中医药抑制SphK1-S1P通路治疗糖尿病肾病研究进展
|
摘要
糖尿病肾病的发生、发展与其细胞信号转导通路的失调有着密切的联系,中医药以其低毒性、多靶点的优势在调控信号通路方面有着独特的功效。黄连素、虎杖苷、姜黄素、马钱苷等中药单体、提取物及中药复方均可以通过抑制SphK1/S1P信号通路,来拮抗糖尿病肾纤维化的进程。就目前研究而言:①对单味中药及中药有效成分提取物的研究,不能合理地解释中药多靶点调控细胞信号通路的机制;②中药复方成分复杂、组分不明、结构不清等因素限制了体外实验的细胞学和分子生物学水平研究;③各信号通路之间的关系错综复杂,研究不易开展。今后需更加系统地研究如何发挥中医药低毒性、多靶点的优势,阐明其调控机理,以更好地指导临床。
The occurrence and development of diabetic nephropathy is closely related to the imbalance of its cell signal transduction pathway.Traditional Chinese medicine has unique effects in regulating signaling pathways due to its low toxicity and multi-target advantages.Traditional Chinese medicine monomers,extracts and traditional Chinese medicines such as berberine,polydatin,curcumin and loganin can inhibit the progression of diabetic renal fibrosis by inhibiting the Sphk1/S1 P signaling pathway.As far as the current research is concerned:①The study on the extracts of single-flavored traditional Chinese medicines and active constituents of traditional Chinese medicines cannot reasonably explain the mechanism of multi-target regulation of cellular signaling pathways in traditional Chinese medicines;②the complex composition of traditional Chinese medicine compounds,unclear composition,unclear structure and other factors Limits the cytological and molecular biology levels of in vitro experiments;③the relationship between the various signaling pathways is complex and difficult to develop.In the future,we need to study more systematically how to take advantage of the low toxicity and multi-target of traditional Chinese medicine,and clarify its regulation mechanism to better guide the clinical.
The occurrence and development of diabetic nephropathy is closely related to the imbalance of its cell signal transduction pathway.Traditional Chinese medicine has unique effects in regulating signaling pathways due to its low toxicity and multi-target advantages.Traditional Chinese medicine monomers,extracts and traditional Chinese medicines such as berberine,polydatin,curcumin and loganin can inhibit the progression of diabetic renal fibrosis by inhibiting the Sphk1/S1 P signaling pathway.As far as the current research is concerned:①The study on the extracts of single-flavored traditional Chinese medicines and active constituents of traditional Chinese medicines cannot reasonably explain the mechanism of multi-target regulation of cellular signaling pathways in traditional Chinese medicines;②the complex composition of traditional Chinese medicine compounds,unclear composition,unclear structure and other factors Limits the cytological and molecular biology levels of in vitro experiments;③the relationship between the various signaling pathways is complex and difficult to develop.In the future,we need to study more systematically how to take advantage of the low toxicity and multi-target of traditional Chinese medicine,and clarify its regulation mechanism to better guide the clinical.
引文
[1]TUTTLE K R,BAKRIS G L,BILOUS R W,et al.Diabetic kidney disease:a report from an ADA Consensus Conference[J].Am J Kidney Dis,2014,64(4):510-533.
[2]GEOFFROY K,WIERNSPERGER N,LAGARDE M,et al.Bimodal effect of advanced glycation end products on mesangial cell proliferation is mediated byneutral ceramidase regulation and endogenous sphingolipids[J].J Biol Chem,2004,279(33):34343-34352.
[3]SATIRAPOJ B.Nephropafhy in diabetes[J].Adv Exp Med Biol,2012,771:107-122.
[4]JIANG Q,LIU P,WU X,et al.Berberine attenuates lipopolysaccharide-induced extracelluar matrix accumulation and inflammation in ratmesangial cells:involvement of NF-kappa B signaling pathway[J].Mol Cell Endocrinol,2011,331(1):34-40.
[5]YOU B,REN A,YAN G,et al.Activation of sphingosinekinase-lmediates inhibition of vascular smooth muscle cell apoptpsisby hyperglycemia[J].Diabetes,2007,56(5):1445-1453.
[6]KLAWITTER S,HOFMANN L P,PFEILSCHIFTER J,et al.Extracellularnucleotides induce migration of renal mesangial cells by upregulatingsphingosine kinase-1 expression and activity[J].Br J Pharmacol,2007,150(3):271-280.
[7]GEOFFROY K,TRONCY L,WIERNSPERGER N,et al.Glomerularproliferation during early stages of diabetic nephropathy is associatedwith local increase of sphingosine-1-phosphate levels[J].Febs Lett,2005,579(5):1249-1254.
[8]兰天,常秀亭,勾红菊,等.SphK-S1P信号通路的激活参与糖尿病大鼠肾损伤的研究[J].重庆医学,2013,22(8):2571-2573.
[9]LAN T,LIU W,XIE X,et al.Sphingosine kinase-1 pathway medi-ates high glucose-induced fibronectin expression in glomerular me-sangial cells[J].Mol Endocrinol,2011,25(12):2094-2105.
[10]REN S,BABELOVA A,MORETH K,et al.Transforming growth factor-beta2 upregulates sphingosine kinase-1 activity,which in turn atten-uates the fibrotic response to TGF-beta2 by impeding CTGF expression[J].Kidney Int,2009,76(8):857-867.
[11]KOCH A,VOLZKE A,WUNSCHE C,et al.Thiazolidinedione-dependent activation of sphin-gosine kinase 1 causes an anti-fibrotic effect inrenal mesangial cells[J].Br J Pharmacol,2012,166(3):1018-1032.
[12]ZHANG H,DESAI N N,OLIVER A A,et al.Sphingosine-1-phosphate,a novel lipid,involved in cellular proliferation[J].J Cell Biol,1991,114(1):155-167.
[13]SNIDER A J,ORR GANDY K A,OBEID L M.Sphingosine kinase:role in regulation of bioactive sphingolipid mediators in inflammation[J].Biochimie,2010,92(6):707-715.
[14]KUHAD A,CHOPRA K.Attenuation of diabetic nephropathy by tocotrienol:involvement of NF-κB signaling pathway[J].Life Sci,2009,84(9/10):296-301.
[15]LIU W,LAN T,XIE X,et al.S1P2 receptor mediates sphingosine-1-phosphate-induced fibronectin expression via MAPK signalin pathway in mesangial cells under high glucose condition[J].Exp Cell Res,2012,318(8):936-943.
[16]LIM A K,TESCH G H.Inflammation in diabetic nephropathy[J].Mediators Inflamm,2012,2012(5):146154.
[17]KO H M,JOO S H,KIM P,et al.Effects of Korean red ginseng extract on tissue plasminogen activator and plasminogen activator inhibitor-1 expression in cultured rat primary astrocytes[J].Journal of Ginseng Research,2013,37(4):401-412.
[18]GUAN Z,BUCKMAN S Y,PENTLAND A P,et al.Induction of cyclooxygenase-2 by the activated MEKK1-SEK1/MKK4-p38 mitogen-activated protein kinase path-way[J].J Biol Chem,1998,273(21):12901-12908.
[19]XIN C,REN S,KLEUSER B,et al.Sphingosine 1-phosphate cross-activates the Smad signaling cascade and mimics transforminggrowth factor-beta-induced cell responses[J].J Biol Chem,2004,279(34):35255-35262.
[20]HUANG K,HUANG J,CHEN C,et al.AP-1 regulates sphingosine kinase 1 expression in a positive feedback manner in glomerular mesangial cells exposed to high glucose[J].Cell Signal,2014,26(3):629-638.
[21]彭晶,兰天,黄凯鹏,等.黄连素调节鞘氨醇激酶-1-磷酸鞘氨醇信号通路抗糖尿病小鼠肾损伤的研究[J].中国药理学通报,2011,27(11):1544.
[22]LAN T,SHEN X,LIU P,et al.Berberine ameliorates renal injury indiabetic C57BL/6 mice:involvement of suppression of SphK-S1P signaling pathway[J].Arch Biochem Biophys,2010,502(2):112-120.
[23]HUANG K,LIU W,LAN T,et al.Berberine reduces fibronectin expression by suppressing the S1P-S1P2 receptor pathway inexperimental diabetic nephropathy models[J].Plos One,2012,7(8):43874.
[24]CHEN L,LAN Z,LIN Q,et al.Polydatin ameliorates renal injury by attenuating oxidative stress-related inflammatory responses in fructose-induced urate nephropathic mice[J].Food Chem Toxicol,2013,52:28-35.
[25]CHEN C,HUANG K,HAO J,et al.Polydatin attenuates AGEs-induced upregulation of fibronectin and ICAM-1 in rat glomerular mesangial cells and db/db diabetic mice kidneys by inhibiting the activation of the SphK1-S1P signaling pathway[J].Mol Cell Endocrinol,2016,427:45-56.
[26]STRIMPAKOS A S,SHARMA R A.Curcumin:Preventive and therapeutic prop-erties in laboratory studies and clinical trials.Antioxid Redox Signal,2008,10(3):511-545.
[27]TIKOO K,MEENA R L,KABRA DG,et al.Change in post-translationalmodifications of histone H3,heat-shock protein-27 and MAP kinase p38 ex-pression by curcumin in streptozotocin-induced type I diabetic nephropathy.Br J Pharmacol,2009,153(6):1225-1231.
[28]郝洁,黄娟,陈诚,等.姜黄素通过鞘氨醇激酶-1-磷酸鞘氨醇信号通路抗糖尿病大鼠肾脏纤维化的研究[J].中药药理与临床,2013,29(6):10-13.
[29]吕兴,许惠琴,吕高虹.AGEs/RAGE/SPHK1信号通路介导马钱苷抗AGEs损伤GMCs的机制研究[J].南京中医药大学学报,2017,33(4):382-385.
[30]崔玉枝.基于Sphk1-S1P信号通路研究益肾解毒通络胶囊对早期糖尿病肾病的影响[D].郑州:河南中医药大学,2015.
[31]WANG L,XING X P,HOLMES A,et al.Activation of the sphingosine ki-nase-signaling pathway by high glucose mediates the proinflammatory pheno-type of endothelial cells[J].Circ Res,2005,97(9):891-899.
[32]YOU B,REN A,YAN G,et al.Activation of sphingosine kinase-1 medi-ates inhibition of vascular smooth muscle cell apoptosis by hyperglycemia[J].Diabetes,2007,56(5):1445-1453.
[33]XIN C Y,REN S Y,BURKHARDT K,et al.Sphingosine 1-phosphate cross-ac-tivates the Smad signaling cascade and mimics transforming growth factor-beta-induced cell responses[J].J Biol Chem,2004,279(34):35255-35262.
[2]GEOFFROY K,WIERNSPERGER N,LAGARDE M,et al.Bimodal effect of advanced glycation end products on mesangial cell proliferation is mediated byneutral ceramidase regulation and endogenous sphingolipids[J].J Biol Chem,2004,279(33):34343-34352.
[3]SATIRAPOJ B.Nephropafhy in diabetes[J].Adv Exp Med Biol,2012,771:107-122.
[4]JIANG Q,LIU P,WU X,et al.Berberine attenuates lipopolysaccharide-induced extracelluar matrix accumulation and inflammation in ratmesangial cells:involvement of NF-kappa B signaling pathway[J].Mol Cell Endocrinol,2011,331(1):34-40.
[5]YOU B,REN A,YAN G,et al.Activation of sphingosinekinase-lmediates inhibition of vascular smooth muscle cell apoptpsisby hyperglycemia[J].Diabetes,2007,56(5):1445-1453.
[6]KLAWITTER S,HOFMANN L P,PFEILSCHIFTER J,et al.Extracellularnucleotides induce migration of renal mesangial cells by upregulatingsphingosine kinase-1 expression and activity[J].Br J Pharmacol,2007,150(3):271-280.
[7]GEOFFROY K,TRONCY L,WIERNSPERGER N,et al.Glomerularproliferation during early stages of diabetic nephropathy is associatedwith local increase of sphingosine-1-phosphate levels[J].Febs Lett,2005,579(5):1249-1254.
[8]兰天,常秀亭,勾红菊,等.SphK-S1P信号通路的激活参与糖尿病大鼠肾损伤的研究[J].重庆医学,2013,22(8):2571-2573.
[9]LAN T,LIU W,XIE X,et al.Sphingosine kinase-1 pathway medi-ates high glucose-induced fibronectin expression in glomerular me-sangial cells[J].Mol Endocrinol,2011,25(12):2094-2105.
[10]REN S,BABELOVA A,MORETH K,et al.Transforming growth factor-beta2 upregulates sphingosine kinase-1 activity,which in turn atten-uates the fibrotic response to TGF-beta2 by impeding CTGF expression[J].Kidney Int,2009,76(8):857-867.
[11]KOCH A,VOLZKE A,WUNSCHE C,et al.Thiazolidinedione-dependent activation of sphin-gosine kinase 1 causes an anti-fibrotic effect inrenal mesangial cells[J].Br J Pharmacol,2012,166(3):1018-1032.
[12]ZHANG H,DESAI N N,OLIVER A A,et al.Sphingosine-1-phosphate,a novel lipid,involved in cellular proliferation[J].J Cell Biol,1991,114(1):155-167.
[13]SNIDER A J,ORR GANDY K A,OBEID L M.Sphingosine kinase:role in regulation of bioactive sphingolipid mediators in inflammation[J].Biochimie,2010,92(6):707-715.
[14]KUHAD A,CHOPRA K.Attenuation of diabetic nephropathy by tocotrienol:involvement of NF-κB signaling pathway[J].Life Sci,2009,84(9/10):296-301.
[15]LIU W,LAN T,XIE X,et al.S1P2 receptor mediates sphingosine-1-phosphate-induced fibronectin expression via MAPK signalin pathway in mesangial cells under high glucose condition[J].Exp Cell Res,2012,318(8):936-943.
[16]LIM A K,TESCH G H.Inflammation in diabetic nephropathy[J].Mediators Inflamm,2012,2012(5):146154.
[17]KO H M,JOO S H,KIM P,et al.Effects of Korean red ginseng extract on tissue plasminogen activator and plasminogen activator inhibitor-1 expression in cultured rat primary astrocytes[J].Journal of Ginseng Research,2013,37(4):401-412.
[18]GUAN Z,BUCKMAN S Y,PENTLAND A P,et al.Induction of cyclooxygenase-2 by the activated MEKK1-SEK1/MKK4-p38 mitogen-activated protein kinase path-way[J].J Biol Chem,1998,273(21):12901-12908.
[19]XIN C,REN S,KLEUSER B,et al.Sphingosine 1-phosphate cross-activates the Smad signaling cascade and mimics transforminggrowth factor-beta-induced cell responses[J].J Biol Chem,2004,279(34):35255-35262.
[20]HUANG K,HUANG J,CHEN C,et al.AP-1 regulates sphingosine kinase 1 expression in a positive feedback manner in glomerular mesangial cells exposed to high glucose[J].Cell Signal,2014,26(3):629-638.
[21]彭晶,兰天,黄凯鹏,等.黄连素调节鞘氨醇激酶-1-磷酸鞘氨醇信号通路抗糖尿病小鼠肾损伤的研究[J].中国药理学通报,2011,27(11):1544.
[22]LAN T,SHEN X,LIU P,et al.Berberine ameliorates renal injury indiabetic C57BL/6 mice:involvement of suppression of SphK-S1P signaling pathway[J].Arch Biochem Biophys,2010,502(2):112-120.
[23]HUANG K,LIU W,LAN T,et al.Berberine reduces fibronectin expression by suppressing the S1P-S1P2 receptor pathway inexperimental diabetic nephropathy models[J].Plos One,2012,7(8):43874.
[24]CHEN L,LAN Z,LIN Q,et al.Polydatin ameliorates renal injury by attenuating oxidative stress-related inflammatory responses in fructose-induced urate nephropathic mice[J].Food Chem Toxicol,2013,52:28-35.
[25]CHEN C,HUANG K,HAO J,et al.Polydatin attenuates AGEs-induced upregulation of fibronectin and ICAM-1 in rat glomerular mesangial cells and db/db diabetic mice kidneys by inhibiting the activation of the SphK1-S1P signaling pathway[J].Mol Cell Endocrinol,2016,427:45-56.
[26]STRIMPAKOS A S,SHARMA R A.Curcumin:Preventive and therapeutic prop-erties in laboratory studies and clinical trials.Antioxid Redox Signal,2008,10(3):511-545.
[27]TIKOO K,MEENA R L,KABRA DG,et al.Change in post-translationalmodifications of histone H3,heat-shock protein-27 and MAP kinase p38 ex-pression by curcumin in streptozotocin-induced type I diabetic nephropathy.Br J Pharmacol,2009,153(6):1225-1231.
[28]郝洁,黄娟,陈诚,等.姜黄素通过鞘氨醇激酶-1-磷酸鞘氨醇信号通路抗糖尿病大鼠肾脏纤维化的研究[J].中药药理与临床,2013,29(6):10-13.
[29]吕兴,许惠琴,吕高虹.AGEs/RAGE/SPHK1信号通路介导马钱苷抗AGEs损伤GMCs的机制研究[J].南京中医药大学学报,2017,33(4):382-385.
[30]崔玉枝.基于Sphk1-S1P信号通路研究益肾解毒通络胶囊对早期糖尿病肾病的影响[D].郑州:河南中医药大学,2015.
[31]WANG L,XING X P,HOLMES A,et al.Activation of the sphingosine ki-nase-signaling pathway by high glucose mediates the proinflammatory pheno-type of endothelial cells[J].Circ Res,2005,97(9):891-899.
[32]YOU B,REN A,YAN G,et al.Activation of sphingosine kinase-1 medi-ates inhibition of vascular smooth muscle cell apoptosis by hyperglycemia[J].Diabetes,2007,56(5):1445-1453.
[33]XIN C Y,REN S Y,BURKHARDT K,et al.Sphingosine 1-phosphate cross-ac-tivates the Smad signaling cascade and mimics transforming growth factor-beta-induced cell responses[J].J Biol Chem,2004,279(34):35255-35262.