Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes

Pancreatic -cell dysfunction and insulin resistance are observed in type 2 diabetes. Under diabetic conditions, oxidative stress and ER stress are induced in various tissues, leading to activation of the JNK pathway. This JNK activation suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of the JNK pathway in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the JNK pathway plays a central role in pathogenesis of type 2 diabetes and may be a potential target for diabetes therapy.     

上皮间质转化(EMT)及其分子机制

上皮细胞受到细胞外因子刺激后向间质细胞转化的现象与肿瘤的浸润转移密切相关。在此过程中上皮细胞的极性丧失，迁移和运动能力增强，同时上皮表型丢失而逐渐获得间质表型。参与这一过程的细胞内信号转导途径有受体酪氨酸激酶Ras-MAPK途径，Src激酶，Rho家族激酶，PI3K/AKT途径，Wnt信号通路，转录因子等。     

胸腹水组织因子及组织因子途径抑制物的检测及其意义

目的研究三组疾病胸腹水组织因子(Tissue factor,TF)及组织因子途径抑制物(Tissue factor pathway inhibitor,TFPI)的表达及其鉴别诊断意义。方法TF和TFPI采用ELISA法测定抗原表达。结果胸腹水TF水平和TFPI水平,恶性肿瘤组(570.04±627.53)ng/L,(28.60±15.57)μg/L和结核病组(283.82±143.16)ng/L,(31.16±12.26)μg/L明显高于肝硬化组(60.83±66.87)ng/L,(7.84±5.45)μg/L,P<0.01。TF/TFPI比值则为恶性肿瘤组(32.17±44.19)明显高于结核病组(13.55±13.15)和肝硬化组(11.22±9.05,P<0.05)。在恶性肿瘤组中,胸腹水癌细胞阳性组的TF表达(1106.92±1244.28)ng/L高于阴性组(331.08±295.84)ng/L,P<0.05。而阳性组的TFPI水平(27.35±17.75)μg/L与阴性组(30.34±13.20)μg/L无明显差异(P>0.05)。TF/TFPI比值则为阳性组(59.59±65.10)明显高于阴性组(11.54±8.37,P<0.01)。结论检测胸腹水TF和TFPI并分析TF/TFPI比值可以作为临床实验室有鉴别诊断意义的辅助指标,同时还可了解疾病的某些病理机制,尤其是肿瘤的某些生物学行为。     

降钙素基因相关肽通过ERK1/2信号通路对角质形成细胞增殖的影响

目的： 研究降钙素基因相关肽（CGRP）对角质形成细胞增殖活性的影响，并探讨其可能涉及的信号转导通路。方法： ①胸腺嘧啶掺入法（［3H］-TdR）观察CGRP诱导的角质形成细胞株HaCaT细胞增殖，及CGRP受体拮抗剂CGRP8-37、细胞外信号调节激酶ERK1/2特异性抑制剂PD98059对CGRP诱导的增殖活性的影响；②免疫印迹技术观察CGRP诱导后ERK1/2的磷酸化，及CGRP8-37、PD98059对ERK1/2磷酸化的影响。结果： ①CGRP在一定范围内可剂量依赖性地诱导HaCaT细胞增殖，该作用可被CGRP8-37和 PD98059阻断；②CGRP可时间依赖性地诱导HaCaT细胞ERK1/2的磷酸化，CGRP8-37和PD98059可减弱其作用。结论： CGRP可诱导HaCaT细胞增殖，CGRP受体及其相关的ERK1/2信号通路参与其调控机制。     

Migration and distribution of circumpharyngeal crest cells in the chick embryo

The cardiac neural crest is located in a transitional area on the neuraxis between trunk and cephalic regions and gives rise to both the dorsolateral and ventrolateral crest cell populations. Around stage 18 of chick development, a mass of E/C8⁺ cells surrounds the postotic pharyngeal arches and forms a crescent-shaped arch, termed the circumpharyngeal ridge. Using immunohistochemistry and quail-chick chimeras, it was determined that the E/C8⁺ cell mass located in the circumpharyngeal ridge derives from the dorsolateral component of the cardiac neural crest. The ventrolateral cell population of the cardiac crest is located more medially and shows long-persistent HNK-1 immunoreactivity dorsolateral to the foregut. The crest cells that populate the gut arise from the caudal portion of the circumpharyngeal crest and are always located caudal to the caudalmost pharyngeal ectomesenchyme. Circumpharyngeal crest cells continuously populate the pharyngeal arch ectomesenchyme and enteric nervous system on the lateral side of the foregut wall, as well as the hypoglossal pathway which develops within the ventral portion of the circumpharyngeal ridge. E/C8 and HNK-1 immunoreactivity are associated with the cells migrating via the dorsolateral (circumpharyngeal) and ventrolateral pathways, respectively, with one exception: there is a population of putative crest cells along the proximal course of the vagal intestinal branch that shows both immunoreactivities around stage 20. Dil labeling of the cells in the circumpharyngeal ridge suggests that the cells are contributed from the circumpharyngeal ridge to this population. Thus, the distribution of the circumpharyngeal crest cells and their derivatives coincides with the peripheral branch distribution of the cranial nerves IX, X, and XII, whose development is selectively affected in the absence of the cardiac neural crest, the source of the circumpharyngeal crest.© Willey-Liss, Inc.     

Functional reactivation of the deafferented hippocampus by embryonic septal grafts as assessed by measurements of local glucose utilization

Summary Transection of the septo-hippocampal connections through fimbria-fornix damage in the rat results in profound hippocampal cholinergic deafferentation, and, when applied bilaterally, leads to severe and long-lasting impairments in learning and memory. Previous studies have shown that intrahippocampal septal grafts can reestablish a new cholinergic innervation in the inititally denervated hippocampal formation and at least partly compensate for the lesion-induced learning impairments in fimbria-fornix lesioned rats. The purpose of the present study was to determine the magnitude of lesion-induced alterations in cerebral function as reflected in local glucose use measured by (¹⁴C)-2-deoxyglucose (2-DG) autoradiography, and the degree to which this index of functional activity could be normalized following reinnervation from transplants of fetal cerebral tissue from the primordial septal region. Six months after unilateral fimbriafornix transection the rate of glucose utilization was reduced markedly throughout the ipsilateral hippocampus when compared to the intact contralateral side, while in the neocortex only the cingulate cortex showed long-lasting reductions in glucose use. Rats that received a transplant of fetal septal-diagonal band tissue at the time of fimbria-fornix transection, and were sacrificed 6 months later, displayed significantly greater glucose utilization in the ipsilateral hippocampus and cingulate cortex than was measured in these areas in rats with lesion alone. The recovery in glucose use was paralleled by a significant increase in acetylcholinesterase (AChE) staining in several areas of the ipsilateral hippocampal formation and cingulate cortex. This index of graft-induced cholinergic reinnervation was, moreover, significantly correlated with the rate of glucose use. Thus, in the fimbria-fornix transected animals the magnitude of glucose depression correlated with the extent of reduction in AChE staining, and in the grafted animals the degree of normalization of glucose use was correlated with the graft-induced increase in AChE-staining density. These results thus indicate that the 2-DG autoradiographic technique can provide a unique opportunity to map both altered functional activity in localized areas of the brain following specific lesions and the extent to which transplant-derived reinnervation of the host may induce a return to normal functional levels in the target site.ETP and Royal Society (London) visiting fellow     

NM23基因相关信号通路在肿瘤转移中作用机制的研究进展

浸润和转移是恶性肿瘤的重要特征,也给肿瘤的治疗带来困难,是预后不良的重要因素.转移抑制因子23(non-metastasis,NM23)基因是最早发现的抗肿瘤转移基因之一.现在已经发现NM23是一个基因家族,包括NM23-H1、NM23-H2等重要的基因家族成员.研究表明NM23基因表达与实体瘤转移抑制有关,在很多实体瘤中可以作为进展和预后的分子标记.随着对NM23基因调控肿瘤转移的分子机制的研究的进一步开展,已经发现了一些NM23肿瘤转移抑制通路上下游的相关调控分子,为进一步的信号通路研究创造了条件.本文概述了近年来对NM23基因转移抑制通路研究的新近展,提出了以后可能的研究方向和需要解决的关键问题.     

CDK4-pRB-E2F1通路是Aβ1-40诱导皮层神经元凋亡的可能途径

目的:探讨β淀粉样肽_1-40(beta-amyloidpeptide_1-40, Aβ_1-40)诱导大鼠皮层神经元凋亡的可能分子机制。方法:以40mg/L的Aβ_1-40诱导离体培养的大鼠皮层神经元凋亡, 流式细胞仪及免疫印迹方法检测细胞周期相关的周期依赖性激酶4(CDK4)、磷酸化的视网膜神经胶质瘤蛋白(pRB)水平;RT-PCR技术检测E2F1mRNA表达水平;荧光分光光度计检测半胱氨酸基天冬氨酸特异性蛋白酶3(caspase-3)活力;观察在Aβ_1-40诱导凋亡过程中是否伴随上述指标的变化。结果:①CDK4、磷酸化pRB水平在Aβ_1-40作用后2-4h显著升高;②Aβ_1-40孵育3h后皮层神经元E2F1基因表达上调;③Aβ_1-40作用12-24h后caspase-3活力明显升高。结论:CDK4-pRB-E2F1信号转导通路可能在Aβ_1-40诱导的大鼠皮层神经元凋亡中起主要作用。     

大鼠三叉神经本体觉中枢通路二级神经元中继咬肌本体觉传入的微超结构证据

将Ricin注入大鼠咬肌神经,存活2周左右,再将HRP分别定位电泳于作为三叉神经本体觉中枢通路三级传入神经元所在地的三叉神经感觉主核背内侧部(Vpdm)和三叉神经运动核腹侧区(AVM)。电镜观察结果表明,在三叉神经本体觉中枢通路二级传入神经元所在地的三叉神经脊束核吻侧亚核背内侧部(Vodm),初级传入的溃变终末与HRP逆标的树突间形成非对称型突触,确证了Vodm是三叉神经本体觉中枢通路的中继核团。突触后树突多为中间树突和近侧树突。此外,在Vodm区还发现来自Vpdm的顺行标记终末与非标记的树突形成突触。本研究证明Vodm区超微结构有以下几个特征:(1)轴-体突触极少见;(2)轴-棘突触少见;(3)突触小球结构少见;(4)大扇贝形终末较少见;(5)这一区域也有小颗粒泡和大颗粒泡终末。这些超微结构特征,可能是Vodm与三叉神经感觉核簇其它部位区别之点,也可能是本体感觉中继核团特有的结构特征。