四物汤与JAK2-STAT5信号通路对造血功能调控的研究进展
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摘要
四物汤的补血机制之一是促进生长因子如白细胞介素-6(interleukin-6,IL-6)、促红细胞生成素(erythropoietin,EPO)等的表达。而这些生长因子正是Janus激酶2-信号传导子与转录激活子5(janus kinase-signal transducer and activator of transcription,JAK2-STAT5)的上游因子,可以激活该通路的表达从而促进造血细胞的增殖和分化。JAK2-STAT5信号通路可以通过促进造血细胞增殖、分化和抑制其凋亡从而调控机体的造血功能。JAK2-STAT5信号途径可以通过上调增殖相关cyclinD1及下调p21基因的表达来促进细胞的增殖,同时下调靶基因Bcl-2和Bcl-xL的表达从而抑制造血细胞的凋亡。SHP-1作为STAT5的负调控因子,可以负向调节JAK2-STAT5信号通路,防止细胞过度增殖和分化。当该通路受到抑制时,能抑制造血细胞的增殖并促进其凋亡,进而导致机体造血功能障碍,产生贫血等症状。
One of the blood-tonifying mechanisms of Siwu Decoction is to promote the expression of growth factors such as interleukin-6(IL-6) and erythropoietin(EPO).These growth factors are upstream factors of Janus kinase 2-signal transducer and activator of transcription(JAK2-STAT5),which can activate the expression of this pathway and promote the proliferation and differentiation of hematopoietic cells.JAK2-STAT5 pathway can regulate hematopoietic function by promoting proliferation,differentiate and inhibit of apoptosis to regulate hematopoietic function.JAK2-STAT5 signaling pathway can promote cell proliferation by up-regulating proliferation-related cyclinD1 and down-regulating the expression of p21 gene,while down-regulating the expression of target genes Bcl-2 and Bcl-xL to inhibit apoptosis of hematopoietic cells.SHP-1,as a negative regulator of STAT5,can negatively regulate JAK2-STAT5 pathway and prevent cell proliferation and differentiation.When this pathway is inhibited,it can inhibit the proliferation of hematopoietic cells and promote their apoptosis,leading to hematopoietic dysfunction,anemia and other symptoms.
One of the blood-tonifying mechanisms of Siwu Decoction is to promote the expression of growth factors such as interleukin-6(IL-6) and erythropoietin(EPO).These growth factors are upstream factors of Janus kinase 2-signal transducer and activator of transcription(JAK2-STAT5),which can activate the expression of this pathway and promote the proliferation and differentiation of hematopoietic cells.JAK2-STAT5 pathway can regulate hematopoietic function by promoting proliferation,differentiate and inhibit of apoptosis to regulate hematopoietic function.JAK2-STAT5 signaling pathway can promote cell proliferation by up-regulating proliferation-related cyclinD1 and down-regulating the expression of p21 gene,while down-regulating the expression of target genes Bcl-2 and Bcl-xL to inhibit apoptosis of hematopoietic cells.SHP-1,as a negative regulator of STAT5,can negatively regulate JAK2-STAT5 pathway and prevent cell proliferation and differentiation.When this pathway is inhibited,it can inhibit the proliferation of hematopoietic cells and promote their apoptosis,leading to hematopoietic dysfunction,anemia and other symptoms.
引文
[1]苗明三,王智明,孙艳红.怀熟地黄多糖对血虚大鼠血像及细胞因子水平的影响[J].中药药理与临床,2007,23(1):39-40.
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[7]KOYAMA M,OKA T,OUCHIDA M,et al.Activated proliferation of B-cell lymphomas/leukemias with the SHP1 gene silencing by aberrant CpG methylation[J].Lab Invest,2003,83(12):1849-1858.
[8]VALENT P.Targeting the JAK2-STAT5 pathway in CML[J].Blood,2014,124(9):1386-1388.
[9]HELTEMES-HARRIS L M,WILLETTE M J L,VANG K B,et al.The role of STAT5 in the development,function,and transformation of B and T lymphocytes[J].Ann N Y Acad Sci,2011,1217:18-31.
[10]陈怡欣.骨髓增殖性肿瘤中JAK2V617F突变和p-STAT5的定量测定及与临床特征的相关性研究[D].济南:山东大学,2013.
[11]RANE S G,REDDY E P.JAKs,STATs and Src kinases in hematopoiesis[J].Oncogene,2002,21(21):3334.
[12]GNANASAMBANDAN K,SAYESKI P P.A structure-function perspective of Jak2 mutations and implications for alternate drug design strategies:the road not taken[J].Curr Med Chem,2011,18(30):4659-4673.
[13]AKADA H,AKADA S,HUTCHISON R E,et al.Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells[J].Stem Cells,2014,32(7):1878-1889.
[14]LEVY D E,JR D J.STATS:transcriptional control and biological impact[J].Nat Rev Mol Cell Biol,2002,3(9):651.
[15]LIN J X,DU N,LI P,et al.Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells[J].Nat Commun,2017,8(1):1320.
[16]BUNTING K D,BRADLEY H L,HAWLEY T S,et al.Reduced lymphomyeloid repopulating activity from adult bone marrow and fetal liver of mice lacking expression of STAT5[J].Blood,2002,99(2):479-487.
[17]PHAM H,MAURER B,PRCHALMURPHY M,et al.STAT5BN642H is a driver mutation for T cell neoplasia[J].Journal of Clinical Investigation,2017,128(1):387-401.
[18]LI G,MISKIMEN K L,WANG Z,et al.STAT5 requires the N-domain for suppression of miR15/16,induction of bcl-2,and survival signaling in myeloproliferative disease[J].Blood,2010,115(7):1416.
[19]LI S,CHENG D,ZHU B,et al.The Overexpression of CARM1 Promotes Human Osteosarcoma Cell Proliferation through the pGSK3β/β-Catenin/cyclinD1 Signaling Pathway[J].Int J Biol Sci,2017,13(8):976.
[20]TANG J,LIAO Y,HE S,et al.Autocrine parathyroid hormone-like hormone promotes intrahepatic cholangiocarcinoma cell proliferation via increased ERK/JNK-ATF2-cyclinD1 signaling[J].J Transl Med,2017,15(1):238.
[21]GUH J Y,HUANG J S,CHEN H C,et al.Advanced glycation end product-induced proliferation in NRK- 49F cells is dependent on the JAK2/STAT5 pathway and cyclin D1[J].Am J Kidney Dis,2001,38(5):1096-1104.
[22]MI H P,LEE H J,LEE H L,et al.Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21[J].Theranostics,2017,7(7):2033-2045.
[23]LI X,WILSON A F,DU W,et al.Cell-Cycle-Specific Function of p53 in Fanconi Anemia Hematopoietic Stem and Progenitor Cell Proliferation[J].Stem Cell Reports,2018,10(2):339-346.
[24]TU X,ZHANG Y,ZHENG X,et al.TGF-β-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice[J].Sci Rep,2017,7(1):2957.
[25]YOSEF R,PILPEL N,PAPISMADOV N,et al.p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling[J].Embo Journal,2017,36(15):2280.
[26]RATHORE R,MCCALLUM J E,VARGHESE E,et al.Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins(IAPs)[J].Apoptosis,2017,22(7):898.
[27]ADAMS J M,CORY S.The BCL-2 arbiters of apoptosis and their growing role as cancer targets[J].Cell Death Differ,2018,25(1):27-36.
[28]KANG Q,ZOU H,YANG X,et al.Characterization and prognostic significance of mortalin,Bcl-2 and Bax in intrahepatic cholangiocarcinoma[J].Oncol Lett,2018,15(2):2161-2168.
[29]陈媛清,崔森.Bcl-2蛋白家族与慢性高原病造血细胞凋亡变化[J].高原医学杂志,2014,24(2):60-63.
[30]OLA M S,NAWAZ M,AHSAN H.Role of Bcl-2 family proteins and caspases in the regulation of apoptosis[J].Mol Cell Biochem,2011,351(1/2):41-58.
[31]YANG X,ZHU F,YU C,et al.N-myc downstream-regulated gene 1 promotes oxaliplatin-triggered apoptosis in colorectal cancer cells via enhancing the ubiquitination of Bcl-2[J].Oncotarget,2017,8(29):47709-47724.
[32]CARTER B Z,MARK P Y,MU H,et al.Combined targeting of Bcl-2 and BCR-ABL tyrosine kinase eradicates chronic myrloid leukemia stem cells[J].Sci Transl Med,2016,8(355):355ra117.
[33]LINDSAY J,ESPOSTI M D,GILMORE A P.Mcl-2 proteins and mitochondria srecificity in membrane targeting for death[J].Biochim Biophys Acta,2011,1813(4):532-539.
[34]PANG A L,XIONG L L,XIA Q J,et al.Neural Stem Cell Transplantation Is Associated with Inhibition of Apoptosis,Bcl-xL Upregulation,and Recovery of Neurological Function in a Rat Model of Traumatic Brain Injury[J].Cell Transplant,2017,26(7):1262-1275.
[35]OPFERMAN J T,KOTHARI A.Anti-apoptotic Bcl-2 family members in development[J].Cell Death Differ,2018,25(1):37-45.
[36]MARTINEZ R J,MORRIS A B,NEELD D K,et al.Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection[J].Eur J Immunol,2016,46(9):2103-2110.
[37]CAO R,QIAN D,LI P,et al.SHP1-mediated cell cycle redistribution inhibits radiosensitivity of non-small cell lung cancer[J].Radiat Oncol,2013,8:178.
[38]FAN L C,TENG H W,SHIAU C W,et al.Pharmacological targeting SHP-1-STAT3 signaling is a promising therapeutic approach for the treatment of colorectal cancer12[J].Neoplasia,2015,17(9):687-696.
[39]TAI W T,SHIAU C W,CHEN P J,et al.Discovery of novel Src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma[J].Hepatology,2014,59(1):190-201.
[40]FAN L C,TENG H W,SHIAU C W,et al.SHP-1 is a target of regorafenib in colorectal cancer[J].Oncotarget,2014,5(15):6243-6251.
[41]郭平,马增春,李鹰飞,等.四物汤对放射线致血虚证小鼠骨髓蛋白质表达的影响[J].中国中药杂志,2004,29(9):893-896.
[42]郭平,王升启.四物汤对血虚证小鼠骨髓细胞IL-6和IL-18基因表达的影响[J].山东中医杂志,2013,32(4):272-274.
[2]刘福君,赵修南,汤建芳,等.地黄低聚糖对快速老化模型小鼠造血功能的影响[J].中国药理学通报,1997,13(6):31-34.
[3]李秀,初杰,李影迪,等.当归/黄芪多糖对腹腔注射环磷酰胺小鼠骨髓造血影响随机平行对照研究[J].实用中医内科杂志,2017,31(5):52-58.
[4]杨宜花,陈爱民,丁舸.四物汤构成补血类方核心药组之论证[J].现代中医药,2015,35(5):114-116.
[5]SUN J J,LAN J F,ZHAO X F,et al.Binding of a C-type lectin′s coiled-coil domain to the Domeless receptor directly activates the JAK/STAT pathway in the shrimp immune response to bacterial infection[J].Plos Pathogens,2017,13(9):e1006626.
[6]SEIF F,KHOSHMIRSAFA M,AAZAMI H,et al.The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells[J].Cell Commun Signal,2017,15(1):23.
[7]KOYAMA M,OKA T,OUCHIDA M,et al.Activated proliferation of B-cell lymphomas/leukemias with the SHP1 gene silencing by aberrant CpG methylation[J].Lab Invest,2003,83(12):1849-1858.
[8]VALENT P.Targeting the JAK2-STAT5 pathway in CML[J].Blood,2014,124(9):1386-1388.
[9]HELTEMES-HARRIS L M,WILLETTE M J L,VANG K B,et al.The role of STAT5 in the development,function,and transformation of B and T lymphocytes[J].Ann N Y Acad Sci,2011,1217:18-31.
[10]陈怡欣.骨髓增殖性肿瘤中JAK2V617F突变和p-STAT5的定量测定及与临床特征的相关性研究[D].济南:山东大学,2013.
[11]RANE S G,REDDY E P.JAKs,STATs and Src kinases in hematopoiesis[J].Oncogene,2002,21(21):3334.
[12]GNANASAMBANDAN K,SAYESKI P P.A structure-function perspective of Jak2 mutations and implications for alternate drug design strategies:the road not taken[J].Curr Med Chem,2011,18(30):4659-4673.
[13]AKADA H,AKADA S,HUTCHISON R E,et al.Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells[J].Stem Cells,2014,32(7):1878-1889.
[14]LEVY D E,JR D J.STATS:transcriptional control and biological impact[J].Nat Rev Mol Cell Biol,2002,3(9):651.
[15]LIN J X,DU N,LI P,et al.Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells[J].Nat Commun,2017,8(1):1320.
[16]BUNTING K D,BRADLEY H L,HAWLEY T S,et al.Reduced lymphomyeloid repopulating activity from adult bone marrow and fetal liver of mice lacking expression of STAT5[J].Blood,2002,99(2):479-487.
[17]PHAM H,MAURER B,PRCHALMURPHY M,et al.STAT5BN642H is a driver mutation for T cell neoplasia[J].Journal of Clinical Investigation,2017,128(1):387-401.
[18]LI G,MISKIMEN K L,WANG Z,et al.STAT5 requires the N-domain for suppression of miR15/16,induction of bcl-2,and survival signaling in myeloproliferative disease[J].Blood,2010,115(7):1416.
[19]LI S,CHENG D,ZHU B,et al.The Overexpression of CARM1 Promotes Human Osteosarcoma Cell Proliferation through the pGSK3β/β-Catenin/cyclinD1 Signaling Pathway[J].Int J Biol Sci,2017,13(8):976.
[20]TANG J,LIAO Y,HE S,et al.Autocrine parathyroid hormone-like hormone promotes intrahepatic cholangiocarcinoma cell proliferation via increased ERK/JNK-ATF2-cyclinD1 signaling[J].J Transl Med,2017,15(1):238.
[21]GUH J Y,HUANG J S,CHEN H C,et al.Advanced glycation end product-induced proliferation in NRK- 49F cells is dependent on the JAK2/STAT5 pathway and cyclin D1[J].Am J Kidney Dis,2001,38(5):1096-1104.
[22]MI H P,LEE H J,LEE H L,et al.Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21[J].Theranostics,2017,7(7):2033-2045.
[23]LI X,WILSON A F,DU W,et al.Cell-Cycle-Specific Function of p53 in Fanconi Anemia Hematopoietic Stem and Progenitor Cell Proliferation[J].Stem Cell Reports,2018,10(2):339-346.
[24]TU X,ZHANG Y,ZHENG X,et al.TGF-β-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice[J].Sci Rep,2017,7(1):2957.
[25]YOSEF R,PILPEL N,PAPISMADOV N,et al.p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling[J].Embo Journal,2017,36(15):2280.
[26]RATHORE R,MCCALLUM J E,VARGHESE E,et al.Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins(IAPs)[J].Apoptosis,2017,22(7):898.
[27]ADAMS J M,CORY S.The BCL-2 arbiters of apoptosis and their growing role as cancer targets[J].Cell Death Differ,2018,25(1):27-36.
[28]KANG Q,ZOU H,YANG X,et al.Characterization and prognostic significance of mortalin,Bcl-2 and Bax in intrahepatic cholangiocarcinoma[J].Oncol Lett,2018,15(2):2161-2168.
[29]陈媛清,崔森.Bcl-2蛋白家族与慢性高原病造血细胞凋亡变化[J].高原医学杂志,2014,24(2):60-63.
[30]OLA M S,NAWAZ M,AHSAN H.Role of Bcl-2 family proteins and caspases in the regulation of apoptosis[J].Mol Cell Biochem,2011,351(1/2):41-58.
[31]YANG X,ZHU F,YU C,et al.N-myc downstream-regulated gene 1 promotes oxaliplatin-triggered apoptosis in colorectal cancer cells via enhancing the ubiquitination of Bcl-2[J].Oncotarget,2017,8(29):47709-47724.
[32]CARTER B Z,MARK P Y,MU H,et al.Combined targeting of Bcl-2 and BCR-ABL tyrosine kinase eradicates chronic myrloid leukemia stem cells[J].Sci Transl Med,2016,8(355):355ra117.
[33]LINDSAY J,ESPOSTI M D,GILMORE A P.Mcl-2 proteins and mitochondria srecificity in membrane targeting for death[J].Biochim Biophys Acta,2011,1813(4):532-539.
[34]PANG A L,XIONG L L,XIA Q J,et al.Neural Stem Cell Transplantation Is Associated with Inhibition of Apoptosis,Bcl-xL Upregulation,and Recovery of Neurological Function in a Rat Model of Traumatic Brain Injury[J].Cell Transplant,2017,26(7):1262-1275.
[35]OPFERMAN J T,KOTHARI A.Anti-apoptotic Bcl-2 family members in development[J].Cell Death Differ,2018,25(1):37-45.
[36]MARTINEZ R J,MORRIS A B,NEELD D K,et al.Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection[J].Eur J Immunol,2016,46(9):2103-2110.
[37]CAO R,QIAN D,LI P,et al.SHP1-mediated cell cycle redistribution inhibits radiosensitivity of non-small cell lung cancer[J].Radiat Oncol,2013,8:178.
[38]FAN L C,TENG H W,SHIAU C W,et al.Pharmacological targeting SHP-1-STAT3 signaling is a promising therapeutic approach for the treatment of colorectal cancer12[J].Neoplasia,2015,17(9):687-696.
[39]TAI W T,SHIAU C W,CHEN P J,et al.Discovery of novel Src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma[J].Hepatology,2014,59(1):190-201.
[40]FAN L C,TENG H W,SHIAU C W,et al.SHP-1 is a target of regorafenib in colorectal cancer[J].Oncotarget,2014,5(15):6243-6251.
[41]郭平,马增春,李鹰飞,等.四物汤对放射线致血虚证小鼠骨髓蛋白质表达的影响[J].中国中药杂志,2004,29(9):893-896.
[42]郭平,王升启.四物汤对血虚证小鼠骨髓细胞IL-6和IL-18基因表达的影响[J].山东中医杂志,2013,32(4):272-274.