花姜酮通过NF-κB保护重症急性胰腺炎大鼠胰腺损伤
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摘要
目的探讨花姜酮对重症急性胰腺炎大鼠胰腺损伤可能的保护作用,为重症急性胰腺炎防治提供理论依据。方法 70只Wistar大鼠,雄性,按照随机数字表法随机分为4组,即正常对照组(NC组,n=10)、重症急性胰腺炎组(SAP组,n=40)、花姜酮预处理组(ZER组,n=10)及花姜酮药物对照组(ZER-CON组,n=10),SAP组又分为建模后1、3、6及12 h 4个时间点组(n=10)。SAP组及ZER组大鼠采用胆胰管逆行注射5%硫磺胆酸钠溶液(0.1 m L/100 g)制备SAP模型,NC组及ZER-CON组则向胆胰管注入等量生理盐水。ZER组及ZER-CON组于模型制备前30 min由股静脉穿刺给予10 mg/kg的花姜酮溶液。NC组、ZER组及ZER-CON组于建模后12 h处死大鼠,SAP组分别于建模后1、3、6及12 h处死大鼠。分别观察各组大鼠的死亡情况,测定其腹水量、血清淀粉酶(AMY)和磷脂酶A2水平;光镜下观察胰腺组织的病理学改变;采用免疫组化法检测各组大鼠胰腺组织中核因子-κB(Nuclear Factor-kappa B,NF-κB)p65的表达。结果 ZER-CON组大鼠的死亡情况、腹水量、AMY及磷脂酶A2水平和胰腺组织的病理学评分以及NF-κB p65蛋白表达与NC组相近,其差异均无统计学意义(P>0.05);SAP组上述指标均明显高于NC组(P<0.05)。ZER组组大鼠的上述指标与SAP组相比明显降低(P<0.05),但均高于NC组(P<0.05)。结论应用花姜酮可以减少SAP大鼠的死亡,减少腹水量,减轻胰酶及胰腺病理学损伤,同时可降低胰腺NF-κB p65蛋白的表达。提示花姜酮可能通过核因子NF-κB途径对SAP大鼠胰腺起保护作用。
Objective To investigate the possible protective effect of zerumbone on pancreatic injury in severe acute pancreatitis(SAP) rats,and to provide a theoretical basis for prevention and treatmen of severe acute pancreatitis.Methods Seventy male Wistar rats were randomly divided into four groups:normal control group(NC group,n=10),SAP group(n=40),Zerumbone pretreatment group(ZER group,n=10),and Zerumbone drug control group(ZERCON group,n=10).Rats of SAP group were divided into four time points of 1 h,3 h,6 h,and 12 h(n=10 each time point).SAP models were induced by retrograde injection of 5%sodium taurocholate(0.1 mL/100 g) in biliopancreatic duct in SAP group and ZER group.Rats were injected isotonic saline solution instead of taurocholate as a control in NC group and ZER-CON group.Zerumbone solution(10 mg/kg) was administered via femoral vein half an hour prior to establishing models in ZER group and ZER-CON group.All rats except SAP group were sacrificed at 12 h time point after the induction of SAP.The rats in SAP group were sacrificed at 1 h,1 h,3 h,6 h and 12 h time point after induction of SAP.The mortality,ascites,serum amylase(AMY),phospholipase,and pathological examination of pancreas were observated or detected.The expression of nuclear factor-kappa B(NF-κB) p65 in pancreatic tissues was evaluated by immunohistochemistry assay.Results There were no difference of the levels of mortality,ascites,serum AMY,phospholipase,pathological examination,and NF-κB p65 location expression of pancreas between the ZER-CON group and NC group(P>0.05).The above indexes in SAP group were significantly higher than those in NC group(P<0.05).However,those in ZER group were significantly lower than in SAP group(P<0.05),and higher than in NC group(P<0.05).Conclusions Zerumbone can reduce the mortality and ascites,effectively alleviate the enzyme,pathological injury,and NF-κB p65 location expression in pancreatic tissue following SAP.It may indicate that zerumbone can protect pancreatic injury in SAP via NF-κB pathway.
Objective To investigate the possible protective effect of zerumbone on pancreatic injury in severe acute pancreatitis(SAP) rats,and to provide a theoretical basis for prevention and treatmen of severe acute pancreatitis.Methods Seventy male Wistar rats were randomly divided into four groups:normal control group(NC group,n=10),SAP group(n=40),Zerumbone pretreatment group(ZER group,n=10),and Zerumbone drug control group(ZERCON group,n=10).Rats of SAP group were divided into four time points of 1 h,3 h,6 h,and 12 h(n=10 each time point).SAP models were induced by retrograde injection of 5%sodium taurocholate(0.1 mL/100 g) in biliopancreatic duct in SAP group and ZER group.Rats were injected isotonic saline solution instead of taurocholate as a control in NC group and ZER-CON group.Zerumbone solution(10 mg/kg) was administered via femoral vein half an hour prior to establishing models in ZER group and ZER-CON group.All rats except SAP group were sacrificed at 12 h time point after the induction of SAP.The rats in SAP group were sacrificed at 1 h,1 h,3 h,6 h and 12 h time point after induction of SAP.The mortality,ascites,serum amylase(AMY),phospholipase,and pathological examination of pancreas were observated or detected.The expression of nuclear factor-kappa B(NF-κB) p65 in pancreatic tissues was evaluated by immunohistochemistry assay.Results There were no difference of the levels of mortality,ascites,serum AMY,phospholipase,pathological examination,and NF-κB p65 location expression of pancreas between the ZER-CON group and NC group(P>0.05).The above indexes in SAP group were significantly higher than those in NC group(P<0.05).However,those in ZER group were significantly lower than in SAP group(P<0.05),and higher than in NC group(P<0.05).Conclusions Zerumbone can reduce the mortality and ascites,effectively alleviate the enzyme,pathological injury,and NF-κB p65 location expression in pancreatic tissue following SAP.It may indicate that zerumbone can protect pancreatic injury in SAP via NF-κB pathway.
引文
1 GrangerJ,Remick D.Acute pancreatitis:models,markers,and mediators.Shock,2005,24 Suppl 1:45-51.
2殷涛,王春友.重症急性胰腺炎多学科综合治疗的重点和难点.中华普通外科杂志,2015,30(1):1-3.
3 Sulaiman MR,Perimal EK,Akhtar MN,et al.Anti-inflammatory effect of zerumbone on acute and chronic inflammation models in mice.Fitoterapia,2010,81(7):855-858.
4 Chien TY,Chen LG,Lee CJ,et al.Anti-inflammatory constituents of Zingiber zerumbet.Food Chemistry,2008,110(3):584-589.
5 Chan ML,Liang JW,Hsu LC,et al.Zerumbone,a ginger sesquiterpene,induces apoptosis and autophagy in human hormone-refractory prostate cancers through tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult.Naunyn Schmiedebergs Arch Pharmacol,2015,388(11):1223-1236.
6李金友,王卫星,邓文宏,等.不同剂量花姜酮对大鼠重症急性胰腺炎的影响.微循环学杂志,2010,20(3):14-15.
7 Schmidt J,Rattner DW,Lewandrowski K,et al.A better model of acute pancreatitis for evaluating therapy.Ann Surg,1992,215(1):44-56.
8 Banks PA,Bollen TL,Dervenis C,et al.Classification of acute pancreatitis—2012:revision of the Atlanta classification and definitions by international consensus.Gut,2013,62(1):102-111.
9陈宏,孙家邦,朱研,等.重症急性胰腺炎早期液体治疗策略的探讨.中国普外基础与临床杂志,2012,19(5):507-511.
10姚欣敏,张抒,李云涛,等.不同时期重症急性胰腺炎治疗的对照研究.中国普外基础与临床杂志,2011,18(3):245-249.
11叶健,莫显斌.CT分级诊断在急性胰腺炎临床治疗中的价值.中国普外基础与临床杂志,2010,17(12):1322-1325.
12吴丽,蔡宝昌.重症急性胰腺炎肝损伤机制及中医药治疗的研究进展.南京中医药大学学报,2013,29(4):393-396.
13钟健,刘丽,刘大晟,等.桃核承气汤对重症急性胰腺炎模型大鼠炎症因子的调控作用及机制.中国老年学杂志,2015,35(12):3223-3226.
14 Kitayama T,Okamoto T,Hill RK,et al.Chemistry of zerumbone.1.Simplified isolation,conjugate addition reactions,and a unique ring contracting transannular reaction of its dibromide.J Org Chem,1999,64(8):2667-2672.
15 Shanmugam MK,Rajendran P,Li F,et al.Abrogation of STAT3signaling cascade by zerumbone inhibits proliferation and induces apoptosis in renal cell carcinoma xenograft mouse model.Mol Carcinog,2015,54(10):971-985.
16 Shieh YH,Huang HM,Wang CC,et al.Zerumbone enhances the Th1 response and ameliorates ovalbumin-induced Th2 responses and airway inflammation in mice.Int Immunopharmacol,2015,24(2):383-391.
17 Wang CY,Zou SB,Cui ZJ,et al.Zerumbone protects INS-1 rat pancreatic beta cells from high glucose-induced apoptosis through generation of reactive oxygen species.Biochem Biophys Res Commun,2015,460(2):205-209.
18 Murakami A,Hayashi R,Tanaka T,et al.Suppression of dextran sodium sulfate-induced colitis in mice by zerumbone,a subtropical ginger sesquiterpene,and nimesulide:separately and in combination.Biochem Pharmacol,2003,66(7):1253-1261.
19 Murakami A,Ohigashi H.Targeting NOX,INOS and COX-2 in inflammatory cells:chemoprevention using food phytochemicals.Int J Cancer,2007,121(11):2357-2363.
20 Murakami A,Takahashi D,Kinoshita T,et al.Zerumbone,a Southeast Asian ginger sesquiterpene,markedly suppresses free radical generation,proinflammatory protein production,and cancer cell proliferation accompanied by apoptosis:the alpha,betaunsaturated carbonyl group is a prerequisite.Carcinogenesis,2002,23(5):795-802.
21 Telek G,Ducroc R,Scoazec JY,et al.Differential upregulation of cellular adhesion molecules at the sites of oxidative stress in experimental acute pancreatitis.J Surg Res,2001,96(1):56-67.
22 Chen X,Ji B,Han B,et al.NF-kappaB activation in pancreas induces pancreatic and systemic inflammatory response.Gastroenterology,2002,122(2):448-457.
23 Ding J,Song D,Ye X,et al.A pivotal role of endothelial-specific NF-kappaB signaling in the pathogenesis of septic shock and septic vascular dysfunction.J Immunol,2009,183(6):4031-4038.
24郑邦瑞,沈文律,文军,等.丹参注射液对重症急性胰腺炎大鼠胰腺NF-κB活化的影响.中国普外基础与临床杂志,2007,14(4):392-395.
25 Manavalan B,Basith S,Choi YM,et al.Structure-function relationship of cytoplasmic and nuclear IκB proteins:an in silico analysis.PLoS One,2010,5(12):el5782.
26 Murakami A,Matsumoto K,Koshimizu K,et al.,Effects of selected food factors with chemopreventive properties on combined lipopolysaccharide-and interferon-gamma-induced I kappa B degradation in RAW264.7 macrophages.Cancer Lett,2003,195(1):17-25.
27 Sung B,Murakami A,Oyajobi BO,et al.Zerumbone abolishes RANKL-induced NF-kappaB activation,inhibits osteoclastogenesis,and suppresses human breast cancer-induced bone loss in athymic nude mice.Cancer Res,2009,69(4):1477-1484.
28 Takada Y,Murakami A,Aggarwal BB.Zerumbone abolishes NFkappa B and I kappa B alpha kinase activation leading to suppression of antiapoptotic and metastatic gene expression,upregulation of apoptosis,and downregulation of invasion.Oncogene,2005,24(46):6957-6969.
29 Aggarwal BB,Kunnumakkara AB,Harikumar KB,et al.Potential of spice-derived phytochemicals for cancer prevention.Planta Med,2008,74(13):1560-1569.
2殷涛,王春友.重症急性胰腺炎多学科综合治疗的重点和难点.中华普通外科杂志,2015,30(1):1-3.
3 Sulaiman MR,Perimal EK,Akhtar MN,et al.Anti-inflammatory effect of zerumbone on acute and chronic inflammation models in mice.Fitoterapia,2010,81(7):855-858.
4 Chien TY,Chen LG,Lee CJ,et al.Anti-inflammatory constituents of Zingiber zerumbet.Food Chemistry,2008,110(3):584-589.
5 Chan ML,Liang JW,Hsu LC,et al.Zerumbone,a ginger sesquiterpene,induces apoptosis and autophagy in human hormone-refractory prostate cancers through tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult.Naunyn Schmiedebergs Arch Pharmacol,2015,388(11):1223-1236.
6李金友,王卫星,邓文宏,等.不同剂量花姜酮对大鼠重症急性胰腺炎的影响.微循环学杂志,2010,20(3):14-15.
7 Schmidt J,Rattner DW,Lewandrowski K,et al.A better model of acute pancreatitis for evaluating therapy.Ann Surg,1992,215(1):44-56.
8 Banks PA,Bollen TL,Dervenis C,et al.Classification of acute pancreatitis—2012:revision of the Atlanta classification and definitions by international consensus.Gut,2013,62(1):102-111.
9陈宏,孙家邦,朱研,等.重症急性胰腺炎早期液体治疗策略的探讨.中国普外基础与临床杂志,2012,19(5):507-511.
10姚欣敏,张抒,李云涛,等.不同时期重症急性胰腺炎治疗的对照研究.中国普外基础与临床杂志,2011,18(3):245-249.
11叶健,莫显斌.CT分级诊断在急性胰腺炎临床治疗中的价值.中国普外基础与临床杂志,2010,17(12):1322-1325.
12吴丽,蔡宝昌.重症急性胰腺炎肝损伤机制及中医药治疗的研究进展.南京中医药大学学报,2013,29(4):393-396.
13钟健,刘丽,刘大晟,等.桃核承气汤对重症急性胰腺炎模型大鼠炎症因子的调控作用及机制.中国老年学杂志,2015,35(12):3223-3226.
14 Kitayama T,Okamoto T,Hill RK,et al.Chemistry of zerumbone.1.Simplified isolation,conjugate addition reactions,and a unique ring contracting transannular reaction of its dibromide.J Org Chem,1999,64(8):2667-2672.
15 Shanmugam MK,Rajendran P,Li F,et al.Abrogation of STAT3signaling cascade by zerumbone inhibits proliferation and induces apoptosis in renal cell carcinoma xenograft mouse model.Mol Carcinog,2015,54(10):971-985.
16 Shieh YH,Huang HM,Wang CC,et al.Zerumbone enhances the Th1 response and ameliorates ovalbumin-induced Th2 responses and airway inflammation in mice.Int Immunopharmacol,2015,24(2):383-391.
17 Wang CY,Zou SB,Cui ZJ,et al.Zerumbone protects INS-1 rat pancreatic beta cells from high glucose-induced apoptosis through generation of reactive oxygen species.Biochem Biophys Res Commun,2015,460(2):205-209.
18 Murakami A,Hayashi R,Tanaka T,et al.Suppression of dextran sodium sulfate-induced colitis in mice by zerumbone,a subtropical ginger sesquiterpene,and nimesulide:separately and in combination.Biochem Pharmacol,2003,66(7):1253-1261.
19 Murakami A,Ohigashi H.Targeting NOX,INOS and COX-2 in inflammatory cells:chemoprevention using food phytochemicals.Int J Cancer,2007,121(11):2357-2363.
20 Murakami A,Takahashi D,Kinoshita T,et al.Zerumbone,a Southeast Asian ginger sesquiterpene,markedly suppresses free radical generation,proinflammatory protein production,and cancer cell proliferation accompanied by apoptosis:the alpha,betaunsaturated carbonyl group is a prerequisite.Carcinogenesis,2002,23(5):795-802.
21 Telek G,Ducroc R,Scoazec JY,et al.Differential upregulation of cellular adhesion molecules at the sites of oxidative stress in experimental acute pancreatitis.J Surg Res,2001,96(1):56-67.
22 Chen X,Ji B,Han B,et al.NF-kappaB activation in pancreas induces pancreatic and systemic inflammatory response.Gastroenterology,2002,122(2):448-457.
23 Ding J,Song D,Ye X,et al.A pivotal role of endothelial-specific NF-kappaB signaling in the pathogenesis of septic shock and septic vascular dysfunction.J Immunol,2009,183(6):4031-4038.
24郑邦瑞,沈文律,文军,等.丹参注射液对重症急性胰腺炎大鼠胰腺NF-κB活化的影响.中国普外基础与临床杂志,2007,14(4):392-395.
25 Manavalan B,Basith S,Choi YM,et al.Structure-function relationship of cytoplasmic and nuclear IκB proteins:an in silico analysis.PLoS One,2010,5(12):el5782.
26 Murakami A,Matsumoto K,Koshimizu K,et al.,Effects of selected food factors with chemopreventive properties on combined lipopolysaccharide-and interferon-gamma-induced I kappa B degradation in RAW264.7 macrophages.Cancer Lett,2003,195(1):17-25.
27 Sung B,Murakami A,Oyajobi BO,et al.Zerumbone abolishes RANKL-induced NF-kappaB activation,inhibits osteoclastogenesis,and suppresses human breast cancer-induced bone loss in athymic nude mice.Cancer Res,2009,69(4):1477-1484.
28 Takada Y,Murakami A,Aggarwal BB.Zerumbone abolishes NFkappa B and I kappa B alpha kinase activation leading to suppression of antiapoptotic and metastatic gene expression,upregulation of apoptosis,and downregulation of invasion.Oncogene,2005,24(46):6957-6969.
29 Aggarwal BB,Kunnumakkara AB,Harikumar KB,et al.Potential of spice-derived phytochemicals for cancer prevention.Planta Med,2008,74(13):1560-1569.
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