中文摘要
　　在人類潰瘍的產生多存在於幽門部，尤其是與胃體部的交界處。很可惜地，大部分經由動物所誘導出來的潰瘍模式為急性且為表淺層的胃體部潰瘍，相對於臨床上所產生的潰瘍卻是深及黏膜肌肉層之幽門部潰瘍。再餵食大白鼠的動物模式目前是最被廣泛應用於誘導胃幽門部潰瘍產生的模式。有趣地是此已被證實和高胰島素血症現象有關。另一方面，血清中胰島素增加與胰島素敏感度下降也被報導於胰島素阻抗性狀態。然而，胰島素阻抗性在胃幽門部潰瘍中扮演何種角色目前尚未釐清。

　　本篇研究目的主要在探討在胰島素阻抗性大白鼠以indomethacin所誘導產生的胃幽門出血性潰瘍與其保護性藥物，如：溶菌酶素以及穿心蓮內酯，並與傳統常用的胃潰瘍治療藥物-cimetidine比較保護效果；另外，面對傷害時，辣椒素敏感性傳入神經因會啟動立即且快速反應的保護機制而被認為對胃黏膜完整性的維持建立有關。故此傳入神經對此潰瘍的影響也將一併探討。

　　高含量的果糖提供一個誘導胰島素阻抗性的飲食模式，且與高胰島素血症，胰島素敏感度降低及高三酸甘油脂血症相關。我們取用雄性Wistar大白鼠，給予一般實驗室標準鼠飼料與30% (v/v)之果糖溶液持續21天。禁食12小時後，進行耐糖試驗以確定周邊胰島素敏感性降低的產生。葡萄糖胰島素指標是由耐糖試驗各採血點連結的葡萄糖與胰島素曲線之曲線下面積計算而來。此指標為周邊胰島素對葡萄糖分佈作用(也就是周邊胰島素敏感度)的間接性指標。在給予耐糖試驗六小時後，鼠胃以人工胃液溶液刺激3小時，再將胃分離出並觀察測定。

　　實驗結果顯示，各種潰瘍參數（如：胃潰瘍面積、胃酸逆擴散現象，血紅素含量、脂質過氧化物濃度和組織氨濃度等）的惡化，以及防禦物質(包括麩胺基硫濃度，黏液含量等)的減少，也都能在這些大白鼠中被觀察到。胰島素敏感度降低的程度與胃幽門部出血性潰瘍間存在正相關關係。

　　在保護藥物的部份，cimetidine獨對胃體部有防止傷害的能力，對胃幽門部的保護能力則非常有限：相對於cimetidine，以溶菌酶素的效果最好，能同時防止胃體及胃幽門部的潰瘍產生；然而，穿心連內酯雖有相當強的抗自由基的活性，但無論是對胃體或是胃幽門部潰瘍都沒有明顯的保護能力。以高劑量的辣椒素皮下投予至大白鼠，而將辣椒素敏感性傳入神經破壞後，所預期的胃幽門部潰瘍惡化並沒有呈現出來，對於此結果，我則以辣椒素作用機轉以及此神經再生修復的訊息傳導的觀點作更進一步的討論。

　　綜合以上結果，indomethacin的確可以在胰島素阻抗性大白鼠所產生深部胃幽門部潰瘍，並且推論與氧化壓力，黏液減少及發炎反應有關；若血中胰島素增加則此潰瘍會更加惡化，並且可以藉由溶菌酶素達到最佳保護效果。

Abstract
　In humans, gastric ulcers are located mainly in the antral portion along the lesser curvature. Unfortunately, most widely used animal models of gastric injury are characterized by acute, superficial erosion in the corpus region of the stomach, whereas the clinically significant injury in man occur principally in the antrum and, by definition, penetrate the muscularis mucosae. Antral ulcer which occurs in refed rats is associated with hyperinsulinemia. The increased serum insulin and decreased peripheral insulin sensitivity are reported in insulin resistant condition. Whether or not this insulin resistance plays a role in antral ulcer formation in normal rats, however, is totally unknown.

　The aim is to study hemorrhagic antral ulcer induced by indomethacin and its protective effects of lysozyme and andrographolide, and compared them with traditional anti-secreted drugs- cimetidine in fructose-induced insulin resistance rats. Furthermore, it is demonstrated that capsaicin-sensitive peptidergic sensory fibers play a pivotal role in the maintenance of gastric mucosal integrity against injurious interventions. The influence of capsaicin-sensitive efferent nerves in antral ulcer formation is further investigated in this study.

　In rats, feeding a high-fructose diet provides a dietary model of insulin resistance associated with hyperinsulinemia, decreased insulin sensitivity and hypertriglyceridemia. Male Wistar rats were fed with pellet diet and drinking water containing 30% (v/v) fructose for 21 days. The rats were fasted for 12 hours before an oral glucose tolerance test (OGTT) that was performed to assure of decreased insulin sensitivity. The glucose-insulin index, calculated as the product of the glucose and insulin AUC (total areas under the curve) during the OGTT, is an indirect index of peripheral insulin action on glucose disposal, which also refers to peripheral insulin sensitivity. Six hours after challenged with glucose (1.7mg/kg), rat stomachs were irrigated for 3 hours with gastric juice. Various gastric parameters were determined.

　Aggravation of ulcerogenic parameters, such as acid back diffusion, hemoglobin content, and lipid peroxide, as well as decreased concentration of defensive substances, including glutathione and mucus content were observed in these rats. A decreased insulin sensitivity and an increased antral hemorrhagic ulcer were achieved in insulin resistance rats after administrated indomethacin.

　Cimetidine can prevent corpus from injury but not antral ulcers. Lysozyme chloride exhibits the best gastroprotective effect; andrographolide possesses strong anti-oxidative activity, however, it failed to protect corpus or antral ulcer. Documents demonstrate that high concentrations of capsaicin applied into the stomach of the rats can induce damage of capsaicin-sensitive nerve endings with a loss of their sensory-efferent functions and leads to gastric ulceration. With the views of mechanisms of capsaicin and nerve regeneration, this discrepancy was discussed in the present.

　In conclusion, indomethacin could produce deeper and more extensive antral mucosal hemorrhagic ulcer in insulin resistance rats than normal rats that is associated with oxidative stress, decreased mucus and inflammation in rats. Exogenous insulin leading to hyperinsulinemia could exacerbate antral ulcer produced in insulin resistant rats which was most effectively ameliorated by lysozyme.

1. Adamek RJ, Freitag M, Opferkuch W, Ruhl GH & Wegener M. Intravenous omeprazole/amoxillin and omeprazole pretreatment in Helicobacter pylori-positive acute peptic ulcer bleeding. A pilot study. Scand. J. Gastroenterol. 29:880-883 (1994)
2. Alberti KGMM: The costs of non-insulin-dependent diabetes mellitus. Diabet. Med. 14:7-9 (1997)
3. Asakura K, Kojima T, Shirasaki H & Kataura A. Evaluation of the effects of antigen specific immunotherapy on chronic sinusitis in children with allergy. Auris Nasus Larynx 17: 33-38 (1990)
4. Axelson J, Hakanson R & Hedenbro JL. Insulin-induced gastric ulcers in the rat. Scand. J. Gastroenterol. 22:737-742 (1987)
5. Bahari HM, Ross IN & Turnberg LA. Demonstration of a pH gradient across the mucus layer on the surface of human gastric mucosa in vitro. Gut 23:513-516 (1982)
6. Beck-Nielsen H, Pedersen O & Lindskov HO. Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects. Am. J. Clin. Nutr. 33:273-278 (1980)
7. Bienen H. & Raus I. Therapeutic comparison of throat lozenges. MMW-Munchener Medizinische Wochenschrift. 123: 745-747 (1981)
8. Biziulevichius GA & Arestov IG. In vivo studies on lysosubtilin. I. Efficacy for prophylaxis and treatment of gastrointestinal disorders in newborn calves. Vet. Res. 28:19-35 (1997)
9. Blakely SR, Hallfrisch J, Reiser S & Prather ES. Long-term effects of moderate fructose feeding on glucose tolerance parameters in rats. J Nutr. 111, 307-314 (1981)
10. Blakely SR, Hallfrisch J, Reiser S & Prather ES. Long-term effects of moderate fructose feeding on glucose tolerance parameters in rats. J Nutr. 111:307-314 (1981)
11. Body SC, Sasame HA & Body MR. High concentrations of glutathione in glandular stomach: possible implications for carcinogenesis. Science 205:1010-1012 (1979)
12. Bonney RJ, Naruns P, Davies P & Humes JL. Antigen-antibody complexes stimulate the synthesis and release of prostaglandins by mouse peritoneal macrophages. Prostaglandins 18: 605-616 (1979)
13. Boykin JV Jr. & Manson NH. Mechanisms of cimetidine protection following thermal injury.Am J Med. 83:76-81 (1987)
14. Brzozowski T, Konturek PC, Sliwowski Z, Pytko-Polonczyk J, Szlachcic A & Drozdowicz D. Role of capsaicin-sensitive sensory nerves in gastroprotection against acid-independent and acid-dependent ulcerogens. Digestion 57:424-432 (1996)
15. Bugat R, Thompson MR, Aures D & Grossman MI. Gastric mucosal lesions produced by intravenous infusion of aspirin in cats. Gastroenterology 71:754-759 (1976)
16. Cadet J, Delatour T, Douki T, Gasparutto D, Pouget JP, Ravanat JL & Sauvaigo S. Hydroxyl radicals and DNA base damage. Mutat. Res.. 424:9-21 (1999)
17. Catto-Smith AG, Patrick MK, Scott RB, Davison JS & Gall DG. Gastric response to mucosal IgE-mediated reactions. Am. J. Physiol.. 257:G704-708 (1989)
18. Chen SH & Pan S. Sources of superoxide radicals involved in the pathogenesis of diethyldithiocarbamate-induced gastric antral ulcer in rats. J. Formos. Med. Assoc. 97:131-134 (1998)
19. Chen SH, Pan S, Okita K & Takemoto T. Role of superoxide dismutase in mechanism of diethyldithiocarbamate-induced gastric antral ulcer in rats: protective effect of prostaglandin, cimetidine and pirenzepine. J. Gastroenterol. Hepatol. 85:457-461 (1993)
20. Chiou WF, Chen CF &. Lin JJ. Mechanisms of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by andrographolide. Br. J. Pharmacol.. 129:1553-1560 (2000)
21. Chung RS, Field M & Silen W. Permeability of gastric mucosa to hydrogen and lithium. Gastroenterology. 64:593-598 (1973)
22. Consensus Development Conference on Insulin Resistance. 5-6 November 1997. American Diabetes Association (ADA), Diabetes Care 21: 310-314 (1998)
23. Corne SJ, Morrissey SM & Woods RJ. Proceedings, A method for the quantitative estimation of gastric barrier mucus. Am. J. Physiol. 242: 116-117 (1974)
24. Das D. Bandyopadhyay D. Bhattacharjee M. Banerjee RK. Hydroxyl radical is the major causative factor in stress-induced gastric ulceration. Free Radic. Biol. Med. 23:8-18 (1997)
25. Davenport H.W., Gastric mucosal hemorrhage in dogs. Effects of acid, aspirin and alcohol. Gastroenterology 56:439-449 (1969)
26. De Courten M, Zimmet P, Hodge A, Collins V, Nicolson M, Staten M, Dowse G & Alberti KG. Hyperleptinaemia, the missing link in the, metabolic syndrome? Diabet. Med. 14:200–208 (1997)
27. Donnerer J, Amann R, Schuligoi R & Skofitsch G. Complete recovery by nerve growth factor of neuropeptide content and function in capsaicin- impaired sensory neurons. Brain Res. 741:103–108 (1996)
28. Donnerer J. Regeneration of primary sensory neurons. Pharmacology. 67:169-181 (2003)
29. Elliott SS, Keim NL, Stern JS, Teff K & Havel PJ. Fructose, weight gain, and the insulin resistance syndrome. Am. J. Clin. Nutr. 76:911-922 (2002)
30. Fleming A. On a remarkable bacteriolytic element found in tissues and secretions. Proc Roy Soc Ser B 93:306-317 (1922)
31. Forstner JF. Intestinal mucins in health and disease. Digestion. 17:234-263 (1978)
32. Frank WO. Gastric acid secretion and mucosal defense mechanisms with special reference to the role of cimetidine in critically ill patients. Clin Ther. 8 Suppl A:2-13 (1986)
33. Garner A, Flemstrom G, Allen A, Heylings JR & McQueen S. Gastric mucosal protective mechanisms: roles of epithelial bicarbonate and mucus secretions. Scand. J. Gastroenterol. Suppl. 101:79-86 (1984)
34. Gasior-Chrzan B. Clinical trail of lysozyme treatment of crural ulcers in humans. Przeglad Dermatologiczny. 75: 435-438 (1988)
35. Gerich JE: The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev 19:491-503 (1998)
36. Goddard PJ, Kao YC & Lichtenberger LM. Luminal surface hydrophobicity of canine gastric mucosa is dependent on a surface mucous gel. Gastroenterology. 98:361-70 (1990)
37. Grisham MB, Von Ritter C, Smith BF, Lamont JT & Granger DN. Interaction between oxygen radicals and gastric mucin. Am. J. Physiol. 253:G93-96 (1987)
38. Hallfrisch J, Lazar F, Jorgensen C & Reiser S. Insulin and glucose responses in rats fed sucrose or starch. Am. J. Clin. Nutr. 32:787-793 (1979)
39. Hallfrisch J. Ellwood KC. Michaelis OE 4th. Reiser S. O'Dorisio TM. Prather ES. Effects of dietary fructose on plasma glucose and hormone responses in normal and hyperinsulinemic men. J. Nutr. 113:1819-1826 (1983)
40. Hanusch-Enserer U, Cauza E, Spak M, Endler G, Dunky A, Tura A, Wagner O, Rosen HR, Pacini G & Prager R. Improvement of insulin resistance and early atherosclerosis in patients after gastric banding. Obes Res. 12:284-291 (2004)
41. Hast R. Bernell P & Hansson M. Cimetidine as an immune response modifier. Med Oncol Tumor Pharmacother. 6:111-113 (1989)
42. Henriksen EJ & Saengsirisuwan V. Exercise training and antioxidants: relief from oxidative stress and insulin resistance. Exerc. & Sport Sci. Rev. 31:79-84 (2003)
43. Hills BA, Butler BD & Lichtenberger LM. Gastric mucosal barrier: hydrophobic lining to the lumen of the stomach. Am. J. Physiol.. 244:G561-568, (1983)
44. Hincke MT, Gautron J, Panheleux M, Garcia-Ruiz J, McKee MD & Nys Y. Identification and localization of lysozyme as a component of eggshell membranes and eggshell matrix. Matrix Biol 19: 443-453 (2000)
45. Hirschowitz BI. An update on histamine receptors and the gastrointestinal tract. Dig. Dis. & Sci. 30:998-1004 (1985)
46. Holst D & Grimaldi PA. New factors in the regulationof adipose differentiation and metabolism. Curr. Opin. Lipidol. 13:241–245 (2002)
47. Holzer P & Lippe IT. Stimulation of afferent nerve endings by intragastric capsaicin protects against ethanol-induced damage of gastric mucosa. Neuroscience 27:981-987 (1988)
48. Holzer P & Sametz W. Gastric mucosal protection against ulcerogenic factors in the rat mediated by capsaicin-sensitive afferent neurons. Gastroenterology 91:975-981 (1986)
49. Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol. rev. 43:143-201 (1991)
50. Holzer P. Neural emergency system in the stomach. Gastroenterology. 114:823-39 (1998)
51. Holzer P., Pabst M.A. & Lippe I. Intragastric capsaicin protects against aspirin-induced lesion formation and bleeding in the rat gastric mucosa. Gastroenterology 96, 1425-1433 (1989)
52. Holzer P: Capsaicin: Cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacological reviews. 43:143–201(1991)
53. Hoppenkamps R. Thies E. Younes M. Siegers CP. Glutathione and GSH-dependent enzymes in the human gastric mucosa. Klin. Wochenschr. 62:183-186 (1984)
54. Horiuchi H, Abe S, Maeda K & Watanabe M. Anti-inflammatory, analgesic effect of lysozyme chloride following direct pulpectomy and root canal filling. Dent Outl 58:1007-1012 (1981)
55. Hsu PI, Lin XZ, Chan SH, Lin CY, Chang TT, Shin JS, Hsu LY, Yang CC, Chen KW. Bleeding peptic ulcer-risk factors for rebleeding and sequential changes in endoscopic findings. Gut 35:746-749 (1994)
56. Hung C.R. & Hwang Y.Y. Role of acid back-diffusion in the formation of mucosal ulceration and its treatment with drugs in diabetic rats. J. Pharm. Pharmacol. 47:493-498 (1995)
57. Hung C.R. & Wang P.S. Role of acid back-diffusion, glutathione, oxyradical, and histamine in antral hemorrhagic ulcer in rats, the protective effect of lysozyme chloride and antioxidants. J. Lab. Clin. Med. 140:142-151 (2002)
58. Hung CR, Wang PS. Gastric oxidative stress and hemorrhagic ulcer in Salmonella typhimurium-infected rats. Eur. J. Pharmacol. 61-68 (2004)
59. Hwang, I. S., Ho, H., Hoffman, B. B. & Reaven, G. M. Fructose-induced insulin resistance and hypertension in rats. Hypertension 10:512-516 (1987)
60. Inouye K. The effects of lysozyme chloride on the immune response of patients with head and neck cancer. Gan No Rinsho 33:627-632 (1987)
61. J. Szolcsa’ nyi, Actions of capsaicin on sensory receptors, in: J.N. Wood (Ed.), Capsaicin in the study of pain, Academic Press, London , 1993, pp. 1–23.
62. Jequier E & Tappy L. Regulation of body weight in humans. Physiol. Rev. 79:451-80 (1999)
63. Jones M, Sasaki E, Halter F, Pai R, Nakamura T, Arakawa T, Kuroki T & Tarnawski A: HGF triggers activation of the COX-2 gene in rat gastric epithelial cells: action mediated through the ERK 2 signaling pathway. FASEB J 13:2186-2194 (1999)
64. Kao YC & Lichtenberger LM. Effect of 16,16-dimethyl prostaglandin E2 on lipidic organelles of rat gastric surface mucous cells. Gastroenterology. 104:103-113 (1993)
65. Katunuma N, Shiota H & Le QT. Medical significance of cysteine protease inhibitors in mammalian secretory fluids. J. Med. Invest. 50:154-161 (2003)
66. King H, Aubert RE, Herman WH: Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 21 :1414-1431 (1998)
67. Kolbasa KP, Lancaster C, Olafsson AS, Gilbertson SK & Robert A. Indomethacin-induced gastric antral ulcers in hamsters. Gastroenterology. 95:932-944 (1988)
68. Laine L & Peterson, WL. Bleeding peptic ulcer. N Engl J Med 331:717-727 (1994)
69. Lichtenberger LM, Wang ZM, Romero JJ, Ulloa C, Perez JC, Giraud MN & Barreto JC. Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury. Nat. Med. 1:154-158 (1995)
70. Lichtenberger LM. The hydrophobic barrier properties of gastrointestinal mucus. Annu. Rev. Physiol. 57:565-583 (1995)
71. Lillioja S & Bogardus C: Obesity and insulin resistance: lessons learned from the Pima Indians. Diabete Metab Rev 4:517 –540 (1988)
72. Lippe IT & Holzer P. Participation of endothelium-derived nitric oxide but not prostacyclin in the gastric mucosal hyperaemia due to acid back-diffusion. Br. J. Pharmacol.. 105:708-714 (1992)
73. MacGlashan D Jr. Histamine: A mediator of inflammation. J. Allergy Clin. Immunol. 112:S53-59 (2003)
74. Mason DY & Taylor CR The distribution of muramidase (lysozyme) in human tissues. J. Clin. Pathol. 28:124-132 (1975)
75. Mason DY & Taylor CR. The distribution of muramidase (lysozyme) in human tissues. J. Clin. Pathol. 28:124-132 (1975)
76. Meier U & Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem. 50:1511-1525. (2004)
77. Meister A & Anderson ME. Glutathione. Annu. Rev. Biochem. 52:711-760 (1983)
78. Mercer SW & Williamson DH. Time course of changes in plasma glucose and insulin concentrations and mammary-gland lipogenesis during re-feeding of starved conscious lactating rats. Biochem. J. 239:489-492 (1986)
79. Montgomery,1984;Steel and Torrie,1960
80. Nourooz-Zadeh J, Rahimi A, Tajaddini-Sarmadi J, Tritschler H, Rosen P, Halliwell B & Betteridge DJ. Relationships between plasma measures of oxidative stress and metabolic control in NIDDM. Diabetologia. 40:647-653 (1997)
81. Ohkawa H., Ohishi N. & Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95:351-358 (1979)
82. Oi M, Ito Y, Kumagai F, Yoshida K, Tanaka Y, Yoshikawa K, Miho O & Kijima MA. Possible dual control mechanism in the origin of peptic ulcer. A study on ulcer location as affected by mucosa and musculature. Gastroenterology 57:280-293 (1969)
83. Okabe S. & Pfeiffer CJ. Chronicity of acetic acid ulcer in the rat stomach. Am. J. Dig. Dis. 17:619-629 (1972)
84. Olefsky JM, Farguhar JW & Reaven GM: Relationship between fasting plasma insulin level and resistance to insulin-mediated glucose uptake in normal and diabetic subjects. Diabetes 22:507 (1973)
85. Olson CE. Glutathione modulates toxic oxygen metabolite injury of canine chief cell monolayers in primary culture. Am. J. Physiol.. 254:G49-56 (1988)
86. P. Holzer, Neural injury, repair, and adaptation in the GI tract II. The elusive action of capsaicin on the vagus nerve, The Am. J. Physiol.. 275:G8–G13 (1998)
87. Palmieri B. and Boraldi F.: Topical treatment of some dystrophic inflammatory lesions of the skin and soft tissue. Archivio Per Le Scienze Mediche. 134:481-485 (1977)
88. Panossian A. Hovhannisyan A. Mamikonyan G. Abrahamian H. Hambardzumyan E, Gabrielian E, Goukasova G, Wikman G & Wagner H Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine 7:351-364 (2000)
89. Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DE, Johnson O & Walker BR. Tissue-specific dysregulation of cortisol metabolism in human obesity. J. Clin. Endocrinol. Metab. 86:1418-1421, (2001)
90. Raybould HE, Sternini C, Eysselein VE, Yoneda M & Holzer P. Selective ablation of spinal afferent neurons containing CGRP attenuates gastric hyperemic response to acid. Peptides 13:249-254 (1992)
91. Raybould HE. Li DS. Guth PH. Calcitonin gene-related peptide mediates the gastric hyperemic response to acid back-diffusion. Ann. N. Y. Acad. Sci. 657:536-537 (1992)
92. Relimpio F. "The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes", by Kahn SE Diabetologia. 46:1707 (2003)
93. Ren J, Young RL, Lassiter DC & Harty RF Calcitonin gene-related peptide mediates capsaicin-induced neuroendocrine responses in rat antrum. Gastroenterology. 104:485-491 (1993)
94. Repka-Ramirez MS. New concepts of histamine receptors and actions. Curr. Allergy Asthma. Rep. 3:227-231 (2003)
95. Reusens-Billen B, Clercq L, Barreira VI, Hanotier CJ & Remacle C. Prevention of the cytotoxic effect of IL-1 by human lysozyme on isolated rat islets. Diabetes Res Clin Pr 23:85-94 (1994)
96. Roglans N, Sanguino E, Peris C, Alegret M, Vazquez M, Adzet T, Diaz C, Hernandez G, Laguna JC & Sanchez RM. Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats. J. Pharmacol. Exp. Ther.. 302：232-239 (2002)
97. Ronnberg AL & Hakanson R. A simplified procedure for the fluorometric determination of histamine in rat stomach. Agents Actions. 14:195-199 (1984)
98. Rosenbaum T, Sanchez-Soto MC & Hiriart M. Nerve growth factor increases insulin secretion and barium current in pancreatic beta-cells. Diabetes. 508:1755-1762 (2001)
99. Ross D. Glutathione, free radicals and chemotherapeutic agents. Mechanisms of free-radical induced toxicity and glutathione-dependent protection. Pharmacol. Ther. 37:231-249 (1988)
100. Rudich A. Tirosh A. Potashnik R. Hemi R. Kanety H. Bashan N. Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. Diabetes. 47:1562-1569 (1998)
101. Rydning A. Lyng O. Falkmer S. Gronbech JE. Histamine is involved in gastric vasodilation during acid back diffusion via activation of sensory neurons. Am. J. Physiol. 283:G603-611 (2002)
102. Ryu JK, Kim DJ, Lee T, Kang YS, Yoon SM & Suh JK. The role of free radical in the pathogenesis of impotence in streptozotocin-induced diabetic rats. Yonsei Med. J. 44:236-241 (2003)
103. Saengsirisuwan V, Perez FR, Sloniger JA, Maier T & Henriksen EJ. Interactions of exercise training and alpha-lipoic acid on insulin signaling in skeletal muscle of obese Zucker rats. Am. J. Physiol. 287:E529-536 (2004)
104. Salim AS. Protection against stress-induced acute gastric mucosal injury by free radical scavengers. Intensive Care Med. 17:455-460 (1991)
105. Saltiel AR. Decker SJ. Diversity in cellular signaling for nerve growth factor and insulin: variations on a common theme. Journal of Investigative Dermatology. 98:17S-20S (1992)
106. Saltzman JR & Zawacki JK. Therapy for bleeding peptic ulcers. New Engl J Med. 336:1091-1093 (1997)
107. Sato M, Oe H, Nakano M, Kawasaki H & Hirayama C. A random controlled study of the prophylactic effect of lysozyme chloride on post-transfusion hepatitis. Hepato-Gastroenterology 28:135-138 (1981)
108. Satoh H., Inada I., Hirata T. & Maki Y. Indomethacin produces gastric antral ulcers in the refed rat. Gastroenterology 81:719-725 (1981)
109. Schicho R, Skofitsch G & Donnerer J: Regenerative effect of human recombinant NGF on capsaicin- lesioned sensory neurons in the adult rat. Brain Res. 815:60–69. (1999)
110. Schwartz MW. Boyko EJ. Kahn SE. Ravussin E. Bogardus C. Reduced insulin secretion: an independent predictor of body weight gain. Journal of Clinical Endocrinology & Metabolism. 80:1571-6, (1995)
111. Shafi MA & Fleischer DE. Risk factors of acute ulcer bleeding. Hepato-Gastroenterol 6:727-731 (1999)
112. Shay H., Komarov S.A. & Gruenstein M. Effects of vagotomy in the rat. Arch.Surg.59:210-26 (1949)
113. Shen YC. Chen CF & Chiou WF. Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect. Br. J. Pharmacol. 135:399-406 (2002)
114. Shen YC. Chen CF & Chiou WF. Suppression of rat neutrophil reactive oxygen species production and adhesion by the diterpenoid lactone andrographolide. Planta Medica 66:314-317 (2000)
115. Siegers CP. Andresen S. Keogh JP. Does cimetidine improve prospects for cancer patients?. A reappraisal of the evidence to date. Digestion. 60:415-421, (1999)
116. Stein HJ, Hinder RA & Oosthuizen MM. Gastric mucosal injury caused by hemorrhagic shock and reperfusion: protective role of the antioxidant glutathione. Surgery. 108:467-473 (1990).
117. Suttorp N. Toepfer W & Roka L. Antioxidant defense mechanisms of endothelial cells: glutathione redox cycle versus catalase. Am. J. Physiol. 251:C671-680 (1986)
118. Szelenyi I & Brune K. Possible role of oxygen free radicals in ethanol-induced gastric mucosal damage in rats. Dig. Dis. & Sci. 33:865-871 (1988)
119. Takeuchi K, Ueki S & Okabe S. Importance of gastric motility in the pathogenesis of indomethacin-induced gastric lesions in rats. Dig. Dis.& Sci. 31:1114-1122 (1986)
120. Takeuchi K. Ueshima K. Matsumoto J. Okabe S. Role of capsaicin-sensitive sensory nerves in acid-induced bicarbonate secretion in rat stomach. Dig. Dis.& Sci. 37:737-743 (1992)
121. Thorburn AW. Storlien LH. Jenkins AB. Khouri S & Kraegen EW. Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats. Am. J. Clin. Nutr.. 49:1155-1163 (1989)
122. Tobey, T. A., Mondon, C. E., Zavaroni, I. & Reaven, G. M. Mechanism of insulin resistance in fructose-fed rats. Metabolism 31,608-612 (1982)
123. Tramontana M, Renzi D, Calabro A, Panerai C, Milani S, Surrenti C & Evangelista S. Influence of capsaicin-sensitive afferent fibers on acetic acid-induced chronic gastric ulcers in rats. Scand. J. Gastroenterol. 29:406-413 (1994)
124. Uchida M, Yano S & Watanabe K. Involvement of CGRP, substance P and blood circulation in aggravating mechanism of absolute ethanol-induced antral lesions by capsaicin treatment in rats. Jpn. J. Pharmacol. 62:123-129 (1993)
125. Vaananen PM. Meddings JB & Wallace JL. Role of oxygen-derived free radicals in indomethacin-induced gastric injury. Am. J. Physiol.. 261:G470-475 (1991)
126. Walder CE. Thiemermann C & Vane JR. Endothelium-derived relaxing factor participates in the increased blood flow in response to pentagastrin in the rat stomach mucosa. Proceedings of the Royal Society of London - Series B: Biological Sciences. 241:195-200 (1990)
127. Wallace J.L. & Granger D.N. The cellular and molecular basis of gastric mucosal defense. FASEB J. 10, 731-740 (1996)
128. Wallace JL. & McKnight GW. Characterization of a simple animal model for nonsteroidal anti-inflammatory drug induced antral ulcer. Can. J. Physiol. Pharmacol. 71, 447-452 (1993)
129. Wardzala LJ, Hirshman M, Pofcher E, Horton ED, Mead PM, Cushman SW & Horton ES. Regulation of glucose utilization in adipose cells and muscle after long-term experimental hyperinsulinemia in rats. J. Clin. Invest.76:460-469 (1985)
130. Watson KE, Horowitz BN & Matson G. Lipid abnormalities in insulin resistant states. Rev. Cardiovasc. Med. 4:228-236 (2003)
131. Webster HV, Bone AJ, Webster KA & Wilkin TJ. Comparison of an enzyme-linked immunosorbent assay (ELISA) with a radioimmunoassay (RIA) for the measurement of rat insulin. J. Immunol. Methods 134:95-100 (1990)
132. Wickremesekera K, Miller G, Naotunne TD, Knowles G & Stubbs RS. Loss of insulin resistance after Roux-en-Y gastric bypass surgery: a time course study. Obes Surg. 15:474-481 (2005)
133. Yamamoto T, Horikawa N, Komuro Y, Hara Y. Effect of topical application of a stable prostacyclin analogue, SM-10902 on wound healing in diabetic mice. European Journal of Pharmacology 302: 53-60, (1996)
134. Yegen BC. Alican I. Yalcin AS. Oktay S. Calcium channel blockers prevent stress-induced ulcers in rats. Agents & Actions. 35:130-134 (1992)
135. Yu B.C., Hung C.R., Chen W.C. & Cheng J.T. Antihyperglycemic effect of andrographolide in streptozotocin-induced diabetic rats. Planta Medica 69, 1075-1079 (2003)
136. 劉新建, 等. 穿心蓮內酯及其衍生物的藥理研究發展.中藥材 26:135-138 (2003)
137. 卲文龍, 等.脫水穿心蓮內酯琥珀酸半酯藥理作用研究 I. 抗炎作用 15 : 590 (1980)
138. 趙洪, 等. 穿心蓮內酯的電化學研究. 分析試驗室 16: 1 (1997)