BRD对乙酸诱发胃溃疡大鼠治疗作用的实验研究
摘要
本实验以首次合成的正丁胺基罗沙替丁乙酸酯(Butylamine Roxatidine derivate,BRD)为研究对象,采用免疫组化技术检测和观察对乙酸烧灼型胃溃疡大鼠溃疡边缘粘膜细胞凋亡及凋亡抑制基因Bcl-2蛋白表达的影响,采用生化技术检测胃溃疡大鼠血清及胃组织中的超氧化物歧化酶(superoxide dismutase,SOD)和丙二醛(malondialdehyde,MDA)的含量。结果显示,BRD能够增加凋亡抑制基因Bcl-2蛋白表达,减少溃疡边缘粘膜细胞凋亡,凋亡指数明显下降,其中28mg/kg和14mg/kg组与模型组比较差异显著(P<0.01);BRD能够提高血清及胃组织中SOD活性,降低MDA含量(与模型组相比P<0.05-0.01)。结果表明,BRD可以通过抑制溃疡边缘粘膜细胞凋亡来促进溃疡愈合,其上调Bcl-2蛋白表达,可能是其抑制溃疡边缘粘膜细胞凋亡的机制之一;BRD可以降低胃粘膜损伤因子MDA含量,促进胃粘膜保护因子SOD合成与释放,从而增强胃粘膜防御能力,对胃溃疡粘膜有保护和治疗作用。
Objective:
The chemical formular of BRD is C18H29N3O2,which is a new Roxatidine derivate(The chemical formular is C17H26N2O3) from the revised and modified Acetid Roxatiding.It is a new H2-recepton imtagonist that first combined by us in the world and reported by CA.Test shows the compound has comparaci linger lipid solubility and stronger imtiacid effect compared with RD.The related researches on pharmcological action and it is system has not been reported at home on abroad. Apoptosis plays an important control role in the recovery of the ulcer through the system research on the pharmacological effect and it is system of the new compound ,we want to find its pharmcological action and the molecular action system against gastric ulcer.The research of the project may fill the blank of how BRD defense gastric ulcer both in and outside China,and provide valuable research proof for exploiting new and effective H2-receptor antagonist.
Method:
1. Divide the animals into groups and prepare a acetic acid injured A-rat model.
2. Observe the change of behavion and the ulcer morphology afare A-rat affer given medicine.
3. Measure the SOD dose in the serum and gastric tissue of A-rat though Biochemical method.
4. Measure the dose of MDA in the serum and gastric tissue of A-rat though Biochemical method.
5. Measure the apoptosis of the ulcer mucosa cell though TUNEL method.
6. Measure the protein expression of apoptosis inhibiting gene Bcl-2 though immunity combination and chemical method.
Result:
1.BRD promotes the recovery of the ulcered rat,improve its symptoms of tireness,languidness and hypersomnia,alleviates its histological and pathological injury.
2.The dose messuremert of SOD and MDA in the rat’s serum and gastric tissue shows,large and small close of BRD both promote the SOD in its serum and gastric tissue,bring down the MDA,and depend on the dose,P<0.01-0.05 compared with the control group.
3.The protein expression measure of the apoptosis inhibiting gene Bcl-2 shows BRD could inhibit the aptosis of the gastric mucosa cell and decrease AI,P<0.01-0.05compared with control group.BRD promotes Bcl-2 increase of the mucosa cell;as a result,over-apoptosis is inhibited and mucosa injury is alleviated.
Discussion:
It has proved that the loss of gastric mucosa epithelium was mainly through apoptosis instead of amotic and the integration of gastric mucosa depends on the balance between cell multiple and cell loss. Grastric ulcer is mainly related to the defensive factors and injure factors of the gastric mucosa.Loss of gastric mucosa epithelium is mainly throuph apoptosis.The experiment proves that BRD promotes protein expression,inhibit apoptosis of the gastric mucosa cell,decrease ulcer index and accelerate ulcer recovery.
Radical are toxic product by the organism and injury the servers,It could indute lipid peroxidation effect and produce lipid peroxidation,of with MDA is the most toxious.SOD and MDA could indirectly reflect radical metabolism level.The test shows,BRD could promote SOD level , decrease MDA level , so radicals eliminated,surplus superoxide anions which couse the injury of mucosa reduced,all these suggest that the medicine would improve the ability of antioxidation and eliminating radicals,inhibiting lipid peroxidation anf improving radical metabolism.
The tset proves that BRD could promote the recovery of the rat’s gastric ulcer mucosa induced by aceric acid and effectively prevent the incidence and development of gastric ulcer.All these results proviod reliable test basis for treating peptic ulcer.
Conclusion:
BRD could promote the recvery of the rat’s gastric ulcer,improve the rat’s tireness,languidness,hypersomnia symptoms,alleviate its histological and pathological injury the rat’s gastric ulcer mucosa.Promote SOD and decease MDA in the rat’s serum and gastric tissue,inhibit apoptosis of the mucosa cell,strengthen the Bcl-2 expression of its mucosa cell.As a result,it inhibit the over-apoptosis of the cell,alleviate the gastric mucosa injury and actively prevented the incidence of getting ulcer or being developed.
Objective:
The chemical formular of BRD is C18H29N3O2,which is a new Roxatidine derivate(The chemical formular is C17H26N2O3) from the revised and modified Acetid Roxatiding.It is a new H2-recepton imtagonist that first combined by us in the world and reported by CA.Test shows the compound has comparaci linger lipid solubility and stronger imtiacid effect compared with RD.The related researches on pharmcological action and it is system has not been reported at home on abroad. Apoptosis plays an important control role in the recovery of the ulcer through the system research on the pharmacological effect and it is system of the new compound ,we want to find its pharmcological action and the molecular action system against gastric ulcer.The research of the project may fill the blank of how BRD defense gastric ulcer both in and outside China,and provide valuable research proof for exploiting new and effective H2-receptor antagonist.
Method:
1. Divide the animals into groups and prepare a acetic acid injured A-rat model.
2. Observe the change of behavion and the ulcer morphology afare A-rat affer given medicine.
3. Measure the SOD dose in the serum and gastric tissue of A-rat though Biochemical method.
4. Measure the dose of MDA in the serum and gastric tissue of A-rat though Biochemical method.
5. Measure the apoptosis of the ulcer mucosa cell though TUNEL method.
6. Measure the protein expression of apoptosis inhibiting gene Bcl-2 though immunity combination and chemical method.
Result:
1.BRD promotes the recovery of the ulcered rat,improve its symptoms of tireness,languidness and hypersomnia,alleviates its histological and pathological injury.
2.The dose messuremert of SOD and MDA in the rat’s serum and gastric tissue shows,large and small close of BRD both promote the SOD in its serum and gastric tissue,bring down the MDA,and depend on the dose,P<0.01-0.05 compared with the control group.
3.The protein expression measure of the apoptosis inhibiting gene Bcl-2 shows BRD could inhibit the aptosis of the gastric mucosa cell and decrease AI,P<0.01-0.05compared with control group.BRD promotes Bcl-2 increase of the mucosa cell;as a result,over-apoptosis is inhibited and mucosa injury is alleviated.
Discussion:
It has proved that the loss of gastric mucosa epithelium was mainly through apoptosis instead of amotic and the integration of gastric mucosa depends on the balance between cell multiple and cell loss. Grastric ulcer is mainly related to the defensive factors and injure factors of the gastric mucosa.Loss of gastric mucosa epithelium is mainly throuph apoptosis.The experiment proves that BRD promotes protein expression,inhibit apoptosis of the gastric mucosa cell,decrease ulcer index and accelerate ulcer recovery.
Radical are toxic product by the organism and injury the servers,It could indute lipid peroxidation effect and produce lipid peroxidation,of with MDA is the most toxious.SOD and MDA could indirectly reflect radical metabolism level.The test shows,BRD could promote SOD level , decrease MDA level , so radicals eliminated,surplus superoxide anions which couse the injury of mucosa reduced,all these suggest that the medicine would improve the ability of antioxidation and eliminating radicals,inhibiting lipid peroxidation anf improving radical metabolism.
The tset proves that BRD could promote the recovery of the rat’s gastric ulcer mucosa induced by aceric acid and effectively prevent the incidence and development of gastric ulcer.All these results proviod reliable test basis for treating peptic ulcer.
Conclusion:
BRD could promote the recvery of the rat’s gastric ulcer,improve the rat’s tireness,languidness,hypersomnia symptoms,alleviate its histological and pathological injury the rat’s gastric ulcer mucosa.Promote SOD and decease MDA in the rat’s serum and gastric tissue,inhibit apoptosis of the mucosa cell,strengthen the Bcl-2 expression of its mucosa cell.As a result,it inhibit the over-apoptosis of the cell,alleviate the gastric mucosa injury and actively prevented the incidence of getting ulcer or being developed.
引文
[1] 叶任高,陆再英.内科学.北京:人民卫生出版社,第 6 版,2006:384-392.
[2] 王国村 .乙 酰 罗 沙 替 丁 的 药 动学,药效学和疗效 .中国新药杂志,1994,3(2):17-18.
[3] 张辉,赵冬梅,程卯生,等 .苯氧丙胺类化合物的合成与抑酸活性的研究.中国新药杂志,2005,14(3):316-319.
[4] 邱世犹,陈文力.消化性溃疡药物治疗进展.中国医院用药评价与分析2002,2(3):177-178.
[5] Guisset M,Coton T,Rey P,et al. Helicobacter pylori infection in developing countries.Med Trop Mars,1997,57(1):77-82.
[6] watanabe K,Tanaka A,Lmase K,et al.Amoxicilin Resistance in Helicobacter pylori:Studies from Tokyo , Japan from 1985 to 2003.Helicobacter,2005,10:4-10.
[7] Kerr JFR,Wyllie AH,Currie AR.Apoptosis:a basic biological phenomenon with wide ranging implications in tissue kinetics[J]. Br J Cancer.1972,26:239-257.
[8] 刘陶文. Fas/FasL 调控细胞凋亡途径与血液恶性肿瘤.华夏医学,2007,13(4):554-555.
[9] Houghton J,Korah RM,Condon MR,et al.Apoptosis in Helicobacter pylori associated gastric and duodenal ulcer disease is mediated via the Fas antigen pathway. Dig Dis Sci,1999,44:465-478.
[10] Slomiany BL,Piotrowski J,Slomiany A.Role of interleuki-4 in down regulation of endothelin-1 during gastric ulcer healing :effect of sucralfate. J Physiol Pharmacol,2000,3,51:69-83.
[11] 李奎,刘英,康相涛,等.主要凋亡基因对细胞凋亡的调控.解剖科学进展,2007,13(l):62-65.
[12] Tsujimoto Y,Cesaeran J ,Jaffe E ,et al. Involvement of bcl-2 gene in human follicular lymphoma[J].Science,1985,228(4706) :1440-1443.
[13] Kane DJ,Sarafian TA, Anton R,et al.BCL-2 inhibition of neural death:decreased generation of reactive oxygen species.Science, 1993, 262(5137): 1274～1277.
[14] 张敏燕,张正民,韩仲明,等.凋亡调控基因 Bcl-2、Bax 与肿瘤.国外医学耳鼻咽喉科学分册,2004,28(1):40-42.
[15] 刘陶文.凋亡调控基因Bcl-2 家族研究的新进展.生物化学和生物物理学研究进展,1999,26(3):29-31.
[16] Baffy G, Miyashita T,Williamson J R,et al.Apoptosis induced by withdrawal of interleukin-3(IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production. J Biol Chem, 1993, 268(9): 6511～6519.
[17] Barros MH,Netto ES,Kowultowski A.H2O2 generation in saccharomyces cerevisiae respiratory pet mutants:effect of cytochrome C.Biol Med,2003,35(2):179-188.
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[19] Burger MM,Harris C.UICCS tudy Group on basic and clinical cancer research:apoptosis in normal and tumor cells.Int J Cancer , 1995 ,60:590-592.
[20] 姚峰,陶林,陈倩,等.凋亡抑制基因 Survivin 在非小细胞肺癌中的表达及其与 Caspase-3、Bcl-2 蛋白表达的关系.中国癌症杂志,2004,14(2):109-112.
[21] 曹银芳,关泽红,于晓鸿,等.凋亡抑制基因 Bcl-2 在肿瘤中的应用研究进展.内蒙古医学杂志,2007,39(8):961-963.
[22] Fenney DM,Boyseson MG,Linn RT,et a1.Responses to cortical injury:Methodo1ogy and local efects of contusions in the rat[J].Brain Res,1981(211) :67-77.
[23] Hua R,Wa1z W.Minocycline treatment prevents cavitation in rats after a cortical devascu1arizing lesion.Brain Res,2006,23:172-181.
[24] 谢萍.自由基与细胞凋亡.生物学教学,2004,29(l):3-4.
[25] 曹淑华,查向东.超氧化物歧化酶研究综述. 安徽农业科学,2003,31(4):599-601.
[26] 钱淑英,夏兆雄,许建芬.恶性肿瘤患者血一氧化氮、内皮素和超氧化物歧化酶的变化.肿瘤学杂志,2001,7(5):270-271.
[27] 黄俊,罗和生,李颖,等. 大鼠实验性溃疡性结肠炎中 NO、MDA、SOD的变化.医学文选,2001,20(6):757-759.
[28] 叶盛英,王世岭.表皮生长因子在消化性溃疡应用方面研究进展. 中国医院药学杂志,2002,22(10) :622-625.
[29] 陈怡,朱长清等.罗沙替丁治疗消化性溃疡或急性胃粘膜病变引起上消化道出血的临床研究.中国全科医学,2007,(18):1511-1513.
[30] Piotrowiski J,Yamaki K,Morita M,et al.Ebrotidine-a new H2-receptor antagonist with mucosal strengthening activity.Biochem Int,1992,26(1) :659-667.
[31] Konturek PC , Brzozowski T , Konturek SI , et al. Studies on the cytoprotective and antisecretory activity of ebrotidine,a review.Arzneimittelforschung,1997,47(4A) :578-583.
[32] Palacin C , Tarrago C.In vitro anti-Helicobacter pylori activity of ebrotidine.Arzneimittelforschung,1997,47(4A) :471-476.
[33] Sanjny S,Michelle IW.Ebrotidine.Drugs,1996,51(6) :974-979.
[34] 穆殿平,高仲阳,徐为人,等.H2受体拮抗剂在消化性溃疡治疗中的作用. 天津药学,1998,10(1):19-23.
[35] 张静,于爱莲,张树榕,等. 消化性溃疡治疗进展之一—药物治疗进展与评价.医学综述,1995,1(5):219-223.
[36] 何饮军.H2受体拮抗剂的不良反应.医学情报通讯,1993,11(2):39-40.
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[2] 王国村 .乙 酰 罗 沙 替 丁 的 药 动学,药效学和疗效 .中国新药杂志,1994,3(2):17-18.
[3] 张辉,赵冬梅,程卯生,等 .苯氧丙胺类化合物的合成与抑酸活性的研究.中国新药杂志,2005,14(3):316-319.
[4] 邱世犹,陈文力.消化性溃疡药物治疗进展.中国医院用药评价与分析2002,2(3):177-178.
[5] Guisset M,Coton T,Rey P,et al. Helicobacter pylori infection in developing countries.Med Trop Mars,1997,57(1):77-82.
[6] watanabe K,Tanaka A,Lmase K,et al.Amoxicilin Resistance in Helicobacter pylori:Studies from Tokyo , Japan from 1985 to 2003.Helicobacter,2005,10:4-10.
[7] Kerr JFR,Wyllie AH,Currie AR.Apoptosis:a basic biological phenomenon with wide ranging implications in tissue kinetics[J]. Br J Cancer.1972,26:239-257.
[8] 刘陶文. Fas/FasL 调控细胞凋亡途径与血液恶性肿瘤.华夏医学,2007,13(4):554-555.
[9] Houghton J,Korah RM,Condon MR,et al.Apoptosis in Helicobacter pylori associated gastric and duodenal ulcer disease is mediated via the Fas antigen pathway. Dig Dis Sci,1999,44:465-478.
[10] Slomiany BL,Piotrowski J,Slomiany A.Role of interleuki-4 in down regulation of endothelin-1 during gastric ulcer healing :effect of sucralfate. J Physiol Pharmacol,2000,3,51:69-83.
[11] 李奎,刘英,康相涛,等.主要凋亡基因对细胞凋亡的调控.解剖科学进展,2007,13(l):62-65.
[12] Tsujimoto Y,Cesaeran J ,Jaffe E ,et al. Involvement of bcl-2 gene in human follicular lymphoma[J].Science,1985,228(4706) :1440-1443.
[13] Kane DJ,Sarafian TA, Anton R,et al.BCL-2 inhibition of neural death:decreased generation of reactive oxygen species.Science, 1993, 262(5137): 1274～1277.
[14] 张敏燕,张正民,韩仲明,等.凋亡调控基因 Bcl-2、Bax 与肿瘤.国外医学耳鼻咽喉科学分册,2004,28(1):40-42.
[15] 刘陶文.凋亡调控基因Bcl-2 家族研究的新进展.生物化学和生物物理学研究进展,1999,26(3):29-31.
[16] Baffy G, Miyashita T,Williamson J R,et al.Apoptosis induced by withdrawal of interleukin-3(IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production. J Biol Chem, 1993, 268(9): 6511～6519.
[17] Barros MH,Netto ES,Kowultowski A.H2O2 generation in saccharomyces cerevisiae respiratory pet mutants:effect of cytochrome C.Biol Med,2003,35(2):179-188.
[18] Oltvai ZN, Milliman CL, Korsmeyer SL.Bcl-2 heterodimerizes in vivo with a conserved homolog , Bax , that accelerates programmed cell death.Cell.1993,74:609-619.
[19] Burger MM,Harris C.UICCS tudy Group on basic and clinical cancer research:apoptosis in normal and tumor cells.Int J Cancer , 1995 ,60:590-592.
[20] 姚峰,陶林,陈倩,等.凋亡抑制基因 Survivin 在非小细胞肺癌中的表达及其与 Caspase-3、Bcl-2 蛋白表达的关系.中国癌症杂志,2004,14(2):109-112.
[21] 曹银芳,关泽红,于晓鸿,等.凋亡抑制基因 Bcl-2 在肿瘤中的应用研究进展.内蒙古医学杂志,2007,39(8):961-963.
[22] Fenney DM,Boyseson MG,Linn RT,et a1.Responses to cortical injury:Methodo1ogy and local efects of contusions in the rat[J].Brain Res,1981(211) :67-77.
[23] Hua R,Wa1z W.Minocycline treatment prevents cavitation in rats after a cortical devascu1arizing lesion.Brain Res,2006,23:172-181.
[24] 谢萍.自由基与细胞凋亡.生物学教学,2004,29(l):3-4.
[25] 曹淑华,查向东.超氧化物歧化酶研究综述. 安徽农业科学,2003,31(4):599-601.
[26] 钱淑英,夏兆雄,许建芬.恶性肿瘤患者血一氧化氮、内皮素和超氧化物歧化酶的变化.肿瘤学杂志,2001,7(5):270-271.
[27] 黄俊,罗和生,李颖,等. 大鼠实验性溃疡性结肠炎中 NO、MDA、SOD的变化.医学文选,2001,20(6):757-759.
[28] 叶盛英,王世岭.表皮生长因子在消化性溃疡应用方面研究进展. 中国医院药学杂志,2002,22(10) :622-625.
[29] 陈怡,朱长清等.罗沙替丁治疗消化性溃疡或急性胃粘膜病变引起上消化道出血的临床研究.中国全科医学,2007,(18):1511-1513.
[30] Piotrowiski J,Yamaki K,Morita M,et al.Ebrotidine-a new H2-receptor antagonist with mucosal strengthening activity.Biochem Int,1992,26(1) :659-667.
[31] Konturek PC , Brzozowski T , Konturek SI , et al. Studies on the cytoprotective and antisecretory activity of ebrotidine,a review.Arzneimittelforschung,1997,47(4A) :578-583.
[32] Palacin C , Tarrago C.In vitro anti-Helicobacter pylori activity of ebrotidine.Arzneimittelforschung,1997,47(4A) :471-476.
[33] Sanjny S,Michelle IW.Ebrotidine.Drugs,1996,51(6) :974-979.
[34] 穆殿平,高仲阳,徐为人,等.H2受体拮抗剂在消化性溃疡治疗中的作用. 天津药学,1998,10(1):19-23.
[35] 张静,于爱莲,张树榕,等. 消化性溃疡治疗进展之一—药物治疗进展与评价.医学综述,1995,1(5):219-223.
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