Life Extension Spring Clearance Sale

Life Extension Magazine

Life Extension Magazine January 2014
Report  

Turn Off the Cytokine Switch

By Morris Eagleton

Summary

Chronic inflammation accelerates aging, producing symptoms that we recognize as diseases that cause early death. Scientists have now discovered the accelerator switch, in the form of HMGB1, the molecule that triggers the release of inflammatory cytokines under a wide variety of circumstances.

Anti-HMGB1 therapies, therefore, are avidly sought-after by big pharma companies. While producing dramatic results in the laboratory, however, no anti-HMGB1 drug is anywhere near market-ready because treatments to date use large antibody molecules that can’t be given orally and that have unacceptable side effects.

But mung beans and green tea, in use for thousands of years in traditional Chinese medicine, contain safe, powerful HMGB1-fighting substances. Extract s of mung bean seed coat and EGCG from green tea leaf extract can be given orally, and in preclinical studies have proven to be highly effective at shutting down HMGB1-induced inflammation in a life-saving fashion.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

References

  1. Nogueira-Machado JA, de Oliveira Volpe CM. HMGB-1 as a target for inflammation controlling. Recent Pat Endocr Metab Immune Drug Discov. 2012 Sep;6(3):201-9.
  2. Chilosi M, Carloni A, Rossi A, Poletti V. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Transl Res. 2013 Jul 2.
  3. Liezmann C, Stock D, Peters EM. Stress induced neuroendocrine-immune plasticity: A role for the spleen in peripheral inflammatory disease and inflammaging? Dermatoendocrinol. 2012 Jul 1;4(3):271-9.
  4. Yao H, Rahman I. Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence. Biochem Pharmacol. 2012 Nov 15;84(10):1332-9.
  5. Zhu S, Li W, Li J, Jundoria A, Sama AE, Wang H. It is not just folklore: The aqueous extract of mung bean coat is protective against sepsis. Evid Based Complement Alternat Med. 2012;2012:498467.
  6. Li W, Ashok M, Li J, Yang H, Sama AE, Wang H. A major ingredient of green tea rescues mice from lethal sepsis partly by inhibiting HMGB1. PLoS One. 2007;2(11):e1153.
  7. Klune JR, Dhupar R, Cardinal J, Billiar TR, Tsung A. HMGB1: endogenous danger signaling. Mol Med. 2008 Jul-Aug;14(7-8):476-84.
  8. Zhu S, Li W, Ward MF, Sama AE, Wang H. High mobility group box 1 protein as a potential drug target for infection- and injury-elicited inflammation. Inflamm Allergy Drug Targets. 2010 Mar;9(1):60-72.
  9. Kruttgen A, Rose-John S. Interleukin-6 in sepsis and capillary leakage syndrome. J Interferon Cytokine Res. 2012 Feb;32(2):60-5.
  10. Lotze MT, Buchser WJ, Liang X. Blocking the interleukin 2 (IL2)-induced systemic autophagic syndrome promotes profound antitumor effects and limits toxicity. Autophagy. 2012 Aug;8(8):1264-6.
  11. Ye C, Choi JG, Abraham S, et al. Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model. Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):21052-7.
  12. Available at: http://www.omicsonline.org/2153-0645/2153-0645-3-e131.php?aid=10050#4. Accessed October 14, 2013.
  13. Li Y, Chen M, Cao H, Zhu Y, Zheng J, Zhou H. Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response. Microbes Infect. 2013 Feb;15(2):88-95.
  14. Theron M, Huang KJ, Chen YW, Liu CC, Lei HY. A probable role for IFN-gamma in the development of a lung immunopathology in SARS. Cytokine. 2005 Oct 7;32(1):30-8.
  15. Available at: http://www.cidrap.umn.edu/news-perspective/2013/08/study-shows-cytokine-storm-fatal-2009-h1n1-cases. Accessed October 17, 2013.
  16. Cheng Z, Kang Y, Wu QG, et al. Levels of HMGB1 in induced sputum from patients with asthma and chronic obstructive pulmonary disease. Zhonghua Yi Xue Za Zhi. 2011 Nov 15;91(42):2981-4.
  17. Kanazawa H, Tochino Y, Asai K, Ichimaru Y, Watanabe T, Hirata K. Validity of HMGB1 measurement in epithelial lining fluid in patients with COPD. Eur J Clin Invest. 2012 Apr;42(4):419-26.
  18. Shim EJ, Chun E, Lee HS, et al. The role of high-mobility group box-1 (HMGB1) in the pathogenesis of asthma. Clin Exp Allergy. 2012 Jun;42(6):958-65.
  19. Zhou Y, Jiang YQ, Wang WX, et al. HMGB1 and RAGE levels in induced sputum correlate with asthma severity and neutrophil percentage. Hum Immunol. 2012 Nov;73(11):1171-4.
  20. Andrassy M, Volz HC, Schuessler A, et al. HMGB1 is associated with atherosclerotic plaque composition and burden in patients with stable coronary artery disease. PLoS One. 2012;7(12):e52081.
  21. He M, Zhang B, Wei X, et al. HDAC4/5-HMGB1 signalling mediated by NADPH oxidase activity contributes to cerebral ischaemia/reperfusion injury. J Cell Mol Med. 2013 Apr;17(4):531-42.
  22. Jin D, Wu Y, Zhao L, Guo J, Zhang K, Chen Z. Atorvastatin reduces serum HMGB1 levels in patients with hyperlipidemia. Exp Ther Med. 2012 Dec;4(6):1124-26.
  23. Mazarati A, Maroso M, Iori V, Vezzani A, Carli M. High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and Receptor for Advanced Glycation End Products. Exp Neurol. 2011 Dec;232(2):143-8.
  24. Menini T, Ikeda H, Kimura S, Gugliucci A. Circulating soluble RAGE increase after a cerebrovascular event. Clin Chem Lab Med. 2013 Mar 13:1-8.
  25. Moreno JA, Sastre C, Madrigal-Matute J, et al. HMGB1 expression and secretion are increased via TWEAK-Fn14 interaction in atherosclerotic plaques and cultured monocytes. Arterioscler Thromb Vasc Biol. 2013 Mar;33(3):612-20.
  26. Volz HC, Laohachewin D, Schellberg D, HMGB1 is an independent predictor of death and heart transplantation in heart failure. Clin Res Cardiol. 2012 Jun;101(6):427-35.
  27. Volz HC, Seidel C, Laohachewin D, et al. HMGB1: the missing link between diabetes mellitus and heart failure. Basic Res Cardiol. 2010 Nov;105(6):805-20.
  28. Zhao D, Wang Y, Tang K, Xu Y. Increased serum HMGB1 related with HbA1c in coronary artery disease with type 2 diabetes mellitus. Int J Cardiol. 2013 Jan 18.
  29. Fang P, Schachner M, Shen YQ. HMGB1 in development and diseases of the central nervous system. Mol Neurobiol. 2012 Jun;45(3):499-506.
  30. He Z, Shotorbani SS, Jiao Z, et al. HMGB1 promotes the differentiation of Th17 via up-regulating TLR2 and IL-23 of CD14+ monocytes from patients with rheumatoid arthritis. Scand J Immunol. 2012 Nov;76(5):483-90.
  31. Morimoto-Yamashita Y, Ito T, Kawahara K, et al. Periodontal disease and type 2 diabetes mellitus: is the HMGB1-RAGE axis the missing link? Med Hypotheses. 2012 Oct;79(4):452-5.
  32. Hwang CS, Liu GT, Chang MD, Liao IL, Chang HT. Elevated serum autoantibody against high mobility group box 1 as a potent surrogate biomarker for amyotrophic lateral sclerosis. Neurobiol Dis. 2013 Oct;58:13-8.
  33. Wen Z, Xu L, Chen X, et al. Autoantibody induction by DNA-containing immune complexes requires HMGB1 with the TLR2/MicroRNA-155 pathway. J Immunol. 2013 Apr 24.
  34. Zhang S, Zhong J, Yang P, Gong F, Wang CY. HMGB1, an innate alarmin, in the pathogenesis of type 1 diabetes. Int J Clin Exp Pathol. 2009;3(1):24-38.
  35. Dong YD, Cui L, Peng CH, Cheng DF, Han BS, Huang F. Expression and clinical significance of HMGB1 in human liver cancer: Knockdown inhibits tumor growth and metastasis in vitro and in vivo. Oncol Rep. 2013 Jan;29(1):87-94.
  36. Li ML, Wang XF, Tan ZJ, et al. Ethyl pyruvate administration suppresses growth and invasion of gallbladder cancer cells via downregulation of HMGB1-RAGE axis. Int J Immunopathol Pharmacol. 2012 Oct-Dec;25(4):955-65.
  37. Skrha J, Jr., Kalousova M, Svarcova J, et al. Relationship of soluble RAGE and RAGE ligands HMGB1 and EN-RAGE to endothelial dysfunction in type 1 and type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2012 May;120(5):277-81.
  38. McDonnell M, Liang Y, Noronha A, et al. Systemic Toll-like receptor ligands modify B-cell responses in human inflammatory bowel disease. Inflamm Bowel Dis. 2011 Jan;17(1):298-307.
  39. Vitali R, Stronati L, Negroni A, et al. Fecal HMGB1 is a novel marker of intestinal mucosal inflammation in pediatric inflammatory bowel disease. Am J Gastroenterol. 2011 Nov;106(11):2029-40.
  40. Arrigo T, Chirico V, Salpietro V, et al. High-mobility group protein B1: a new biomarker of metabolic syndrome in obese children. Eur J Endocrinol. 2013 Apr;168(4):631-8.
  41. Degos V, Maze M, Vacax S, et al. Bone fracture exacerbates murine eschemic cerebral injury. Anesthesiology. 2013 Feb 22.
  42. Li Y, Xiang M, Yuan Y, et al. Hemorrhagic shock augments lung endothelial cell activation: role of temporal alterations of TLR4 and TLR2. Am J Physiol Regul Integr Comp Physiol. 2009 Dec;297(6):R1670-80.
  43. Liu A, Dirsch O, Fang H, et al. HMGB1 translocation and expression is caused by warm ischemia reperfusion injury, but not by partial hepatectomy in rats. Exp Mol Pathol. 2011 Oct;91(2):502-8.
  44. Guo F, Shi Y, Xu H, Ding J. High mobility group box 1 as a mediator of endotoxin administration after hemorrhagic shock-primed lung injury. Braz J Med Biol Res. 2009 Sep;42(9):804-11.
  45. Okuma Y, Liu K, Wake H, et al. Anti-high mobility group box-1 antibody therapy for traumatic brain injury. Ann Neurol. 2012 Sep;72(3):373-84.
  46. Ong SP, Lee LM, Leong YF, Ng ML, Chu JJ. Dengue virus infection mediates HMGB1 release from monocytes involving PCAF acetylase complex and induces vascular leakage in endothelial cells. PLoS One. 2012;7(7):e41932.
  47. Moisy D, Avilov SV, Jacob Y, et al. HMGB1 protein binds to influenza virus nucleoprotein and promotes viral replication. J Virol. 2012 Sep;86(17):9122-33.
  48. Andersson U, Tracey KJ. HMGB1 as a mediator of necrosis-induced inflammation and a therapeutic target in arthritis. Rheum Dis Clin North Am. 2004 Aug;30(3):627-37, xi.
  49. Andersson U, Harris HE. The role of HMGB1 in the pathogenesis of rheumatic disease. Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):141-8.
  50. Uzawa A, Mori M, Taniguchi J, Masuda S, Muto M, Kuwabara S. Anti-high mobility group box 1 monoclonal antibody ameliorates experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2013 Apr;172(1):37-43.
  51. Robinson AP, Caldis MW, Harp CT, Goings GE, Miller SD. High-mobility group box 1 protein (HMGB1) neutralization ameliorates experimental autoimmune encephalomyelitis. J Autoimmun. 2013 Mar 17.
  52. Maeda S, Hikiba Y, Shibata W, et al. Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer. Biochem Biophys Res Commun. 2007 Aug 24;360(2):394-400.
  53. Andersson UG, Tracey KJ. HMGB1, a pro-inflammatory cytokine of clinical interest: introduction. J Intern Med. 2004 Mar;255(3):318-9.
  54. Han J, Zhong J, Wei W, et al. Extracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice. Diabetes. 2008 Aug;57(8):2118-27.
  55. Yang H, Hreggvidsdottir HS, Palmblad K, et al. A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11942-7.
  56. Cozzani E, Burlando M, Parodi A. Detection of antibodies to anti-TNF agents in psoriatic patients: a preliminary study. G Ital Dermatol Venereol. 2013 Apr;148(2):171-4.
  57. Adsule RN, Kadam SS, Salunkhe DK. Chemistry and technology of green gram (Vigna radiata [L.] Wilczek). Crit Rev Food Sci Nutr. 1986;25(1):73-105.
  58. Cao D, Li H, Yi J, et al. Antioxidant properties of the mung bean flavonoids on alleviating heat stress. PLoS One. 2011;6(6):e21071.
  59. Recio MC, Andujar I, Rios JL. Anti-inflammatory agents from plants: progress and potential. Curr Med Chem. 2012;19(14):2088-103.
  60. Chen X, Li W, Wang H. More tea for septic patients?--Green tea may reduce endotoxin-induced release of high mobility group box 1 and other pro-inflammatory cytokines. Med Hypotheses. 2006;66(3):660-3.
  61. Kuang X, Huang Y, Gu HF, et al. Effects of intrathecal epigallocatechin gallate, an inhibitor of Toll-like receptor 4, on chronic neuropathic pain in rats. Eur J Pharmacol. 2012 Feb 15;676(1-3):51-6.
  62. Li W, Zhu S, Li J, et al. EGCG stimulates autophagy and reduces cytoplasmic HMGB1 levels in endotoxin-stimulated macrophages. Biochem Pharmacol. 2011 May 1;81(9):1152-63.
  63. Saiwichai T, Sangalangkarn V, Kawahara K, et al. Green tea extract supplement inhibition of HMGB1 release in rats exposed to cigarette smoke. Southeast Asian J Trop Med Public Health. 2010 Jan;41(1):250-8.
  64. Zhu S, Li W, Li J, Sama AE, Wang H. Caging a beast in the inflammation arena: Use of Chinese medicinal herbs to inhibit a late mediator of lethal sepsis, HMGB1. Int J Clin Exp Med. 2008;1(1):64-75.
  65. Cai B, Deitch EA, Ulloa L. Novel insights for systemic inflammation in sepsis and hemorrhage. Mediators Inflamm. 2010;2010:642462.
  66. Naglova H, Bucova M. HMGB1 and its physiological and pathological roles. Bratisl Lek Listy. 2012;113(3):163-71.
  67. Khalil AA, Hall JC, Aziz FA, Price P. Tumour necrosis factor: implications for surgical patients. ANZ J Surg. 2006 Nov;76(11):1010-6.
  68. Qiu P, Cui X, Barochia A, Li Y, Natanson C, Eichacker PQ. The evolving experience with therapeutic TNF inhibition in sepsis: considering the potential influence of risk of death. Expert Opin Investig Drugs. 2011 Nov;20(11):1555-64.
  69. Sama AE, D’Amore J, Ward MF, Chen G, Wang H. Bench to bedside: HMGB1-a novel proinflammatory cytokine and potential therapeutic target for septic patients in the emergency department. Acad Emerg Med. 2004 Aug;11(8):867-73.
  70. Hohensinner PJ, Goronzy JJ, Weyand CM. Telomere dysfunction, autoimmunity and aging. Aging Dis. 2011 Dec;2(6):524-37.
  71. Pedersen-Lane JH, Zurier RB, Lawrence DA. Analysis of the thiol status of peripheral blood leukocytes in rheumatoid arthritis patients. J Leukoc Biol. 2007 Apr;81(4):934-41.