The role of Jak/STAT signaling in heart tissue renin-angiotensin system

The involvement of the Renin Angiotensin System (RAS) and the role of its primary effector, angiotensin II (Ang II), in etiology of myocardial hypertrophy and ischemia is well documented. In several animal models, the RAS is activated in cardiac cell types that express the receptor AT₁, and/or AT₂, through which the Ang II mediated effects are promoted. In this article, we briefly review recent experimental evidence on the critical role of a prominent signaling pathway, the Jak/Stat pathway in activation and maintenance of the local RAS in cardiac hypertrophy and ischemia. Recent studies in our laboratory document that the promoter of the prohormone angiotensinogen (Ang) gene serves as the target site for STAT proteins, thereby linking the Jak/Stat pathway to activation of heart tissue autocrine Ang II loop. Stat5A and Stat6, are selectively activated when the heart is subjected to ischemic injury, whereas activation of Stat3 and Stat5A is involved in myocardial hypertrophy. Blockage of RAS activation by treatment with specific inhibitor promotes a remarkable recovery in functional hemodynamics of the myocardium. Thus, activation of selective sets of Stat proteins constitutes the primary signaling event in the pathogenesis of myocardial hypertrophy and ischemia.     

Notch信号通路参与卵巢生殖干细胞的调控及卵巢的衰老进程

卵巢生殖干细胞(ovarian germline stem cells, OGSCs)的发现,打破了生殖医学领域传统的"固定卵泡池"理论。近年来,OGSCs新的研究成果不断涌现,但关于OGSCs体内调控机制的研究仍然较少。Notch通路广泛参与多种成体干细胞不对称分裂的过程,并与细胞衰老密切相关,但其是否参与OGSCs的体内调控机制及卵巢的衰老进程尚不清楚。本研究以原代培养技术提取OGSCs,通过荧光双标染色发现,OGSCs标志基因MVH、Oct4与Notch信号通路相关分子Notch1、Hes1在OGSCs中存在共表达;抑制Notch信号通路活性后,cck-8检测发现,OGSCs的增殖活性呈下降趋势;而以免疫组化、荧光双标、Western印迹法检测性成熟期(2月龄)、不孕和衰老(20月龄)小鼠卵巢皮层中MVH、Oct4、Notch1和Hes1的表达变化,发现2月龄小鼠卵巢皮层中MVH、Oct4、Notch1和Hes1的表达量较高(P<0.05),而不孕和衰老小鼠卵巢皮层中,MVH、Oct4、Notch1和Hes1的表达量均明显下降。上述结果表明,Notch信号通路在小鼠OGSCs中高表达,并可能参与调控OGSCs的增殖机制及卵巢的衰老进程。     

Apoptosis induced by butyrate is independent of Jak/STAT signaling in a fibrosarcoma cell line

The aim of this study was to evaluate the participation of the Jak-1 and STAT-1 proteins in sodium butyrate-induced apoptosis in 2C4 cells derived from human fibrosarcoma. Making use of Jak-1 or STAT-1 deficient cell lines, we demonstrated that the apoptotic process induced by butyrate is independent of the presence of these proteins. In addition, this work showed that, although the constitutive expression of pro-caspases-2 and -3 is reduced in STAT-1 cells, the activity of caspase-3 is preserved in both Jak-1 and STAT-1 deficient cells and is similar to that seen in 2C4 parental cells. In conclusion, we demonstrated that the absence of functionally active Jak-1 or STAT-1 protein directly affects the TNF-alpha-induced apoptosis, but does not alter the sodium butyrate-induced apoptosis in cells derived from human fibrosarcoma.     

综述: 干细胞衰老的表观遗传调控

干细胞衰老理论认为,组织器官特异的成体干细胞随着衰老出现功能性衰退,从而导致组织器官生理功能的衰退甚至衰老相关疾病的发生.表观遗传机制通过精密调控基因表达,在成体干细胞的衰老过程中发挥着重要作用.近年来,机体衰老过程中成体干细胞的表观遗传调控已经成为衰老研究的热点.本综述主要总结了衰老过程中成体干细胞命运的表观遗传调控,并详细介绍了DNA甲基化与组蛋白共价修饰在成体干细胞衰老中的作用,以期为深入认识衰老本质、实现健康长寿提供启示.     

Notch信号通路与生殖干细胞研究进展

Notch信号通路是一个在进化中高度保守的信号通道,具有调控细胞增殖、分化及凋亡的作用。近年来,随着研究的不断深入,发现Notch信号通路与生殖干细胞的增殖分化及干细胞微环境的作用机理密切关联,Notch信号通路在生殖系统发育及疾病治疗中的作用机制逐渐引起人们的广泛关注。该文综合论述了Notch信号通路的生理特性及功能,重点阐述Notch信号通路在精原干细胞、卵巢生殖干细胞及生殖干细胞微环境系统中的调控机制。     

骨髓间充质干细胞通过JAK／STAT3信号通路抑制树突状细胞成熟

骨髓间充质干细胞（bone marrow mesenchymal stem cells,bMSCs）具有自我更新、支持造血、多向分化和低免疫原性等特点,在调控树突状细胞（dendritic cells,DCs）成熟的过程中发挥重要作用。为了探讨bMSCs调控DCs成熟的机制,本研究通过分离培养正常捐献者bMSCs,并分离获取外周静脉血单个核细胞,诱导未成熟的树突状细胞（immature dendritic cells,imDCs）和成熟的树突状细胞（mature dendritic cells,mDCs）生成。根据Genebank中人STAT3全长基因序列,设计针对STAT3的siRNA。根据培养条件不同设计实验分组：正常bMSCs与imDCs共培养（阴性对照组）,转染siRNA的bMSCs与imDCs共培养（siRNA组）、加入JAK/STAT通路抑制剂AG490的bMSCs与imDCs共培养（AG490组）、加入TNF-α诱导的mDCs（阳性对照组）共4组,共培养72 h,流式细胞术分析DCs表型变化,ELISA检测培养液上清中IL-12水平变化。结果显示,阴性对照组不表达CD40、CD80、CD83、CD86和HLA DR标志树突细胞成熟的分子,而表达CD11b,其表型与imDCs一致;而siRNA组和AG490组的DCs表达CD40、CD80、CD83、CD86和HLA-DR等标志分子,而不表达CD11b,其表型与TNF-α诱导成熟的mDCs表型一致;siRNA组、AG490组和阳性对照组的IL-12水平较阴性对照组的IL-12水平显著升高（P＜0.05）,但siRNA组、AG490组和阳性对照组之间无明显差异（P＞0.05）。以上结果表明,通过siRNA和抑制剂AG490阻断bMSCs中JAK/STAT3通路促进了imDCs的成熟,提示bMSCs通过JAK/STAT3通路参与调控imDCs成熟。     

Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging

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Cell polarity opposes Jak/STAT-mediated Escargot activation that drives intratumor heterogeneity in a Drosophila tumor model

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Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain

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Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment

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过氧亚硝基阴离子通过JAK/STAT信号途径促进系膜细胞纤连蛋白的合成

氧化应激是糖尿病肾病的重要发病机制之一。过氧亚硝基阴离子(peroxynitrite,ONOO–)是参与氧化应激损伤的重要成员,与糖尿病及其并发症密切相关。该文观察高糖环境下ONOO–对系膜细胞合成纤连蛋白(fibronectin,FN)的影响,并探讨其作用机制。实验中,人肾小球系膜细胞分为4组:正常对照组、高糖组、高糖+尿酸组及高糖+AG490组。培养12,24,48 h后收集细胞及其上清液、并提取细胞总蛋白。采用酶联免疫吸附实验(ELISA)检测细胞上清液中FN的含量,采用免疫细胞化学和Western blot检测NT总蛋白(ONOO–生成的生物标志物)、p-JAK2及p-STAT3蛋白的表达。结果显示,与同期正常组相比,高糖组NT总蛋白、p-JAK2及p-STAT3的表达及FN含量明显增高(P<0.05),并且随着时间的延长表达逐渐增多,以48 h组最为显著;高糖+尿酸组,NT、p-JAK2、p-STAT3及FN较高糖组明显减少(P<0.05);高糖+AG490组,p-JAK2、p-STAT3及FN较高糖组明显减少(P<0.05),但NT表达与高糖组差异无统计学意义(P>0.05)。由此可见,高糖环境下系膜细胞中存在ONOO–的过量表达,ONOO–通过JAK/STAT信号途径促进系膜细胞FN的合成。     

Reduction of Lobe leads to TORC1 hypoactivation that induces ectopic Jak/STAT signaling to impair Drosophila eye development

The TOR and Jak/STAT signal pathways are highly conserved from Drosophila to mammals, but it is unclear whether they interact during development. The proline-rich Akt substrate of 40 kDa (PRAS40) mediates the TOR signal pathway through regulation of TORC1 activity, but its functions in TORC1 proved in cultured cells are controversial. The Drosophila gene Lobe (L) encodes the PRAS40 ortholog required for eye cell survival. L mutants exhibit apoptosis and eye-reduction phenotypes. It is unknown whether L regulates eye development via regulation of TORC1 activity. We found that reducing the L level, by hypomorphic L mutation or heterozygosity of the null L mutation, resulted in ectopic expression of unpaired (upd), which is known to act through the Jak/STAT signal pathway to promote proliferation during eye development. Unexpectedly, when L was reduced, decreasing Jak/STAT restored the eye size, whereas increasing Jak/STAT prevented eye formation. We found that ectopic Jak/STAT signaling and apoptosis are mutually dependent in L mutants, indicating that L reduction makes Jak/STAT signaling harmful to eye development. In addition, our genetic data suggest that TORC1 signaling is downregulated upon L reduction, supporting the idea that L regulates eye development through regulation of TORC1 activity. Similar to L reduction, decreasing TORC1 signaling by dTOR overexpression results in ectopic upd expression and apoptosis. A novel finding from our data is that dysregulated TORC1 signaling regulates the expression of upd and the function of the Jak/STAT signal pathway in Drosophila eye development.     

Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors

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硫利达嗪对肝癌干细胞的杀伤作用研究

硫利达嗪(Thioridazine,THO)在临床上通常用于治疗精神类疾病;近年来,研究发现THO对肿瘤细胞具有杀伤效果,但其对肝癌干细胞的杀伤作用还未曾有报道。肿瘤干细胞在肿瘤的转移、复发及耐药性方面起着十分重要的作用。利用体外悬浮培养富集肿瘤干细胞并检测药物THO对其杀伤效果,并以此评价THO对肿瘤生长的体外抑制效应。通过检测体外悬浮培养肝癌干细胞在肿瘤干细胞相关因子表达、耐药性及细胞周期等方面因素,显示在一定程度上其具备肿瘤干细胞样特征,磷酸化STAT3、NANOG和XIAP表达显著上调,而Albumin表达下调;进一步运用MTT、Western blotting和细胞流式等实验验证了THO对肝癌干细胞具有较强的杀伤效果并能诱导caspase依赖的细胞凋亡,而对分化的肝癌细胞影响较弱;此外,THO和化疗药物盐酸阿霉素(DOX)的联合使用显著增强了其对肝癌干细胞和分化的肝癌细胞的杀伤作用。因此,该结果首次显示THO对肝癌干细胞具有较强的杀伤能力,可能为今后肝癌的临床治疗带来新的希望。     

毛蕊异黄酮通过JAK2/STAT3信号通路抑制大鼠动脉粥样硬化

摘要 目的：探究毛蕊异黄酮（CA）治疗动脉粥样硬化（AS）的作用及其机制。方法：将10只未建模和给药的Wistar大鼠作为对照组（Control组）,50只AS建模Wistar大鼠随机分为AS模型组（AS组）、低剂量CA组（L-CA组,10 mg/kg）、中剂量CA组（M-CA组,50 mg/kg）、高剂量CA组（H-CA组,100 mg/kg）和阳性药物辛伐他汀组（Sim组,2 mg/kg）,每组10只。每天给药1次,连续4周。通过苏木精伊红（HE）染色观察大鼠胸主动脉组织的病理变化。按照试剂盒说明书测定各组大鼠血清总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、丙二醛（MDA）和超氧化物歧化酶（SOD）水平。将大鼠血管平滑肌细胞（VSMC）分为6组,Control组、血管紧张素Ⅱ（Ang Ⅱ）组（10-6 mmol/L Ang Ⅱ）、Ang Ⅱ+0.1 CA组（10^-6 mmol/L Ang Ⅱ+0.1 mg/L CA）、Ang Ⅱ+1 CA组（10^-6 mmol/L Ang Ⅱ+1 mg/L CA）、Ang Ⅱ+10 CA组（10^-6 mmol/L Ang Ⅱ+10 mg/L CA）、Ang Ⅱ+1 CA+AG490（10^-6 mmol/L Ang Ⅱ+50 μmol/L AG490）组。通过CCK-8法和EdU染色测定VSMC的增殖,Transwell测定VSMC的迁移。通过免疫荧光染色检测VSMC中的α-平滑肌肌动蛋白（α-SMA）表达。通过Western blot检测大鼠胸主动脉组织和VSMC中的α-SMA、骨桥蛋白（OPN）、JAK2、p-JAK2、STAT3、p-STAT3的蛋白表达。结果：L-CA组、M-CA组、H-CA组和Sim组大鼠胸主动脉的病变均较AS组减轻,其中H-CA组和Sim组形态改善最明显。与AS组相比,M-CA组、H-CA组和Sim组大鼠的血清中TC、TG、LDL-C和MDA水平降低（P<0.05）,血清HDL-C和SOD水平升高,胸主动脉组织中的α-SMA蛋白表达水平升高（P<0.05）,OPN的蛋白表达水平及JAK2和STAT3的蛋白磷酸化水平降低（P<0.05）。与Ang Ⅱ组相比,Ang Ⅱ+1 CA组、Ang Ⅱ+10 CA组和Ang Ⅱ+1 CA+AG490组的相对细胞活力和EdU阳性率降低（P<0.05）,迁移细胞数降低（P<0.05）,α-SMA相对荧光强度和蛋白表达水平升高（P<0.05）,OPN的蛋白表达水平及JAK2和STAT3的蛋白磷酸化水平降低（P<0.05）。结论：CA可减轻AS大鼠的胸主动脉病变、纠正血脂代谢和氧化应激失衡,其机制可能与CA对VSMC表型转化和JAK2/STAT3信号通路的抑制有关。     

Reducing Hypothalamic Stem Cell Senescence Protects against Aging-Associated Physiological Decline

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