Psoriasis,a prevalent inherited skin condition,involves an inflammatory response as a key pathogenic mechanism.The Optimized Yinxieling Formula(OYF),rooted in traditional Chinese medicine,is extensively utilized in cl...Psoriasis,a prevalent inherited skin condition,involves an inflammatory response as a key pathogenic mechanism.The Optimized Yinxieling Formula(OYF),rooted in traditional Chinese medicine,is extensively utilized in clinical settings to treat psoriasis.Although previous studies have demonstrated OYF’s significant anti-inflammatory effects in psoriasis,its potential molecular targets and active components remain unexplored.This study aimed to unveil the anti-psoriasis molecular targets and active components of OYF.Our findings indicated that OYF extract markedly reduced the production of several inflammatory mediators,including IL-23,nitric oxide,TNF-α,and IL-1β,in LPS-induced RAW264.7 cells.We synthesized OYF extract-crosslinked beads to isolate pharmacological targets from RAW264.7 lysates using an affinity purification strategy,known as Target Fishing.The enriched target proteins were subsequently identified via LC-MS/MS,followed by bioinformatics analysis to map the psoriasis-associated pathway-gene network.We identified a total of 76 potential target proteins,which were highly associated with mRNA transcription mechanisms.In particular,pathway-gene network analysis revealed that the IL-23 inflammatory pathway was involved in the anti-psoriasis effect of OYF extract.We further utilized a target protein-based affinity capture strategy,combined with LC-MS and SPR analysis,to globally screen OYF’s active components,focusing on the mRNA transcription regulator,fused in sarcoma(FUS).This process led to the identification of umbelliferone,vanillic acid,protocatechuic acid,gentisic acid,and echinacoside as key compounds targeting FUS to inhibit IL-23 expression.Additionally,we formulated a compound cocktail(CpdC),which significantly reduced psoriasis area and severity index(PASI)scores and the expressions of IL-23 and Ki67 in an imiquimod(IMQ)-induced psoriasis mouse model.Collectively,our study elucidates the primary molecular targets and active components of OYF,offering novel insights for psoriasis treatment.展开更多
Prostate cancer is a major public health concern world-wide, being one of the most prevalent cancers in men. Great improvements have been made both in terms of early diagnosis and therapeutics. However, there is still...Prostate cancer is a major public health concern world-wide, being one of the most prevalent cancers in men. Great improvements have been made both in terms of early diagnosis and therapeutics. However, there is still an urgent need for reliable biomarkers that could overcome the lack of cancer-specifcity of prostate-specifc antigen, as well as alternative therapeutic targets for advanced metastatic cases. Reversible phosphorylation of proteins is a post-translational modifcation critical to the regulation of numerous cellular processes. Phosphoprotein phosphatase 1 （PPP1） is a major serine/threonine phos-phatase, whose specifcity is determined by its interacting proteins. These interactors can be PPP1 substrates, regulators, or even both. Deregulation of this protein-protein interaction network alters cell dynamics and underlies the development of several cancer hallmarks. Therefore, the identification of PPP1 interactome in specific cellular context is of crucial importance. The knowledge on PPP1 complexes in prostate cancer remains scarce, with only 4 holoenzymes characterized in human prostate cancer models. However, an increasing number of PPP1 interactors have been identifed as expressed in human prostate tissue, including the tumor suppressors TP53 and RB1. Efforts should be made in order to identify the role of such proteins in prostate carcinogenesis, since only 26 have yet well-recognized roles. Here, we revise literature and human protein databases to provide an in-depth knowledge on the biological significance of PPP1 complexes in human prostate carcinogenesis and their potential use as therapeutic targets for the development of new therapies for prostate cancer.展开更多
目的:基于网络药理学方法,初步探讨如意珍宝片治疗中风的作用机制。方法:构建中风相关的蛋白质-蛋白质相互作用(protein-protein interaction,PPI)网络;选取如意珍宝片含有的112个活性成分,预测其作用靶点;进而构建如意珍宝片"活...目的:基于网络药理学方法,初步探讨如意珍宝片治疗中风的作用机制。方法:构建中风相关的蛋白质-蛋白质相互作用(protein-protein interaction,PPI)网络;选取如意珍宝片含有的112个活性成分,预测其作用靶点;进而构建如意珍宝片"活性成分-预测靶点"网络,构建与中风相关的如意珍宝片"活性成分-潜在靶点"网络,进行基因本体(gene ontology,GO)富集分析、京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)的生物通路富集分析,研究如意珍宝片治疗中风的作用机制。结果:与中风相关的如意珍宝片"活性成分-潜在靶点"网络包含29个靶点,关键靶点涉及诱导型一氧化氮合酶、内皮型一氧化氮合酶、磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基、钠通道蛋白5型α亚基、转录因子AP-1、半胱氨酸天冬氨酸蛋白酶-3和雌激素受体等;GO条目12个,主要包括蛋白结合、酶结合和RNA聚合酶Ⅱ启动子转录调控;KEGG通路13条,主要涉及肿瘤信号通路、黏着斑和肿瘤中的蛋白多糖等。结论:本研究结果初步验证和预测了如意珍宝片治疗中风的作用机制,为进一步深入揭示其作用机制奠定了良好的基础。展开更多
基金supported by the State Key Laboratory of Dampness Syndrome of Chinese Medicine,the Second Affiliated Hospital of Guangzhou University of Chinese Medicine(No.SZ2021ZZ51)the National Key R&D Program of China(No.2022YFC3501601)+1 种基金the National Natural Sciences Foundation of China(Nos.82174008,81973505)Jinan New 20 Policies for Higher Education Funding(No.202228048)and the Fundamental Research Funds for the Central Universities.
文摘Psoriasis,a prevalent inherited skin condition,involves an inflammatory response as a key pathogenic mechanism.The Optimized Yinxieling Formula(OYF),rooted in traditional Chinese medicine,is extensively utilized in clinical settings to treat psoriasis.Although previous studies have demonstrated OYF’s significant anti-inflammatory effects in psoriasis,its potential molecular targets and active components remain unexplored.This study aimed to unveil the anti-psoriasis molecular targets and active components of OYF.Our findings indicated that OYF extract markedly reduced the production of several inflammatory mediators,including IL-23,nitric oxide,TNF-α,and IL-1β,in LPS-induced RAW264.7 cells.We synthesized OYF extract-crosslinked beads to isolate pharmacological targets from RAW264.7 lysates using an affinity purification strategy,known as Target Fishing.The enriched target proteins were subsequently identified via LC-MS/MS,followed by bioinformatics analysis to map the psoriasis-associated pathway-gene network.We identified a total of 76 potential target proteins,which were highly associated with mRNA transcription mechanisms.In particular,pathway-gene network analysis revealed that the IL-23 inflammatory pathway was involved in the anti-psoriasis effect of OYF extract.We further utilized a target protein-based affinity capture strategy,combined with LC-MS and SPR analysis,to globally screen OYF’s active components,focusing on the mRNA transcription regulator,fused in sarcoma(FUS).This process led to the identification of umbelliferone,vanillic acid,protocatechuic acid,gentisic acid,and echinacoside as key compounds targeting FUS to inhibit IL-23 expression.Additionally,we formulated a compound cocktail(CpdC),which significantly reduced psoriasis area and severity index(PASI)scores and the expressions of IL-23 and Ki67 in an imiquimod(IMQ)-induced psoriasis mouse model.Collectively,our study elucidates the primary molecular targets and active components of OYF,offering novel insights for psoriasis treatment.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29030104)the National Natural Science Foundation of China (31870731, 31971129)+3 种基金the Fundamental Research Funds for the Central Universities (WK9100000001)USTC New Medicine Joint Fund Training Program(WK9110000136)China Postdoctoral Science Foundation(2020M670084ZX)Hefei Comprehensive National Science Center (BJ9100000005)。
基金Supported by Fundao para a Ciência e Tecnologia(FCT)(PTDC/QUI-BIQ/118492/2010)Fundo Europeu de Desenvolvimento Regional(FEDER)(FCOMP-01-0124-FEDER-020895),Portugal
文摘Prostate cancer is a major public health concern world-wide, being one of the most prevalent cancers in men. Great improvements have been made both in terms of early diagnosis and therapeutics. However, there is still an urgent need for reliable biomarkers that could overcome the lack of cancer-specifcity of prostate-specifc antigen, as well as alternative therapeutic targets for advanced metastatic cases. Reversible phosphorylation of proteins is a post-translational modifcation critical to the regulation of numerous cellular processes. Phosphoprotein phosphatase 1 （PPP1） is a major serine/threonine phos-phatase, whose specifcity is determined by its interacting proteins. These interactors can be PPP1 substrates, regulators, or even both. Deregulation of this protein-protein interaction network alters cell dynamics and underlies the development of several cancer hallmarks. Therefore, the identification of PPP1 interactome in specific cellular context is of crucial importance. The knowledge on PPP1 complexes in prostate cancer remains scarce, with only 4 holoenzymes characterized in human prostate cancer models. However, an increasing number of PPP1 interactors have been identifed as expressed in human prostate tissue, including the tumor suppressors TP53 and RB1. Efforts should be made in order to identify the role of such proteins in prostate carcinogenesis, since only 26 have yet well-recognized roles. Here, we revise literature and human protein databases to provide an in-depth knowledge on the biological significance of PPP1 complexes in human prostate carcinogenesis and their potential use as therapeutic targets for the development of new therapies for prostate cancer.
文摘目的:基于网络药理学方法,初步探讨如意珍宝片治疗中风的作用机制。方法:构建中风相关的蛋白质-蛋白质相互作用(protein-protein interaction,PPI)网络;选取如意珍宝片含有的112个活性成分,预测其作用靶点;进而构建如意珍宝片"活性成分-预测靶点"网络,构建与中风相关的如意珍宝片"活性成分-潜在靶点"网络,进行基因本体(gene ontology,GO)富集分析、京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)的生物通路富集分析,研究如意珍宝片治疗中风的作用机制。结果:与中风相关的如意珍宝片"活性成分-潜在靶点"网络包含29个靶点,关键靶点涉及诱导型一氧化氮合酶、内皮型一氧化氮合酶、磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基、钠通道蛋白5型α亚基、转录因子AP-1、半胱氨酸天冬氨酸蛋白酶-3和雌激素受体等;GO条目12个,主要包括蛋白结合、酶结合和RNA聚合酶Ⅱ启动子转录调控;KEGG通路13条,主要涉及肿瘤信号通路、黏着斑和肿瘤中的蛋白多糖等。结论:本研究结果初步验证和预测了如意珍宝片治疗中风的作用机制,为进一步深入揭示其作用机制奠定了良好的基础。
