Regulatory Roles of Metabolites in Cell Signaling Networks

Mounting evidence suggests that cellular metabolites, in addition to being sources of fuel and macromolecular substrates, are actively involved in signaling and epigenetic regulation. Many metabolites, such as cyclic AMP, which regulates phosphorylation/dephosphorylation, have been identified to modulate DNA and histone methylation and protein stability. Metabolite-driven cellular regulation occurs through two distinct mechanisms: proteins allosterically bind or serve as substrates for protein signaling pathways, and metabolites covalently modify proteins to regulate their functions. Such novel protein metabolites include fumarate, succinyl-CoA, propionyl-CoA, butyryl-CoA and crontonyl-CoA. Other metabolites, including α-ketoglutarate, succinate and fumarate, regulate epigenetic processes and cell signaling via protein binding. Here, we summarize recent progress in metabolite-derived post-translational protein modification and metabolite-binding associated signaling regulation. Uncovering metabolites upstream of cell signaling and epigenetic networks permits the linkage of metabolic disorders and human diseases, and suggests that metabolite modulation may be a strategy for innovative therapeutics and disease prevention techniques.     

胶质细胞源性神经营养因子引发精原干细胞自我更新的信号通路

胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)是TGF-β超家族的一个相关成员。哺乳动物睾丸曲细精管内支持细胞分泌的GDNF,能促进精原干细胞(spermatogonial stem cells,SSCs)的自我更新与增殖。SSCs去分化诱导产生的多能干细胞已被广泛应用于再生医学领域,且SSCs在制作转基因动物、男性不育治疗和体外实施精子发生过程等方面,具有极大的应用价值。所以,GDNF引发SSCs自我更新的作用机理非常值得探索。通过对GDNF引发SSCs自我更新的信号通路进行系统梳理,我们发现了如下的作用过程:GDNF与GFR-α1特异性结合,活化Ret蛋白酪氨酸激酶,随后激活Ras/ERK1/2、PI3K-Akt和SFK信号通路,促进SSCs的自我更新;同时,在该过程中还存在信号通路间的交联对话现象。     

Different Gene Networks Are Disturbed by Zika Virus Infection in A Mouse Microcephaly Model

The association of Zika virus (ZIKV) infection with microcephaly has raised alarm worldwide. Their causal link has been confirmed in different animal models infected by ZIKV. However, the molecular mechanisms underlying ZIKV pathogenesis are far from clear. Hence, we performed global gene expression analysis of ZIKV-infected mouse brains to unveil the biological and molecular networks underpinning microcephaly. We found significant dysregulation of the sub-networks associated with brain development, immune response, cell death, microglial cell activation, and autophagy amongst others. We provided detailed analysis of the related complicated gene networks and the links between them. Additionally, we analyzed the signaling pathways that were likely to be involved. This report provides systemic insights into not only the pathogenesis, but also a path to the development of prophylactic and therapeutic strategies against ZIKV infection.     

PNmerger: 一个整合生物学通路和蛋白质相互作用网络的Cytoscape插件

Cytoscape是一个广泛应用于分子相互作用网络可视化的软件．发展了一个基于java的Cytoscape插件PNmerger．对于一个蛋白质相互作用网络,PNmerger能够使用KEGG数据库中的通路信息自动注释网络中的蛋白质．并通过网络和通路的比较发现网络中已知的通路元件,预测可能的通路元件及通路交联元件．该软件可以可视化网络中存在的通路模块,并将连接不同通路间的潜在交联元件显示出来．PNmerger软件能够有效地帮助实验人员发现网络中重要的功能线索,帮助实验人员进行实验设计．用户可以通过网站http://www.hupo.org.cn/PNmerger下载PNmerger插件．     

绞股蓝总皂苷对光老化人皮肤成纤维细胞凋亡及Caspase-3信号通路的影响

目的:探讨绞股蓝总皂苷(Gyp)对光老化人皮肤成纤维细胞(HSF细胞)凋亡以及Caspase-3信号通路的影响。方法:分别以80、160、320 mg/d剂量的Gyp生理盐水溶液灌胃大鼠7d后取血并分离血清,长波紫外线(UVA)照射方法(照射剂量36 J/cm3)构建光老化HSF细胞模型以得到低剂量组、中剂量组、高剂量组,同时以空白对照组(未照射细胞)、UVA模型组、正常组为对照。UVA诱导的细胞活性氧表达采用二氯荧光素(DCF)法测定,细胞凋亡情况采用TUNEL法测定,HSF细胞活性采用四甲基偶氮唑盐微量酶反应比色法(MTT法)测定,Bax、Bcl-2、Caspase-3基因和蛋白表达分别采用反转录-聚合酶链反应(RT-PCR)和Western-blotting方法进行测定。结果:与空白对照组比较,其余5组的OD值、HSF细胞凋亡数、活性氧(平均荧光强度)、活性氧水平、Bax、Bcl-2、Caspase-3 mRNA及蛋白表达水平差异具有统计学意义(P0.05);与UVA模型组和正常组比较,低、中、高剂量组OD值、HSF细胞凋亡数、活性氧(平均荧光强度)、活性氧水平、Bax、Bcl-2、Caspase-3 mRNA及蛋白表达水平差异具有统计学意义(P0.05);低、中、高剂量组随着剂量增加OD值、Bcl-2mRNA和蛋白表达水平逐渐升高,细胞凋亡数、活性氧(平均荧光强度)、活性氧水平、Bax、Caspase-3 mRNA和蛋白表达水平逐渐降低(P0.05)。结论:Gyp通过抑制细胞内活性氧的产生以及Bax的表达,以及激活Bcl-2、Caspase-3信号通路而逆转UVA诱导的HSF细胞凋亡,进而延缓HSF细胞的光老化现象。     

Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer’s Disease Progression

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Signaling dynamics and embryonic development

Comment on: Warmflash A, et al. Proc Natl Acad Sci USA 2012; 109:E1947-56.     

PyMINEr Finds Gene and Autocrine-Paracrine Networks from Human Islet scRNA-Seq

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An Improved Boosting to Amplify Signal with Isobaric Labeling (iBASIL) Strategy for Precise Quantitative Single-cell Proteomics

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Highlights

• •Higher AGC significantly improves quantitation quality in single-cell analysis.
• •The boosting-to-sample ratio should be carefully evaluated and optimized.
• •iBASIL allows for precise quantitation of 1,500 proteins from 104 AML single cells.
• •iBASIL recapitulates major biological differences in different AML single cells.

     

Transcriptional Heterogeneity in Naive and Primed Human Pluripotent Stem Cells at Single-Cell Resolution

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Dynamic Ligand Discrimination in the Notch Signaling Pathway

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Signaling networks in Leishmania macrophages deciphered through integrated systems biology: a mathematical modeling approach

Network of signaling proteins and functional interaction between the infected cell and the leishmanial parasite, though are not well understood, may be deciphered computationally by reconstructing the immune signaling network. As we all know signaling pathways are well-known abstractions that explain the mechanisms whereby cells respond to signals, collections of pathways form networks, and interactions between pathways in a network, known as cross-talk, enables further complex signaling behaviours. In silico perturbations can help identify sensitive crosstalk points in the network which can be pharmacologically tested. In this study, we have developed a model for immune signaling cascade in leishmaniasis and based upon the interaction analysis obtained through simulation, we have developed a model network, between four signaling pathways i.e., CD14, epidermal growth factor (EGF), tumor necrotic factor (TNF) and PI3 K mediated signaling. Principal component analysis of the signaling network showed that EGF and TNF pathways can be potent pharmacological targets to curb leishmaniasis. The approach is illustrated with a proposed workable model of epidermal growth factor receptor (EGFR) that modulates the immune response. EGFR signaling represents a critical junction between inflammation related signal and potent cell regulation machinery that modulates the expression of cytokines.