Preclinical studies suggest complex nutraceutical strategies may have potential for preventing and managing sepsis

Alternative Therapies in Health and Medicine

Volumn 21, Issue , 2015, Pages 56-67

  McCarty, Mark F ^a  

^a Catalytic Longevity in Carlsbad   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMAL; DIET SUPPLEMENTATION; DRUG SCREENING; HUMAN; SEPSIS;

ANIMALS; DIETARY SUPPLEMENTS; DRUG EVALUATION, PRECLINICAL; HUMANS; SEPSIS;

EID: 84942597738     PISSN: 10786791     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (195)

1. Bosshart H, Heinzelmann M. Targeting bacterial endotoxin: two sides of a coin. Ann N Y Acad Sci. January 2007;1096:1-17.
2. Mathurin P, Deng QG, Keshavarzian A, Choudhary S, Holmes EW, Tsukamoto H. Exacerbation of alcoholic liver injury by enteral endotoxin in rats. Hepatology. 2000;32(5):1008-1017.
3. Roh YS, Seki E. Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J Gastroenterol Hepatol. 2013;28(suppl 1):38-42.
4. Frasinariu OE, Ceccarelli S, Alisi A, Moraru E, Nobili V. Gut-liver axis and fibrosis in nonalcoholic fatty liver disease: an input for novel therapies. Dig Liver Dis. 2013;45(7):543-551.
5. Ilan Y. Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis. World J Gastroenterol. 2012;18(21):2609-2618.
6. Kristof AS, Marks-Konczalik J, Moss J. Mitogen-activated protein kinases mediate activator protein-1-dependent human inducible nitric-oxide synthase promoter activation. J Biol Chem. 2001;276(11):8445-8452.
7. De Stefano D, Maiuri MC, Iovine B, Ialenti A, Bevilacqua MA, Carnuccio R. The role of NF-kappaB, IRF-1, and STAT-1alpha transcription factors in the iNOS gene induction by gliadin and IFN-gamma in RAW 264.7 macrophages. J Mol Med (Berl). 2006;84(1):65-74.
8. Huang H, Rose JL, Hoyt DG. p38 Mitogen-activated protein kinase mediates synergistic induction of inducible nitric-oxide synthase by lipopolysaccharide and interferon-gamma through signal transducer and activator of transcription 1 Ser727 phosphorylation in murine aortic endothelial cells. Mol Pharmacol. 2004;66(2):302-311.
9. Xie QW, Whisnant R, Nathan C. Promoter of the mouse gene encoding calciumindependent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med. 1993;177(6):1779-1784.
10. Horiuchi M, Hayashida W, Akishita M, et al. Interferon-gamma induces AT(2) receptor expression in fibroblasts by Jak/STAT pathway and interferon regulatory factor- 1. Circ Res. 2000;86(2):233-240.
11. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1(2):135-145.
12. Matsuzawa A, Saegusa K, Noguchi T, et al. ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat Immunol. 2005;6(6):587-592.
13. Ichijo H, Nishida E, Irie K, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997;275(5296):90-94.
14. Winzen R, Kracht M, Ritter B, et al. The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. EMBO J. 1999;18(18):4969-4980.
15. Rousseau S, Morrice N, Peggie M, Campbell DG, Gaestel M, Cohen P. Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs. EMBO J. 2002;21(23):6505-6514.
16. Murakami A. Chemoprevention with phytochemicals targeting inducible nitric oxide synthase. Forum Nutr. 2009;61:193-203.
17. Fechir M, Linker K, Pautz A, et al. Tristetraprolin regulates the expression of the human inducible nitric-oxide synthase gene. Mol Pharmacol. 2005;67(6):2148-2161.
18. Lasa M, Mahtani KR, Finch A, Brewer G, Saklatvala J, Clark AR. Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade. Mol Cell Biol. 2000;20(12):4265-4274.
19. Winzen R, Gowrishankar G, Bollig F, Redich N, Resch K, Holtmann H. Distinct domains of AU-rich elements exert different functions in mRNA destabilization and stabilization by p38 mitogen-activated protein kinase or HuR. Mol Cell Biol. 2004;24(11):4835-4847.
20. Subbaramaiah K, Marmo TP, Dixon DA, Dannenberg AJ. Regulation of cyclooxgenase-2 mRNA stability by taxanes: evidence for involvement of p38, MAPKAPK-2, and HuR. J Biol Chem. 2003;278(39):37637-37647.
21. Jin SH, Kim TI, Yang KM, Kim WH. Thalidomide destabilizes cyclooxygenase-2 mRNA by inhibiting p38 mitogen-activated protein kinase and cytoplasmic shuttling of HuR. Eur J Pharmacol. 2007;558(1-3):14-20.
22. Farooq F, Balabanian S, Liu X, Holcik M, MacKenzie A. p38 Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR. Hum Mol Genet. 2009;18(21):4035-4045.
23. Tiedje C, Ronkina N, Tehrani M, et al. The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation. PLoS Genet. 2012;8(9):e1002977.
24. Xu J, Su X, Shi JX, Sun H, Wu T, Shi Y. Mitogen-activated protein kinaseactivated protein kinase 2 regulates tumor necrosis factor-induced interleukin-6 expression via human antigen R. Chin Med J (Engl). 2013;126(22):4322-4326.
25. Cho JH, Lee JH, Lee EJ, et al. 8beta-hydroxy-3-oxopimar-15-ene exerts antiinflammatory effects by inhibiting ROS-mediated activation of the TRAF6- ASK1-p38 signaling pathway. Immunopharmacol Immunotoxicol. 2013;35(5):549-557.
26. Simi A, Ingelman-Sundberg M, Tindberg N. Neuroprotective agent chlomethiazole attenuates c-fos, c-jun, and AP-1 activation through inhibition of p38 MAP kinase. J Cereb Blood Flow Metab. 2000;20(7):1077-1088.
27. Peng SS, Chen CY, Xu N, Shyu AB. RNA stabilization by the AU-rich element binding protein, HuR, an ELAV protein. EMBO J. 1998;17(12):3461-3470.
28. Miletic AV, Graham DB, Montgrain V, et al. Vav proteins control MyD88- dependent oxidative burst. Blood. 2007;109(8):3360-3368.
29. Park HS, Jung HY, Park EY, Kim J, Lee WJ, Bae YS. Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B. J Immunol. 2004;173(6):3589-3593.
30. Simon F, Fernandez R. Early lipopolysaccharide-induced reactive oxygen species production evokes necrotic cell death in human umbilical vein endothelial cells. J Hypertens. 2009;27(6):1202-1216.
31. Wu F, Tyml K, Wilson JX. iNOS expression requires NADPH oxidase-dependent redox signaling in microvascular endothelial cells. J Cell Physiol. 2008;217(1):207-214.
32. Wheeler MD, Thurman RG. Production of superoxide and TNF-alpha from alveolar macrophages is blunted by glycine. Am J Physiol. 1999;277(5, pt 1):L952-L959.
33. Check J, Byrd CL, Menio J, Rippe RA, Hines IN, Wheeler MD. Src kinase participates in LPS-induced activation of NADPH oxidase. Mol Immunol. 2010;47(4):756-762.
34. Saitoh M, Nishitoh H, Fujii M, et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998;17(9):2596-2606.
35. Liu Y, Min W. Thioredoxin promotes ASK1 ubiquitination and degradation to inhibit ASK1-mediated apoptosis in a redox activity-independent manner. Circ Res. 2002;90(12):1259-1266.
36. Lin WN, Lin CC, Cheng HY, Yang CM. Regulation of cyclooxygenase-2 and cytosolic phospholipase A2 gene expression by lipopolysaccharide through the RNA-binding protein HuR: involvement of NADPH oxidase, reactive oxygen species and mitogen-activated protein kinases. Br J Pharmacol. 2011;163(8):1691-1706.
37. Asehnoune K, Strassheim D, Mitra S, Kim JY, Abraham E. Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B. J Immunol. 2004;172(4):2522-2529.
38. Ryan KA, Smith MF Jr, Sanders MK, Ernst PB. Reactive oxygen and nitrogen species differentially regulate Toll-like receptor 4-mediated activation of NF-kappa B and interleukin-8 expression. Infect Immun. 2004;72(4):2123-2130.
39. Hsing CH, Lin MC, Choi PC, et al. Anesthetic propofol reduces endotoxic inflammation by inhibiting reactive oxygen species-regulated Akt/IKKbeta/ NF-kappaB signaling. PLoS One. 2011;6(3):e17598.
40. Lin CC, Lee IT, Yang YL, Lee CW, Kou YR, Yang CM. Induction of COX-2/ PGE(2)/IL-6 is crucial for cigarette smoke extract-induced airway inflammation: role of TLR4-dependent NADPH oxidase activation. Free Radic Biol Med. 2010;48(2):240-254.
41. Yu Q, Nie SP, Wang JQ, et al. Toll-like receptor 4-mediated ROS signaling pathway involved in Ganoderma atrum polysaccharide-induced tumor necrosis factor-alpha secretion during macrophage activation. Food Chem Toxicol. April 2014;66:14-22.
42. Sanlioglu S, Williams CM, Samavati L, et al. Lipopolysaccharide induces Rac1- dependent reactive oxygen species formation and coordinates tumor necrosis factor-alpha secretion through IKK regulation of NF-kappa B. J Biol Chem. 2001;276(32):30188-30198.
43. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitindependent kinase of MKK and IKK. Nature. 2001;412(6844):346-351.
44. Fraczek J, Kim TW, Xiao H, et al. The kinase activity of IL-1 receptor-associated kinase 4 is required for interleukin-1 receptor/toll-like receptor-induced TAK1- dependent NFkappaB activation. J Biol Chem. 2008;283(46):31697-31705.
45. Li X. IRAK4 in TLR/IL-1R signaling: possible clinical applications. Eur J Immunol. 2008;38(3):614-618.
46. Kim TW, Staschke K, Bulek K, et al. A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity. J Exp Med. 2007;204(5):1025-1036.
47. Li Q, Harraz MM, Zhou W, et al. Nox2 and Rac1 regulate H2O2-dependent recruitment of TRAF6 to endosomal interleukin-1 receptor complexes. Mol Cell Biol. 2006;26(1):140-154.
48. Ojaniemi M, Glumoff V, Harju K, Liljeroos M, Vuori K, Hallman M. Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages. Eur J Immunol. 2003;33(3):597-605.
49. Sizemore N, Lerner N, Dombrowski N, Sakurai H, Stark GR. Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappa B. J Biol Chem. 2002;277(6):3863-3869.
50. Lanone S, Bloc S, Foresti R, et al. Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats. FASEB J. 2005;19(13):1890-1892.
51. Matsumoto H, Ishikawa K, Itabe H, Maruyama Y. Carbon monoxide and bilirubin from heme oxygenase-1 suppresses reactive oxygen species generation and plasminogen activator inhibitor-1 induction. Mol Cell Biochem. 2006;291(1-2):21-28.
52. Jiang F, Roberts SJ, Datla SR, Dusting GJ. NO modulates NADPH oxidase function via heme oxygenase-1 in human endothelial cells. Hypertension. 2006;48(5):950-957.
53. Datla SR, Dusting GJ, Mori TA, Taylor CJ, Croft KD, Jiang F. Induction of heme oxygenase-1 in vivo suppresses NADPH oxidase derived oxidative stress. Hypertension. 2007;50(4):636-642.
54. Basuroy S, Bhattacharya S, Leffler CW, Parfenova H. Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF-alpha in cerebral vascular endothelial cells. Am J Physiol Cell Physiol. 2009;296(3):C422-C432.
55. Oh SW, Lee ES, Kim S, et al. Bilirubin attenuates the renal tubular injury by inhibition of oxidative stress and apoptosis. BMC Nephrol. May 2013;14:105.
56. Fujii M, Inoguchi T, Sasaki S, et al. Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. Kidney Int. 2010;78(9):905-919.
57. Wang WW, Smith DL, Zucker SD. Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats. Hepatology. 2004;40(2):424-433.
58. Sarady-Andrews JK, Liu F, Gallo D, et al. Biliverdin administration protects against endotoxin-induced acute lung injury in rats. Am J Physiol Lung Cell Mol Physiol. 2005;289(6):L1131-L1137.
59. Overhaus M, Moore BA, Barbato JE, Behrendt FF, Doering JG, Bauer AJ. Biliverdin protects against polymicrobial sepsis by modulating inflammatory mediators. Am J Physiol Gastrointest Liver Physiol. 2006;290(4):G695-G703.
60. Ahanger AA, Leo MD, Gopal A, Kant V, Tandan SK, Kumar D. Pro-healing effects of bilirubin in open excision wound model in rats [published online ahead of print June 20, 2014]. Int Wound J. doi:10.1111/iwj.12319.
61. Wegiel B, Baty CJ, Gallo D, et al. Cell surface biliverdin reductase mediates biliverdin-induced anti-inflammatory effects via phosphatidylinositol 3-kinase and Akt. J Biol Chem. 2009;284(32):21369-21378.
62. Sinal CJ, Bend JR. Aryl hydrocarbon receptor-dependent induction of cyp1a1 by bilirubin in mouse hepatoma hepa 1c1c7 cells. Mol Pharmacol. 1997;52(4):590-599.
63. Phelan D, Winter GM, Rogers WJ, Lam JC, Denison MS. Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch Biochem Biophys. 1998;357(1):155-163.
64. Quintana FJ, Murugaiyan G, Farez MF, et al. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2010;107(48):20768-20773.
65. Bock KW, Kohle C. Contributions of the Ah receptor to bilirubin homeostasis and its antioxidative and atheroprotective functions. Biol Chem. 2010;391(6):645-653.
66. Benson JM, Shepherd DM. Dietary ligands of the aryl hydrocarbon receptor induce anti-inflammatory and immunoregulatory effects on murine dendritic cells. Toxicol Sci. 2011;124(2):327-338.
67. Cai LJ, Yu DW, Gao Y, Yang C, Zhou HM, Chen ZH. Activation of aryl hydrocarbon receptor prolongs survival of fully mismatched cardiac allografts. J Huazhong Univ Sci Technolog Med Sci. 2013;33(2):199-204.
68. Wagage S, John B, Krock BL, et al. The aryl hydrocarbon receptor promotes IL-10 production by NK cells. J Immunol. 2014;192(4):1661-1670.
69. Wang C, Ye Z, Kijlstra A, Zhou Y, Yang P. Activation of the aryl hydrocarbon receptor affects activation and function of human monocyte-derived dendritic cells. Clin Exp Immunol. 2014;177(2):521-530.
70. Apetoh L, Quintana FJ, Pot C, et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol. 2010;11(9):854-861.
71. Wegiel B, Gallo D, Csizmadia E, et al. Biliverdin inhibits Toll-like receptor-4 (TLR4) expression through nitric oxide-dependent nuclear translocation of biliverdin reductase. Proc Natl Acad Sci U S A. 2011;108(46):18849-18854.
72. McCarty MF. Clinical potential of Spirulina as a source of phycocyanobilin. J Med Food. 2007;10(4):566-570.
73. Zheng J, Inoguchi T, Sasaki S, et al. Phycocyanin and phycocyanobilin from Spirulina platensis protect against diabetic nephropathy by inhibiting oxidative stress. Am J Physiol Regul Integr Comp Physiol. 2013;304(2):R110-R120.
74. Terry MJ, Maines MD, Lagarias JC. Inactivation of phytochrome- and phycobiliprotein-chromophore precursors by rat liver biliverdin reductase. J Biol Chem. 1993;268(35):26099-26106.
75. Romay C, Delgado R, Remirez D, Gonzalez R, Rojas A. Effects of phycocyanin extract on tumor necrosis factor-alpha and nitrite levels in serum of mice treated with endotoxin. Arzneimittelforschung. 2001;51(9):733-736.
76. Cherng SC, Cheng SN, Tarn A, Chou TC. Anti-inflammatory activity of c-phycocyanin in lipopolysaccharide-stimulated RAW 264.7 macrophages. Life Sci. 2007;81(19-20):1431-1435.
77. Leung PO, Lee HH, Kung YC, Tsai MF, Chou TC. Therapeutic effect of C-phycocyanin extracted from blue green algae in a rat model of acute lung injury induced by lipopolysaccharide. Evid Based Complement Alternat Med. 2013;2013:916590.
78. Chen JC, Liu KS, Yang TJ, Hwang JH, Chan YC, Lee IT. Spirulina and C-phycocyanin reduce cytotoxicity and inflammation-related genes expression of microglial cells [published online ahead of print June 7, 2012]. Nutr Neurosci.
79. Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med. 2008;74(13):1526-1539.
80. Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M. Keap1 is a redoxregulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol. 2004;24(24):10941-10953.
81. Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL. Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem. 1999;274(37):26071-26078.
82. Wild AC, Moinova HR, Mulcahy RT. Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf 2. J Biol Chem. 1999;274(47):33627-33636.
83. Lee JS, Surh YJ. Nrf2 as a novel molecular target for chemoprevention. Cancer Lett. 2005;224(2):171-184.
84. Rushworth SA, Chen XL, Mackman N, Ogborne RM, O’Connell MA. Lipopolysaccharide-induced heme oxygenase-1 expression in human monocytic cells is mediated via Nrf2 and protein kinase C. J Immunol. 2005;175(7):4408-4415.
85. Fourquet S, Guerois R, Biard D, Toledano MB. Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation. J Biol Chem. 2010;285(11):8463-8471.
86. Thimmulappa RK, Lee H, Rangasamy T, et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest. 2006;116(4):984-995.
87. Kong X, Thimmulappa R, Kombairaju P, Biswal S. NADPH oxidase-dependent reactive oxygen species mediate amplified TLR4 signaling and sepsis-induced mortality in Nrf2-deficient mice. J Immunol. 2010;185(1):569-577.
88. Flier J, Van Muiswinkel FL, Jongenelen CA, Drukarch B. The neuroprotective antioxidant alpha-lipoic acid induces detoxication enzymes in cultured astroglial cells. Free Radic Res. 2002;36(6):695-699.
89. Cao Z, Tsang M, Zhao H, Li Y. Induction of endogenous antioxidants and phase 2 enzymes by alpha-lipoic acid in rat cardiac H9C2 cells: protection against oxidative injury. Biochem Biophys Res Commun. 2003;310(3):979-985.
90. Jia Z, Hallur S, Zhu H, Li Y, Misra HP. Potent upregulation of glutathione and NAD(P)H:quinone oxidoreductase 1 by alpha-lipoic acid in human neuroblastoma SH-SY5Y cells: protection against neurotoxicant-elicited cytotoxicity. Neurochem Res. 2008;33(5):790-800.
91. Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365-2370.
92. Demarco VG, Scumpia PO, Bosanquet JP, Skimming JW. Alpha-lipoic acid inhibits endotoxin-stimulated expression of iNOS and nitric oxide independent of the heat shock response in RAW 264.7 cells. Free Radic Res. 2004;38(7):675-682.
93. Sung MJ, Kim W, Ahn SY, et al. Protective effect of alpha-lipoic acid in lipopolysaccharide-induced endothelial fractalkine expression. Circ Res. 2005;97(9):880-890.
94. De Marco VG, Bosanquet JP, Rawlani VR, Skimming JW. Lipoic acid decreases exhaled nitric oxide concentrations in anesthetized endotoxemic rats. Vascul Pharmacol. 2005;43(6):404-410.
95. Skibska B, Jozefowicz-Okonkwo G, Goraca A. Protective effects of early administration of alpha-lipoic acid against lipopolysaccharide-induced plasma lipid peroxidation. Pharmacol Rep. 2006;58(3):399-404.
96. Goraca A, Jozefowicz-Okonkwo G. Protective effects of early treatment with lipoic acid in LPS-induced lung injury in rats. J Physiol Pharmacol. 2007;58(3):541-549.
97. Goraca A, Skibska B. Beneficial effect of alpha-lipoic acid on lipopolysaccharideinduced oxidative stress in bronchoalveolar lavage fluid. J Physiol Pharmacol. 2008;59(2):379-386.
98. Vanasco V, Cimolai MC, Evelson P, Alvarez S. The oxidative stress and the mitochondrial dysfunction caused by endotoxemia are prevented by alpha-lipoic acid. Free Radic Res. 2008;42(9):815-823.
99. Goraca A, Piechota A, Huk-Kolega H. Effect of alpha-lipoic acid on LPS-induced oxidative stress in the heart. J Physiol Pharmacol. 2009;60(1):61-68.
100. Lin YC, Lai YS, Chou TC. The protective effect of alpha-lipoic acid in lipopolysaccharide-induced acute lung injury is mediated by heme oxygenase-1. Evid Based Complement Alternat Med. 2013;2013:590363.
101. Meng J, Guo M, Yu J, et al. Effects of lipoic acid on cytokines and chemokines in astrocytes stimulated with lipopolysaccharide [in Chinese]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2014;30(4):346-350.
102. Zhang WJ, Wei H, Hagen T, Frei B. Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc Natl Acad Sci U S A. 2007;104(10):4077-4082.
103. Vanasco V, Cimolai MC, Evelson P, Alvarez S. The oxidative stress and the mitochondrial dysfunction caused by endotoxemia are prevented by alpha-lipoic acid. Free Radic Res. 2008;42(9):815-823.
104. Goraca A, Asłanowicz-Antkowiak K. Prophylaxis with alpha-lipoic acid against lipopolysaccharide-induced brain injury in rats. Arch Immunol Ther Exp (Warsz). 2009;57(2):141-146.
105. Cadirci E, Altunkaynak BZ, Halici Z, et al. Alpha-lipoic acid as a potential target for the treatment of lung injury caused by cecal ligation and puncture-induced sepsis model in rats. Shock. 2010;33(5):479-484.
106. Tian YF, Hsieh CH, Hsieh YJ, Chen YT, Peng YJ, Hsieh PS. Alpha-lipoic acid prevents mild portal endotoxaemia-induced hepatic inflammation and beta cell dysfunction. Eur J Clin Invest. 2012;42(6):637-648.
107. Jiang S, Zhu W, Li C, et al. Alpha-lipoic acid attenuates LPS-induced cardiac dysfunction through a PI3K/Akt-dependent mechanism. Int Immunopharmacol. 2013;16(1):100-107.
108. Tian YF, He CT, Chen YT, Hsieh PS. Lipoic acid suppresses portal endotoxemiainduced steatohepatitis and pancreatic inflammation in rats. World J Gastroenterol. 2013;19(18):2761-2771.
109. Suh SH, Lee KE, Kim IJ, et al. Alpha-lipoic acid attenuates lipopolysaccharideinduced kidney injury. Clin Exp Nephrol. 2015;19(1):82-91.
110. Li G, Gao L, Jia J, Gong X, Zang B, Chen W. Alpha-lipoic acid prolongs survival and attenuates acute kidney injury in a rat model of sepsis. Clin Exp Pharmacol Physiol. 2014;41(7):459-468.
111. Li G, Fu J, Zhao Y, Ji K, Luan T, Zang B. Alpha-lipoic acid exerts antiinflammatory effects on lipopolysaccharide-stimulated rat mesangial cells via inhibition of nuclear factor kappa B (NF-kappaB) signaling pathway [published online ahead of print June 25, 2014]. Inflammation. 2015;38(2):510-519.
112. Ward NE, Pierce DS, Chung SE, Gravitt KR, O’Brian CA. Irreversible inactivation of protein kinase C by glutathione. J Biol Chem. 1998;273(20):12558-12566.
113. Domenicotti C, Marengo B, Verzola D, et al. Role of PKC-delta activity in glutathione-depleted neuroblastoma cells. Free Radic Biol Med. 2003;35(5):504-516.
114. Bindoli A, Rigobello MP. Principles in redox signaling: from chemistry to functional significance. Antioxid Redox Signal. 2013;18(13):1557-1593.
115. Conte ML, Carroll KS. The redox biochemistry of protein sulfenylation and sulfinylation. J Biol Chem. 2013;288(37):26480-26488.
116. Yadav V, Marracci G, Lovera J, et al. Lipoic acid in multiple sclerosis: a pilot study. Mult Scler. 2005;11(2):159-165.
117. Hotchkiss RS, Bowling WM, Karl IE, Osborne DF, Flye MW. Calcium antagonists inhibit oxidative burst and nitrite formation in lipopolysaccharidestimulated rat peritoneal macrophages. Shock. 1997;8(3):170-178.
118. Hijioka T, Rosenberg RL, Lemasters JJ, Thurman RG. Kupffer cells contain voltage-dependent calcium channels. Mol Pharmacol. 1992;41(3):435-440.
119. Lin CY, Tsai PS, Hung YC, Huang CJ. L-type calcium channels are involved in mediating the anti-inflammatory effects of magnesium sulphate. Br J Anaesth. 2010;104(1):44-51.
120. Lin TY, Tseng SH, Li SJ, Chen JC, Shieh JS, Chen Y. Tetrandrine increased the survival rate of mice with lipopolysaccharide-induced endotoxemia. J Trauma. 2009;66(2):411-417.
121. Mustafa SB, Olson MS. Effects of calcium channel antagonists on LPS-induced hepatic iNOS expression. Am J Physiol. 1999;277(2, pt 1):G351-G360.
122. Liu X, Yao M, Li N, Wang C, Zheng Y, Cao X. CaMKII promotes TLR-triggered proinflammatory cytokine and type I interferon production by directly binding and activating TAK1 and IRF3 in macrophages. Blood. 2008;112(13):4961-4970.
123. Zhou X, Li J, Yang W. Calcium/calmodulin-dependent protein kinase II regulates cyclooxygenase-2 expression and prostaglandin E2 production by activating cAMP-response element-binding protein in rat peritoneal macrophages. Immunology. 2014;143(2):287-299.
124. Chen F, Sun S, Kuhn DC, et al. Tetrandrine inhibits signal-induced NF-kappa B activation in rat alveolar macrophages. Biochem Biophys Res Commun. 1997;231(1):99-102.
125. Ikejima K, Qu W, Stachlewitz RF, Thurman RG. Kupffer cells contain a glycinegated chloride channel. Am J Physiol. 1997;272(6, pt 1):G1581-G1586.
126. Froh M, Thurman RG, Wheeler MD. Molecular evidence for a glycine-gated chloride channel in macrophages and leukocytes. Am J Physiol Gastrointest Liver Physiol. 2002;283(4):G856-G863.
127. Ikejima K, Iimuro Y, Forman DT, Thurman RG. A diet containing glycine improves survival in endotoxin shock in the rat. Am J Physiol. 1996;271(1, pt 1):G97-G103.
128. Diaz-Flores M, Cruz M, Duran-Reyes G, et al. Oral supplementation with glycine reduces oxidative stress in patients with metabolic syndrome, improving their systolic blood pressure. Can J Physiol Pharmacol. 2013;91(10):855-860.
129. Xu FL, You HB, Li XH, Chen XF, Liu ZJ, Gong JP. Glycine attenuates endotoxininduced liver injury by downregulating TLR4 signaling in Kupffer cells. Am J Surg. 2008;196(1):139-148.
130. Wheeler MD, Rose ML, Yamashima S, et al. Dietary glycine blunts lung inflammatory cell influx following acute endotoxin. Am J Physiol Lung Cell Mol Physiol. 2000;279(2):L390-L398.
131. Feng D, Zhou Y, Xia M, Ma J. Folic acid inhibits lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages by suppressing MAPKs and NF-kappaB activation. Inflamm Res. 2011;60(9):817-822.
132. Zhao M, Chen YH, Chen X, et al. Folic acid supplementation during pregnancy protects against lipopolysaccharide-induced neural tube defects in mice. Toxicol Lett. 2014;224(2):201-208.
133. Zhao M, Chen YH, Dong XT, et al. Folic acid protects against lipopolysaccharide-induced preterm delivery and intrauterine growth restriction through its anti-inflammatory effect in mice. PLoS One. 2013;8(12):e82713.
134. Rezk BM, Haenen GR, van der Vijgh WJ, Bast A. Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity: identification of the antioxidant pharmacophore. FEBS Lett. 2003;555(3):601-605.
135. Antoniades C, Shirodaria C, Warrick N, et al. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation. 2006;114(11):1193-1201.
136. McCarty MF, Barroso-Aranda J, Contreras F. High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals—clinical potential in inflammatory disorders. Med Hypotheses. 2009;73(5):824-834.
137. Stroes ES, van Faassen EE, Yo M, et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res. 2000;86(11):1129-1134.
138. Tawakol A, Migrino RQ, Aziz KS, et al. High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease. J Am Coll Cardiol. 2005;45(10):1580-1584.
139. Moens AL, Claeys MJ, Wuyts FL, et al. Effect of folic acid on endothelial function following acute myocardial infarction. Am J Cardiol. 2007;99(4):476-481.
140. Moens AL, Champion HC, Claeys MJ, et al. High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of highenergy phosphates and reduces postreperfusion injury. Circulation. 2008;117(14):1810-1819.
141. Gori T, Saunders L, Ahmed S, Parker JD. Effect of folic acid on nitrate tolerance in healthy volunteers: differences between arterial and venous circulation. J Cardiovasc Pharmacol. 2003;41(2):185-190.
142. Lazalde-Ramos BP, Zamora-Perez AL, Sosa-Macias M, Guerrero-Velazquez C, Zuniga-Gonzalez GM. DNA and oxidative damages decrease after ingestion of folic acid in patients with type 2 diabetes. Arch Med Res. 2012;43(6):476-481.
143. McCarty MF. Oster rediscovered—mega-dose folate for symptomatic atherosclerosis. Med Hypotheses. 2007;69(2):325-332.
144. Cuzzocrea S, Mazzon E, Di Paola R, et al. A role for nitric oxide-mediated peroxynitrite formation in a model of endotoxin-induced shock. J Pharmacol Exp Ther. 2006;319(1):73-81.
145. Seija M, Baccino C, Nin N, et al. Role of peroxynitrite in sepsis-induced acute kidney injury in an experimental model of sepsis in rats. Shock. 2012;38(4):403-410.
146. Nin N, El-Assar M, Sanchez C, et al. Vascular dysfunction in sepsis: effects of the peroxynitrite decomposition catalyst MnTMPyP. Shock. 2011;36(2):156-161.
147. Soriano FG, Lorigados CB, Pacher P, Szabo C. Effects of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. Shock. 2011;35(6):560-566.
148. Sundararaj KP, Samuvel DJ, Li Y, et al. Simvastatin suppresses LPS-induced MMP-1 expression in U937 mononuclear cells by inhibiting protein isoprenylation-mediated ERK activation. J Leukoc Biol. 2008;84(4):1120-1129.
149. Guha M, O’Connell MA, Pawlinski R, et al. Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression. Blood. 2001;98(5):1429-1439.
150. Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res. 2012;129(3):290-295.
151. Arai M, Uchiba M, Komura H, Mizuochi Y, Harada N, Okajima K. Metformin, an antidiabetic agent, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro. J Pharmacol Exp Ther. 2010;334(1):206-213.
152. Gao MY, Chen L, Yang L, Yu X, Kou JP, Yu BY. Berberine inhibits LPS-induced TF procoagulant activity and expression through NF-kappaB/p65, Akt and MAPK pathway in THP-1 cells. Pharmacol Rep. 2014;66(3):480-484.
153. Tsoyi K, Jang HJ, Nizamutdinova IT, et al. Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice. Br J Pharmacol. 2011;162(7):1498-1508.
154. Gras V, Bouffandeau B, Montravers PH, Lalau JD. Effect of metformin on survival rate in experimental sepsis. Diabetes Metab. 2006;32(2):147-150.
155. Bergheim I, Luyendyk JP, Steele C, et al. Metformin prevents endotoxininduced liver injury after partial hepatectomy. J Pharmacol Exp Ther. 2006;316(3):1053-1061.
156. Gu L, Li N, Gong J, Li Q, Zhu W, Li J. Berberine ameliorates intestinal epithelial tight-junction damage and down-regulates myosin light chain kinase pathways in a mouse model of endotoxinemia. J Infect Dis. 2011;203(11):1602-1612.
157. Feng AW, Yu C, Mao Q, Li N, Li QR, Li JS. Berberine hydrochloride attenuates cyclooxygenase-2 expression in rat small intestinal mucosa during acute endotoxemia. Fitoterapia. 2011;82(7):976-982.
158. Li HM, Wang YY, Wang HD, et al. Berberine protects against lipopolysaccharide-induced intestinal injury in mice via alpha 2 adrenoceptorindependent mechanisms. Acta Pharmacol Sin. 2011;32(11):1364-1372.
159. Feng AW, Gao W, Zhou GR, et al. Berberine ameliorates COX-2 expression in rat small intestinal mucosa partially through PPARgamma pathway during acute endotoxemia. Int Immunopharmacol. 2012;12(1):182-188.
160. Wu YH, Chuang SY, Hong WC, Lai YJ, Chang GJ, Pang JH. Berberine reduces leukocyte adhesion to LPS-stimulated endothelial cells and VCAM-1 expression both in vivo and in vitro. Int J Immunopathol Pharmacol. 2012;25(3):741-750.
161. Kumar P, Shen Q, Pivetti CD, Lee ES, Wu MH, Yuan SY. Molecular mechanisms of endothelial hyperpermeability: implications in inflammation. Expert Rev Mol Med. June 2009;11:e19.
162. Gertzberg N, Neumann P, Rizzo V, Johnson A. NAD(P)H oxidase mediates the endothelial barrier dysfunction induced by TNF-alpha. Am J Physiol Lung Cell Mol Physiol. 2004;286(1):L37-L48.
163. Chen W, Pendyala S, Natarajan V, Garcia JG, Jacobson JR. Endothelial cell barrier protection by simvastatin: GTPase regulation and NADPH oxidase inhibition. Am J Physiol Lung Cell Mol Physiol. 2008;295(4):L575-L583.
164. Wu F, Wilson JX. Peroxynitrite-dependent activation of protein phosphatase type 2A mediates microvascular endothelial barrier dysfunction. Cardiovasc Res. 2009;81(1):38-45.
165. Gandhirajan RK, Meng S, Chandramoorthy HC, et al. Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. J Clin Invest. 2013;123(2):887-902.
166. Rochfort KD, Collins LE, Murphy RP, Cummins PM. Downregulation of bloodbrain barrier phenotype by proinflammatory cytokines involves NADPH oxidase-dependent ROS generation: consequences for interendothelial adherens and tight junctions. PLoS One. 2014;9(7):e101815.
167. Zhang L, Li J, Young LH, Caplan MJ. AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc Natl Acad Sci U S A. 2006;103(46):17272-17277.
168. Zheng B, Cantley LC. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc Natl Acad Sci U S A. 2007;104(3):819-822.
169. Xing J, Wang Q, Coughlan K, Viollet B, Moriasi C, Zou MH. Inhibition of AMPactivated protein kinase accentuates lipopolysaccharide-induced lung endothelial barrier dysfunction and lung injury in vivo. Am J Pathol. 2013;182(3):1021-1030.
170. Takata F, Dohgu S, Matsumoto J, et al. Metformin induces up-regulation of blood-brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells. Biochem Biophys Res Commun. 2013;433(4):586-590.
171. Castanares-Zapatero D, Bouleti C, Sommereyns C, et al. Connection between cardiac vascular permeability, myocardial edema, and inflammation during sepsis: role of the alpha1AMP-activated protein kinase isoform. Crit Care Med. 2013;41(12):e411-e422.
172. Jian MY, Alexeyev MF, Wolkowicz PE, Zmijewski JW, Creighton JR. Metforminstimulated AMPK-alpha1 promotes microvascular repair in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2013;305(11):L844-L855.
173. Dixit M, Bess E, Fisslthaler B, et al. Shear stress-induced activation of the AMPactivated protein kinase regulates FoxO1a and angiopoietin-2 in endothelial cells. Cardiovasc Res. 2008;77(1):160-168.
174. Creighton J, Jian M, Sayner S, Alexeyev M, Insel PA. Adenosine monophosphateactivated kinase alpha1 promotes endothelial barrier repair. FASEB J. 2011;25(10):3356-3365.
175. Fiedler U, Reiss Y, Scharpfenecker M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006;12(2):235-239.
176. Benest AV, Kruse K, Savant S, et al. Angiopoietin-2 is critical for cytokineinduced vascular leakage. PLoS One. 2013;8(8):e70459.
177. Li N, Gu L, Qu L, et al. Berberine attenuates pro-inflammatory cytokine-induced tight junction disruption in an in vitro model of intestinal epithelial cells. Eur J Pharm Sci. 2010;40(1):1-8.
178. Amasheh M, Fromm A, Krug SM, et al. TNFalpha-induced and berberineantagonized tight junction barrier impairment via tyrosine kinase, Akt and NFkappaB signaling. J Cell Sci. December 2010;123(pt 23):4145-4155.
179. Gu L, Li N, Gong J, Li Q, Zhu W, Li J. Berberine ameliorates intestinal epithelial tight-junction damage and down-regulates myosin light chain kinase pathways in a mouse model of endotoxinemia. J Infect Dis. 2011;203(11):1602-1612.
180. Gu L, Li N, Yu W, et al. Berberine reduces rat intestinal tight junction injury induced by ischemia-reperfusion associated with the suppression of inducible nitric oxide synthesis. Am J Chin Med. 2013;41(6):1297-1312.
181. Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377(9768):849-862.
182. Okumura A, Pitha PM, Yoshimura A, Harty RN. Interaction between Ebola virus glycoprotein and host toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS 1. J Virol. 2010;84(1):27-33.
183. Martinez O, Valmas C, Basler CF. Ebola virus-like particle-induced activation of NF-kappaB and Erk signaling in human dendritic cells requires the glycoprotein mucin domain. Virology. 2007;364(2):342-354.
184. Chang TH, Kubota T, Matsuoka M, et al. Ebola Zaire virus blocks type I interferon production by exploiting the host SUMO modification machinery. PLoS Pathog. 2009;5(6):e1000493.
185. Yen B, Mulder LC, Martinez O, Basler CF. Molecular basis for ebolavirus VP35 suppression of human dendritic cell maturation. J Virol. 2014;88(21):12500-12510.
186. Gupta M, Spiropoulou C, Rollin PE. Ebola virus infection of human PBMCs causes massive death of macrophages, CD4 and CD8 T cell sub-populations in vitro. Virology. 2007;364(1):45-54.
187. Wahl-Jensen VM, Afanasieva TA, Seebach J, Stroher U, Feldmann H, Schnittler HJ. Effects of Ebola virus glycoproteins on endothelial cell activation and barrier function. J Virol. 2005;79(16):10442-10450.
188. Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E, Hensley LE. Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J Infect Dis. 2003;188(11):1618-1629.
189. Hill-Batorski L, Halfmann P, Neumann G, Kawaoka Y. The cytoprotective enzyme heme oxygenase-1 suppresses Ebola virus replication. J Virol. 2013;87(24):13795-13802.
190. Ogborne RM, Rushworth SA, O’Connell MA. Alpha-lipoic acid-induced heme oxygenase-1 expression is mediated by nuclear factor erythroid 2-related factor 2 and p38 mitogen-activated protein kinase in human monocytic cells. Arterioscler Thromb Vasc Biol. 2005;25(10):2100-2105.
191. Horsfall LJ, Nazareth I, Pereira SP, Petersen I. Gilbert’s syndrome and the risk of death: a population-based cohort study. J Gastroenterol Hepatol. 2013;28(10):1643-1647.
192. El Hafidi M, Perez I, Zamora J, Soto V, Carvajal-Sandoval G, Banos G. Glycine intake decreases plasma free fatty acids, adipose cell size, and blood pressure in sucrose-fed rats. Am J Physiol Regul Integr Comp Physiol. 2004;287(6):R1387-R1393.
193. Wheeler MD, Ikejema K, Enomoto N, et al. Glycine: a new anti-inflammatory immunonutrient. Cell Mol Life Sci. 1999;56(9-10):843-856.
194. McCarty MF. AMPK activation—protean potential for boosting healthspan. Age (Dordr). 2014;36(2):641-663.
195. Bannister CA, Holden SE, Jenkins-Jones S, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014;16(11):1165-1173.