Reg基因蛋白家族的研究进展

Reg基因蛋白（regenerating gene protein）属于钙依赖的植物血凝素超家族,其功能类似应激蛋白、抗凋亡因子或生长因子。Reg基因蛋白的促进胰岛β细胞分裂和诱导再生作用最早是在糖尿病研究中被发现。Reg基因蛋白在人体多种组织中均表达,与细胞增殖、炎症创伤、感染和神经系统发育关系密切。随着研究的深入,Reg基因蛋白在胰腺损伤修复、神经系统损伤、消化系统肿瘤、脓毒血症及其他疾病中的作用逐渐引起人们重视。     

性别与自身免疫性疾病

自身免疫性疾病在人群中感染率5-10％,具有明显的性别差异,女性患者显著高于男性,具体机制仍未研究清楚。研究发现。除了机体自身的遗传易感体质外,雌激素,微嵌合体和性染色体都与自身免疫性疾病发病有关。     

清胰汤对大鼠急性坏死性胰腺炎IL-6,IL-10 及肠道通透性影响

目的:探讨清胰汤改善大鼠急性坏死性胰腺炎(acute necrotizing pancreatitis)ANP炎症反应及肠道通透性功能的治疗效果及机制。方法:将72只雄性SD大鼠随机分为3组,其中2组大鼠采用从胰腺被膜下多点缓慢均匀注入3.8%牛黄胆酸钠(0.5ml/100g)建立大鼠急性坏死性胰腺炎模型,再分为急性坏死性胰腺炎常规治疗组(A组)、清胰汤干预治疗组(B组),其他24只大鼠为假手术组(S组),每组再随机分为24h、48h、72h组。各组于12h后给于肠内营养,B组肠内营养后给于2次清胰汤2.5ml/100g,A组、S组给于同等剂量生理盐水。各组于建模后24h、48h、72h处死,腹腔动脉取血检测血清淀粉酶浓度、IL-6、IL-10、D-乳酸水平。结果:48h时点B组IL-10水平较A组高(P<0.05);72时点B组血清淀粉酶水平较A组低(P<0.01),IL-6水平较A组低(P<0.01),IL-10水平较A组高(P<0.01),D-乳酸水平较A组低(P<0.01)。结论:清胰汤可以上调IL-10改善大鼠急性胰腺炎炎症反应从而降低肠道通透性。     

The TREX1 C-terminal Region Controls Cellular Localization through Ubiquitination

TREX1 is an autonomous 3′-exonuclease that degrades DNA to prevent inappropriate immune activation. The TREX1 protein is composed of 314 amino acids; the N-terminal 242 amino acids contain the catalytic domain, and the C-terminal region (CTR) localizes TREX1 to the cytosolic compartment. In this study, we show that TREX1 modification by ubiquitination is controlled by a highly conserved sequence in the CTR to affect cellular localization. Transfection of TREX1 deletion constructs into human cells demonstrated that this sequence is required for ubiquitination at multiple lysine residues through a “non-canonical” ubiquitin linkage. A proteomic approach identified ubiquilin 1 as a TREX1 CTR-interacting protein, and this interaction was verified in vitro and in vivo. Cotransfection studies indicated that ubiquilin 1 localizes TREX1 to cytosolic punctate structures dependent upon the TREX1 CTR and lysines within the TREX1 catalytic core. Several TREX1 mutants linked to the autoimmune diseases Aicardi-Goutières syndrome and systemic lupus erythematosus that exhibit full catalytic function were tested for altered ubiquitin modification and cellular localization. Our data show that these catalytically competent disease-causing TREX1 mutants exhibit differential levels of ubiquitination relative to WT TREX1, suggesting a novel mechanism of dysfunction. Furthermore, these differentially ubiquitinated disease-causing mutants also exhibit altered ubiquilin 1 co-localization. Thus, TREX1 post-translational modification indicates an additional mechanism by which mutations disrupt TREX1 biology, leading to human autoimmune disease.     

Impact of diet and genes on murine autoimmune pancreatitis

The impact of environmental factors, such as diet, and the genetic basis of autoimmune pancreatitis (AIP) are largely unknown. Here, we used an experimental murine AIP model to identify the contribution of diet to AIP development, as well as to fine‐map AIP‐associated genes in outbred mice prone to develop the disease. For this purpose, we fed mice of an autoimmune‐prone intercross line (AIL) three different diets (control, calorie‐reduced and western diet) for 6 months, at which point the mice were genotyped and phenotyped for AIP. Overall, 269 out of 734 mice (36.6%) developed AIP with signs of parenchymal destruction, equally affecting mice of both sexes. AIP prevalence and severity were reduced by approximately 50% in mice held under caloric restriction compared to those fed control or western diet. We identified a quantitative trait locus (QTL) on chromosome 4 to be associated with AIP, which is located within a previously reported QTL. This association does not change when considering diet or sex as an additional variable for the mapping. Using whole‐genome sequences of the AIL founder strains, we resolved this QTL to a single candidate gene, namely Map3k7. Expression of Map3k7 was largely restricted to islet cells as well as lymphocytes found in the exocrine pancreas of mice with AIP. Our studies suggest a major impact of diet on AIP. Furthermore, we identify Map3k7 as a novel susceptibility gene for experimental AIP. Both findings warrant clinical translation.     

Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc

The structure–activity relationships of T0901317 analogs were explored as RORc inverse agonists using the principles of property- and structure-based drug design. An X-ray co-crystal structure of T0901317 and RORc was obtained and provided molecular insight into why T0901317 functioned as an inverse agonist of RORc; whereas, the same ligand functioned as an agonist of FXR, LXR, and PXR. The structural data was also used to design inhibitors with improved RORc biochemical and cellular activities. The improved inhibitors possessed enhanced selectivity profiles (rationalized using the X-ray crystallographic data) against other nuclear receptors.     

Association between pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections disease and tumor necrosis factor-α gene?308 g/a, ?850 c/t polymorphisms in 4-12-year-old children in Adana/Turkey

OBJECTIVES:

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is a newly defined disease in neuropsychiatry and occurs with an autoimmune mechanism after Group A Beta Hemolytic Streptococcus (GABHS) infection. Tumor necrosis factor (TNF), encoded by TNF-α gene has an important role in the apoptotic mechanisms of autoimmune diseases. Recently, TNF-α polymorphisms and autoimmune/psychiatric disorders have been reported to be related. In this regard, we focused on to investigate a possible relation between the TNF-α gene promoter region−308 G/A and − 850 C/T polymorphisms and PANDAS.

MATERIALS AND METHODS:

In this study, ages of PANDAS patient and control groups were ranging from 4 years to 12-year-old. Patient group includes childhood onset PANDAS patients (n = 42) and control group includes healthy children (n = 58). Diagnoses have been carried out according to Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria with Affective Disorders and Schizophrenia-Present and Lifetime (KSAD-S-PL) and Children Yale-Brown Obsessive Compulsive Scale Moreover, PANDAS criteria established by the American National Psychiatry Institute have been employed for diagnoses. For identifying polymorphisms; Polymerase Chain Reaction, Restriction Fragment Length Polymorphism and Polyacrylamid Gel Electrophoresis were used.

RESULTS AND DISCUSSION:

For −308 polymorphism, 37 of 42 PANDAS patients’ results and for −850 C/T polymorphism, 38 of 42 PANDAS patients’ results were obtained. According to our statistical analysis there is a positive relationship between PANDAS patients for −308 G/A polymorphism but not for −850 C/T polymorphism. There is no positive relationship between −308 G/A polymorphism and antistrep-tolysin O (ASO) titers and no relationship between −850 C/T polymorphism and ASO titers. We found, however, positive relationship between genders of patients (boys) and the disease. According to our results, we propose that the AA polymorphism of −308 G/A polymorphism can be used as a molecular indicator for PANDAS.     

双歧杆菌乳杆菌三联活菌片联合血必净注射液对急性胰腺炎患者炎性介质、细胞免疫指标及肠黏膜屏障功能的影响

目的:探讨血必净注射液联合双歧杆菌乳杆菌三联活菌片治疗急性胰腺炎(SAP)患者的临床疗效。方法:选取2016年9月～2019年4月期间我院收治的SAP患者119例,根据随机数字表法将患者随机分为对照组(n=59)和研究组(n=60),对照组给予血必净注射液治疗,研究组在对照组的基础上联合双歧杆菌乳杆菌三联活菌片治疗,比较两组临床疗效,炎性介质、细胞免疫指标水平、肠黏膜屏障功能及不良反应发生情况。结果:研究组治疗7d后总有效率高于对照组(P0.05)。两组治疗期间未见药品不良反应发生。两组血清内毒素、二胺氧化酶(DAO)、白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)以及C反应蛋白(CRP)、CD8~+水平均降低,且研究组低于对照组(P0.05),CD4~+/CD8~+、CD4~+、NK细胞水平升高,且研究组高于对照组(P0.05)。结论:SAP患者在血必净的基础上联合双歧杆菌乳杆菌三联活菌片治疗,可提高机体细胞免疫功能,改善炎性因子水平和肠黏膜屏障功能,且用药安全性较好,临床应用价值较高。     

电针联合ICE抑制剂在急性胰腺炎的治疗中的作用及机制

观察和探讨电针联合白细胞介素(IL-1β)转化酶(ICE)抑制剂对炎症介质抑制和诱导急性胰腺炎腺泡细胞凋亡的作用。选取90只SD大鼠随机分为对照组、模型组和干预组,每组30只。各组造模后在第6小时、第12小时和第24小时各时间点分别检测10只大鼠。抑制剂组于造模前48 h采用电针并开始腹腔注射ICE抑制剂2.5 mg/100 mg体质量,间隔12 h注射1次。胰腺炎组仅在相同时间注射同等量的生理盐水。应用细胞凋亡原位标记(TUNEL)染色、ELISA方法等,检测血清中淀粉酶、肿瘤坏死因子-α(TNF-α)、IL-1β和胰腺细胞凋亡。HE染色见胰腺组织中典型的细胞核固缩及凋亡小体形成。干预组各个时间点病理学评分和血淀粉酶、TNF-α、IL-1β浓度均低于胰腺炎组,胰腺细胞凋亡指数高于胰腺炎组(p<0.05)。电针联合ICE抑制剂能减轻急性胰腺炎严重程度,其机制可能与其对炎症介质的抑制和诱导胰腺细胞的凋亡有关。