Oxidative stress in intensive care unit patients: a review of glutathione linked metabolism and lipid peroxidation
Abstract
Despite clear evidence of increased oxidative stress in the blood and tissues of critically ill intensive care unit patients, consistent beneficial effects of many different antioxidants have not been observed, and antioxidant therapy has not yet translated into widely accepted clinical practice. The reasons for this are unclear, likely rooted in the complex and context dependent free radical behavior of antioxidants interacting with the process of lipid peroxidation. Control of lipid peroxidation is a crucial requirement for the beneficial effects of antioxidants, but the interactions of biological antioxidant defenses with the potentially harmful free radical behavior of pharmacological antioxidants complicates the dose and selection of the optimal antioxidants. Glutathione, the primary small molecule antioxidant in biological systems, is the primary enzymatic oxidative stress defense that operates in the context of glutathione-linked antioxidant enzymes to metabolize many harmful products of lipid peroxidation to mercapturic acids. Recently, the mercapturic acid transporter protein, RLIP76 (human RALBP1 gene), has been shown to have a critical role in glutathione linked oxidative stress defenses. These findings provide a rationale for new approaches towards selection and dosing of antioxidant to improve their clinical benefit.
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Darling GE, Duff JH, Mustard RA, et al. Multiorgan failure in critically ill patients. Can J Surg 1988;31(3):172-6.
Silfvast T, Pettila V, Ihalainen A, et al. Multiple organ failure and outcome of critically ill patients with haematological malignancy. Acta Anaesthesiol Scand 2003;47(3):301-6.
Sakr Y, Lobo SM, Moreno RP, et al. Patterns and early evolution of organ failure in the intensive care unit and their relation to outcome. Critical Care 2012;16(6): R222.
Ulldemolins M, Roberts JA, Lipman J, et al. Antibiotic dosing in multiple organ dysfunction syndrome. Chest 2011;139(5):1210-20.
Karapetsa M, Pitsika M, Goutzourelas N, et al. Oxidative status in ICU patients with septic shock. Food Chem Toxicol 2013; 61:106-11.
Trentadue R, Fiore F, Massaro F, et al. Induction of mitochondrial dysfunction and oxidative stress in human fibroblast cultures exposed to serum from septic patients. Life Sci 2012;91(7-8):237-43.
Barja G. Updating the mitochondrial free radical theory of aging: an integrated view, key aspects, and confounding concepts. Antioxid Redox Signal 2013;19(12):1420-45.
Hong SH, Kwak JH, Paik JK, et al. Association of polymorphisms in FADS gene with age-related changes in serum phospholipid polyunsaturated fatty acids and oxidative stress markers in middle-aged nonobese men. Clin Interv Aging 2013; 8:585-96.
Liguori I, Russo G, Curcio F, et al. Oxidative stress, aging, and diseases. Clin Interv Aging 2018; 13:757-72.
Cervantes Gracia K, Llanas-Cornejo D, Husi H. CVD and Oxidative Stress. J Clin Med 2017;6(2).
Higdon JV, Frei B. Obesity and oxidative stress: a direct link to CVD? Arterioscler Thromb Vasc Biol 2003;23(3):365-7.
Yang Y, Sharma R, Sharma A, et al. Lipid peroxidation and cell cycle signaling: 4-hydroxynonenal, a key molecule in stress mediated signaling. Acta Biochim Pol 2003;50(2):319-36.
Sharma A, Patrick B, Li J, et al. Glutathione S-transferases as antioxidant enzymes: small cell lung cancer (H69) cells transfected with hGSTA1 resist doxorubicin-induced apoptosis. Arch Biochem Biophys 2006;452(2):165-73.
Awasthi S, Singhal SS, Yadav S, et al. A central role of RLIP76 in regulation of glycemic control. Diabetes 2010;59(3):714-25.
Zimniak P. What is the proximal cause of aging? Front Genet 2012; 3:189.
Zimniak P. Relationship of electrophilic stress to aging. Free Radic Biol Med 2011;51(6):1087- 105.
Zimniak P. 4-Hydroxynonenal and fat storage: A paradoxical pro-obesity mechanism? Cell Cycle 2010;9(17):3393-4.
McKee T, McKee JR. Biochemistry: The molecular basis of life: Oxford University Press; 2015.
Nelson DL, Cox MM, Lehninger AL. Lehninger principles of biochemistry: W.H. Freeman; 2004.
Prasad S, Gupta SC, Tyagi AK. Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals. Cancer Lett 2017; 387:95-105.
Sakanyan V. Reactive chemicals and electrophilic stress in cancer: A minireview. High Throughput 2018;7(2):12.
Octavia Y, Tocchetti CG, Gabrielson KL, et al. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 2012;52(6):1213-25.
Helmreich E. The biochemistry of cell signaling. Oxford: Oxford University Press; 2001.
Armstrong D, Stratton RD. Oxidative stress and antioxidant protection: The science of free radical biology and disease: Wiley; 2016.
Dormandy TL. Free-radical reaction in biological systems. Ann R Coll Surg Engl 1980;62(3):188-94.
Anastassopoulou J. Free radicals in biological systems. Properties and chemistry of biomolecular systems Dordrecht: Springer Netherlands 1994.
Birben E, Sahiner UM, Sackesen C, et al. Oxidative stress and antioxidant defense. World Allergy Organ J 2012;5(1):9-19.
Quan H, Galbraith PD, Norris CM, et al. Opinions on chelation therapy in patients undergoing coronary angiography: cross-sectional survey. Can J Cardiol 2007;23(8):635-40.
Lu JM, Lin PH, Yao Q, et al. Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J Cell Mol Med 2010;14(4):840-60.
Lobo V, Patil A, Phatak A, et al. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn Rev 2010;4(8):118-26.
Mathur P, Ding Z, Saldeen T, et al. Tocopherols in the prevention and treatment of atherosclerosis and related cardiovascular disease. Clin Cardiol 2015;38(9):570-6.
Kammeyer A, Luiten RM. Oxidation events and skin aging. Ageing Res Rev 2015; 21:16-29.
Forman HJ, Davies KJ, Ursini F. How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo. Free Radic Biol Med 2014;66(0):24-35.
Park LK, Friso S, Choi SW. Nutritional influences on epigenetics and age-related disease. Proc Nutr Soc 2012;71(1):75-83.
Manzanares W, Dhaliwal R, Jiang X, et al. Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis. Critical Care 2012;16(2): R66.
Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: A retrospective before-after study. Chest 2017;151(6):1229-38.
Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J 1999;13(9):1007-24.
Naidu SD, Suzuki T, Yamamoto M, et al. Phenethyl isothiocyanate, a dual activator of transcription factors NRF2 and HSF1. Mol Nutr Food Res 2018;62(18): e1700908.
Shen T, Jiang T, Long M, et al. A curcumin derivative that inhibits vinyl carbamate-induced lung carcinogenesis via activation of the Nrf2 protective response. Antioxid Redox Signal 2015;23(8):651-64.
Sadowska-Bartosz I, Bartosz G. Effect of antioxidants supplementation on aging and longevity. Biomed Res Int 2014; 2014:404680.
Biswas S, Hwang JW, Kirkham PA, Rahman I. Pharmacological and dietary antioxidant therapies for chronic obstructive pulmonary disease. Current medicinal chemistry. 2013;20(12):1496-530.
Ho E, Beaver LM, Williams DE, et al. Dietary factors and epigenetic regulation for prostate cancer prevention. Adv Nutr 2011;2(6):497-510.
Zhou Y, Zheng J, Li Y, et al. Natural polyphenols for prevention and treatment of cancer. Nutrients 2016;8(8):515.
Laughton MJ, Halliwell B, Evans PJ, et al. Antioxidant and pro-oxidant actions of the plant phenolics quercetin, gossypol and myricetin. Effects on lipid peroxidation, hydroxyl radical generation and bleomycin-dependent damage to DNA. Biochem Pharmacol 1989; 38(17):2859-65.
Goodyear-Bruch C, Pierce JD. Oxidative stress in critically ill patients. Am J Crit Care 2002;11(6):543-51.
Oldham KM, Bowen PE. Oxidative stress in critical care: Is antioxidant supplementation beneficial? J Am Diet Assoc 1998;98(9):1001-8.
Crimi E, Sica V, Williams-Ignarro S, et al. The role of oxidative stress in adult critical care. Free Radic Biol Med 2006;40(3):398-406.
Alonso de Vega JM, Diaz J, Serrano E, et al. Oxidative stress in critically ill patients with systemic inflammatory response syndrome. Crit Care Med 2002; 30(8):1782-6.
Goode HF, Cowley HC, Walker BE, Howdle PD, Webster NR. Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Crit Care Med 1995;23(4):646-51.
Nathens AB, Neff MJ, Jurkovich GJ, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 2002;236(6):814-22.
Abiles J, de la Cruz AP, Castano J, et al. Oxidative stress is increased in critically ill patients according to antioxidant vitamins intake, independent of severity: a cohort study. Critical Care 2006;10(5): R146.
Gaustad JV, Simonsen TG, Andersen LM, et al. The effect of sunitinib treatment in human melanoma xenografts: Associations with angiogenic profiles. Transl Oncol 2017;10(2):158-67.
Borrelli E, Roux-Lombard P, Grau GE, et al. Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit Care Med 1996;24(3):392-7.
Roth E, Manhart N, Wessner B. Assessing the antioxidative status in critically ill patients. Curr Opin Clin Nutr Metab Care 2004;7(2):161-8.
Gutteridge JM, Mitchell J. Redox imbalance in the critically ill. Br Med Bull 1999;55(1):49-75.
Motoyama T, Okamoto K, Kukita I, et al. Possible role of increased oxidant stress in multiple organ failure after systemic inflammatory response syndrome. Crit Care Med 2003;31(4):1048-52.
Schorah CJ, Downing C, Piripitsi A, et al. Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients. Am J Clin Nutr 1996;63(5):760-5.
Metnitz PG, Bartens C, Fischer M, et al. Antioxidant status in patients with acute respiratory distress syndrome. Intensive Care Med 1999;25(2):180-5.
Bunnell E, Pacht ER. Oxidized glutathione is increased in the alveolar fluid of patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1993;148(5):1174-8.
Richard C, Lemonnier F, Thibault M, et al. Vitamin E deficiency and lipoperoxidation during adult respiratory distress syndrome. Crit Care Med 1990;18(1):4-9.
Bertrand Y, Pincemail J, Hanique G, et al. Differences in tocopherol-lipid ratios in ARDS and non-ARDS patients. Intensive Care Med 1989;15(2):87-93.
Blackwell TS, Blackwell TR, Holden EP, et al. In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation. J Immunol 1996;157(4):1630-7.
Schwartz MD, Moore EE, Moore FA, et al. Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Crit Care Med 1996;24(8):1285-92.
Spapen HD, Diltoer MW, Nguyen DN, et al. Effects of N-acetylcysteine on microalbuminuria and organ failure in acute severe sepsis: results of a pilot study. Chest 2005;127(4):1413-9.
Rank N, Michel C, Haertel C, et al. N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study. Crit Care Med 2000;28(12):3799-807.
Heller AR, Groth G, Heller SC, et al. N-acetylcysteine reduces respiratory burst but augments neutrophil phagocytosis in intensive care unit patients. Crit Care Med 2001;29(2):272-6.
Aruoma OI, Halliwell B, Hoey BM, et al. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 1989;6(6):593-7.
Meydani SN, Wu D, Santos MS, et al. Antioxidants and immune response in aged persons: overview of present evidence. Am J Clin Nutr 1995;62(6 Suppl):1462S-76S.
Gomez H, Ince C, De Backer D, et al. A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock 2014;41(1):3-11.
McClung JM, Kavazis AN, Whidden MA, et al. Antioxidant administration attenuates mechanical ventilation-induced rat diaphragm muscle atrophy independent of protein kinase B (PKB Akt) signalling. J Physiol 2007;585(Pt 1):203-15.
Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med 2008;358(13):1327-35.
Kavazis AN, Talbert EE, Smuder AJ, et al. Mechanical ventilation induces diaphragmatic mitochondrial dysfunction and increased oxidant production. Free Radic Biol Med 2009;46(6):842-50.
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation 2016;133(4): e38-360.
Mannan H, Stevenson C, Peeters A, et al. Framingham risk prediction equations for incidence of cardiovascular disease using detailed measures for smoking. Heart Int 2010;5(2): e11.
Keaney JF, Larson MG, Vasan RS, et al. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arterioscler Thromb Vasc Biol 2003;23(3):434-9.
Harris T, Cook EF, Garrison R, et al. Body mass index and mortality among nonsmoking older persons. The Framingham heart study. JAMA 1988;259(10):1520-4.
Patel SS, Truong U, King M, et al. Obese adolescents with polycystic ovarian syndrome have elevated cardiovascular disease risk markers. Vasc Med 2017;22(2):85-95.
Erhardt L. Cigarette smoking: an undertreated risk factor for cardiovascular disease. Atherosclerosis 2009;205(1):23-32.
Jugdutt BI, editor. Aging and Heart Failure: Mechanisms and Management. New York: Springer; 2014.
Strait JB, Lakatta EG. Aging-associated cardiovascular changes and their relationship to heart failure. Heart Fail Clin 2012;8(1):143-64.
Yabluchanskiy A, Ma Y, Chiao YA, et al. Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction. Am J Physiol Heart Circ Physiol 2014;306(10):H1398-407.
Mitra S, Goyal T, Mehta JL. Oxidized LDL, LOX-1 and atherosclerosis. Cardiovasc Drugs Ther 2011;25(5):419-29.
Lu J, Mitra S, Wang X, et al. Oxidative stress and lectin-like ox-LDL- receptor LOX-1 in atherogenesis and tumorigenesis. Antioxid Redox Signal 2011;15(8):2301- 33.
Singla S, Hu C, Mizeracki A, et al. Decorin in atherosclerosis. Ther Adv Cardiovasc Dis 2011;5(6):305-14.
Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 1996;19(3):257-67.
Sims CR, Singh SP, Mu S, et al. Rolipram improves outcome in a rat model of infant sepsis-induced cardiorenal syndrome. Front Pharmacol 2017;8(237):237.
Wang H, Chen X, Su Y, et al. p47(phox) contributes to albuminuria and kidney fibrosis in mice. Kidney Int 2015;87(5):948-62.
Sureshbabu A, Ryter SW, Choi ME. Oxidative stress and autophagy: crucial modulators of kidney injury. Redox Biol 2015; 4:208-14.
Marine A, Krager KJ, Aykin-Burns N, et al. Peroxynitrite induced mitochondrial biogenesis following MnSOD knockdown in normal rat kidney (NRK) cells. Redox Biol 2014; 2:348-57.
Kalyanaraman B. Teaching the basics of redox biology to medical and graduate students: Oxidants, antioxidants and disease mechanisms. Redox Biol 2013;1(1):244-57.
Salvadori M, Rosso G, Bertoni E. Update on ischemia-reperfusion injury in kidney transplantation: Pathogenesis and treatment. World J Transplant 2015;5(2):52-67.
Kaushal GP, Kaushal V, Hong X, et al. Role and regulation of activation of caspases in cisplatin-induced injury to renal tubular epithelial cells. Kidney Int 2001;60(5):1726-36.
Gill R, Tsung A, Billiar T. Linking oxidative stress to inflammation: Toll-like receptors. Free Radic Biol Med 2010;48(9):1121-32.
Rosin DL, Okusa MD. Dangers within: DAMP responses to damage and cell death in kidney disease. J Am Soc Nephrol 2011; 22(3):416-25.
Smathers RL, Galligan JJ, Stewart BJ, et al. Overview of lipid peroxidation products and hepatic protein modification in alcoholic liver disease. Chem Biol Interact 2011;192(1- 2):107-12.
Tomita K, Tamiya G, Ando S, et al. AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats. Alcohol Clin Exp Res 2005;29(12 Suppl):240S-5S.
Bose C, Awasthi S, Sharma R, et al. Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model. PloS One 2018;13(3): e0193918.
Singh P, Sharma R, McElhanon K, et al. Sulforaphane protects the heart from doxorubicin-induced toxicity. Free Radic Biol Med 2015; 86:90-101.
D'Archivio M, Scazzocchio B, Filesi C, et al. Oxidised LDL up-regulate CD36 expression by the Nrf2 pathway in 3T3-L1 preadipocytes. FEBS Lett 2008;582(15):2291-8.
Ishii T, Itoh K, Ruiz E, et al. Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal. Circ Res 2004;94(5):609-16.
Zhou R, Lin J, Wu D. Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis. Biochim Biophys Acta 2014;1840(1):209-18.
Wu KC, Liu J, Klaassen CD. Role of Nrf2 in preventing ethanol-induced oxidative stress and lipid accumulation. Toxicol Appl Pharmacol 2012;262(3):321-9.
Rodriguez-Rodriguez A, Egea-Guerrero JJ, Murillo-Cabezas F, et al. Oxidative stress in traumatic brain injury. Curr Med Chem 2014;21(10):1201-11.
Talha S, Bouitbir J, Charles AL, et al. Pretreatment with brain natriuretic peptide reduces skeletal muscle mitochondrial dysfunction and oxidative stress after ischemia-reperfusion. J Appl Physiol 2013;114(2):172-9.
Singhal SS, Singh SP, Singhal P, et al. Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling. Toxicol Appl Pharmacol 2015;289(3):361-70.
Chen G, Waxman DJ. Role of cellular glutathione and glutathione S-transferase in the expression of alkylating agent cytotoxicity in human breast cancer cells. Biochem Pharmacol 1994;47(6):1079-87.
Awasthi S, Srivastava SK, Ahmad F, et al. Interactions of glutathione S- transferase-pi with ethacrynic acid and its glutathione conjugate. Biochim Biophys Acta 1993;1164(2):173-8.
Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The antioxidant in ARDS study group. Chest 1997;112(1):164-72.
Ortolani O, Conti A, De Gaudio AR, et al. Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the lung epithelium during the adult respiratory distress syndrome. Shock 2000;13(1):14-8.
Laurent T, Markert M, Feihl F, et al. Oxidant-antioxidant balance in granulocytes during ARDS. Effect of N-acetylcysteine. Chest 1996;109(1):163-6.
Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral nutrition in ARDS study group. Crit Care Med 1999;27(8):1409-20.
Galley HF, Howdle PD, Walker BE, et al. The effects of intravenous antioxidants in patients with septic shock. Free Radic Biol Med 1997;23(5):768-74.
Angstwurm MW, Schottdorf J, Schopohl J, et al. Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome. Crit Care Med 1999;27(9):1807-13.
Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med 2013;368(16):1489-97.
Manzanares W, Lemieux M, Elke G, et al. High-dose intravenous selenium does not improve clinical outcomes in the critically ill: a systematic review and meta-analysis. Crit Care 2016;20(1):356.
Langlois PL, Hardy G, Manzanares W. Pharmaconutrition with intravenous selenium in intensive care: The end of an era? Nutrition 2018; 45:142-4.
Shishehbor MH, Hazen SL. Inflammatory and oxidative markers in atherosclerosis: relationship to outcome. Curr Atheroscler Rep 2004;6(3):243-50.
Davignon J, Jacob RF, Mason RP. The antioxidant effects of statins. Coron Artery Dis 2004;15(5):251-8.
Moon GJ, Kim SJ, Cho YH, et al. Antioxidant effects of statins in patients with atherosclerotic cerebrovascular disease. J Clin Neurol 2014;10(2):140-7.
Chopra M, Beswick H, Clapperton M, et al. Antioxidant effects of angiotensin-converting enzyme (ACE) inhibitors: free radical and oxidant scavenging are sulfhydryl dependent, but lipid peroxidation is inhibited by both sulfhydryl- and nonsulfhydryl-containing ACE inhibitors. J Cardiovasc Pharmacol 1992;19(3):330-40.
Wen H, Gwathmey JK, Xie LH. Oxidative stress-mediated effects of angiotensin II in the cardiovascular system. World J Hypertens 2012;2(4):34-44.
Ceron CS, Castro MM, Rizzi E, et al. Spironolactone and hydrochlorothiazide exert antioxidant effects and reduce vascular matrix metalloproteinase-2 activity and expression in a model of renovascular hypertension. Br J Pharmacol 2010;160(1):77-87.
Miura T, Muraoka S, Ogiso T. Antioxidant activity of adrenergic agents derived from catechol. Biochem Pharmacol 1998;55(12):2001-6.
Susanna Mak, Newton GE. Vitamin C augments the inotropic response to dobutamine in humans with normal left ventricular function. Circulation 2000; 103:826-30.
Farkhutdinov U, Farkhutdinov S, Yakupova G, et al. The mechanisms of anti- inflammatory action of bronchodilators. Eur Respir J 2013;42(Suppl 57).
Zwicker K, Damerau W, Dikalov S, et al. Superoxide radical scavenging by phenolic bronchodilators under aprotic and aqueous conditions. Biochem Pharmacol 1998;56(3):301-5.
Grant D, Long WF, Mackintosh G, et al. The antioxidant activity of heparins. Biochem Soc Trans 1996;24(2):194S.
Albertini R, Rindi S, Passi A, et al. Heparin protection against Fe2+ -and Cu2+ -mediated oxidation of liposomes. FEBS Lett 1996;383(3):155-8.
Vellinga NA, Veenstra G, Scorcella C, et al. Effects of ketanserin on microcirculatory alterations in septic shock: An open-label pilot study. J Crit Care 2015;30(6):1156-62.
Liu C, Zhang X, Zhou JX, et al. The protective action of ketanserin against lipopolysaccharide-induced shock in mice is mediated by inhibiting inducible NO synthase expression via the MEK/ERK pathway. Free Radic Biol Med 2013; 65:658-66.
Liu C, Zhang GF, Song SW, et al. Effects of ketanserin on endotoxic shock and baroreflex function in rodents. J Infect Dis 2011;204(10):1605-12.
Cazzola M, Guidetti E, Sepe J, et al. Acute respiratory and cardiovascular effects of inhaled ketanserin in chronic obstructive pulmonary disease. A comparative study with intravenously administered ketanserin. Chest 1990;97(4):901-5.
Cazzola M, D'Amato G, Lobefalo G, et al. Ketanserin, a new blocking agent of serotonin S2-receptors. Respiratory functional effects in chronic obstruction of the airways. Chest 1987;92(5):863-6.
Venkataramanujam S, Mahaneem M, Hisanori K. Melatonin in bacterial and viral infections with focus on sepsis: A review. Recent Pat Endocr Metab Immune Drug Discov 2012;6(1):30-9.
Srinivasan V, Pandi-Perumal SR, Spence DW, et al. Melatonin in septic shock: some recent concepts. J Crit Care 2010;25(4):656 e1-6.
Wu JY, Tsou MY, Chen TH, et al. Therapeutic effects of melatonin on peritonitis-induced septic shock with multiple organ dysfunction syndrome in rats. J Pineal Res 2008;45(1):106-16.
D'Amato LA, Mistraletti G, Longhi D, et al. Melatonin blood values and total antioxidant capacity in critically ill patients. Critical Care 2014;18(1): P436.
Alamili M, Bendtzen K, Lykkesfeldt J, et al. Melatonin suppresses markers of inflammation and oxidative damage in a human daytime endotoxemia model. J Crit Care 2014;29(1):184 e9- e13.
Kelso GF, Porteous CM, Coulter CV, et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 2001;276(7):4588-96.
Dhanasekaran A, Kotamraju S, Kalivendi SV, et al. Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. J Biol Chem 2004;279(36):37575-87.
Lowes DA, Thottakam BM, Webster NR, et al. The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis. Free Radic Biol Med 2008;45(11):1559-65.
Bolner A, Micciolo R, Bosello O, et al. A panel of oxidative stress markers in Parkinson's disease. Clin Lab 2016;62(1-2):105-12.
Ho E, Karimi Galougahi K, Liu CC, et al. Biological markers of oxidative stress: Applications to cardiovascular research and practice. Redox Biol 2013;1(1):483-91.
Lin D, Saleh S, Liebler DC. Reversibility of covalent electrophile-protein adducts and chemical toxicity. Chem Res Toxicol 2008;21(12):2361-9.
Blair IA. Analysis of endogenous glutathione-adducts and their metabolites. Biomed Chromatogr 2010;24(1):29-38.
Moss EJ, Neal GE, Judah DJ. The mercapturic acid pathway metabolites of a glutathione conjugate of aflatoxin B1. Chem Biol Interact 1985;55(1-2):139-55.
Pajaud J, Kumar S, Rauch C, et al. Regulation of signal transduction by glutathione transferases. Int J Hepatol 2012; 2012:137676.
Scarbrough PM, Mapuskar KA, Mattson DM, et al. Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG- induced cancer cell killing via oxidative stress. Free Radic Biol Med 2012;52(2):436-43.
Liang A, Wang Y, Woodard LE, et al. Loss of glutathione S-transferase A4 accelerates obstruction-induced tubule damage and renal fibrosis. J Pathol 2012;228(4):448-58.
Singhal J, Nagaprashantha L, Vatsyayan R, et al. RLIP76, a glutathione- conjugate transporter, plays a major role in the pathogenesis of metabolic syndrome. PloS One 2011;6(9): e24688.
Rosse C, L'Hoste S, Offner N, et al. RLIP, an effector of the Ral GTPases, is a platform for Cdk1 to phosphorylate epsin during the switch off of endocytosis in mitosis. J Biol Chem 2003;278(33):30597-604.
Awasthi S, Singhal SS, Sharma R, et al. Transport of glutathione conjugates and chemotherapeutic drugs by RLIP76 (RALBP1): a novel link between G-protein and tyrosine kinase signaling and drug resistance. Int J Cancer 2003;106(5):635-46.
Awasthi S, Cheng JZ, Singhal SS, et al. Functional reassembly of ATP-dependent xenobiotic transport by the N- and C-terminal domains of RLIP76 and identification of ATP binding sequences. Biochemistry 2001;40(13):4159-68.
Awasthi S, Cheng J, Singhal SS, et al. Novel function of human RLIP76: ATP-dependent transport of glutathione conjugates and doxorubicin. Biochemistry 2000;39(31):9327-34.
Singhal SS, Sehrawat A, Mehta A, et al. Functional reconstitution of RLIP76 catalyzing ATP-dependent transport of glutathione-conjugates. Int J Oncol 1992.
Singhal SS, Nagaprashantha L, Singhal P, et al. RLIP76 inhibition: A promising developmental therapy for neuroblastoma. Pharm Res 2017;34(8):1673-82.
Singhal SS, Wickramarachchi D, Yadav S, et al. Glutathione-conjugate transport by RLIP76 is required for clathrin-dependent endocytosis and chemical carcinogenesis. Mol Cancer Ther 2011;10(1):16-28.
Sahu M, Sharma R, Yadav S, et al. Lens specific RLIP76 transgenic mice show a phenotype similar to microphthalmia. Exp Eye Res 2014; 118:125-34.
Singhal SS, Figarola J, Singhal J, et al. RLIP76 protein knockdown attenuates obesity due to a high-fat diet. J Biol Chem. 2013;288(32):23394-406.
Lee S, Wurtzel JG, Singhal SS, et al. RALBP1/RLIP76 depletion in mice suppresses tumor growth by inhibiting tumor neovascularization. Cancer Res 2012;72(20):5165-73.
Singhal SS, Singhal J, Yadav S, et al. RLIP76: a target for kidney cancer therapy. Cancer Res. 2009;69(10):4244-51.
Singhal J, Singhal SS, Yadav S, et al. RLIP76 in defense of radiation poisoning. Int J Radiat Oncol Biol Phys 2008;72(2):553-61.
Figarola JL, Singhal P, Rahbar S, et al. COH-SR4 reduces body weight, improves glycemic control and prevents hepatic steatosis in high fat diet-induced obese mice. PloS One 2013;8(12): e83801.
Awasthi S, Tompkins J, Singhal J, et al. Rlip depletion prevents spontaneous neoplasia in TP53 null mice. Proc Natl Acad Sci USA 2018;115(15):3918-23.
Singhal J, Yadav S, Nagaprashantha LD, et al. Targeting p53-null neuroblastomas through RLIP76. Cancer Prev Res (Phila) 2011;4(6):879-89.
Singhal SS, Singhal J, Yadav S, et al. Regression of lung and colon cancer xenografts by depleting or inhibiting RLIP76 (Ral-binding protein 1). Cancer Res 2007;67(9):4382-9.
Singhal SS, Awasthi YC, Awasthi S. Regression of melanoma in a murine model by RLIP76 depletion. Cancer Res 2006;66(4):2354-60.
Awasthi YC, Sharma R, Cheng JZ, et al. Role of 4- hydroxynonenal in stress-mediated apoptosis signaling. Mol Aspects Med 2003;24(4-5):219-30.
Hu Y, Mivechi NF. HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo. J Biol Chem 2003;278(19):17299-306.
Cantor SB, Urano T, Feig LA. Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases. Mol Cell Biol 1995;15(8):4578-84.
Jullien-Flores V, Dorseuil O, Romero F, et al. Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. J Biol Chem 1995;270(38):22473-7.
Kashatus DF, Lim KH, Brady DC, et al. RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat Cell Biol 2011;13(9):1108-15.
Moskalenko S, Henry DO, Rosse C, et al. The exocyst is a Ral effector complex. Nat Cell Biol 2002;4(1):66-72.
Park SH, Weinberg RA. A putative effector of Ral has homology to Rho/Rac GTPase activating proteins. Oncogene 1995;11(11):2349-55.
Morimoto RI. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 1998;12(24):3788-96.
Jullien-Flores V, Mahe Y, Mirey G, et al. RLIP76, an effector of the GTPase Ral, interacts with the AP2 complex: involvement of the Ral pathway in receptor endocytosis. J Cell Sci 2000;113 (Pt 16):2837-44.
Morinaka K, Koyama S, Nakashima S, et al. Epsin binds to the EH domain of POB1 and regulates receptor-mediated endocytosis. Oncogene 1999;18(43):5915-22.
Nakashima S, Morinaka K, Koyama S, et al. Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors. EMBO J 1999;18(13):3629-42.
Tazat K, Harsat M, Goldshmid-Shagal A, et al. Dual effects of Ral-activated pathways on p27 localization and TGF-beta signaling. Mol Biol Cell 2013;24(11):1812-24.
Awasthi S, Singhal SS, Pikula S, et al. ATP-Dependent human erythrocyte glutathione-conjugate transporter. II. Functional reconstitution of transport activity. Biochemistry 1998;37(15):5239-48.
Awasthi S, Sharma R, Yang Y, et al. Transport functions and physiological significance of 76 kDa Ral-binding GTPase activating protein (RLIP76). Acta Biochim Pol 2002;49(4):855-67.
Awasthi S, Singhal SS, Srivastava Sked, et al. ATP-Dependent human erythrocyte glutathione-conjugate transporter. I. Purification, photoaffinity labeling, and kinetic characteristics of ATPase activity. Biochemistry 1998;37(15):5231-8.
Awasthi S, Sharma R, Singhal SS, et al. Modulation of cisplatin cytotoxicity by sulphasalazine. Br J Cancer 1994;70(2):190-4.
Awasthi YC, Sharma R, Singhal SS. Human glutathione S-transferases. Int J Biochem 1994;26(3):295-308.
Sharma R, Singhal SS, Wickramarachchi D, et al. RLIP76 (RALBP1)- mediated transport of leukotriene C4 (LTC4) in cancer cells: implications in drug resistance. Int J Cancer 2004;112(6):934-42.
Nagaprashantha L, Vartak N, Awasthi S, et al. Novel anti-cancer compounds for developing combinatorial therapies to target anoikis-resistant tumors. Pharm Res 2012;29(3):621-36.
Awasthi S, Singhal SS, Awasthi YC, et al. RLIP76 and cancer. Clin Cancer Res 2008;14(14):4372-7.
Stuckler D, Singhal J, Singhal SS, et al. RLIP76 transports vinorelbine and mediates drug resistance in non-small cell lung cancer. Cancer Res 2005;65(3):991- 8.
Yang Y, Sharma A, Sharma R, et al. Cells preconditioned with mild, transient UVA irradiation acquire resistance to oxidative stress and UVA-induced apoptosis: role of 4-hydroxynonenal in UVA-mediated signaling for apoptosis. J Biol Chem 2003;278(42):41380-8.
Chikara S, Nagaprashantha LD, Singhal J, et al. Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment. Cancer Lett 2018; 413:122-34.
Singhal SS, Singhal J, Figarola JL, et al. 2'-Hydroxyflavanone: A promising molecule for kidney cancer prevention. Biochem Pharmacol 2015;96(3):151-8.
Singhal J, Chikara S, Horne D, et al. 2'-Hydroxyflavanone inhibits in vitro and in vivo growth of breast cancer cells by targeting RLIP76. Mol Carcinog 2018;57(12):1751-62.
Nagaprashantha LD, Singhal J, Li H, et al. 2'-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer. Oncotarget 2018;9(26):18053-68.
Singhal J, Nagaprashantha L, Chikara S, et al. 2'-Hydroxyflavanone: A novel strategy for targeting breast cancer. Oncotarget. 2017;8(43):75025-37.
Tijani L, Awasthi S. PS01.34: Differential modulation of glutathione metabolism in adeno and squamous NSCLC by 2HF. J Thorac Oncol 2016;11(11S): S289-S90.
Wu K, Ning Z, Zhou J, et al. 2'-hydroxyflavanone inhibits prostate tumor growth through inactivation of AKT/STAT3 signaling and induction of cell apoptosis. Oncol Rep 2014;32(1):131-8.
Singhal J, Nagaprashantha LD, Vatsyayan R, et al. Didymin induces apoptosis by inhibiting N-Myc and upregulating RKIP in neuroblastoma. Cancer Prev Res (Phila) 2012;5(3):473-83.
Nagaprashantha LD, Vatsyayan R, Singhal J, et al. 2'- hydroxyflavanone inhibits proliferation, tumor vascularization and promotes normal differentiation in VHL-mutant renal cell carcinoma. Carcinogenesis 2011;32(4):568-75.
