Sonic hedgehog信号通路调节痛觉敏化的研究进展

神经病理性痛是一种由于躯体感觉神经系统的损伤或疾病而直接造成的疼痛。Sonic hedgehog(Shh)信号转导通路是经典的控制胚胎发育的信号转导途径。近年来发现,该信号途径不仅参与胚胎神经系统模式发育,在成熟机体的稳态调节中也发挥重要作用,因此正逐渐成为信号转导领域新的研究热点。最新文献表明,Shh通路调节神经病理性疼痛的痛觉敏化,且其可能机制与星形胶质细胞激活,炎症因子以及突触可塑性的改变相关。     

Shh、Gli1和MMP-9在胃癌组织中的表达及临床意义

目的 探讨胃癌组织中Hedgehog(Hh)信号通路分子(Shh和Gli1)与基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)的表达以及临床意义.方法 采用免疫组织化学方法检测54例人胃癌组织、癌旁组织和30例正常胃黏膜组织中Shh、Gli1和MMP-9蛋白的表达.结果 胃癌组织中Shh、Gli1和MMP-9的阳性表达率分别为68.52％、61.11％和64.81％,明显高于癌旁组织(阳性表达率分别为27.78％、24.07％和22.22％)和正常组织(阳性表达率分别为36.67％、26.67％和33.33％)(P＜0.05);三者的表达均与胃癌患者性别、年龄、部位无关(P＞0.05);而与分化程度、浸润深度以及淋巴结转移相关(P ＜0.05);Shh、Gli1分别与MMP-9表达呈正相关.结论 Hedgehog( Hh)信号通路可能通过上调MMP-9的表达促进胃癌的侵袭转移.联合检测胃癌组织中Shh、Gli1和MMP-9蛋白水平,可作为胃癌预后的客观参考指标.     

右美托咪定对老年脓毒症大鼠Shh信号通路及认知功能的影响研究

背景右美托咪定可透过血-脑脊液屏障并对脓毒症大鼠具有一定保护作用,但目前关于其对脓毒症所致认知障碍改善效果的研究报道较少见。目的探讨右美托咪定对老年脓毒症大鼠Shh信号通路及认知功能的影响。方法2019年1—9月,选取健康雄性SD大鼠54只,采用随机数字表法分为Sham组、CLP组、Dex组,每组18只。Sham组大鼠仅行剖腹探查术,CLP组大鼠采用盲肠结扎穿孔法制备脓毒症模型,Dex组大鼠于脓毒症模型制备后6 h腹腔注射右美托咪定。比较三组大鼠给药后逃避潜伏期,穿越平台次数,处于平台所在象限时间,脑组织含水量,海马组织Shh、Gli-1、Ptc含量及ZO-1、Claudin-5相对表达量。结果与Sham组比较,CLP组、Dex组大鼠给药后逃避潜伏期延长,穿越平台次数减少,处于平台所在象限时间缩短(P<0.05);与CLP组比较,Dex组大鼠给药后逃避潜伏期缩短,穿越平台次数增多,处于平台所在象限时间长(P<0.05)。与Sham组比较,CLP组、Dex组大鼠给药后脑组织含水量增多(P<0.05);与CLP组比较,Dex组大鼠给药后脑组织含水量少(P<0.05)。与Sham组比较,CLP组、Dex组大鼠给药后海马组织Shh、Gli-1含量降低,Ptc含量升高(P<0.05);与CLP组比较,Dex组大鼠给药后海马组织Shh、Gli-1含量升高,Ptc含量降低(P<0.05)。(4)与Sham组比较,CLP组、Dex组大鼠给药后海马组织ZO-1、Claudin-5相对表达量降低(P<0.05);与CLP组比较,Dex组大鼠给药后24 h海马组织ZO-1、Claudin-5蛋白相对表达量升高(P<0.05)。结论右美托咪定可有效改善老年脓毒症大鼠认知功能,降低血-脑脊液屏障通透性,其作用机制可能与激活Shh信号通路有关。     

The sonic hedgehog signaling pathway is suppressed following PCB1254 exposure during retinal development

Polychlorinated biphenyl (PCB) has been reported to have detrimental effects on retinal development. In order to explore the role of Shh signaling in retinal development after PCB₁₂₅₄ exposure in vivo and in vitro, zebrafish and RGC‐5 retinal cell line were used. Compared with the controls, PCB exposure inhibited proliferation and increased the apoptosis levels. The expression of Shh mRNA decreased in the PCB₁₂₅₄‐treated groups both in vivo and in vitro compared with that of the controls. The ptch2 mRNA expression increased in the experimental groups. The expression of gli2 mRNA decreased in the PCB₁₂₅₄‐treated groups. Immunofluorescence and western blotting assays confirmed that the expression of Shh proteins decreased in PCB₁₂₅₄‐treated groups compared with control groups. Moreover, ptch2 protein levels increased in the PCB₁₂₅₄‐treated groups as well as the decreased protein expressions of gli1 and gli2. These results demonstrated that Shh signaling pathway may participate in the damage of retinal development caused by PCB₁₂₅₄ exposure, providing evidence that eye diseases could be caused by environmental pollutants.     

三草尿毒灵通过调控Shh/Gli信号通路表达减轻肾脏纤维化的实验研究

目的 探究三草尿毒灵调控Shh/Gli信号通路抑制肾脏纤维化的作用与机制。方法：选取24只雄性BALB/c小鼠并随机分为假手术组、模型组、三草尿毒灵组以及CPN组,每组6只。制备单侧肾缺血再灌注损伤模型后第3天起,三草尿毒灵组每天给予三草尿毒灵汤剂（9g/kg）灌胃,CPN组每天给予CPN（5mg/kg）腹腔注射。术后第10天切除小鼠右侧肾脏,第11天处死小鼠,获取小鼠血清和肾脏进行肾功能检测、免疫组化、Western Blot和qRT-PCR分析。结果：与假手术组相比,模型组的血肌酐和尿素氮水平明显升高,而且相关纤维化指标的表达显著上调（P<0.05）。而三草尿毒灵与CPN均可明显保护小鼠肾功能,减轻肾脏纤维化（P<0.05）。进一步研究发现三草尿毒灵可以抑制肾脏Shh/Gli信号表达及成纤维细胞的活化。结论：三草尿毒灵可通过调控Shh/Gli信号通路的表达以减轻肾脏纤维化。     

Evolution and development of the mammalian dentition: Insights from the marsupial Monodelphis domestica

To understand developmental mechanisms of evolutionary change, we must first know how different morphologies form. The vast majority of our knowledge on the developmental genetics of tooth formation derives from studies in mice, which have relatively derived mammalian dentitions. The marsupial Monodelphis domestica has a more plesiomorphic heterodont dentition with incisors, canines, premolars, and molars on both the upper and the lower jaws, and a deciduous premolar. The complexity of the M. domestica dentition ranges from simple, unicusped incisors to conical, sharp canines to multicusped molars. We examine the development of the teeth in M. domestica, with a specific focus on the enamel knot, a signaling center in the embryonic tooth that controls shape. We show that the tooth germs of M. domestica express fibroblast growth factor (FGF) genes and Sprouty genes in a manner similar to wild‐type mouse molar germs, but with a few key differences. Developmental Dynamics, 2011. © 2010 Wiley‐Liss, Inc.     

Multipotent mesenchymal stromal cells increase tPA expression and concomitantly decrease PAI-1 expression in astrocytes through the sonic hedgehog signaling pathway after stroke (in vitro study)

Multipotent mesenchymal stromal cells (MSCs) increase tissue plasminogen activator (tPA) activity in astrocytes of the ischemic boundary zone, leading to increased neurite outgrowth in the brain. To probe the mechanisms that underlie MSC-mediated activation of tPA, we investigated the morphogenetic gene, sonic hedgehog (Shh) pathway. In vitro oxygen and glucose deprivation and coculture of astrocytes and MSCs were used to mimic an in vivo ischemic condition. Both real-time-PCR and western blot showed that MSC coculture significantly increased the Shh level and concomitantly increased tPA and decreased plasminogen activator inhibitor 1 (PAI-1) levels in astrocytes. Inhibiting the Shh signaling pathway with cyclopamine blocked the increase of tPA and the decrease of PAI-1 expression in astrocytes subjected to MSC coculture or recombinant mouse Shh (rm-Shh) treatment. Both MSCs and rm-Shh decreased the transforming growth factor-β1 level in astrocytes, and the Shh pathway inhibitor cyclopamine reversed these decreases. Both Shh-small-interfering RNA (siRNA) and Glil-siRNA downregulated Shh and Gli1 (a key mediator of the Shh transduction pathway) expression in cultured astrocytes and concomitantly decreased tPA expression and increased PAI-1 expression in these astrocytes after MSC or rm-Shh treatment. Our data indicate that MSCs increase astrocytic Shh, which subsequently increases tPA expression and decreases PAI-1 expression after ischemia.     

Shh、Glil和p-Akt在食管癌中的表达及临床意义

目的观测SHh信号通路关键因子Shh、Glil和P13K／Akt信号通路的父键因子p-Akt在食管鳞状细胞癌（ESCC）中的表达情况,探讨上述因子的表达与ESCC各临床病理特征的关系和意义。方法采用免疫组织化学EnVision法检测108例手术治疗的ESCC组织及相应的癌旁正常食管黏膜标本Shh、Glil和p-Akt的表达情况。结果存108例ESCC组织中Shh、Glil和p-Akt的阳性表达率分别为70．1％（76／108）、76．9％（83／108）和65．7％（71／108）。108例癌旁正常食管黏膜中Shh、Glil和p-Akt的阳性表达率分别为13．9％（15／108）、13％（14／108）和15．7％（17／108）。ESCC组织中Shh、Glil锄p-Akt的阳性表达率显著高于相应的癌旁正常食管黏膜的表达（P〈0．05）;Shh、Glil和p-Akt表达与肿瘤是否有淋巴结转移密切相关（P〈0．05）,ESCC中Shh的表达与Glil的表达成正相关（r1=0．750,P〈0．01）,Glil表达与p-Akt表达呈正相关（r2=0．621,P〈0．01）。结论ESCC中SHh通路和P13K／Akt通路是普遍激活的,Glil与p-Akt可作为预测转移潜能和预后状况的有价值的指标,联合抑制SHh通路和P13K／Akt通路对于治疗食管癌可能更有效。     

Transventricular delivery of Sonic hedgehog is essential to cerebellar ventricular zone development

Cerebellar neurons are generated from two germinal neuroepithelia: the ventricular zone (VZ) and rhombic lip. Signaling mechanisms that maintain the proliferative capacity of VZ resident progenitors remain elusive. We reveal that Sonic hedgehog (Shh) signaling is active in the cerebellar VZ and essential to radial glial cell proliferation and expansion of GABAergic interneurons. We demonstrate that the cerebellum is not the source of Shh that signals to the early VZ, and suggest a transventricular path for Shh ligand delivery. In agreement, we detected the presence of Shh protein in the circulating embryonic cerebrospinal fluid. This study identifies Shh as an essential proliferative signal for the cerebellar ventricular germinal zone, underscoring the potential contribution of VZ progenitors in the pathogenesis of cerebellar diseases associated with deregulated Shh signaling, and reveals a transventricular source of Shh in regulating neural development.