異丙酚是一種短效性的靜脈注射麻醉劑，不僅具有麻醉作用，還包括抗氧化、保護神經和免疫調節的作用。異丙酚注輸症候群是給予過量的異丙酚所導致，此症狀會造成心肌細胞、骨骼肌細胞、神經細胞及免疫細胞死亡。然而，其中的分子機制依然尚未明瞭。肝醣合成酶激酶-3β (GSK)-3β 在細胞生長、發炎及凋亡中扮演多因子的角色。此研究中，為了找尋一個能防止與異丙酚注輸症候群相關細胞死亡的策略，我們假設過量異丙酚係透過肝醣合成酶激酶-3β 誘導巨噬細胞進行細胞凋亡。過量的異丙酚在老鼠的巨噬細胞RAW264.7和BV2會引起吞噬作用的抑制及細胞凋亡。異丙酚造成溶酶體胞膜通透性增加 (LMP) 及粒線體穿膜電位 (MTP) 減低，隨之導致細胞凋亡。粒線體穿膜電位的穩定者環孢靈和硫胱天門冬氨酸蛋白酶抑制劑的前處理降低異丙酚引起的細胞凋亡。此外，異丙酚誘導細胞自溶酵素B活化，而細胞自溶酵素B的抑制劑z-FA-fmk可以降低異丙酚引起的LMP、MTP減低和細胞凋亡。我們發現異丙酚導致Bcl-2家族蛋白表現量的失衡。藉由抑制劑藥物或慢病毒-基底短髮夾狀核醣核酸的方式抑制肝醣合成酶激酶-3β 可以阻止異丙酚引起的溶酶體胞膜通透性增加、粒線體穿膜電位減低和細胞凋亡。減低肝醣合成酶激酶-3β 可以回復異丙酚引起的Mcl-1降解及吞噬作用的抑制。同樣地，過度表現Mcl-1抵抗異丙酚引起的溶酶體/粒線體細胞凋亡。根據機制的研究，我們證明過量異丙酚藉由未知的機制抑制肝醣合成酶激酶-3β 的負向調節者如Akt、胞外訊息調控激酶和p70 S6激酶而活化肝醣合成酶激酶-3β。根據研究的結果，給予巨噬細胞過量異丙酚會透過抑制Akt、胞外訊息調控激酶和p70 S6激酶進而活化肝醣合成酶激酶-3β 使Mcl-1不穩定，隨後引發溶酶體功能失常、粒線體的損害和硫胱天門冬氨酸蛋白酶媒介的細胞凋亡訊息引起吞噬作用的抑制和細胞凋亡。綜觀而論，抑制肝醣合成酶激酶-3β 在臨床上可能可以提供做為一個新的有效方法去避免因異丙酚注輸症候群造成的免疫抑制及細胞死亡。

Propofol, a short-acting intravenous anesthetic agent, has not only sedative effects but also antioxidant, neuroprotective, and immunomodulatory effects. Propofol infusion syndrome is caused by overdose treatment of propofol which causes cell death including cardiomyocytes, skeletal muscle cells, neuronal cells, and immune cells; however, its molecular mechanism remains unclear. Glycogen synthase kinase-3β (GSK)-3β plays multifactorial roles in cell growth, inflammation, and apoptosis. In searching a strategy for preventing propofol infusion syndrome-associated cell death, in this study, we hypothesize that overdose treatment of propofol induces macrophages undergoing cell apoptosis through GSK-3β. Overdose propofol caused phagocytic inhibition and apoptosis in murine macrophages RAW264.7 as well as BV2. Propofol caused lysosomal membrane permeabilization (LMP) and loss of mitochondrial transmembrane potential (MTP) followed by cell apoptosis. MTP stabilizer cyclosporine A and caspase inhibitors decrease propofol-induced cell apoptosis. Furthermore, propofol caused activation of cathepsin B and z-FA-fmk, a cathepsin B inhibitor, decreases propofol-induced LMP, MTP loss, and cell apoptosis. We found that propofol deregulated Bcl-2 family proteins. Inhibiting GSK-3β by pharmacological inhibitor or lentiviral-based short hairpin RNA approach prevented propofol-induced LMP, MTP loss, and cell apoptosis. Knockdown of GSK-3β rescued propofol-induced Mcl-1 degradation and phagocytic inhibition. Similarly, Mcl-1 overexpression resisted propofol-induced lysosomal/mitochondrial apoptosis. Mechanistic studies demonstrated that overdose propofol activated GSK-3β by inhibiting the upstream negative regulators of GSK-3β, such as Akt, ERK, and p70 S6K through unknown mechanisms. Finally, we proved that overdose propofol-induced phagocytic inhibition was through a GSK-3β-regulated manner in macrophages. According to these results, overdose treatment of propofol causes phagocytic inhibition and cell apoptosis are through inhibiting Akt, ERK, and p70 S6K, and further induces activation of GSK-3β to destabilize Mcl-1 followed by lysosomal dysfunction, mitochondrial injury, and caspase-mediated apoptotic signaling in macrophages. Taken together, inhibition of GSK-3βmay provide a new effective way on clinical to avoid immunosuppression and cell death in propofol infusion syndrome

Aoyagi Y, Fujita N, Tsuruo T (2005). Stabilization of integrin-linked kinase by binding to Hsp90. Biochem Biophys Res Commun 331(4): 1061-1068.

Ayala A, Chaudry IH (1996). Immune dysfunction in murine polymicrobial sepsis: mediators, macrophages, lymphocytes and apoptosis. Shock 6 Suppl 1: S27-38.

Azar ZM, Mehdi MZ, Srivastava AK (2006). Activation of insulin-like growth factor type-1 receptor is required for H2O2-induced PKB phosphorylation in vascular smooth muscle cells. Can J Physiol Pharmacol 84(7): 777-786.

Beurel E, Jope RS (2006). The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol 79(4): 173-189.

Bikkavilli RK, Feigin ME, Malbon CC (2008). p38 mitogen-activated protein kinase regulates canonical Wnt-beta-catenin signaling by inactivation of GSK3beta. J Cell Sci 121(Pt 21): 3598-3607.

Bivik C, Ollinger K (2008). JNK mediates UVB-induced apoptosis upstream lysosomal membrane permeabilization and Bcl-2 family proteins. Apoptosis 13(9): 1111-1120.

Blomgran R, Zheng L, Stendahl O (2007). Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization. J Leukoc Biol 81(5): 1213-1223.

Boya P, Kroemer G (2008). Lysosomal membrane permeabilization in cell death. Oncogene 27(50): 6434-6451.

Branca D, Roberti MS, Lorenzin P, Vincenti E, Scutari G (1991). Influence of the anesthetic 2,6-diisopropylphenol on the oxidative phosphorylation of isolated rat liver mitochondria. Biochem Pharmacol 42(1): 87-90.

Brasil LJ, San-Miguel B, Kretzmann NA, Amaral JL, Zettler CG, Marroni N, et al. (2006). Halothane induces oxidative stress and NF-kappaB activation in rat liver: protective effect of propofol. Toxicology 227(1-2): 53-61.

Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC (2003). Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22(53): 8608-8618.

Brewster JL, Linseman DA, Bouchard RJ, Loucks FA, Precht TA, Esch EA, et al. (2006). Endoplasmic reticulum stress and trophic factor withdrawal activate distinct signaling cascades that induce glycogen synthase kinase-3 beta and a caspase-9-dependent apoptosis in cerebellar granule neurons. Mol Cell Neurosci 32(3): 242-253.

Cantley LC, Neel BG (1999). New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 96(8): 4240-4245.

Chen J, Gu Y, Shao Z, Luo J, Tan Z (2010). Propofol protects against hydrogen peroxide-induced oxidative stress and cell dysfunction in human umbilical vein endothelial cells. Mol Cell Biochem 339(1-2): 43-54.

Chen RM, Wu CH, Chang HC, Wu GJ, Lin YL, Sheu JR, et al. (2003). Propofol suppresses macrophage functions and modulates mitochondrial membrane potential and cellular adenosine triphosphate synthesis. Anesthesiology 98(5): 1178-1185.

Chiu WT, Lin YL, Chou CW, Chen RM (2009). Propofol inhibits lipoteichoic acid-induced iNOS gene expression in macrophages possibly through downregulation of toll-like receptor 2-mediated activation of Raf-MEK1/2-ERK1/2-IKK-NFkappaB. Chem Biol Interact 181(3): 430-439.

Chwieralski CE, Welte T, Buhling F (2006). Cathepsin-regulated apoptosis. Apoptosis 11(2): 143-149.

Cirman T, Oresic K, Mazovec GD, Turk V, Reed JC, Myers RM, et al. (2004). Selective disruption of lysosomes in HeLa cells triggers apoptosis mediated by cleavage of Bid by multiple papain-like lysosomal cathepsins. J Biol Chem 279(5): 3578-3587.

Cremer OL (2009). The propofol infusion syndrome: more puzzling evidence on a complex and poorly characterized disorder. Crit Care 13(6): 1012.

Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559): 785-789.

De Giorgi F, Lartigue L, Bauer MK, Schubert A, Grimm S, Hanson GT, et al. (2002). The permeability transition pore signals apoptosis by directing Bax translocation and multimerization. FASEB J 16(6): 607-609.

Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S (1998). Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci U S A 95(19): 11211-11216.

Diehl AM, Hoek JB (1999). Mitochondrial uncoupling: role of uncoupling protein anion carriers and relationship to thermogenesis and weight control "the benefits of losing control". J Bioenerg Biomembr 31(5): 493-506.

Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, et al. (2005). Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 19(2): 159-170.

Eldar-Finkelman H, Seger R, Vandenheede JR, Krebs EG (1995). Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. J Biol Chem 270(3): 987-990.

Embi N, Rylatt DB, Cohen P (1980). Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 107(2): 519-527.

Feldstein AE, Werneburg NW, Li Z, Bronk SF, Gores GJ (2006). Bax inhibition protects against free fatty acid-induced lysosomal permeabilization. Am J Physiol Gastrointest Liver Physiol 290(6): G1339-1346.

Ferri KF, Kroemer G (2001). Organelle-specific initiation of cell death pathways. Nat Cell Biol 3(11): E255-263.

Fudickar A, Bein B (2009). Propofol infusion syndrome: update of clinical manifestation and pathophysiology. Minerva Anestesiol 75(5): 339-344.

Garrido R, Mattson MP, Hennig B, Toborek M (2001). Nicotine protects against arachidonic-acid-induced caspase activation, cytochrome c release and apoptosis of cultured spinal cord neurons. J Neurochem 76(5): 1395-1403.

Guicciardi ME, Leist M, Gores GJ (2004). Lysosomes in cell death. Oncogene 23(16): 2881-2890.

Hartigan JA, Xiong WC, Johnson GV (2001). Glycogen synthase kinase 3beta is tyrosine phosphorylated by PYK2. Biochem Biophys Res Commun 284(2): 485-489.

Hashiramoto A, Murata M, Kawazoe T, Yoshida K, Akiyama C, Shiozawa K, et al. (2010). Heat shock protein 90 maintains the tumour-like character of rheumatoid synovial cells by stabilizing integrin-linked kinase, extracellular signal-regulated kinase and protein kinase B. Rheumatology (Oxford).

Heller A, Heller S, Blecken S, Urbaschek R, Koch T (1998). Effects of intravenous anesthetics on bacterial elimination in human blood in vitro. Acta Anaesthesiol Scand 42(5): 518-526.

Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, et al. (1999). Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 27(7): 1230-1251.

Hsu BG, Yang FL, Lee RP, Peng TC, Chen HI (2005). Effects of post-treatment with low-dose propofol on inflammatory responses to lipopolysaccharide-induced shock in conscious rats. Clin Exp Pharmacol Physiol 32(1-2): 24-29.

Huang WC, Lin YS, Chen CL, Wang CY, Chiu WH, Lin CF (2009). Glycogen synthase kinase-3beta mediates endoplasmic reticulum stress-induced lysosomal apoptosis in leukemia. J Pharmacol Exp Ther 329(2): 524-531.

Ivaska J, Nissinen L, Immonen N, Eriksson JE, Kahari VM, Heino J (2002). Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2A and dephosphorylation of Akt and glycogen synthase kinase 3 beta. Molecular and cellular biology 22(5): 1352-1359.

Jaattela M, Cande C, Kroemer G (2004). Lysosomes and mitochondria in the commitment to apoptosis: a potential role for cathepsin D and AIF. Cell Death Differ 11(2): 135-136.

Jawan B, Kao YH, Goto S, Pan MC, Lin YC, Hsu LW, et al. (2008). Propofol pretreatment attenuates LPS-induced granulocyte-macrophage colony-stimulating factor production in cultured hepatocytes by suppressing MAPK/ERK activity and NF-kappaB translocation. Toxicol Appl Pharmacol 229(3): 362-373.

Jeon YK, Park CH, Kim KY, Li YC, Kim J, Kim YA, et al. (2007). The heat-shock protein 90 inhibitor, geldanamycin, induces apoptotic cell death in Epstein-Barr virus-positive NK/T-cell lymphoma by Akt down-regulation. J Pathol 213(2): 170-179.

Jope RS, Johnson GV (2004). The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29(2): 95-102.

Karashima Y, Oike M, Takahashi S, Ito Y (2002). Propofol prevents endothelial dysfunction induced by glucose overload. Br J Pharmacol 137(5): 683-691.

Kim R, Emi M, Tanabe K (2006). Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol 57(5): 545-553.

Kroemer G, Blomgren K (2007). Mitochondrial cell death control in familial Parkinson disease. PLoS Biol 5(7): e206.

Kroemer G, Jaattela M (2005). Lysosomes and autophagy in cell death control. Nature reviews 5(11): 886-897.

Kwak SH, Choi JI, Park JT (2004). Effects of propofol on endotoxin-induced acute lung injury in rabbit. J Korean Med Sci 19(1): 55-61.

Li J, Han B, Ma X, Qi S (2010). The effects of propofol on hippocampal caspase-3 and Bcl-2 expression following forebrain ischemia-reperfusion in rats. Brain Res 1356: 11-23.

Lin CF, Chen CL, Chiang CW, Jan MS, Huang WC, Lin YS (2007). GSK-3beta acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis. J Cell Sci 120(Pt 16): 2935-2943.

Linseman DA, Butts BD, Precht TA, Phelps RA, Le SS, Laessig TA, et al. (2004). Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 24(44): 9993-10002.

Liu YC, Chang AY, Tsai YC, Chan JY (2009). Differential protection against oxidative stress and nitric oxide overproduction in cardiovascular and pulmonary systems by propofol during endotoxemia. J Biomed Sci 16: 8.

Lochhead PA, Kinstrie R, Sibbet G, Rawjee T, Morrice N, Cleghon V (2006). A chaperone-dependent GSK3beta transitional intermediate mediates activation-loop autophosphorylation. Mol Cell 24(4): 627-633.

Marik PE (2005). Propofol: an immunomodulating agent. Pharmacotherapy 25(5 Pt 2): 28S-33S.

Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006). Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21(6): 749-760.

Mikawa K, Akamatsu H, Nishina K, Shiga M, Maekawa N, Obara H, et al. (1998). Propofol inhibits human neutrophil functions. Anesth Analg 87(3): 695-700.

Motsch J, Roggenbach J (2004). [Propofol infusion syndrome]. Anaesthesist 53(10): 1009-1022; quiz 1023-1004.

Pap M, Cooper GM (1998). Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J Biol Chem 273(32): 19929-19932.

Perrier ND, Baerga-Varela Y, Murray MJ (2000). Death related to propofol use in an adult patient. Crit Care Med 28(8): 3071-3074.

Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A (2009). Glycogen synthase kinase 3: more than a namesake. Br J Pharmacol 156(6): 885-898.

Rodriguez-Lopez JM, Sanchez-Conde P, Lozano FS, Nicolas JL, Garcia-Criado FJ, Cascajo C, et al. (2006). Laboratory investigation: effects of propofol on the systemic inflammatory response during aortic surgery. Can J Anaesth 53(7): 701-710.

Schenkman KA, Yan S (2000). Propofol impairment of mitochondrial respiration in isolated perfused guinea pig hearts determined by reflectance spectroscopy. Crit Care Med 28(1): 172-177.

Seeling JM, Miller JR, Gil R, Moon RT, White R, Virshup DM (1999). Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A. Science (New York, N.Y 283(5410): 2089-2091.

Shao H, Li J, Zhou Y, Ge Z, Fan J, Shao Z, et al. (2008). Dose-dependent protective effect of propofol against mitochondrial dysfunction in ischaemic/reperfused rat heart: role of cardiolipin. Br J Pharmacol 153(8): 1641-1649.

Song HK, Jeong DC (2004). The effect of propofol on cytotoxicity and apoptosis of lipopolysaccharide-treated mononuclear cells and lymphocytes. Anesth Analg 98(6): 1724-1728, table of contents.

Song XM, Wang YL, Li JG, Wang CY, Zhou Q, Zhang ZZ, et al. (2009). Effects of propofol on pro-inflammatory cytokines and nuclear factor kappaB during polymicrobial sepsis in rats. Mol Biol Rep 36(8): 2345-2351.

Stambolic V, Woodgett JR (1994). Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J 303 ( Pt 3): 701-704.

Stoka V, Turk B, Schendel SL, Kim TH, Cirman T, Snipas SJ, et al. (2001). Lysosomal protease pathways to apoptosis. Cleavage of bid, not pro-caspases, is the most likely route. J Biol Chem 276(5): 3149-3157.

Stoka V, Turk B, Turk V (2005). Lysosomal cysteine proteases: structural features and their role in apoptosis. IUBMB life 57(4-5): 347-353.

Straiko MM, Young C, Cattano D, Creeley CE, Wang H, Smith DJ, et al. (2009). Lithium protects against anesthesia-induced developmental neuroapoptosis. Anesthesiology 110(4): 862-868.

Strasser A, O'Connor L, Dixit VM (2000). Apoptosis signaling. Annu Rev Biochem 69: 217-245.

Sutherland C, Leighton IA, Cohen P (1993). Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J 296 ( Pt 1): 15-19.

Takaono M, Yogosawa T, Okawa-Takatsuji M, Aotsuka S (2002). Effects of intravenous anesthetics on interleukin (IL)-6 and IL-10 production by lipopolysaccharide-stimulated mononuclear cells from healthy volunteers. Acta Anaesthesiol Scand 46(2): 176-179.

Takemoto Y (2005). Dose effects of propofol on hemodynamic and cytokine responses to endotoxemia in rats. J Anesth 19(1): 40-44.

Taniguchi T, Kanakura H, Takemoto Y, Kidani Y, Yamamoto K (2003). Effects of ketamine and propofol on the ratio of interleukin-6 to interleukin-10 during endotoxemia in rats. Tohoku J Exp Med 200(2): 85-92.

Taniguchi T, Kanakura H, Yamamoto K (2002). Effects of posttreatment with propofol on mortality and cytokine responses to endotoxin-induced shock in rats. Crit Care Med 30(4): 904-907.

Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements JL, et al. (2008). Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science 320(5876): 667-670.

Troussard AA, Mawji NM, Ong C, Mui A, St -Arnaud R, Dedhar S (2003). Conditional knock-out of integrin-linked kinase demonstrates an essential role in protein kinase B/Akt activation. J Biol Chem 278(25): 22374-22378.

Tsuchiya M, Asada A, Arita K, Utsumi T, Yoshida T, Sato EF, et al. (2002). Induction and mechanism of apoptotic cell death by propofol in HL-60 cells. Acta Anaesthesiol Scand 46(9): 1068-1074.

Turk B, Turk V (2009). Lysosomes as "suicide bags" in cell death: myth or reality? J Biol Chem 284(33): 21783-21787.

Vanlersberghe C, Camu F (2008). Propofol. Handb Exp Pharmacol(182): 227-252.

Vasile B, Rasulo F, Candiani A, Latronico N (2003). The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 29(9): 1417-1425.

Wang B, Luo T, Chen D, Ansley DM (2007). Propofol reduces apoptosis and up-regulates endothelial nitric oxide synthase protein expression in hydrogen peroxide-stimulated human umbilical vein endothelial cells. Anesth Analg 105(4): 1027-1033, table of contents.

Wang CY, Lin YS, Su WC, Chen CL, Lin CF (2009). Glycogen synthase kinase-3 and Omi/HtrA2 induce annexin A2 cleavage followed by cell cycle inhibition and apoptosis. Mol Biol Cell 20(19): 4153-4161.

Wang Q, Wang X, Hernandez A, Hellmich MR, Gatalica Z, Evers BM (2002). Regulation of TRAIL expression by the phosphatidylinositol 3-kinase/Akt/GSK-3 pathway in human colon cancer cells. J Biol Chem 277(39): 36602-36610.

Wang QM, Fiol CJ, DePaoli-Roach AA, Roach PJ (1994). Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation. J Biol Chem 269(20): 14566-14574.

Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, et al. (2001). Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292(5517): 727-730.

Werneburg NW, Guicciardi ME, Bronk SF, Kaufmann SH, Gores GJ (2007). Tumor necrosis factor-related apoptosis-inducing ligand activates a lysosomal pathway of apoptosis that is regulated by Bcl-2 proteins. J Biol Chem 282(39): 28960-28970.

Wong JM (2010). Propofol infusion syndrome. Am J Ther 17(5): 487-491.

Woodgett JR (1991). cDNA cloning and properties of glycogen synthase kinase-3. Methods Enzymol 200: 564-577.

Woodgett JR (1990). Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J 9(8): 2431-2438.

Wu GJ, Tai YT, Chen TL, Lin LL, Ueng YF, Chen RM (2005). Propofol specifically inhibits mitochondrial membrane potential but not complex I NADH dehydrogenase activity, thus reducing cellular ATP biosynthesis and migration of macrophages. Ann N Y Acad Sci 1042: 168-176.

Xia Z, Luo T, Liu HM, Wang F, Xia ZY, Irwin MG, et al. (2010). L-arginine enhances nitrative stress and exacerbates tumor necrosis factor-alpha toxicity to human endothelial cells in culture: prevention by propofol. J Cardiovasc Pharmacol 55(4): 358-367.

Ypsilantis P, Politou M, Mikroulis D, Pitiakoudis M, Lambropoulou M, Tsigalou C, et al. (2007). Organ toxicity and mortality in propofol-sedated rabbits under prolonged mechanical ventilation. Anesth Analg 105(1): 155-166.