A review on the possible molecular mechanism of action of N-acetylcysteine against insulin resistance and type-2 diabetes development

Clinical Biochemistry

Volumn 48, Issue 16-17, 2014, Pages 1200-1208

  Lasram, Mohamed Montassar ^a   Dhouib, Ines Bini ^a   Annabi, Alya ^a   El Fazaa, Saloua ^a   Gharbi, Najoua ^a  

^a FACULTÉ DES SCIENCES DE TUNIS   (Tunisia)

Author keywords

Anti apoptotic; Anti inflammatory; Antioxidant; Insulin resistance; N acetylcysteine

Indexed keywords

ACETYLCYSTEINE; ENDOTHELIAL NITRIC OXIDE SYNTHASE; FREE RADICAL; GLUCOSE; GLUCOSE TRANSPORTER 4; GLUTATHIONE; INSULIN; PHOSPHATIDYLINOSITOL 3 KINASE; STAT3 PROTEIN; ANTIINFLAMMATORY AGENT; ANTIOXIDANT;

ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; BLOOD GLUCOSE MONITORING; CLINICAL PRACTICE; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG STRUCTURE; ENZYME ACTIVITY; GLUCOSE BLOOD LEVEL; GLUCOSE METABOLISM; HUMAN; IN VITRO STUDY; INSULIN RELEASE; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIPID METABOLISM; MAXIMUM PLASMA CONCENTRATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; TREATMENT DURATION; ANIMAL; DIABETES MELLITUS, TYPE 2; DRUG EFFECTS; PHYSIOLOGY;

ACETYLCYSTEINE; ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTIOXIDANTS; APOPTOSIS; DIABETES MELLITUS, TYPE 2; HUMANS; INSULIN RESISTANCE;

EID: 84947021154     PISSN: 00099120     EISSN: 18732933     Source Type: Journal    
DOI: 10.1016/j.clinbiochem.2015.04.017     Document Type: Review

References (143)

1. Wild S., Roglic G., Green A., Sicree R., King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27(5):1047-1053.
2. Wright A.D., Cull C.A., Macleod K.M., Holman R.R. Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6years from diagnosis: UKPDS73. J Diabetes Complications 2006, 20(6):395-401.
3. Festa A., Hanley A.J., Tracy R.P., D'Agostino R., Haffner S.M. Inflammation in the prediabetic state is related to increased insulin resistance rather than decreased insulin secretion. Circulation 2003, 108:1822-1830.
4. Samuel V.T., Shulman G.I. Mechanisms for insulin resistance: common threads and missing links. Cell 2012, 148:852-871.
5. Darmaun D., Smith S.D., Sweeten S., Hartman B.K., Welch C., Mauras N. Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance to N-acetylcysteine supplementation. Pediatr Diabetes 2008, 9:577-582.
6. Rains J., Jain S.K. Oxidative stress, insulin signaling and diabetes. Free Radic Biol Med 2011, 50(5):567-575.
7. Droge W. Oxidative aging and insulin receptor signaling. J Gerontol A Biol Sci Med Sci 2005, 60:1378-13785.
8. Baker R.G., Hayden M.S., Ghosh S. NF-κB, inflammation, and metabolic disease. Cell Metab 2011, 13:11-22.
9. Hasanein P., Shahidi S. Effects of combined treatment with vitamins C and E on passive avoidance learning and memory in diabetic rats. Neurobiol Learn Mem 2010, 93:472-478.
10. Celik S., Erdogan S., Tuzcu M. Caffeic acid phenethyl ester (CAPE) exhibits significant potential as an antidiabetic and liver-protective agent in streptozotocin-induced diabetic rats. Pharmacol Res 2009, 60:270-276.
11. Masha A., Brocato L., Dinatale S., Mascia C., Biasi F., Martina V. N-acetylcysteine is able to reduce the oxidation status and the endothelial activation after a high-glucose content meal in patients with Type 2 diabetes mellitus. J Endocrinol Invest 2009, 32(4):352-356.
12. Ceriello A., Testa R. Antioxidant anti-inflammatory treatment in type 2 diabetes. Diabetes Care 2009, 32:232-236.
13. Hurst G.A., Shaw P.B., LeMaistre C.A. Laboratory and clinical evaluation of the mucolytic properties of acetylcysteine. Am Rev Respir Dis 1967, 96:962-970.
14. Prescott L.F., Park J., Ballantyne A., Adriaenssens P., Proudfoot A.T. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet 1977, 2:432-434.
15. Prescott L.F., Illingworth R.N., Critchley J.A.J.H., Stewart M.J., Adam R.D., Proudfoot A.T. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J 1979, 2:1097-1100.
16. Thong-Ngam D., Samuhasaneeto S., Kulaputana O., Klaikeaw N. N-Acetylcysteine attenuates oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis. World J Gastroenterol 2007, 13:5127-5132.
17. Gibson K.R., Neilson I.L., Barrett F., Winterburn T.J., Sharma S., MacRury S.M., et al. Evaluation of the antioxidant properties of N-acetylcysteine in human platelets: prerequisite for bioconversion to glutathione for antioxidant and antiplatelet activity. J Cardiovasc Pharmacol 2009, 54(4):319-326.
18. Witschi A., Reddy S., Stofer-Vogel B., Lauterburg B.H. The systemic availability of oral glutathione. Eur J Clin Pharmacol 1992, 43:667-669.
19. Dodd S., Dean O., Copolov D.L., Malhi G.S., Berk M. N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility. Expert Opin Biol Ther 2008, 8:1955-1962.
20. Ziment I. Acetylcysteine: a drug that is much more than a mucokinetic. Biomed Pharmacother 1988, 42(8):513-519.
21. Dekhuijzen P. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J 2004, 23:629-636.
22. Borgstrom L., Kagedal B., Paulsen O. Pharmacokinetics of N-acetylcysteine in man. Eur J Clin Pharmacol 1986, 31:217-222.
23. Olsson B., Johansson M., Gabrielsson J., Holme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. Eur J Clin Pharmacol 1988, 34:77-82.
24. De Caro L., Ghizzi A., Costa R., Longo A., Ventresca G.P., Lodola E. Pharmacokinetics and bioavailability of oral acetylcysteine in healthy volunteers. Arzneim-Forsch/Drug Res 1989, 39:382-386.
25. McLellan L.I., Lewis A.D., Hall D.J., Ansell J.D., Wolf C.R. Uptake and distribution of N-acetylcysteine in mice. tissue-specific effects on glutathione concentrations. Carcinogenesis 1995, 16:2099-2106.
26. Cotgreave I.A., Eklund A., Larsson K., Moldeus P. No penetration of orally administered N-acetylcysteine into bronchoalveolar lavage fluid. Eur J Respir Dis 1987, 70:73-77.
27. Corcoran G.B., Wong B.K. Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-l-cysteine in vivo: studied with N-acetyl-d-cysteine. J Pharmacol Exp Ther 1986, 238:54-61.
28. Prescott L. Oral or intravenous N-acetylcysteine for acetaminophen poisoning?. Ann Emerg Med 2005, 45:409-413.
29. Pastor A., Collado P.S., Almar M., Gonzalez-Gallego J. Antioxidant enzyme status in biliary obstructed rats: effects of N-acetylcysteine. J Hepatol 1997, 27:363-370.
30. Rushworth G.F., Megson I.L. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits 2014, 141:150-159.
31. De Flora S., Izzotti A., D'Agostini F., Balansky R.M. Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points. Carcinogenesis 2001, 22:999-1013. [2001].
32. Lee M.F., Chan C.Y., Hung H.C., Chou I.T., Yee A.S., Huang C.Y. N-acetylcysteine (NAC) inhibits cell growth by mediating the EGFR/Akt/HMG box-containing protein 1 (HBP1) signaling pathway in invasive oral cancer. Oral Oncol 2013, 49:129-135. [2013].
33. Hanczko R., Fernandez D.R., Doherty E., Qian Y., Vas G., Niland B., et al. Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine. J Clin Invest 2009, 119:1546-1557.
34. Balansky R., Ganchev G., Iltcheva M., Steele V.E., De Flora S. Prevention of cigarette smoke-induced lung tumors in mice by budesonide, phenethyl isothiocyanate, and N-acetylcysteine. Int J Cancer 2010, 126:1047-1054.
35. Finn N.A., Kemp M.L. Pro-oxidant and antioxidant effects of N-acetylcysteine regulate doxorubicin-induced NF-kappa B activity in leukemic cells. Mol Biosyst 2012, 8:650-662.
36. De Flora S., Bennicelli C., Camoirano A., Serra D., Romano M., Rossi G.A., et al. In vivo effects of N-acetylcysteine on glutathione metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds. Carcinogenesis 1985, 6:1735-1745.
37. Petersen A.C., McKenna M.J., Medved I., Murphy K.T., Brown M.J., Della Gatta P., et al. Infusion with the antioxidant N-acetylcysteine attenuates early adaptive responses to exercise in human skeletal muscle. Acta Physiol 2012, 204:382-392.
38. Cheng X., Xia Z., Leo J.M., Pang C.C. The effect of N-acetylcysteine on cardiac contractility to dobutamine in rats with streptozotocin-induced diabetes. Eur J Pharmacol 2005, 519:118-126.
39. Korou L.M., Agrogiannis G., Pantopoulou A., Vlachos I.S., Iliopoulos D., Karatzas T., et al. Comparative antilipidemic effect of N-acetylcysteine and sesame oil administration in diet-induced hypercholesterolemic mice. Lipids Health Dis 2010, 9:9-23.
40. Steiner J., Haughey N., Li W., Venkatesan A., Anderson C., Reid R., et al. Oxidative stress and therapeutic approaches in HIV dementia. Antioxid Redox Signal 2006, 8:2089-2100.
41. Walters M.T., Rubin C.E., Keightley S.J., Ward C.D. A double-blind, cross-over, study of oral N-acetylcysteine in Sjogren's syndrome. Scand J Rheumatol Suppl 1986, 61:253-258.
42. De Flora S., Grassi C., Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 1997, 10:1535-1541.
43. Grandjean E.M., Berthet P., Ruffmann R., Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials. Clin Ther 2000, 22(2):209-221.
44. Gravish D., Breslow J.I. Lipoprotein (a) reduction by N-acetylcysteine. Lancet 1991, 337:203-204.
45. Hurd R.W., Wilder B.J., Helveston W.R., Uthman B.M. Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine. Neurology 1996, 47:1264-1268.
46. Smilkstein M., Knapp G., Kulig K., Rumack B. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. N Engl J Med 1988, 319:1557-1562.
47. Banner W., Koch M., Capin D.M., Hopf S.B., Chang S., Tong T.G. Experimental chelation therapy in chromium, lead, and boron intoxication with N-acetylcysteine and other compounds. Toxicol Appl Pharmacol 1986, 83(1):142-147.
48. Dröge W., Holm E. Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction. FASEB J 1997, 11(13):1077-1089.
49. Kelly G.S. Clinical applications of N-acetylcysteine. Altern Med Rev 1998, 3:114-127.
50. Ammon H.P., Muller P.H., Eggstein M., Wintermantel C., Aigner B., Safayhi H., et al. Increase in glucose consumption by acetylcysteine during hyperglycemic clamp. A study with healthy volunteers. Arzneimittelforschung 1992, 42:642-645.
51. Ho E., Chen G., Bray T.M. Supplementation of N-acetylcysteine inhibits NF-kappaB activation and protects against alloxan-induced diabetes in CD-1 mice. FASEB J 1999, 13:1845-1854.
52. Kaneto H., Kajimoto Y., Miyagawa J., Matsuoka T., Fujitani Y., Umayahara Y., et al. Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity. Diabetes 1999, 48:2398-2406.
53. Tanaka Y., Gleason C.E., Tran P.O., Harmon J.S., Robertson R.P. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci U S A 1999, 96:10857-10862.
54. Song D., Hutchings S., Pang C.C.Y. Chronic N-acetylcysteine prevents fructose-induced insulin resistance and hypertension in rats. Eur J Pharmacol 2005, 508:205-210.
55. Diniz Y.S., Rocha K., Souza G., Galhardi C., Ebaid G., Novelli Filho J.L., et al. Effects of N-acetylcysteine on sucrose-rich diet-induced hyperglycaemia, dyslipidemia and oxidative stress in rats. Eur J Pharmacol 2006, 543:151-157.
56. Blouet C., Mariotti F., Marnivhe D.A., Mathé V., Mikogami T., Tomé D., et al. Dietary cysteine alleviates sucrose-induced oxidative stress and insulin resistance. Free Radic Biol Med 2007, 42:1089-1097.
57. Ismael M.A., Talbot S., Carbonneau C.L., Beauséjour C.M., Couture R. Blockade of sensory abnormalities and kinin B1 receptor expression by N-Acetyl-l-Cysteine and ramipril in a rat model of insulin resistance. Eur J Pharmacol 2008, 589:66-72.
58. Xia Z., Liu M., Wu Y., Sharma V., Luo T., Ouyang J., et al. N-acetylcysteine attenuates TNF-alpha-induced human vascular endothelial cell apoptosis and restores eNOS expression. Eur J Pharmacol 2006, 550:134-142. [2006].
59. Haber C.A., Lam T.K., Yu Z., Gupta N., Goh T., Bogdanovic E., et al. N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. Am J Physiol Endocrinol Metab 2003, 285:744-753.
60. Lin C.C., Yin M.C., Hsu C.C., Lin M.P. Effect of five cysteine containing compounds on three lipogenic enzymes in Balb/cA mice consuming a high saturated fat diet. Lipids 2004, 39:843-848.
61. Krieger M.H., Santos K.F., Shishido S.M., Wanschel A.C., Estrela H.F., Santos L., et al. Antiatherogenic effects of S-nitroso-N-acetylcysteine in hypercholesterolemic LDL receptor knockout mice. Nitric Oxide 2006, 14:12-20.
62. Yang R., Le G., Li A., Zheng J., Shi Y. Effect of antioxidant capacity on blood lipid metabolism and lipoprotein lipase activity of rats fed a high-fat diet. Nutrition 2006, 22:1185-1191.
63. Souza G.A., Ebaid G.X., Seiva F.R.F., Rocha K.H.R., Galhardi C.M., Novelli E.L.B. N-acetylcysteine an Allium plant compound improves high-sucrose diet-induced obesity and related effects. Evid Based Complement Alternat Med 2008, 11:1-7.
64. Rigotti A., Miettinen H.E., Krieger M. The role of the high-density lipoprotein receptor SR-BI in the lipid metabolism of endocrine and other tissues. Endocr Rev 2003, 24:357-387.
65. Brizzi P., Tonolo G., Carusillo F., Malaguarnera M., Maioli M., Musumeci S. Plasma lipid composition and LDL oxidation. Clin Chem Lab Med 2003, 41:56-60.
66. Schaffer J.E. Lipotoxicity: when tissues overeat. Curr Opin Lipidol 2003, 14:281-287.
67. El Midaoui A., Ismael M.A., Lu H., Fantus I.G., de Champlain J., Couture R. Comparative effects of N-acetyl-l-cysteine and ramipril on arterial hypertension, insulin resistance, and oxidative stress in chronically glucose-fed rats. Can J Physiol Pharmacol 2008, 86:752-760.
68. Shoelson S.E., Herrero L., Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology 2007, 132:2169-2180.
69. Sosa V., Moline T., Somoza R., Paciucci R., Kondoh H., ME L.L. Oxidative stress and cancer: an overview. Ageing Res Rev 2013, 12:376-390.
70. Le Brocq M., Leslie S.J., Milliken P., Megson I.L. Endothelial dysfunction: from molecular mechanisms to measurement, clinical implications, and therapeutic opportunities. Antioxid Redox Signal 2008, 10(9):1631-1674.
71. Stadler K. Oxidative stress in diabetes. Adv Exp Med Biol 2012, 771:272-287.
72. May J.M., de Haen C. The insulin-like effect of hydrogen peroxide on pathways of lipid synthesis in rat adipocytes. J Biol Chem 1979, 254:9017-9021.
73. 2 and vanadate stimulate tyrosine phosphorylation of potential target proteins for the insulin receptor kinase in intact cells. Biochem J 1992, 288:631-635.
74. 2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. Biochem J 1998, 336:241-246. [1998].
75. Saltiel A.R., Pessin J.E. Insulin signaling pathways in time and space. Trends Cell Biol 2002, 12:65-71.
76. Asante-Appiah E., Kennedy B.P. Protein tyrosine phosphatases: the quest for negative regulators of insulin action. Am J Physiol Endocrinol Metab 2003, 284:663-670.
77. Gual P., Le Marchand-Brustel Y., Tanti J.F. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 2005, 87:99-109.
78. Nomiyama T., Igarashi Y., Taka H., Mineki R., Uchida T., Ogihara T., et al. Reduction of insulin-stimulated glucose uptake by peroxynitrite is concurrent with tyrosine nitration of insulin receptor substrate-1. Biochem Biophys Res Commun 2004, 320:639-647.
79. Aruoma O.I., Halliwell B., Hoey B.M., Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 1989, 6:593-597.
80. Samuni Y., Goldstein S., Dean O.M., Berk M. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta 1830, 2013:4117-4129.
81. Issels R.D., Nagele A., Eckert K.G., Wilmanns W. Promotion of cysteine uptake and its utilization for glutathione biosynthesis induced by cysteamine and N-acetylcysteine. Biochem Pharmacol 1988, 37:881-888.
82. Ruffmann R., Wendel A. GSH rescue by N-acetylcysteine. Klin Wochenschr 1991, 69:857-862.
83. Nakata K., Kawase M., Ogino S., Kinoshita C., Murata H., Sakaue T., et al. Effects of age on levels of cysteine, glutathione and related enzyme activities in livers of mice and rats and an attempt to replenish hepatic glutathione level of mouse with cysteine derivatives. Mech Ageing Dev 1996, 90:195-207.
84. Bernard G.R. N-acetylcysteine. Am J Med 1991, 91(3):54-59.
85. Lautt W.W. The HISS story overview: a novel hepatic neurohumoral regulation of peripheral insulin sensitivity in health and diabetes. Can J Physiol Pharmacol 1999, 77:553-562.
86. Guarino M.P., Correia N.C., Lautt W.W., Macedo M.P. Insulin sensitivity is mediated by the activation of the ACh/NO/cGMP pathway in rat liver. Am J Physiol Gastrointest Liver Physiol 2004, 287:527-532.
87. Schenk S., Saberi M., Olefsky J.M. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 2008, 118:2992-3002.
88. Scherer P.E. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 2006, 55:1537-1545.
89. Halberg N., Wernstedt-Asterholm I., Scherer P.E. The adipocyte as an endocrine cell. Endocrinol Metab Clin North Am 2008, 37:753-768.
90. Wang Q., Li Y.C., Wang J., Kong J., Qi Y., Quigg R.J., et al. miR-17-92 cluster accelerates adipocyte differentiation by negatively regulating tumor-suppressor Rb2/p130. Proc Natl Acad Sci U S A 2008, 105:2889-2894.
91. Hotamisligil G.S., Shargill N.S., Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993, 259(5091):87-91.
92. Spranger J., Kroke A., Möhlig M., Hoffmann K., Bergmann M.M., Ristow M., et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003, 52:812-817.
93. Chawla A., Nguyen K.D., Goh Y.P.S. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 2011, 11:738-749.
94. Hirosumi J., Tuncman G., Chang L., Gorgun C.Z., Teoman Uysal K., Maeda K., et al. A central role for JNK is obesity and insulin resistance. Nature 2002, 420:333-336.
95. Bandyopadhyay G.K., Yu J.G., Ofrecio J., Olefsky J.M. Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 2002, 54(8):2351-2359.
96. Hotamisligil G.S., Arner P., Caro J.F., Atkinson R.L., Spiegelman B.M. Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J Clin Invest 1995, 95:2409-2415.
97. Itani S.I., Ruderman N.B., Schmieder F., Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002, 51:2005-2011.
98. Omara F.O., Blakley B.R., Bermier J., Fournier M. Immunomodulatory and protective effects of N-acetylcysteine in mitogen-activated murine splenocytes in vitro. Toxicology 1997, 116:219-226.
99. Emet S., Memis D., Pamukçu Z. The influence of N-acetyl-l-cysteine infusion on cytokine levels and gastric intramucosal pH during severe sepsis. Crit Care 2004, 8:172-179.
100. Nascimento M.M., Suliman M.E., Silva M., Chinaglia T., Marchioro J., Hayashi S.Y., et al. Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo-controlled study. Perit Dial Int 2010, 30:336-342.
101. Khan M., Sekhon B., Jatana M., Giri S., Gilg A.G., Sekhon C., et al. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J Neurosci Res 2004, 76:519-527.
102. Chen G., Shi J., Hu Z., Hang C. Inhibitory effect on cerebral inflammatory response following traumatic brain injury in rats: a potential neuroprotective mechanism of N-acetylcysteine. Mediators Inflamm 2008, 2008:716458.
103. Paintlia M.K., Paintlia A.S., Contreras M.A., Singh I., Singh A.K. Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: attenuation by N-acetylcysteine. Exp Neurol 2008, 210:560-576.
104. Beloosesky R., Gayle D.A., Amidi F., Nunez S.E., Babu J., Desai M., et al. N-acetyl-cysteine suppresses amniotic fluid and placenta inflammatory cytokine responses to lipopolysaccharide in rats. Am J Obstet Gynecol 2006, 194:268-273.
105. Pajonk F., Riess K., Sommer A., McBride W.H. N-acetyl-l-cysteine inhibits 26S proteosome function: implications for effects on NF-kappaB activation. Free Radic Biol Med 2002, 32(6):536-543.
106. Oka S., Kamata H., Kamata K., Yagisawa H., Hirata H. N-acetylcysteine suppresses TNF-induced NF-kappaB activation through inhibition of IkappaB kinases. FEBS Lett 2000, 472:196-202.
107. Jimenez L.A., Thompson J., Brown D.A., Rahman I., Antonicelli F., Duffin R., et al. Activation of NF-jB by PM(10) occurs via an iron-mediated mechanism in the absence of IjB degradation. Toxicol Appl Pharmacol 2000, 166:101-110.
108. Zafarullah M., Li W.Q., Sylvester J., Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci 2003, 60:6-20.
109. Polonsky W.H. Understanding and assessing diabetes-specific quality of life. Diabetes Spectr 2000, 13:36-41.
110. Finegood D.T., Scaglia L., Bonner-Weir S. Dynamics of β-cell mass in the growing rat pancreas: estimation with a simple mathematical model. Diabetes 1995, 44:249-256.
111. Biarnés M., Montolio M., Nacher V., Raurell M., Soler J., Montanya E. β-Cell death and mass in syngeneically transplanted islets exposed to short- and long-term hyperglycaemia. Diabetes 2002, 51:66-72.
112. Aksoy Y., Kesik K., Canpinar H. Does N-acetyl cysteine protect against apoptosis in HL60 cell line?. Turk J Biochem 2010, 35(4):333-339.
113. Abello A.P., Fidler S.A., Bulkley G.B., Timothy G., Buchman T.B. Antioxidants modulate induction of programmed endothelial cell death apoptosis by endotoxin. Arch Surg 1994, 129(2):134-141.
114. Talley A.K., Dewhurst S., Perry S.W., Dollard S.C., Gummuluru S., Fine S.M., et al. Tumor necrosis factor alpha-induced apoptosis in human neuronal cells: protection by the antioxidant N-acetylcysteine and the genes bcl-2, and cmui. Mol Cell Biol 1995, 15:2359-2366.
115. Hong S.Y., Yang J.O., Lee E.Y., Lee Z.W. Effects of N-acetyl-l-cysteine and glutathione on antioxidant status of human serum and 3T3 fibroblasts. J Korean Med Sci 2003, 18(5):649-654.
116. Abe T., Yamamura K., Gotoh S., Kashimura M., Higashi K. Concentration-dependent differential effect of N-acetylc-l-cysteine on the expression of HSP70 and metallothionein genes induced by cadmium in human amniotic cells. Biochim Biophys Acta 1998, 1380:123-132.
117. Wu Y.J., Muldoon L.L., Neuwelt E.A. Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular and in vivo levels. J Pharmacol Exp Ther 2005, 314:1052-1058.
118. Sun L., Gu L., Wang S., Yuan J., Yang H., Zhu J., et al. N-acetylcysteine protects against apoptosis through modulation of group I metabotropic glutamate receptor activity. PLoS One 2012, 7(3):e32503.
119. Park E., Yu K.H., Kim D.K., Kim S., Sapkota K., Kim S.J., et al. Protective effects of N-acetylcysteine against monosodium glutamate-induced astrocytic cell death. Food Chem Toxicol 2014, 67:1-9.
120. Kawada N., Seki S., Inoue M., Kuroki T. Effect of antioxidants resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology 1998, 27:1265-1274.
121. Tsou T.C., Yeh S.C., Tsai F.Y., Chang L.W. The protective role of intracellular GSH status in the arsenite-induced vascular endothelial dysfunction. Chem Res Toxicol 2004, 17:208-217.
122. Chan W.H., Wu C.C., Yu J.S. Curcumin inhibits UV irradiation-induced oxidative stress and apoptotic biochemical changes in human epidermoid carcinoma A431 cells. J Cell Biochem 2003, 90:327-338.
123. Tanel A., Averill-Bates D.A. Inhibition of acrolein-induced apoptosis by the antioxidant N-acetylcysteine. J Pharmacol Exp Ther 2007, 321:73-83.
124. Jessen N., Goodyear L.J. Contraction signaling to glucose transport in skeletal muscle. J App Physiol 2005, 99(1):330-337.
125. Petersen K.F., Shulman G.I. Pathogenesis of skeletal muscle insulin resistance in Type 2 diabetes mellitus. Am J Cardiol 2002, 90:11-18.
126. Bloch-Damti A., Bashan N. Proposed mechanisms for the induction of insulin resistance by oxidative stress. Antioxid Redox Signal 2005, 7:1553-1567.
127. Wang T., Mao X., Li H., Qiao S., Xuc A., Wang J., et al. N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes. Free Radic Biol Med 2013, 63:291-303.
128. Kim H., Seo J.Y., Roh K.H., Lim J.W., Kim K.H. Suppression of NF-κB activation and cytokine production by N-acetylcysteine in pancreatic acinar cells. Free Radic Biol Med 2000, 29:674.
129. 2 and antioxidants have opposite effects on activation of NF-KB and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J 1993, 12:2005-2015.
130. 2 and N-acetyl-l-cysteine regulate expression of c-jun and c-fos in lens systems. Exp Eye Res 1994, 59:179-190.
131. Sen C.K., Packer L. Antioxidant and redox regulation of gene transcription. FASEB J 1996, 10:709-720.
132. Muller B., Kleshyov A.L., Stoclet J. Evidence for N-acetylcysteine sensitive nitric oxide storage as dinitrosyl-iron complexes in lipopolysaccharide-treated rat aorta. Br J Pharmacol 1996, 119:1281-1285.
133. Müller J.M., Cahill M.A., Rupec R.A., Baeuerle P.A., Nordheim A. Antioxidants as well as oxidants activate c-fos via Ras-dependent activation of extracellular-signal-regulated kinase 2 and Elk-1. Eur J Biochem 1997, 244:45-52.
134. Jain S.K., Bull R., Rains J.L., Bass P.F., Levine S.N., Reddy S., et al. Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation?. Antioxid Redox Signal 2010, 12:1333-1337.
135. Whiteman M., Gooding K.M., Whatmore J.L., Ball C.I., Mawson D., Skinner K., et al. Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia 2010, 53:1722-1726.
136. Sekhar R.V., Mckay S.V., Patel S.G., Guthikonda A.P., Reddy V.T., Balasubramanyam A., et al. Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care 2011, 34:162-167.
137. Iyer S.S., Accardi C.J., Ziegler T.R., Blanco R.A., Ritzenthaler J.D., Rojas M., et al. Cysteine redox potential determines pro-inflammatory IL-1beta levels. PLoS One 2009, 4:e5017.
138. Manna P., Jain S.K. Hydrogen sulfide and l-cysteine increase phosphatidylinositol 3,4,5-trisphosphate (PIP3) and glucose utilization by inhibiting phosphatase and tensin homolog (PTEN) protein and activating phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (AKT)/protein kinase C/λ (PKC/λ) in 3T3l1 adipocytes. J Biol Chem 2011, 286(46):39848-39859.
139. Marchetti P., Del Guerra S., Marselli L., Lupi R., Masini M., Pollera M., et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 2004, 89:5535-5541.
140. Del Guerra S., Lupi R., Marselli L., Masini M., Bugliani M., Sbrana S., et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 2005, 54:727-735.
141. Kaneto H., Xu G., Song K.H., Suzuma K., Bonner-Weir S., Sharma A., et al. Activation of the hexosamine pathway leads to deterioration of pancreatic β-cell function by provoking oxidative stress. J Biol Chem 2001, 276:31099-31104.
142. Kamboj S.S., Chopra K., Sandhir R. Hyperglycemia-induced alterations in synaptosomal membrane fluidity and activity of membrane bound enzymes: beneficial effect of N-acetylcysteine supplementation. Neuroscience 2009, 162:349-358.
143. Kamboj S.S., Sandhir R. Protective effect of N-acetylcysteine supplementation on mitochondrial oxidative stress and mitochondrial enzymes in cerebral cortex of streptozotocin-treated diabetic rats. Mitochondrion 2011, 11:214-222.