell firing produced by injection of a depolarising current or the ionophoresis of glutamate onto the apical dendrites. In contrast, the hyperpolarisation following synaptic activation was resistant to EGTA. The results suggest that this potential is not dependent on intracellular Ca2+. Other possible mechanisms are discussed.     

补肺汤对肺纤维化大鼠血清INF-γ IL-4表达水平影响的实验研究

目的：观察补肺汤对肺纤维化大鼠血清IFN-γ、IL-4表达水平的影响,探讨补肺汤对肺纤维化的治疗作用及可能的作用机制。方法：96只SD健康大鼠,随机分为4组（每组各24只）：空白对照组、模型对照组、强的松阳性对照组、补肺汤治疗组。模型对照组和治疗组气管内注射博莱霉素诱导肺纤维化模型,正常对照组在相同条件下给予生理盐水。补肺汤治疗组和强的松阳性对照组分别给予补肺汤流浸膏（2.1g/200g）及强的松片与生理盐水混合制剂（6.3mg/kg）灌胃,其余两组每天给予生理盐水（1mL/100g）灌胃。各组分别于造模后第7、14、28天各处死8只大鼠,取大鼠血清和肺组织。肺组织病理切片HE染色和MASSON染色观察病理变化和肺纤维化分级情况,ELISA法测定血清中INF-γ、IL-4含量的变化。结果：与模型对照组比较,补肺汤治疗组和强的松阳性对照组大鼠各个时期的血清IFN-γ表达明显增高（P〈0.05）;强的松阳性对照组大鼠血清IL-4在各个时期的表达降低明显（P〈0.05）,而补肺汤治疗组在第28天降低明显（P〈0.05）。结论：补肺汤肺纤维化的形成有较好的治疗作用,其机制可能是通过促进血清中IFN-γ的分泌,抑制IL-4的分泌,从而调节了Th1/Th2细胞因子失衡来实现的。     

Upregulation of GAD65 mRNA in the medulla of the rat model of metabolic syndrome

Metabolic syndrome is characterized by obesity, elevated blood pressure (BP), insulin resistance, and hypercholesterolemia. Recently an animal model of this disorder has been proposed in rats selectively bred based on their performance on a treadmill-running task. Accordingly, low capacity runner (LCR) rats exhibited all of the diagnostic criteria for metabolic syndrome, including elevated BP, as compared to their high capacity runner (HCR) counterparts [U. Wisløff, S.M. Najjar, O. Ellingsen, P.M. Haram, S. Swoap, Q. Al-Share, M. Fernstrom, K. Rezaei, S.J. Lee, L.G. Koch, S.L. Britton, Cardiovascular risk factors emerge after artificial selection for low aerobic capacity, Science 307 (2005) 418–420]. Previous studies have highlighted the importance of GABAergic neurotransmission in the medullary cardiovascular-regulatory areas in the central control of BP. Thus, we hypothesized a dysregulation in GABAergic transmission in the medullary cardiovascular-regulatory nuclei of LCR rats. To begin testing this hypothesis we carried out experiments examining expression of the GABA synthetic enzymes, GAD65 and GAD67, mRNAs in the two rat strains via radioactive in situ hybridization. Our results showed GAD65 and GAD67 mRNAs were widely expressed throughout the brainstem; quantification revealed increased GAD65 mRNA expression in LCR animals in the caudal nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (VLM) as compared to HCR rats. Conversely, no differences in the expression of GAD67 were detected in these regions. These data are consistent with the notion of altered GABAergic neurotransmission in the NTS and VLM in metabolic syndrome, and point to the importance of these regions in cardiovascular regulation.     

Mendelian susceptibility to mycobacterial diseases: state of the art

BackgroundMendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to infections caused by intracellular pathogens, such as mycobacteria, due to impaired IFN-γ immunity. To date, 18 different genes associated with MSMD have been reported.ObjectivesThis review describes recent discoveries, a 2020–2021 update, in MSMD through the introduction of three novel genetic disorders, namely, AR IFN-γ, T-bet, and ZNFX1 complete deficiency, as well as molecular mechanisms underlying multifocal osteomyelitis in patients with this condition.SourcesPubMed databases were searched for reports of MSMD since January 2020. Relevant articles and their references were screened.ContentThe review covers a general overview, known genes, classifications, symptoms, and treatments for MSMD. MSMD is classified into two groups: isolated MSMD and syndromic MSMD. Among the 18 genes responsible, 13 cause isolated MSMD, which is characterized by selective predisposition to one or more mycobacterial and related infections, and 8 cause syndromic MSMD, which involves the combination of the mycobacterial disease infectious phenotype with additional clinical phenotypes. Among the three genetic etiologies described herein, AR IFN-γ deficiency is classified as isolated MSMD, whereas AR T-bet and ZNFX1 deficiency are classified as syndromic MSMD. Multifocal osteomyelitis is a representative symptom of MSMD, and a high frequency of multifocal osteomyelitis is reported in MSMD patients due to impaired IFN-γ responses, such as with AD IFN-γR1, AD IFN-γR2, or AD STAT1 deficiency. Impaired inhibition of osteoclast differentiation and bone resorption owing to a poor response to IFN-γ has been shown to be in association with multifocal osteomyelitis in MSMD.ImplicationsOver the past decade, genetic dissection by next-generation sequencing techniques has contributed to the understanding of the molecular bases of human immunity to mycobacteria. However, genetic etiologies are lacking for half of MSMD cases. Further studies will be needed to elucidate the pathogenesis of MSMD.     

p38γMAPK信号通路在肿瘤进展中的作用及机制研究

p38MAPK是一种广泛存在于机体细胞的信号激酶,参与了细胞增殖、分化、死亡、迁移和侵袭等一系列过程.p38γ是p38MAPK家族中研究较少的一个亚型,但近年来其在肿瘤发生发展过程中的作用越来越受到重视,与乳腺癌、肝癌、肾癌、结直肠癌、皮肤T淋巴细胞瘤等多种肿瘤进展关系密切.本文着重对p38γMAPK信号通路在肿瘤进展...     

Placental dimethyl acetal fatty acid derivatives are elevated in preeclampsia

Preeclampsia (PE) was shown to affect the placental content and the transfer of polyunsaturated fatty acids (PUFA) to the fetus. Plasmalogens, a type of phospholipids with a vinyl-ether link at the sn-1 position, play an antioxidant role and are specifically enriched in PUFA at the sn-2 position. In this study, we characterized plasmalogen-derived dimethyl acetal (DMA) fatty acid derivatives, 16:0 DMA, 18:0 DMA, 9c-/11c-18:1 DMA and PUFA in the placenta of normotensive (n = 20) and PE (n = 20) pregnancies, according to the sampling site: peri-insertion or periphery. Phospholipid fatty acids from the placenta and maternal erythrocytes were identified by gas chromatography mass spectrometry and quantified by flame ionization detection. We found elevated total DMA in the PE placenta by 18% when compared to normotensive controls (p = 0.026). Moreover, the 16:0 DMA account for more than 55% of DMA fatty acids measured in the placenta, and its level is significantly higher in PE than controls (p = 0.018). Also, we found elevated placental PUFA, 20:5(n-3), 22:5(n-3) and a low level of 20:4(n-3) in PE compared to controls. Placental DMA was highly correlated with n-6 and n-3 PUFA in both, normotensive and PE pregnancies. In sum, elevated DMA fatty acids in the PE placenta could be an indirect defensive mechanism against oxidative stress and poor placental fatty acid transfer in PE.     

FcγRIIA polymorphism as a risk factor for invasive Streptococcus pneumoniae

Polymorphisms of human Fc gamma receptor IIA (FcγRIIA) have been described and shown to be associated with susceptibility to and severity of certain infectious diseases. Invasive Streptococcus pneumoniae infection continues to be a major cause of morbidity and mortality throughout the world and effective host defense against S. pneumoniae depends on immunoglobulin (Ig) G2-mediated phagocytosis of the bacteria by polymorphonuclear leukocytes. One of the major functions of the FcγRIIA receptor is to play a crucial role in the phagocytosis of IgG2-opsonized bacteria because it is the only receptor able to interact with IgG2 immune complexes. The FcγRIIA polymorphism (FcγRIIA-R131 vs. FcγRIIA-H131) determines the capacity of IgG2-mediated phagocytosis via this receptor. Thus, studies that have examined the direct functional role of R131 and H131 in phagocytosis of the opsonized S. pneumoniae by effector cells in clinically relevant patient groups would provide compelling evidence linking this polymorphism with disease. Here we review the role of FcγRIIA polymorphisms as a host-genetic factor influencing S. pneumoniae infection and describe the in vitro and clinical studies that support the importance of this association.