脂多醣體是構成革蘭氏陰性菌細胞壁的主要成分，也是引起許多動物物種產生發炎反應的重要誘發因子。而芝麻酚，是由芝麻油中所萃取出的天然木質素成分；芝麻酚具有抑制神經膠質細胞經脂多醣體誘導所產生的一氧化氮，然而，芝麻酚是否能降低脂多醣體所引起的發炎反應，進而減緩器官傷害，目前並不清楚。因此，本研究目的，將探討芝麻酚對小鼠經脂多醣體所誘發的發炎反應與器官傷害的影響。研究結果顯示，芝麻酚能有效減緩小鼠經脂多醣體誘導所產生的肝腎傷害，減少小鼠血清中及巨噬細胞RAW264.7所產生的一氧化氮含量，並降低白血球細胞及巨噬細胞RAW264.7經脂多醣體所誘發的誘導型一氧化氮合成酵素蛋白質表現量；雖然芝麻酚能明顯增加小鼠血清中抗發炎細胞激素介白素-10的生成，然而，對發炎細胞激素腫瘤壞死因子-alpha及介白素-1betta的含量則沒有影響；此外，芝麻酚能降低RAW267.4細胞中I-kappaB的磷酸化作用，亦能抑制p65進入細胞核，進而阻斷轉錄因子NF-kappaB的調控作用。總之，芝麻酚可能藉由增加抗發炎物質IL-10的生成，來抑制NF-kappaB的轉錄作用、降低iNOS的活化及NO的生成，並改善小鼠經脂多醣體誘導所產生的發炎反應以及肝腎傷害。

　Lipopolysaccharide (LPS), a main component of Gram-negative bacterial cell wall, is a potent inducer of inflammatory response and organ injury in animals and mammalians. Sesamol, a lignan of sesame oil, has an inhibitory effect on LPS-induced nitric oxide production in glia cell line; however, whether sesamol could protect against LPS-initiated inflammation and organ injury have never been investigated. The aim of this study was to investigate the effect and the possible mechanism of sesamol on inflammation-associated organ injury induced by LPS in mice. Sesamol significantly attenuated LPS-induced hepatic and renal injuries in mice. Sesamol decreased LPS-enhanced nitric oxide production in serum in mice and in RAW264.7 murine macrophage cell line. Sesamol reduced inducible nitric oxide synthase protein expression in LPS-treated leukocytes and RAW264.7 cells. Sesamol markedly increased interleukin-10 generation but failed to affect tumor necrosis factor-alpha and interleukin-1betta levels after LPS challenge in mice. In addition, sesamol significantly decreased the phosphorylation of I-kappaB and blockaded NF-kappaB translocation by avoiding p65 to enter into nucleus in RAW264.7 cells. In summary, sesamol attenuated LPS-induced inflammation and hepatic and renal injuries by inhibiting nitric oxide production, which might be a result of the enhancement of IL-10 production and the inhibition of NF-kappaB translocation, in mice.

Akdis CA, Blaser K. IL-10-induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy. The FASEB Journal 13:603-609, 1999.
Akimoto K, Kitagawa Y, Akamatsu T, Hirose N, Sugano M, Shimizu S, Yamada H. Protective effects of sesamin against liver damage caused by alcohol or carbon tetrachloride in rodents. Annals Nutrition Metbabolism 37:218-224, 1993.
Andrei E, Medvedev, Jorge CG, Blanco, Nilofer Qureshi, Stefanie NV. Limited role of ceramide in lipopolysacchride-mediated mitogen-activated protein kinase activation, transcription factor induction, and Cytokine Release. The Journal of Biological Chemistry 274:9343-9350, 1999.
Arndt JGS, Mayo MW, Sartor RB, Baldwin ASJr. Interleukin-10 signaling blocks inhibitor of B kinase activity and nuclear factor B DNA binding. The Journal of Biological Chemistry 274:31868-31874, 1999.
Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell 87:13-20, 1996.
Baldwin AS Jr. The NF-Kappa B and I kappa B proteins: new discoveries and insights. Annual Review of Immunology 14:649-683, 1996.
Barnes PJ, Karin M. Mechanism of disease: nuclear factor-Kappa B-a pivotal transcription factor in chronic inflammatory disease. The New England Journal of Medicine 336:1066-1071, 1997.
Bartosz G. Peroxynitrite: mediator of the toxic action of nitric oxide. Acta Biochimica Polonica 43:645-659, 1996.
Beck KF, Eberhardt W, Frank S, Huwiler A, Messmer UK, Muhl H, Pfeilschifter J. Inducible NO synthase: role in cellular signalling. Journal of Expeimental Biology 202:645-653, 1999.
Bessler H, Djaldetti R, Salman H, Bergman M, Djaldetti M. IL-1 beta, IL-2, IL-6 and TNF-alpha production by peripheral blood mononuclear cells from patients with Parkinson’s disease. Biomedicine & Pharmacotherapy 53:141-145, 1999.
Blair LA, Leonard B, Maggi Jr, Anna LS, John AC. Role of Interferon Regulatory Factor-1 in Double-stranded RNA-induced iNOS Expression by Mouse IsletsJ. Biological Chemistry 277:359-365, 2002.
Bogdan C, Nathan C. Modulation of macrophage functions by transforming growth factor beta, interleukin-4, and interleukin-10. Annals of the New York Academy of Sciences 685:713-739, 1993.
Calver A, Colier J, Vallance P. Nitric oxide and cardiovascular control. Experimental Physiology 78:303-326, 1993.
Carrico CJ. The elusive pathophysiology of the multiple organ failure syndrome. Annals of Surgery 218:109-110, 1993.
Cavanaugh PF, Jr, Meredith MP, Buchanan W, Dole MJ, Reddy MS, Jeffcoat MK. Coordinate production of PGE2 and IL-1 in the gingival crevicular fluid of adults with periodontitis. Journal of Periodontal Research 33:75-82, 1998.
Chavail SR, Utsunomiya T, Forse RA. Increased survival after cecal ligation and puncture in mice consuming diets enriched with sesame seed oil. Critical Care Medicine 29:140-143, 2001.
Chen L, Zhou J, Gao W, Jiang YZ. Action of NO and TNF-alpha release of rats with cadmium loading in malfunction of multiple system organ. Acta Physiologica Sinica 55:535-540, 2003.
Dantzker D. Oxygen delivery and unilization in sepsis. Critical Care Clinical 5:81-98, 1989.
Davies MG, Fulton GJ, Hagen PO. Clinical biology of nitric oxide. British Journal of Surgery 82:1598-1610, 1995.
de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. The Journal of Experimental Medicine174:1209-1220, 1991.
Delgado M, Ganea D. Inhibition of IFN--induced janus kinase-1-STAT1 activation in macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Journal of Immunology 165:3051-3057, 2000.
Encarnacion MR, Kenneth D. Identification of B/macrophage progenitors in adult bone marrow. Seminars in Immunology 14:371-376, 2002.
Enkhbaatar P, Okajima K, Uchiba M, Isobe H, Okabe H. Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide. Thrombosis & Haemostasis 86:1573-1577, 2001.
Faraci FM. Endothelium-derived vasoactive factors and regulation of the cerebral circulation. Neurosurgery 33:648-658, 1993.
Fink MP, Heard SO. Laboratory models of sepsis and septic shock. Journal of Surgery Research 49:186-196, 1990.
Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. IL-10 inhibits cytokine production by activated macrophages. Journal of Immunology 147:3815-3822, 1991.
Freidovich I. Fundamental aspects of reactive oxygen species, or what’s the matter with oxygen? Annals of the New York Academy of Sciences 893:13-18, 1999.
Ganster RW, Geller DA. Complex regulation of human inducible nitric oxide synthase gene transcription by Stat 1 and NF-B. Proceedings of the National Academy of Sciences 98:8638-8643, 2001.
Gerard C, Bruyns C, Marchant A. Interleukin 10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxaemia. Journal of Experimental Medicine 177:547-550, 1993.
Gupta AK, Diaz RA, Higham S, Kone BC.  MSH inhibits induction of C/EBP-DNA binding activity and NOS2 gene transcription in macrophages. Kidney International 57:2239-2248, 2000.
Hanania T, Hohnson KM. Regulation of neurotransmitter release by endogenous nitric oxide in striatal slices. European Journal of Pharmacology 359:111-117, 1998.
Hartmut K, Schwarz PM, Forstermann U. Regulation of the expression of inducible nitric oxide synthase. Biological Chemistry 384:1343-1364, 2003.
Hayashi H, Yoshimura T, Chen JY. Chemotaxis of macrophage in inflammation. Comparative Immunology, Microbiology and Infectious Diseases 8:73-87, 1985.
Hensmann M, Kwiatkowski D. Cellular basis of early cytokine response to Plasmodium falciparum. Infection and Immunity 66:2364-2371, 2001.
Hon WM, Khoo HE, Moochhala S. Nitric oxide in septic shock: directions for future therapy. Annals of the Academy of Medicine 27: 414-421, 1998.
Hooper WC. The relationship between inflammation and the anticoagulant pathway: the emerging role of endothelial nitric oxide synthase (eNOS). Current Pharmaceutical Design 10:923-927, 2004.
Hou RC, Chen HL, Tzen JT, Jeng KG. Effect of sesame antioxidants on LPS-induced NO production by BV2 microgial cells. Neuroimmunology 14:1815-1819, 2003.
Howard M, O’Garra A. Biological properties of interleukin 10. Immunology Today 13:198-200, 1992.
Hsu DZ, Liu MY. Sesame oil attenuates multiple organ failure and increases survival rate during endotoxemia in rats. Critical Care Medicine 30:1859-1862, 2002.
Hsu DZ, Liu MY. Sesame oil protects against Lipopolysaccharide-stimulated oxidative stress in rats. Critical care Medicine 32:227-231, 2004.
Hsu DZ, Chiang PJ, Chien SP, Huang BM, Liu MY. Parenteral sesame oil attenuates oxidative stress after endotoxin intoxication in rats. Toxicology 196:147-53, 2004.
Ignarro LJ. Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. Journal Physiology and Pharmacology 53:503-514, 2002.
Iskit AB, Guc O. Effects of endothelin and nitric oxide on organ injury, mesenteric ischemia, and survival in experimental models of septic shock. Acta Pharmacologica Sinica 24:953-957, 2003.
Jung F, Palmer LA, Zhou N, Johns RA. Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes. Circulation Research 86:319-325, 2000.
Keller R, Keist R, Joller P, Mulsch A. Coordinate up- and down-modulation of inducible nitric oxide synthase, nitric oxide production, and tumoricidal activity in rat bone-marrow-derived mononuclear phagocytes by lipopolysaccharide and gram-negative bacteria. Biochemical & Biophysical Research Commun-ications 211:183-189, 1995.
Kernacki KA, Goebel DJ, Poosch MS, Hazilett LD. Early cytokine and chemokine gene expression during Pseudomonas aeruginosa corneal infection in mice. Infection and Immunity 66:376-379, 1998.
Heller M, Kerwin JFJr. The arginine-nitric oxide pathway: a target for new drugs. Medicine Research Review 14:23-74, 1994.
Kiss JP. Role of nitric oxide in the regulation of monoaminergic neurotransmission. Brain Research Bulletin 52:459-466, 2000.
Kleinert H, Schwarz PM, and Forstermann U. Regulation of the expression of inducible nitric oxide synthase. Biological Chemistry 384:1343-1364, 2003.
Kristof AS, Marks-Konczalik J, Moss J. Mitogen-activated protein kinases mediate activator protein-1-dependent human inducible nitric-oxide synthase promoter activation. The Journal of Biological Chemistry 274:8445-8452, 2001.
Kubo Y, Yasunaga M, Masuhara M, Terai S, Nakamura T, Okita K. Hepatocyte proliferation induced in rats by lead nitrate is suppressed by several tumor necrosis factor alpha inhibitors. Hepatology 23:104-114, 1996.
Lauw FN, Pajkrt D, Hack CE, Kurimoto M, van Deventer SJ, van der Poll T. Proinflammatory effects of IL-10 during human endotoxaemia. Journal of Immunology 165:2783-2789, 2000.
Lee SW, Kang TM. Effects of nitric oxide on the Ca2+-activated potassium channels in smooth muscle cells of the human corpus cavernosum. Urological Research 29:359-365, 2001.
Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. New England Journal of Medicine 323:236-41, 1990.
Li Z, Miller MW, Luo J. Effects of prenatal exposure to ethanol on the cyclin-dependent kinase system in the developing rat cerebellum. Brain Research 139:237-245, 2002.
Lim I, Gibbons SJ, Lyford GL, Miller SM, Strege PR, Sarr MG, Chatterjee S, Szurszewski JH, Shah VH, Farrugia G. Carbon monoxide activates human intestinal smooth muscle L-type Ca2+ channels through a nitric oxide-dependent mechanism. American Journal of Physiology 228:G7-G14, 2005.
Lowenstein CJ, Alley EW, Raval P, Snowman AM, Snyder SH, Russell S W, Murphy WJ. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proceedings of the National Academy of Sciences 90:9730-9734, 1993.
Macdonald J, Galley HF, Webster NR. Oxidative stress and gene expression in sepsis. British Journal of Anaesthesia 90:221-232, 2003.
MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annual Review of Immunology 15:323-350, 1997.
Malefyt RW, Abrams J, Bennett B, Figdor CG, Vries JE. Interleukin-10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-0 produced by monocytes. Journal of Experimental Medicine 174:1209-1220, 1991.
Marchant A, Devière J, Byl B, Groote DD, Vincent JL, Goldman M. Interleukin-10 production during septicaemia. Lancet 343:707-708, 1994.
Marchetti B, Morale MC, Brouwer J, Tirolo C, Testa N, Caniglia S, Barden N, Amor S, Smith PA, Dijkstra CD. Exposure to a dysfunctional glucocorticoid receptor from early embryonic life programs the resistance to experimental autoimmune encephalo-myelitis via nitric oxide-induced immunosuppression. Journal of Immunology 168:5848-5849, 2002.
Mausumee G, Nigel M. LPS induction of gene expression in human monocytes. Cellular Signaling 13:85-94, 2001.
May MJ, Ghosh S. I-B kinases: kinsmen with different crafts. Science 284:271-273, 1999.
McCord JM. The evolution of free radicals and oxidative stress. The American Journal of Medicine 108:652-659, 2000.
Moncada S, Palmer RJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacological Reviews 43:109-143, 1991.
Moore KW, Riminton DS, Malefyt RW, Vieira P, Mosmann TR. Interleukin 10. Annual Review of Immunology 11:165-190, 1993.
Muijsers RBR, Folkerts G, Henricks PAJ, Sadeghi-Hashjin G, Nijkamp FP. Peroxynitrite: a two-faced metabolite of NO. Life Science 60:1833–1845, 1997.
Murphey ED, Traber DL. Protective effect of tumor necrosis factor-alpha against subsequent endotoxaemia in mice is mediated, in part, by interleukin-10. Critical Care Medicine 29:1761-1766, 2001.
Nathan C, Xie QW. Nitric oxide syntheses: roles, tolls, controls. Cell 78: 915-918, 1994.
Neumann DA, Lane JR, Allen GS, Herskowitz A, Rose NR. Viral myocarditis leading to cardiomyopathy: do cytokines contribute to pathogenesis? Clinical Immunology 68:181-90, 1993.
Numata M, Koizumi S, Horita S, Ueno Y, Yamagami M, Taniguchi N. Different antigen characterization between granulocyte progenitor cells (CFC-G) and monocyte-macrophage progenitor cells (CFC-M). Experimental Hematology 13: 827-832, 1985.
Oswald IP, Wynn TA, Sher A, James SL. NO as an effector molecule of parasite killing: modulation of its synthesis by cytokines. ComparativeBiochemistry and Physiology. Part C, Pharmacology, Toxicology & Endocrinology 108:11-18, 1994.
Patel HJ, Belvisi MG, Donnelly LE, Yacoub MH, Chung KF, Mitchell JA. Constitutive expressions of type I NOS in human airway smooth muscle cells: evidence for an antiproliferative role. FASEB Journal 13:1810-1816, 1999.
Perrella MA, Pellacani A, Wiesel P, Chin MT, Foster LC, Ibanez M, Hsieh CM, Reeves R, Yet SF, Lee ME. High mobility group-I(Y) protein facilitates nuclear factor-B binding and transactivation of the inducible nitric-oxide synthase promoter/enhancer. The Journal of Biological Chemistry 274:9045-9052, 1999.
Prast H, Philippu A. Nitric oxide as modulator of neuronal function, Progress in Neurobiology 64: 51-68, 2001.
Rajasekaran M, Hellstrom WJ, Sikka SC. Nitric oxide induces oxidative stress and mediates cto human cavernosal cells in culture. Journal of Andrology 22:34-39, 2001.
Rangel-Fraysti MS, Pittet D, Costigan M, Hwang T, Davis CS and Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS): A prospective study. The Journal of the American Medical Association 273:117-123, 1995.
Sarkar SR, Kaitwatcharachai C, Levin NW. Nitric oxide and hemodialysis. Seminars in Dialysis 17:224-228, 2004.
Schiffrin EL. The endothelium and control of blood vessel function in health and disease. Clinical & Investigative Medicine 17:602-620, 1994.
Schottelius AJG, Mayo MW, Sartor RB, Baldwin AS Jr. Interleukin-10 signaling blocks inhibitor of B kinase activity and neuclear factor B DNA binding. The Journal of Biological Chemistry 274:31868-31874, 1999.
Schumann RR, Leong SR, Flaggs GW. Structure and function of lipopolysaccharide binding protein. Science 249:1429-1431, 1990.
Sedgwick JD, Riminton DS, Cyster JG, Korner H,: Tumor necrosis factor: a master-regulator of leukocyte movement. Immunology Today 21:110-113, 2000.
Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer seqences. Cell 46:705-716, 1986.
Spector WG. The macrophage in inflammation. Series Haematologica 3:131-144, 1970.
Stefano GB, Goumon Y, Bilfinger TV, Welters ID, Cadet P. Basal nitric oxide limits immune, nervous and cardiovascular excitation: human endothelia express a mu opiate receptor. Progress in Neurobiology 60:513-530, 2000.
Suganuma M, Okabe S, Marino MW, Sakai A, Sueoka E, Fujiki H. Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice. Cancer Research 59:4516-4518, 1999.
Synder SH, Bredt DS. Nitric oxide as a neuronal messenger. Trends in Pharmacological Sciences 12:125-128, 1991.
Takeshita S, Gage JR, Kishimoto T, Vredevoe DL, Martinez-Maza O. Differential regulation of IL-6 gene transcription and expression by IL-4 and IL-10 in human monocyte cell lines. Journal of Immunology 156:2591-2598, 1996.
Thiemermann C. Nitric oxide in septic shock. General Pharmacology 29:159-166, 1997.
Thorup C, Persson AE. Nitric oxide and renal blood pressure regulation. Current Opinion in Nephrology & Hypertension 7:197-202, 1998.
van Deventer SJH, BJH, Bullar HR, ten Cate JW, Sturk A, Pauw W. Endotoxaemia: An early predictor of specticaemia in febrile patients. Lancet 1:605-609, 1988.
Ward PA, Lentsch AB. Endogenous regulation of the acute inflammatory response. Molecular and Cellular Biochemistry 234/235:225-228, 2002.
Wijdicks EF, Stevens M. The role of hypotension in septic encephalopathy following surgical prodedures. Archives of Neurology 49:653-656, 1992.
Willems F, Marchant A, Delville JP, Gerard C, Delvaux A, Velu T, de Boer M, Goldman M. Interleukin-10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes. European Journal of Immunology 24:1007-1009, 1994.
Wollert KC, Drexler H. Regulation of cardiac remodeling by nitric oxide: focus on cardiac myocyte hypertrophy and apoptosis. Heart Failure Reviews 7:317-325, 2002.
Wu CC, Ruetten H, Thiemermann C. Comparison of the effects of aminoguanidine and N omega-nitro-L-arginine methyl ester on the multiple organ dysfunction caused by endotoxaemia in the rat. European Journal of Pharmacology 300:99-104, 1996.
Yakugaku Z. Journal of the Pharmaceutical Society of Japan 114:901-10, 1994.
Yang H, Young DW, Gusovsky F, Chow JC. Cellular events mediated by lipopolysaccharide-stimulated Toll-like receptor 4: MD-2 is required for activation of mitogen-activated protein kinases and Elk-1. The Journal of Biological Chemistry 275:20861-20866, 2000.
Zanzinger J. Mechanisms of action of nitric oxide in the brain stem: role of oxidative stress. Autonomic Neuroscience-Basic & Clinical 98