Study on the gene expression profile in the bone tissue in primary osteoporosis with kidney-yang deficiency syndrome

目的通过检测原发性骨质疏松症不同中医证型患者骨组织基因表达谱的差异,探讨原发性骨质疏松症肾阳虚证相关基因的信息学特征。方法随机选择原发性骨质疏松; 症患者,中医辨证分型为肾阳虚证组3例,肾阴虚证组3例,无肾虚证组3例,并选择正常骨密度人群3例设为正常对照组。用人全基因组表达谱芯片检测4组人群; 骨组织基因表达谱,筛选共同的差异表达基因,并对这些差异表达基因进行基因通路等相关功能分析。结果肾阳虚证组与正常对照组、肾阴虚证组、无肾虚证组的差; 异表达基因分别为2631条、3976条、6184条;肾阳虚证组与其他3组比较共同的差异表达基因有1037条。这些差异基因参与补体与凝血级联反应、; Hedgehog、TGF-beta、细胞周期等22条信号通路。结论原发性骨质疏松症肾阳虚证的相关基因主要与免疫调节、TGF-beta、细胞周期等; 信号通路相关。Objective To investigate the characteristics of genes expression; profiles of primary osteoporosis with kidney yang deficiency through; analyzing the gene expression difference with gene micro-array. Methods; Patient with osteoporosis were rand omly divided into kidney-yang; deficiency group (n = 3),kidney-yin deficiency group (n = 3),non-kidney; deficiency group (n = 3),according to the syndrome differentiation of; traditional Chinese medicine. Another 3 people with normal BMD were; selected as normal control. Expression profiles of the bone tissue from; 4 groups were detected to screen differentiated expression genes.; Analysis of pathway and other function among these genes was conducted.; Results The number of differentiated expression genes in kidney-yang; deficiency group were 3976,6184,and 2631,compared to kidney-yin; deficiency,non-kidney deficiency,and normal control group,respectively.; The number of common differentially expressed genes were 1037. These; genes were involved in 22 pathways,including complement and coagulation; cascades,Hedgehog signaling pathway,TGF-beta signaling pathway,and cell; cycle. Conclusion Genes related to kidney-yang deficiency syndrome in; primary osteoporosis are mainly related to complement and coagulation; cascades,Hedgehog signaling pathway,TGF-beta signaling pathway,and cell; cycle.福建省科技厅省属公益类科研院所基本科研专项; 福建省自然科学基金项

联合应用共刺激通路阻断剂诱导小鼠记忆性心脏移植耐受的研究

目的 探索联合应用共刺激通路阻断剂诱导记忆性心脏移植耐受的方法。方法 皮肤预致敏小鼠,过继转移同种反应性记忆性T细胞(Tm),构建小鼠同种异体心脏移植模型后再联合阻断效应及Tm激活途径,通过观察各组移植物平均存活时间、移植物排斥程度,检测脾脏中CD44高表达细胞数、脾细胞增殖情况和移植物中相关基因相对表达量等指标探讨其可能的作用机制。结果 (1)未处理小鼠脾脏中Tm占6.52﹪,而预致敏小鼠脾脏中Tm占26.5﹪;(2)平均存活时间为对照组5.17d,联合应用CTLA4Ig和anti-CD40L(二联用药)组10.33d,再联合应用anti-LFA-1和anti-OX40L(四联用药)组均>100d;(3)移植物排斥对照组均为4级,二联用药组?3B级,四联用药组为0级;(4)只有对照组脾脏物中CD44高表达;(5)对照组与二联用药组脾细胞增殖程度(t=2.91,P=0.027)明显高于四联用药组;(6)治疗组的移植物中IL-2、IFN-γ和Foxp3基因的表达量明显低于对照组(t=6.51,t=9.94,t=6.15,P=0.00,P=0.00,P=0.00),并且四联用药组IL-10基因表达量明显升高(t=4.71,P=0.003)。结论 对于记忆性心脏移植模型,只有联合阻断效应和Tm才可获得移植物长期耐受,其机制可能是明显降低移植物和移植受者细胞免疫应答水平的同时,诱导移植物中表达大量IL-10分泌性Tr1细胞

Autoimmune regulator initiates the expression of promiscuous genes in thymic epithelial cells

The expression of peripheral antigens in the thymus, known as promiscuous gene expression, has been implicated in T cell tolerance and autoimmunity. Here we identified thymic epithelial cells (TECs) as the main cell type that expresses a diverse range of tissue-restricted antigens (TRAs). The TECs of a common autoimmune (non-obese diabetic [NOD]) mouse model express much lower levels of an autoimmune regulator (Aire) and TRAs than normal (Balb/c) TECs. Transfection of an Aire plasmid led to increased levels of TRA expression in cultured TECs from Balb/c and NOD mice; an increase that was enhanced by the presence of thymocytes. These data show that Aire initiates promiscuous gene expression in TECs, and that this function might be under thymocyte control

An N-(alkylcarbonyl)anthranilic acid derivative prolongs cardiac allograft survival synergistically with cyclosporine A in a high-responder rat model

We investigated the immunosuppressive effects of the dihydroortate dehydrogenase (DHODH) inhibitor compounds ABR-222417 and ABR-224050 from Active Biotech (Sweden). We verified the inhibitory effects of these compounds on the proliferation of CD4(+) and CD8(+) T-cells in vivo by using superantigen staphylococcus enterotoxin A (SEA)-mediated proliferation test. To evaluate their efficacy, the compounds were screened in a low-responder heart allograft transplantation model in rats [heart from Piebald Virol Glaxo (PVG) transplanted to Dark Agouti (DA)]. The immunosuppressive effects of the compounds were then investigated in a high-responder model (DA to PVG). Treatment with ABR-222417 (30 mg/kg) was more efficient than that with ABR-224050 (10 mg/kg), and the former provided a longer graft median survival time (MST, 29.5 days) than the latter (MST, 18.5 days). Furthermore, there was a marked increase in graft survival time (53 days) when low doses of ABR-222417 and cyclosporine A (CsA) were used in combination. No sign of tolerability problems was detected using this combination or when ABR-222417 was used singly at a higher dose. Furthermore, T-cell proliferation studies in vitro support that the anti proliferative effect of ABR-222417 is caused by inhibition of de novo pyrimidine synthesis, which is the consequence of DHODH inhibition. These results show that ABR-222417 had marked immunosuppressive effects on the heart allograft transplantation and that it exerts an even more powerful inhibitory effect on graft rejection when used in combination with CsA, with good tolerability. (C) 2010 Elsevier B.V. All rights reserved

Irinotecan combined with co-stimulatory molecule blockade prolongs survival of cardiac allografts in alloantigen-primed mice

Key Research Project of the Fujian Provincial Natural Science Funds [2010Y0052]Memory T cells play an important role in graft rejection. In this study, we investigated the potential effect of Irinotecan (CPT-11), a topoisomerase I inhibitor used in the treatment of a variety of solid tumor malignancies, on memory T cells. CPT-11 treatment alone or combined with blocking monoclonal antibodies (mAb) against co-stimulatory molecules (LFA-1 and CD154) was evaluated in the prevention of heart transplant rejection in alloantigen-primed mice. Our data suggest that CPT-11 reduced the expression of IL-2/IFN-gamma and increased IL-10/TGF-beta expression in both peripheral blood and within the grafts. CPT-11 could also inhibit alloresponses of memory T cells, while decreasing the proportion of CD4(+) memory T cells in the spleen of the recipients and significantly reducing serum alloantibody levels. Our study highlights obvious synergistic effects of CPT-11 when combined with co-stimulatory molecule blockade in prolonging the survival of cardiac allografts in alloantigen-primed mice. (C) 2013 Elsevier Inc. All rights reserved

Allotransplantation of Sulphate Glucomannan-Alginate Barium (SGA)-Microencapsulated Rat Islets for the Treatment of Diabetes Mellitus

National Natural Science Foundation of China [30600606]; Harbin Medical University [BS2008-37]; Natural Science Foundation of Heilongjiang province [D2004-30]To offer a more effective microencapsulation technique of islets for the treatment of diabetes, we have developed a new type of microcapsule comprising sulphate glucomannan- alginate barium (SGA). We compared it with traditional microencapsulated APA (alginate-poly-L-lysine-alginate) and ABa (Ba(2+)-alginate) microencapsulated islets. These three types of microencapsulated islets were prepared and cultured in vitro and we studied their morphology and activity. To determine their effects on insulin secretion and cytokine production (MCP-1, IL-1, IFN-gamma, TNF-alpha) the islets were transplanted into diabetic rats. There was no difference in the morphologies of the three types of microencapsulated islets or their insulin secretory capacity in vitro. However, the SGA microencapsulated islets had higher activity and produced more insulin than the APA and ABa microencapsulated islets after transplantation. Normoglycemia was maintained for longer in the SGA-transplanted group than in the other two groups. The concentrations of cytokines in the peritoneal fluid were significantly decreased in the SGA group, as was the infiltration of inflammatory cells around the microcapsules. In conclusion, the novel SGA microencapsulated islets can maintain normoglycemia in diabetic rats without immunosuppression for longer than APA and ABa microencapsulated islets

Combination of monoclonal antibodies with DST inhibits accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice

Medical College of Xiamen UniversityDonor-reactive memory T cells mediated accelerated rejection is known as a barrier to the survival of transplanted organs. We investigated the combination of different monoclonal antibodies (mAbs) and donor-specific transfusion (DST) in memory T cells-based adoptive mice model. In the presence of donor reactive memory T cells, the mean survival time (MST) of grafts in the anti-CD40L/LFA-1/DST group was 49.8 d. Adding anti-CD44/CD70 mAbs to anti-CD40L/LFA-1/DST treatment. The MST was more than 100 d (MST > 100 d). Compared with anti-CD40L/LFA-1/DST group, anti-CD40L/LFA-1/CD44/CD70/DST group notably reduced the expansion of memory T cells, enhanced the proportion of CD4(+)Foxp3(+) regulatory T cells (Tregs) and suppressed donor-specific responses. Our data suggest that anti-CD40L/LFA--1/CD44/CD70 mAbs and DST can synergistically inhibit accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice. (C) 2011 Elsevier B.V. All rights reserved

湖北省发现小黑领噪鹛

2015年8~11月,在湖北神农架森林生态系统国家野外科学观测研究站,3次发现一种此前未监测到的鸟类,鉴定为小黑领噪鹛(Garrulax monileger)。8月5日,在湖北宜昌市兴山县龙门河村黄崩口沟口西侧公路上方山坡(31°19′37′′N,110°28′59′′E,海拔1 292 m),小溪边的化香树(Platycarya strobilacea)林发现5只小黑领噪鹛并拍摄照片(图1);10月21日在龙门河东湾白栎子树包(31°19′32″N,110°31′19″E,海拔1 691 m)的巴山水青

湖北省发现小黑领噪鹛

2015年8~11月,在湖北神农架森林生态系统国家野外科学观测研究站,3次发现一种此前未监测到的鸟类,鉴定为小黑领噪鹛(Garrulax monileger)。8月5日,在湖北宜昌市兴山县龙门河村黄崩口沟口西侧公路上方山坡(31°19′37′′N,110°28′59′′E,海拔1 292 m),小溪边的化香树(Platycarya strobilacea)林发现5只小黑领噪鹛并拍摄照片(图1);10月21日在龙门河东湾白栎子树包(31°19′32″N,110°31′19″E,海拔1 691 m)的巴山水青

Combined Costimulation Blockade Inhibits Accelerated Rejection Mediated by Alloantigen-primed Memory T Cells in Mice

Donor-reactive memory T cells threaten the survival of transplanted organs via multiple pathways. This study was undertaken to induce tolerance of cardiac allografts in mice, in which alloreactive memory T cells were adoptively transferred, by combined costimulatory blockade of both effector and memory T cells. We found that the median survival time (MST) of the grafts was 5.17 days in the untreated group, 10.33 days in the CTLA4Ig- and antiCD40L- treated (2-combined) group, and more than 100 days in the CTLA4Ig-, anti-CD40L-, anti-LFA-1-, and anti-OX40L-treated (4-combined) group. Histological analysis revealed that the mean rejection level was Grade 4 in the untreated group, Grade 3 in the 2-combined treatment group, and Grade 0 in the 4-combined treatment group. CD44(high) T cells were detected only in the untreated group. The in vitro proliferation of lymphocytes of both untreated and 2-combined group was higher than that of the 4-combined treatment group (p < 0.01). Compared with the untreated group, the expression levels of IL-2, IFN-gamma, and Foxp3 were lower in the 2-combined treatment group; the expression levels of these genes were the lowest in the 4-combined treatment group. IL-10 expression was significantly higher in the 4-combined treatment group than in the other groups. These results demonstrate the inhibition efficacy of combined costimulation blockade in accelerated-rejection models and the possible mechanisms underlying the suppression of cellular immunity in mice receiving grafts as well as in inducing the activation of IL-10-producing Tr1 cells in grafts