Chaiqin Chengqi decoction inhibits inflammatory mediators and attenuates acute pancreatitis through deactivation of janus kinase/signal transducer and activator of transcription signaling pathway
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摘要
OBJECTIVE: To investigate the effect of Chaiqin Chengqi decoction(CQCQD) on acute pancreatitis(AP) by janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in vitro and in vivo.METHODS: AP was induced by caerulein both in AR42J cells and in mice. AR42J cells were divided into five groups: the control group, the AP group, the CQCQD group, JAK/STAT signaling pathway inhibitor AG490 group, and the CQCQD and AG490 group.After induction, cellular supernatant of five groups were collected for measuring the concentrations of inflammatory cytokine amylase, interleukin 6(IL-6),tumor necrosis factor α(TNF-α), interleukin 1β(IL-1β), nuclear factor κB(NF-κB) by enzyme-linked immunosorbent assay and the expression of JAK-2,STAT-3 signaling transduction proteins by Western blot, respectively. Experiments in mice were performed similar to that of in AR42J cells.RESULTS: Treatment of AR42J cells with CQCQD reduced the pancreatic injury and negatively regulated the activities of amylase, as well as inhibited expression of several inflammatory cytokines such as IL-6, TNF-α, IL-1β, NF-κB. Administration of CQCQD significantly inhibited JAK-2 activation and down-regulated phosphorylation of downstream substrate STAT-3 the same as AG490, resulting in inhibition of inflammatory mediators and amelioration of pancreatitis.CONCLUSION: The results suggested that CQCQD exerted anti-inflammatory effects on AP via reducing expression and phosphorylation of JAK and STAT.
OBJECTIVE: To investigate the effect of Chaiqin Chengqi decoction(CQCQD) on acute pancreatitis(AP) by janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in vitro and in vivo.METHODS: AP was induced by caerulein both in AR42J cells and in mice. AR42J cells were divided into five groups: the control group, the AP group, the CQCQD group, JAK/STAT signaling pathway inhibitor AG490 group, and the CQCQD and AG490 group.After induction, cellular supernatant of five groups were collected for measuring the concentrations of inflammatory cytokine amylase, interleukin 6(IL-6),tumor necrosis factor α(TNF-α), interleukin 1β(IL-1β), nuclear factor κB(NF-κB) by enzyme-linked immunosorbent assay and the expression of JAK-2,STAT-3 signaling transduction proteins by Western blot, respectively. Experiments in mice were performed similar to that of in AR42J cells.RESULTS: Treatment of AR42J cells with CQCQD reduced the pancreatic injury and negatively regulated the activities of amylase, as well as inhibited expression of several inflammatory cytokines such as IL-6, TNF-α, IL-1β, NF-κB. Administration of CQCQD significantly inhibited JAK-2 activation and down-regulated phosphorylation of downstream substrate STAT-3 the same as AG490, resulting in inhibition of inflammatory mediators and amelioration of pancreatitis.CONCLUSION: The results suggested that CQCQD exerted anti-inflammatory effects on AP via reducing expression and phosphorylation of JAK and STAT.
OBJECTIVE: To investigate the effect of Chaiqin Chengqi decoction(CQCQD) on acute pancreatitis(AP) by janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in vitro and in vivo.METHODS: AP was induced by caerulein both in AR42J cells and in mice. AR42J cells were divided into five groups: the control group, the AP group, the CQCQD group, JAK/STAT signaling pathway inhibitor AG490 group, and the CQCQD and AG490 group.After induction, cellular supernatant of five groups were collected for measuring the concentrations of inflammatory cytokine amylase, interleukin 6(IL-6),tumor necrosis factor α(TNF-α), interleukin 1β(IL-1β), nuclear factor κB(NF-κB) by enzyme-linked immunosorbent assay and the expression of JAK-2,STAT-3 signaling transduction proteins by Western blot, respectively. Experiments in mice were performed similar to that of in AR42J cells.RESULTS: Treatment of AR42J cells with CQCQD reduced the pancreatic injury and negatively regulated the activities of amylase, as well as inhibited expression of several inflammatory cytokines such as IL-6, TNF-α, IL-1β, NF-κB. Administration of CQCQD significantly inhibited JAK-2 activation and down-regulated phosphorylation of downstream substrate STAT-3 the same as AG490, resulting in inhibition of inflammatory mediators and amelioration of pancreatitis.CONCLUSION: The results suggested that CQCQD exerted anti-inflammatory effects on AP via reducing expression and phosphorylation of JAK and STAT.
引文
1 Hirota M,Sugita H,Maeda K,Ichibara A,Ogawa M.Concept of SIRS and severe acute pancreatitis.Nihon Rinsho 2004;62(11):2128-2136.
2 LH D.Effects of Chaiqinchengqi decoction on cefotaxime in rats with acute necrotizing pancreatitis.World J Gastroenterol 2009;15(35):4439-4443.
3 Zhang XP,Jiang J,Cheng QH,et al.Protective effects of Ligustrazine,Kakonein and Panax Notoginsenoside on the small intestine and immune organs of rats with severe acute pancreatitis.Hepatobiliary Pancreat Dis Int 2011;10(6):632-637.
4 Huang L,Wang MH,Cheng ZY,et al.Effects of Chai-Qin-Cheng-Qi decoction(CQCQD)on acute pancreatitis-associated lung injury in mice with acute necrotizing pancreatitis.Chin J Integr Med 2012;9:1-7.
5 Surbatovic M,Jovanovic K,Radakovic S,Filipovic N.Pathophysiological aspects of severe acute pancreatitis-associated lung injury.Srp Arh Celok Lek 2005;133(1-2):76-81.
6 Wu W,Guo J,Yang XN,et al.Effect of Chaiqinchengqi decoction on serum amyloid A in severe acute pancreatitis patients.Asian Pac J Trop Med 2012;5(11):901-905.
7 Williams JA.Receptor-mediated signal transduction pathways and the regulation of pancreatic acinar cell function.Curr Opin Gastroenterol 2008;24(5):573-579.
8 Guo J,Jin T,Lin ZQ,et al.Effect of Chaiqin Chengqi decoction on cholecystokinin receptor 1-mediated signal transduction of pancreatic acinar cells in acute necrotizing pancreatitis rats.Chin J Integr Med 2015;21(1):29-35.
9 Migita K,Izumi Y,Torigoshi T,et al.Inhibition of Janus kinase/signal transducer and activator of transcription(JAK/STAT)signalling pathway in rheumatoid synovial fibroblasts using small molecule compounds.Clin Exp Immunol 2013;174(3):356-363.
10 Arbouzova NI,Zeidler MP.JAK/STAT signalling in Drosophila:insights into conserved regulatory and cellular functions.Development 2006;133(14):2605-2616.
11 Springuel L,Renauld JC,Knoops L.JAK kinase targeting in hematologic malignancies:a sinuous pathway from identification of genetic alterations towards clinical indications.Haematologica 2015;100(10):1240-1253.
12 Sweeney SE,Firestein GS.Signal transduction in rheumatoidarthritis.Curr OpinRheumatol2004;16(3):231-237.
13 Zhang W,Chen PL,Du L,Wang FY,Qi C.Recent progress in the the study on structure and its function of JAK2.Natural Science Journal of HAINAN University 2009;27(1):87-90.
14 Liongue C,Taznin T,Ward AC.Signaling via the CytoR/JAK/STAT/SOCS pathway:Emergence during evolution.Mol Immunol 2016;71:166-175.
15 Tao Z,Cheng M,Wang SC,et al.JAK2/STAT3 pathway mediating inflammatory responses in heatstroke-induced rats.Int J Clin Exp Pathol 2015;8(6):6732-6739.
16 Ward AC,Touw I,Yoshimura A.The Jak-Stat pathway in normal and perturbed hematopoiesis.Blood 2000;95(1):19-29.
17 Bopaiah P.Cheppudir A,Thomas H,et al.Clifford,Anti-hyperalgesic effects of AG490,a Janus kinase inhibitor,in a rat model of inflammatory pain.Biomedical Reports2015;(3):703-706.
18 Hu X,Lu H,Deng YL,Wan Q,Yie SM.Effect of rat medicated serum containing Zuo Gui Wan and/or You Gui Wan on the differentiation of stem cells derived from human first trimester umbilical cord into oocyte-like cells in vitro.Evid Based Complement Alternat Med 2015;2015:825805.
19 Wu W,Luo R,Lin Z,Xia Q,Xue P.Key Molecular Mechanisms of Chaiqinchengqi decoction in alleviating the pulmonary albumin leakage caused by endotoxemia in severe acute pancreatitis rats.Evid Based Complement Alternat Med 2016;2016:3265368.
20 Deng LH,Yang XN,Xia Q.Protective effects of Chaiqin Chengqi decoction on isolated pancreatic acinar cells in acute pancreatitis rats and the mechanisms.Zhong Xi Yi Jie He Xue Bao 2008;6(2):176-179.
21 Choi SB,Bae GS,Jo IJ,Wang S,Song HJ,Park SJ.Berberine inhibits inflammatory mediators and attenuates acute pancreatitis through deactivation of JNK signaling pathways.Mol Immunol 2016;74:27-38.
22 Yubero S,Manso MA,Ramudo L,Vicente S,De Dios I.Dexamethasone down-regulates the inflammatory mediators but fails to reduce the tissue injury in the lung of acute pancreatitis rat models.Pulm Pharmacol Ther 2012;25(4):319-324.
23 Ren SJ,Zeng XW,Fu JD.Effect of AG490 on brain edema and inflammatory response after ischemic brain injury of rats.Acta Acad Med Weifang 2013;35(5):334-337.
24 Zhang XP,Tian H,Lai YH,et al.Protective effects and mechanisms of Baicalin and octreotide on renal injury of rats with severe acute pancreatitis.World J Gastroenterol2007;13(38):5079-5089.
25 Du C,Niu R,Chu E,Zhang P,Lin X.Sequence analysis and functional study of thymidylate synthase from zebrafish,Danio rerio.J Biochem 2006;139(5):913-920.
26 Rau B,Uhl W,Buchler MW,Beger HG.Surgical treatment of infected necrosis.World J Surg 1997;21(2):155-161.
27 Liu XB,Jiang JM,Huang ZW,et al.Clinical study on the treatment of severe acute pancreatitis by integrated Traditional Chinese Medicine and Western Medicine.Sichuan Da Xue Xue Bao Yi Xue Ban 2004;35(2):204-208.
28 Souza LJ,Coelho AM,Sampietre SN,Martins JO,Cunha JE,Machado MC.Anti-inflammatory effects of peritoneal lavage in acute pancreatitis.Pancreas 2010;39(8):1180-1184.
29 Browne GW,Pitchumoni CS.Pathophysiology of pulmonary complications of acute pancreatitis.World J Gastroenterol 2006;12(44):7087-7096.
30 Nakamura Y,Franchi L,Kambe N,Meng G,Strober W,Nunez G.Critical role for mast cells in interleukin-1beta-driven skin inflammation associated with an activating mutation in the nlrp3 protein.Immunity 2012;37(1):85-95.
31 Papachristou GI.Prediction of severe acute pancreatitis:current knowledge and novel insights.World J Gastroenterol 2008;14(41):6273-6275.
32 Kettritz R,Choi M,Rolle S,Wellner M,Luft FC.Integrins and cytokines activate nuclear transcription factor-kappaB in human neutrophils.J Biol Chem 2004;279(4):2657-2665.
33 Boutros T,Chevet E,Metrakos P.Mitogen-activated protein(MAP)kinase/MAP kinase phosphatase regulation:roles in cell growth,death,and cancer.Pharmacol Rev2008;60(3):261-310.
2 LH D.Effects of Chaiqinchengqi decoction on cefotaxime in rats with acute necrotizing pancreatitis.World J Gastroenterol 2009;15(35):4439-4443.
3 Zhang XP,Jiang J,Cheng QH,et al.Protective effects of Ligustrazine,Kakonein and Panax Notoginsenoside on the small intestine and immune organs of rats with severe acute pancreatitis.Hepatobiliary Pancreat Dis Int 2011;10(6):632-637.
4 Huang L,Wang MH,Cheng ZY,et al.Effects of Chai-Qin-Cheng-Qi decoction(CQCQD)on acute pancreatitis-associated lung injury in mice with acute necrotizing pancreatitis.Chin J Integr Med 2012;9:1-7.
5 Surbatovic M,Jovanovic K,Radakovic S,Filipovic N.Pathophysiological aspects of severe acute pancreatitis-associated lung injury.Srp Arh Celok Lek 2005;133(1-2):76-81.
6 Wu W,Guo J,Yang XN,et al.Effect of Chaiqinchengqi decoction on serum amyloid A in severe acute pancreatitis patients.Asian Pac J Trop Med 2012;5(11):901-905.
7 Williams JA.Receptor-mediated signal transduction pathways and the regulation of pancreatic acinar cell function.Curr Opin Gastroenterol 2008;24(5):573-579.
8 Guo J,Jin T,Lin ZQ,et al.Effect of Chaiqin Chengqi decoction on cholecystokinin receptor 1-mediated signal transduction of pancreatic acinar cells in acute necrotizing pancreatitis rats.Chin J Integr Med 2015;21(1):29-35.
9 Migita K,Izumi Y,Torigoshi T,et al.Inhibition of Janus kinase/signal transducer and activator of transcription(JAK/STAT)signalling pathway in rheumatoid synovial fibroblasts using small molecule compounds.Clin Exp Immunol 2013;174(3):356-363.
10 Arbouzova NI,Zeidler MP.JAK/STAT signalling in Drosophila:insights into conserved regulatory and cellular functions.Development 2006;133(14):2605-2616.
11 Springuel L,Renauld JC,Knoops L.JAK kinase targeting in hematologic malignancies:a sinuous pathway from identification of genetic alterations towards clinical indications.Haematologica 2015;100(10):1240-1253.
12 Sweeney SE,Firestein GS.Signal transduction in rheumatoidarthritis.Curr OpinRheumatol2004;16(3):231-237.
13 Zhang W,Chen PL,Du L,Wang FY,Qi C.Recent progress in the the study on structure and its function of JAK2.Natural Science Journal of HAINAN University 2009;27(1):87-90.
14 Liongue C,Taznin T,Ward AC.Signaling via the CytoR/JAK/STAT/SOCS pathway:Emergence during evolution.Mol Immunol 2016;71:166-175.
15 Tao Z,Cheng M,Wang SC,et al.JAK2/STAT3 pathway mediating inflammatory responses in heatstroke-induced rats.Int J Clin Exp Pathol 2015;8(6):6732-6739.
16 Ward AC,Touw I,Yoshimura A.The Jak-Stat pathway in normal and perturbed hematopoiesis.Blood 2000;95(1):19-29.
17 Bopaiah P.Cheppudir A,Thomas H,et al.Clifford,Anti-hyperalgesic effects of AG490,a Janus kinase inhibitor,in a rat model of inflammatory pain.Biomedical Reports2015;(3):703-706.
18 Hu X,Lu H,Deng YL,Wan Q,Yie SM.Effect of rat medicated serum containing Zuo Gui Wan and/or You Gui Wan on the differentiation of stem cells derived from human first trimester umbilical cord into oocyte-like cells in vitro.Evid Based Complement Alternat Med 2015;2015:825805.
19 Wu W,Luo R,Lin Z,Xia Q,Xue P.Key Molecular Mechanisms of Chaiqinchengqi decoction in alleviating the pulmonary albumin leakage caused by endotoxemia in severe acute pancreatitis rats.Evid Based Complement Alternat Med 2016;2016:3265368.
20 Deng LH,Yang XN,Xia Q.Protective effects of Chaiqin Chengqi decoction on isolated pancreatic acinar cells in acute pancreatitis rats and the mechanisms.Zhong Xi Yi Jie He Xue Bao 2008;6(2):176-179.
21 Choi SB,Bae GS,Jo IJ,Wang S,Song HJ,Park SJ.Berberine inhibits inflammatory mediators and attenuates acute pancreatitis through deactivation of JNK signaling pathways.Mol Immunol 2016;74:27-38.
22 Yubero S,Manso MA,Ramudo L,Vicente S,De Dios I.Dexamethasone down-regulates the inflammatory mediators but fails to reduce the tissue injury in the lung of acute pancreatitis rat models.Pulm Pharmacol Ther 2012;25(4):319-324.
23 Ren SJ,Zeng XW,Fu JD.Effect of AG490 on brain edema and inflammatory response after ischemic brain injury of rats.Acta Acad Med Weifang 2013;35(5):334-337.
24 Zhang XP,Tian H,Lai YH,et al.Protective effects and mechanisms of Baicalin and octreotide on renal injury of rats with severe acute pancreatitis.World J Gastroenterol2007;13(38):5079-5089.
25 Du C,Niu R,Chu E,Zhang P,Lin X.Sequence analysis and functional study of thymidylate synthase from zebrafish,Danio rerio.J Biochem 2006;139(5):913-920.
26 Rau B,Uhl W,Buchler MW,Beger HG.Surgical treatment of infected necrosis.World J Surg 1997;21(2):155-161.
27 Liu XB,Jiang JM,Huang ZW,et al.Clinical study on the treatment of severe acute pancreatitis by integrated Traditional Chinese Medicine and Western Medicine.Sichuan Da Xue Xue Bao Yi Xue Ban 2004;35(2):204-208.
28 Souza LJ,Coelho AM,Sampietre SN,Martins JO,Cunha JE,Machado MC.Anti-inflammatory effects of peritoneal lavage in acute pancreatitis.Pancreas 2010;39(8):1180-1184.
29 Browne GW,Pitchumoni CS.Pathophysiology of pulmonary complications of acute pancreatitis.World J Gastroenterol 2006;12(44):7087-7096.
30 Nakamura Y,Franchi L,Kambe N,Meng G,Strober W,Nunez G.Critical role for mast cells in interleukin-1beta-driven skin inflammation associated with an activating mutation in the nlrp3 protein.Immunity 2012;37(1):85-95.
31 Papachristou GI.Prediction of severe acute pancreatitis:current knowledge and novel insights.World J Gastroenterol 2008;14(41):6273-6275.
32 Kettritz R,Choi M,Rolle S,Wellner M,Luft FC.Integrins and cytokines activate nuclear transcription factor-kappaB in human neutrophils.J Biol Chem 2004;279(4):2657-2665.
33 Boutros T,Chevet E,Metrakos P.Mitogen-activated protein(MAP)kinase/MAP kinase phosphatase regulation:roles in cell growth,death,and cancer.Pharmacol Rev2008;60(3):261-310.
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