We have developed a protein array system,named"Phospho-Totum",which reproduces the phosphorylation state of a sample on the array.The protein array contains 1471 proteins from 273 known signaling pathways.Ac...We have developed a protein array system,named"Phospho-Totum",which reproduces the phosphorylation state of a sample on the array.The protein array contains 1471 proteins from 273 known signaling pathways.According to the activation degrees of tyrosine kinases in the sample,the corresponding groups of substrate proteins on the array are phosphorylated under the same conditions.In addition to measuring the phosphorylation levels of the 1471 substrates,we have developed and performed the artificial intelligence-assisted tools to further characterize the phosphorylation state and estimate pathway activation,tyrosine kinase activation,and a list of kinase inhibitors that produce phosphorylation states similar to that of the sample.The Phospho-Totum system,which seamlessly links and interrogates the measurements and analyses,has the potential to not only elucidate pathophysiological mechanisms in diseases by reproducing the phosphorylation state of samples,but also be useful for drug discovery,particularly for screening targeted kinases for potential drug kinase inhibitors.展开更多
G protein-coupled receptor kinase 2(GRK2),as a key Ser/Thr protein kinase,belong to the member of the G protein-coupled receptor kinase(GRK)family.The C-terminus of GRK2 including a plekstrin homology domain and the N...G protein-coupled receptor kinase 2(GRK2),as a key Ser/Thr protein kinase,belong to the member of the G protein-coupled receptor kinase(GRK)family.The C-terminus of GRK2 including a plekstrin homology domain and the N-terminus of GRK2 including the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors(GPCRs),G protein,phospholipase C,phosphatidylinositol 4,5-bisphosphate,extracellular signal-regulated kinase,protein kinase A and Gβγ,which can regulate the activity of GRK2.GRK2 can regulate GPCR desensitization and internalization by phosphorylating the GPCR,promoting the affinity of binding to arrestins,and uncoupling the receptors from G proteins,which play an important role in maintaining the balance between the receptors and signal transduction.Previous studies have indicated that cardiac GRK2overexpression can promote the phosphorylation ofβ-adrenergic receptor(βAR)leading toβAR desensitization and internalization,which play a pivotal role in inducing heart failure(HF)-related dysfunction and myocyte death.GRK2,as a regulator of cell function,is overexpression in hypertension.Overexpression GRK2 can inhibit Akt/e NOS signaling pathway and decreased the production and activation of e NOS leading to endothelial dysfunction.Collagen-induced arthritis induces the upregulation of GRK2 expression in fibroblast-like synoviocytes.In this review,we mainly discussed the evidence for the association between GRK2 overexpression and various diseases,which suggests that GRK2 may be an effective drug target for preventing and treating heart failure,hypertension and inflammatory disease.展开更多
The regulating effects of TCM treatments including clearing away heat and toxic materials ,promoting blood circulation and removing blood stasis,and strengthening the spleen and regulating qi on the oncogene transcrip...The regulating effects of TCM treatments including clearing away heat and toxic materials ,promoting blood circulation and removing blood stasis,and strengthening the spleen and regulating qi on the oncogene transcription were observed in the liver cancer model rats.The preliminary results indicated that the mRNA levels of H-ras N-ras and K-ras,and signal moleculs correlated with the ras/MAPK signal transduction pathway were down-regulatedf by the differnet TCM treatment in varying degrees.Also,the regulating effects of the treatment on differently-displayed genes were discrepant.It is suggested that the molecular mechanisms of the TCM treatments for liver cancer was complex with different target genes.展开更多
As a crucial protein kinase,the mammalian target of rapamycin(mTOR)intimately controls essential cellular processes like cell development,proliferation,metabolism,and other crucial activities.Different cancers and dis...As a crucial protein kinase,the mammalian target of rapamycin(mTOR)intimately controls essential cellular processes like cell development,proliferation,metabolism,and other crucial activities.Different cancers and disorders have been linked to imbalances in mTOR's regulatory systems.Multiple mTOR inhibitor therapy has recently acquired popularity as a method of treating cancers brought on by abnormal signal transduction pathways.We also explore potential processes behind tumor cell resistance to mTOR inhibitors and suggest workarounds to overcome this challenge.We hold the potential to pioneer cutting-edge methods for tumor therapy by methodically examining the complex mTOR signaling system and its regulatory complexity.Increasing our knowledge of mTOR-related mechanisms not only creates opportunities for cutting-edge methods to target and treat cancers but also has the potential to improve patient outcomes and general quality of life significantly.This review paper explores the most recent developments in understanding mTOR signaling pathways and the use of mTOR inhibitors in treating tumors.展开更多
背景:活性氧可能与肌腱病发生、发展密切相关,但其确切作用及相关信号转导机制尚未进行全面总结。目的:综述目前临床或临床前原始研究,对活性氧在肌腱病中的作用及相关信号转导通路进行归纳总结,探究其作用特点以及是否存在统一的下游...背景:活性氧可能与肌腱病发生、发展密切相关,但其确切作用及相关信号转导机制尚未进行全面总结。目的:综述目前临床或临床前原始研究,对活性氧在肌腱病中的作用及相关信号转导通路进行归纳总结,探究其作用特点以及是否存在统一的下游通路。方法:通过计算机对PubMed、Embase、Web of Science以及中国知网、万方、维普数据库中的相关原始研究进行检索,依据入选标准对检索结果进行筛选、排除,最终纳入90篇文献进行综述分析。结果与结论:①活性氧可通过同时作用于肌腱细胞和细胞外基质来影响肌腱愈合方向,其作用方式呈双面作用特点,浓度可能是决定其作用方向的关键,低剂量活性氧可以参与肌腱正常生理愈合活动或肌腱组织具有刺激自适应性可能是产生这种作用特点的内在机制。②活性氧主要是通过基质金属蛋白酶、丝裂原活化蛋白激酶、线粒体凋亡、叉头转录因子O家族、自噬、炎症以及抗氧化信号转导通路,来改变肌腱细胞外基质的组成和结构,影响肌腱细胞正常修复、应对外界和维持生存能力,对肌腱状态造成影响。③不同的活性氧刺激强度、时间以及外在环境可能会造成下游分子通路的不同改变,从而对肌腱产生不同影响。④由于目前纳入的活性氧正、负面作用的考察文献数量差距较大,可能对寻找活性氧在肌腱中作用特点的背后因素造成一定的分析误差;另外由于大多数实验干预条件和关注结果比较单一,具体活性氧的时效、量效机制以及与其他干预因素的协同作用未能明确,也未能构建活性氧在肌腱病中的分子作用整体体系。⑤文章结果表明,活性氧未来或许可以作为一种有利因素参与肌腱病的治疗和预防,并促进之后肌腱病中氧化应激信号转导通路和整体分子作用体系的探索,也为不同抗氧化剂在肌腱病中的治疗策略打下研究基础,以更好地达到防治肌腱损伤变性的目的。展开更多
Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,ti...Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,tissue regeneration,and tissue homeostasis,among various others.Considering the multiple functions carried out by this pathway,any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers.In the present review article,we explored a wide range of diseases caused by aberrant Hh signaling,including developmental defects and cancers.Finally,we concluded this mini-review with various treatment strategies for Hh-induced diseases.展开更多
A major problem which is poorly understood in the management of bladder cancer is low sensitivity to chemotherapy and high recurrence after transurethral resection. Insulin-like growth factor 1 receptor (IGF-1R) signa...A major problem which is poorly understood in the management of bladder cancer is low sensitivity to chemotherapy and high recurrence after transurethral resection. Insulin-like growth factor 1 receptor (IGF-1R) signaling plays a very important role in progression, invasion and metastasis of bladder cancer cells. In this study, we investigated whether IGF-1R was involved in the growth stimulating activity and drug resistance of bladder cancer cells. The results showed: The mRNAs of IGF-1, IGF-2 and IGF-1R were strongly expressed in serum-free cultured T24 cell line, whereas normal urothelial cells did not express these factors/receptors or only in trace leve1s; T24 cell responded far better to growth stimulation by IGF-1 than did normal urothelial cells; blockage of IGF1R by antisense oligodeoxynucleotide (ODN) significantly inhibited the growth of T24 cell and enhanced sensitivity and apoptosis of T24 cells to mitomycin (MMC). These results suggested that blockage of IGF-IR signaling might potentially contribute to the treatment of bladder cancer cells which are insensitive to chemotherapy.展开更多
目的检测和评价致心律失常药品不良反应(adverse drug reaction,ADR)药物信号,为临床安全用药提供参考。方法收集2004年第1季度至2020年第4季度美国食品药品监督管理局不良事件报告系统自发呈报系统中接收到的致心律失常ADR信号,采用比...目的检测和评价致心律失常药品不良反应(adverse drug reaction,ADR)药物信号,为临床安全用药提供参考。方法收集2004年第1季度至2020年第4季度美国食品药品监督管理局不良事件报告系统自发呈报系统中接收到的致心律失常ADR信号,采用比例报告比法(proportional reporting ratios,PRR)和报告比值比法(proportional reporting odds ratio,ROR)对进行信号检测,分析ADR报告中对应病人的基本信息(包括性别、年龄、上报年份、上报国家、严重ADR)和安全警告信号。结果收集到的65536份ADR报告中,排除重复,保留首要怀疑药物和伴随药物的ADR报告有20401份。除性别未知和年龄缺失的ADR报告外,纳入报告病人的性别分布女性稍高于男性(9918比8401),年龄范围50~75岁比例较高,其余分布较均衡,上报数量最多的年份分别是2005年、2011年、2012年、2018年和2019年,主要上报国家为美国、德国等。严重的ADR报告有11158份(占54.7%),以“住院或住院时间延长”为主,导致死亡占16.88%。共挖掘得到ADR信号478个,累及心血管系统(122个)、内分泌系统(48个)、抗精神病(43个)、神经系统(32个)、抗感染(22个)、呼吸系统(22个)、血液系统(17个)、抗肿瘤(16个)等19个系统用药。致心律失常ADR信号频数排序前10位的药物分别为罗非考昔(频数1795)、罗非昔布(频数1792)、对乙酰氨基酚(频数1393)、左甲状腺素(频数912)、美托洛尔(频数879)、缬沙坦(频数805)、罗格列酮(频数798)、丙氧酚(频数776)、呋塞米(频数687)、氢氯噻嗪(频数635)。头孢噻吩信号强度值最高,对乙酰氨基酚次之。结论心血管系统、抗精神病、神经系统、抗感染、呼吸系统、血液系统、抗肿瘤等用药致心律失常安全风险较高。用药时应提高警惕,早期发现及时停药,并积极予以对症治疗,降低药源性不良反应的危害。展开更多
基金supported by the State Key Program of National Natural Science Foundation of China(Grant No.82230114 to F.H.)the National Key Research and Development Program of China(Grant No.2022YFE0104800 to F.H.).
文摘We have developed a protein array system,named"Phospho-Totum",which reproduces the phosphorylation state of a sample on the array.The protein array contains 1471 proteins from 273 known signaling pathways.According to the activation degrees of tyrosine kinases in the sample,the corresponding groups of substrate proteins on the array are phosphorylated under the same conditions.In addition to measuring the phosphorylation levels of the 1471 substrates,we have developed and performed the artificial intelligence-assisted tools to further characterize the phosphorylation state and estimate pathway activation,tyrosine kinase activation,and a list of kinase inhibitors that produce phosphorylation states similar to that of the sample.The Phospho-Totum system,which seamlessly links and interrogates the measurements and analyses,has the potential to not only elucidate pathophysiological mechanisms in diseases by reproducing the phosphorylation state of samples,but also be useful for drug discovery,particularly for screening targeted kinases for potential drug kinase inhibitors.
基金supported by National Natural Science Foundation of China(8150212381330081)+1 种基金Natural Science Foundation of Anhui Province(1308085QH130)Provincial Natural Science Research Foundation of Anhui Province(KJ2014A119)
文摘G protein-coupled receptor kinase 2(GRK2),as a key Ser/Thr protein kinase,belong to the member of the G protein-coupled receptor kinase(GRK)family.The C-terminus of GRK2 including a plekstrin homology domain and the N-terminus of GRK2 including the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors(GPCRs),G protein,phospholipase C,phosphatidylinositol 4,5-bisphosphate,extracellular signal-regulated kinase,protein kinase A and Gβγ,which can regulate the activity of GRK2.GRK2 can regulate GPCR desensitization and internalization by phosphorylating the GPCR,promoting the affinity of binding to arrestins,and uncoupling the receptors from G proteins,which play an important role in maintaining the balance between the receptors and signal transduction.Previous studies have indicated that cardiac GRK2overexpression can promote the phosphorylation ofβ-adrenergic receptor(βAR)leading toβAR desensitization and internalization,which play a pivotal role in inducing heart failure(HF)-related dysfunction and myocyte death.GRK2,as a regulator of cell function,is overexpression in hypertension.Overexpression GRK2 can inhibit Akt/e NOS signaling pathway and decreased the production and activation of e NOS leading to endothelial dysfunction.Collagen-induced arthritis induces the upregulation of GRK2 expression in fibroblast-like synoviocytes.In this review,we mainly discussed the evidence for the association between GRK2 overexpression and various diseases,which suggests that GRK2 may be an effective drug target for preventing and treating heart failure,hypertension and inflammatory disease.
文摘The regulating effects of TCM treatments including clearing away heat and toxic materials ,promoting blood circulation and removing blood stasis,and strengthening the spleen and regulating qi on the oncogene transcription were observed in the liver cancer model rats.The preliminary results indicated that the mRNA levels of H-ras N-ras and K-ras,and signal moleculs correlated with the ras/MAPK signal transduction pathway were down-regulatedf by the differnet TCM treatment in varying degrees.Also,the regulating effects of the treatment on differently-displayed genes were discrepant.It is suggested that the molecular mechanisms of the TCM treatments for liver cancer was complex with different target genes.
文摘As a crucial protein kinase,the mammalian target of rapamycin(mTOR)intimately controls essential cellular processes like cell development,proliferation,metabolism,and other crucial activities.Different cancers and disorders have been linked to imbalances in mTOR's regulatory systems.Multiple mTOR inhibitor therapy has recently acquired popularity as a method of treating cancers brought on by abnormal signal transduction pathways.We also explore potential processes behind tumor cell resistance to mTOR inhibitors and suggest workarounds to overcome this challenge.We hold the potential to pioneer cutting-edge methods for tumor therapy by methodically examining the complex mTOR signaling system and its regulatory complexity.Increasing our knowledge of mTOR-related mechanisms not only creates opportunities for cutting-edge methods to target and treat cancers but also has the potential to improve patient outcomes and general quality of life significantly.This review paper explores the most recent developments in understanding mTOR signaling pathways and the use of mTOR inhibitors in treating tumors.
文摘背景:活性氧可能与肌腱病发生、发展密切相关,但其确切作用及相关信号转导机制尚未进行全面总结。目的:综述目前临床或临床前原始研究,对活性氧在肌腱病中的作用及相关信号转导通路进行归纳总结,探究其作用特点以及是否存在统一的下游通路。方法:通过计算机对PubMed、Embase、Web of Science以及中国知网、万方、维普数据库中的相关原始研究进行检索,依据入选标准对检索结果进行筛选、排除,最终纳入90篇文献进行综述分析。结果与结论:①活性氧可通过同时作用于肌腱细胞和细胞外基质来影响肌腱愈合方向,其作用方式呈双面作用特点,浓度可能是决定其作用方向的关键,低剂量活性氧可以参与肌腱正常生理愈合活动或肌腱组织具有刺激自适应性可能是产生这种作用特点的内在机制。②活性氧主要是通过基质金属蛋白酶、丝裂原活化蛋白激酶、线粒体凋亡、叉头转录因子O家族、自噬、炎症以及抗氧化信号转导通路,来改变肌腱细胞外基质的组成和结构,影响肌腱细胞正常修复、应对外界和维持生存能力,对肌腱状态造成影响。③不同的活性氧刺激强度、时间以及外在环境可能会造成下游分子通路的不同改变,从而对肌腱产生不同影响。④由于目前纳入的活性氧正、负面作用的考察文献数量差距较大,可能对寻找活性氧在肌腱中作用特点的背后因素造成一定的分析误差;另外由于大多数实验干预条件和关注结果比较单一,具体活性氧的时效、量效机制以及与其他干预因素的协同作用未能明确,也未能构建活性氧在肌腱病中的分子作用整体体系。⑤文章结果表明,活性氧未来或许可以作为一种有利因素参与肌腱病的治疗和预防,并促进之后肌腱病中氧化应激信号转导通路和整体分子作用体系的探索,也为不同抗氧化剂在肌腱病中的治疗策略打下研究基础,以更好地达到防治肌腱损伤变性的目的。
文摘Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,tissue regeneration,and tissue homeostasis,among various others.Considering the multiple functions carried out by this pathway,any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers.In the present review article,we explored a wide range of diseases caused by aberrant Hh signaling,including developmental defects and cancers.Finally,we concluded this mini-review with various treatment strategies for Hh-induced diseases.
文摘A major problem which is poorly understood in the management of bladder cancer is low sensitivity to chemotherapy and high recurrence after transurethral resection. Insulin-like growth factor 1 receptor (IGF-1R) signaling plays a very important role in progression, invasion and metastasis of bladder cancer cells. In this study, we investigated whether IGF-1R was involved in the growth stimulating activity and drug resistance of bladder cancer cells. The results showed: The mRNAs of IGF-1, IGF-2 and IGF-1R were strongly expressed in serum-free cultured T24 cell line, whereas normal urothelial cells did not express these factors/receptors or only in trace leve1s; T24 cell responded far better to growth stimulation by IGF-1 than did normal urothelial cells; blockage of IGF1R by antisense oligodeoxynucleotide (ODN) significantly inhibited the growth of T24 cell and enhanced sensitivity and apoptosis of T24 cells to mitomycin (MMC). These results suggested that blockage of IGF-IR signaling might potentially contribute to the treatment of bladder cancer cells which are insensitive to chemotherapy.