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Molecular Neurobiology

, Volume 48, Issue 1, pp 190–204 | Cite as

Role of the Toll Like Receptor (TLR) Radical Cycle in Chronic Inflammation: Possible Treatments Targeting the TLR4 Pathway

  • Kurt Lucas
  • Michael MaesEmail author
Article

Abstract

Activation of the Toll-like receptor 4 (TLR4) complex, a receptor of the innate immune system, may underpin the pathophysiology of many human diseases, including asthma, cardiovascular disorder, diabetes, obesity, metabolic syndrome, autoimmune disorders, neuroinflammatory disorders, schizophrenia, bipolar disorder, autism, clinical depression, chronic fatigue syndrome, alcohol abuse, and toluene inhalation. TLRs are pattern recognition receptors that recognize damage-associated molecular patterns and pathogen-associated molecular patterns, including lipopolysaccharide (LPS) from gram-negative bacteria. Here we focus on the environmental factors, which are known to trigger TLR4, e.g., ozone, atmosphere particulate matter, long-lived reactive oxygen intermediate, pentachlorophenol, ionizing radiation, and toluene. Activation of the TLR4 pathways may cause chronic inflammation and increased production of reactive oxygen and nitrogen species (ROS/RNS) and oxidative and nitrosative stress and therefore TLR-related diseases. This implies that drugs or substances that modify these pathways may prevent or improve the abovementioned diseases. Here we review some of the most promising drugs and agents that have the potential to attenuate TLR-mediated inflammation, e.g., anti-LPS strategies that aim to neutralize LPS (synthetic anti-LPS peptides and recombinant factor C) and TLR4/MyD88 antagonists, including eritoran, CyP, EM-163, epigallocatechin-3-gallate, 6-shogaol, cinnamon extract, N-acetylcysteine, melatonin, and molecular hydrogen. The authors posit that activation of the TLR radical (ROS/RNS) cycle is a common pathway underpinning many “civilization” disorders and that targeting the TLR radical cycle may be an effective method to treat many inflammatory disorders.

Keywords

Toll-like receptor LPS Inflammation Oxidative and nitrosative stress Cytokines Depression Chronic fatigue 

List of Abbreviations

ACE

Acephate (organophosphate insecticide)

AHR

Airway hyperresponsiveness

AhR

Aryl hydrocarbon receptor

ALA

Alfa-lipoic acid

CD

Crohn’s disease

CD14

Cluster of differentiation 14

CFS

Chronic fatigue syndrome

COPD

Chronic obstructive pulmonary disease

COX-2

Cyclooxygenase-2 (prostaglandin-endoperoxide synthase 2)

CyP

Cyanobacterial product

DAMPs

Damage-associated molecular patterns

ECM

Extracellular matrix

EGCG

Epigallocatechin-3-gallate

EM-163

EM-163 is a synthetic BB-mimetic of MyD88

GL

Glycyrrhizin

HA

Hyaluronic acid

HMGB1

High-mobility group protein B1

HSPs

Heat shock proteins

IBD

Inflammatory bowel disease

IFNγ

Interferon gamma

IL-1β

Interleukin-1β

IL-6

Interleukin-6

IL-8

Interleukin-8

IL-12

Interleukin-12

ILG

Isoliquiritigenin

iNOS

Inducible nitric oxide synthase

LL37

Cathelicidin

LPB

LPS-binding protein

LPS

Lipopolysaccharide

LPS-RS

LPS from Rhodobactersphaeroides

MD-2

Myeloid differential protein-2

MyD88

Myeloid differentiation primary response gene 88

NAC

N-acetylcysteine

NAFLD

Nonalcoholic fatty liver disease

Ncf1

Neutrophil cytosolic factor 1

NF-κB

Nuclear factor-κB

NO

Nitric oxide

O&NS

Oxidative and nitrosative stress

OxLDL

Oxidized low-density lipoprotein

OxPAPC

1-Palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine

OxPL

Oxidized phospholipids

PAMPs

Pathogen-associated molecular patterns

PCP

Pentachlorophenol

PM

Particular matter

PM 2.5

is the PM fraction of airborne nanoparticles with a diameter <2.5 μm

PRRs

Pattern recognition receptors

rFC

Recombinant factor C

RNS

Reactive nitrogen species

ROIs

Reactive oxygen intermediates

ROS

Reactive oxygen species

Sal B

Salvianolic acid B

SALPs

Synthetic anti-LPS peptides

SARS

Acute respiratory syndrome

siRNA

Small interfering RNA

sLP

Synthetic lipopeptide

TBK1

TANK-binding kinase 1

TCM

Traditional Chinese medicine

TIRAP

Toll–interleukin 1 receptor (TIR) domain containing adaptor protein

TLR1

Toll-like receptor 1

TLR2

Toll-like receptor 2

TLR3

Toll-like receptor 3

TLR4

Toll-like receptor 4

TLR6

Toll-like receptor 6

TLR9

Toll-like receptor 9

TLRs

Toll-like receptors

TNF-α

Tumor necrosis factor-α

VOC

Volatile organic compounds

Notes

Conflict of interest

Kurt Lucas has filed two relevant patent applications, i.e., “Cinnamon extract for the treatment of diseases caused by induced “mismanagement” of the innate immune system (October 2011) and “Compositions for the preparation of hydrogen enriched water” (September 2012). MM does not report any conflict of interest.

References

  1. 1.
    Jeong E, Lee JY (2011) Intrinsic and extrinsic regulation of innate immune receptors. Yonsei Med J 52(3):379–92. doi: 10.3349/ymj.2011.52.3.429 PubMedCrossRefGoogle Scholar
  2. 2.
    Mu HH, Hasebe A, Van Schelt A, Cole BC (2011) Novel interactions of a microbial superantigen with TLR2 and TLR4 differentially regulate IL-17 and Th17-associated cytokines. Cell Microbiol 13(3):374–87. doi: 10.1111/j.1462-5822.2010.01540.x PubMedCrossRefGoogle Scholar
  3. 3.
    Oliveira-Nascimento L, Massari P, Wetzler LM (2012) The role of TLR2 in infection and immunity. Front Immunol 3:79. doi: 10.3389/fimmu.00079 PubMedCrossRefGoogle Scholar
  4. 4.
    Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, Ermolaeva M, Veldhuizen R, Leung YH, Wang H, Liu H, Sun Y, Pasparakis M, Kopf M, Mech C, Bavari S, Peiris JS, Slutsky AS, Akira S, Hultqvist M, Holmdahl R, Nicholls J, Jiang C, Binder CJ, Penninger JM (2008) Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133(2):235–49. doi: 10.1016/j.cell.2008.02.043 PubMedCrossRefGoogle Scholar
  5. 5.
    Lefebvre JS, Lévesque T, Picard S, Paré G, Gravel A, Flamand L, Borgeat P (2011) Extra domain A of fibronectin primes leukotriene biosynthesis and stimulates neutrophil migration through activation of Toll-like receptor 4. Arthritis Rheum 63(6):1527–33. doi: 10.1002/art.30308 PubMedCrossRefGoogle Scholar
  6. 6.
    Sirisinha S (2011) Insight into the mechanisms regulating immune homeostasis in health and disease. Asian Pac J Allergy Immunol 29(1):1–14PubMedGoogle Scholar
  7. 7.
    Kerkhof M, Postma DS, Brunekreef B, Reijmerink NE, Wijga AH, de Jongste JC, Gehring U, Koppelman GH (2010) Toll-like receptor 2 and 4 genes influence susceptibility to adverse effects of traffic-related air pollution on childhood asthma. Thorax 65(8):690–7. doi: 10.1136/thx.2009.119636 PubMedCrossRefGoogle Scholar
  8. 8.
    Budulac SE, Boezen HM, Hiemstra PS, Lapperre TS, Vonk JM, Timens W, Postma DS, GLUCOLD study group (2012) Toll-like receptor (TLR2 and TLR4) polymorphisms and chronic obstructive pulmonary disease. PLoS One 7(8):e43124PubMedCrossRefGoogle Scholar
  9. 9.
    Kashiwagi M, Imanishi T, Ozaki Y, Satogami K, Masuno T, Wada T, Nakatani Y, Ishibashi K, Komukai K, Tanimoto T, Ino Y, Kitabata H, Akasaka T (2012) Differential expression of Toll-like receptor 4 and human monocyte subsets in acute myocardial infarction. Atherosclerosis 221(1):249–53. doi: 10.1016/j.atherosclerosis.2011.12.030 PubMedCrossRefGoogle Scholar
  10. 10.
    Spirig R, Tsui J, Shaw S (2012) The emerging role of TLR and innate immunity in cardiovascular disease. Cardiol Res Pract 2012:181394. doi: 10.1155/2012/181394 PubMedGoogle Scholar
  11. 11.
    Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11(2):155–61. doi: 10.1038/ni.1836 PubMedCrossRefGoogle Scholar
  12. 12.
    Downes CE, Crack PJ (2010) Neural injury following stroke: are Toll-like receptors the link between the immune system and the CNS? Br J Pharmacol 160(8):1872–88. doi: 10.1111/j.1476-5381.2010.00864.x PubMedCrossRefGoogle Scholar
  13. 13.
    Pimentel-Nunes P, Teixeira AL, Pereira C, Gomes M, Brandão C, Rodrigues C, Gonçalves N, Boal-Carvalho I, Roncon-Albuquerque R Jr, Moreira-Dias L, Leite-Moreira AF, Medeiros R, Dinis-Ribeiro M (2013) Functional polymorphisms of Toll-like receptors 2 and 4 alter the risk for colorectal carcinoma in Europeans. Dig Liver Dis 45(1):63–69. doi: 10.1016/j.dld.2012.08.006 PubMedCrossRefGoogle Scholar
  14. 14.
    Ladefoged M, Buschard K, Hansen AM (2013) Increased expression of toll-like receptor 4 and inflammatory cytokines, interleukin-6 in particular, in islets from a mouse model of obesity and type 2 diabetes. APMIS doi:. doi: 10.1111/apm.12018
  15. 15.
    Amyot J, Semache M, Ferdaoussi M, Fontés G, Poitout V (2012) Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-like receptor-4 and NF-κB signalling. PLoS One 7(4):e36200. doi: 10.1371/journal.pone.0036200 PubMedCrossRefGoogle Scholar
  16. 16.
    Ford ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287(3):356–9PubMedCrossRefGoogle Scholar
  17. 17.
    Jialal I, Huet BA, Kaur H, Chien A, Devaraj S (2012) Increased toll-like receptor activity in patients with metabolic syndrome. Diabetes Care 35(4):900–4. doi: 10.2337/dc11-2375 PubMedCrossRefGoogle Scholar
  18. 18.
    McKernan DP, Dennison U, Gaszner G, Cryan JF, Dinan TG (2011) Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype. Transl Psychiatry 1:e36. doi: 10.1038/tp.2011.37 PubMedCrossRefGoogle Scholar
  19. 19.
    Enstrom AM, Onore CE, Van de Water JA, Ashwood P (2010) Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain BehavImmun 24(1):64–71. doi: 10.1016/j.bbi.2009.08.001 Google Scholar
  20. 20.
    Kanuri G, Weber S, Volynets V, Spruss A, Bischoff SC, Bergheim I (2009) Cinnamon extract protects against acute alcohol-induced liver steatosis in mice. J Nutr 139(3):482–7. doi: 10.3945/jn.108.100495 PubMedCrossRefGoogle Scholar
  21. 21.
    Maes M, Kubera M, Leunis JC (2008) The gut–brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett 29(1):117–24PubMedGoogle Scholar
  22. 22.
    Maes M, Mihaylova I, Leunis JC (2007) Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord 99(1–3):237–40PubMedCrossRefGoogle Scholar
  23. 23.
    Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bosmans E (2013) In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand. doi: 10.1111/j.1600-0447.2012.01908.x
  24. 24.
    Lim SG, Menzies IS, Lee CA, Johnson MA, Pounder RE (1993) Intestinal permeability and function in patients infected with human immunodeficiency virus. A comparison with coeliac disease. Scand J Gastroenterol 28(7):573–80PubMedCrossRefGoogle Scholar
  25. 25.
    Sundqvist T, Lindström F, Magnusson KE, Sköldstam L, Stjernström I, Tagesson C (1982) Influence of fasting on intestinal permeability and disease activity in patients with rheumatoid arthritis. Scand J Rheumatol 11(1):33–8PubMedCrossRefGoogle Scholar
  26. 26.
    Kamer AR, Dasanayake AP, Craig RG, Glodzik-Sobanska L, Bry M, de Leon MJ (2008) Alzheimer’s disease and peripheral infections: the possible contribution from periodontal infections, model and hypothesis. J Alzheimers Dis 13(4):437–49PubMedGoogle Scholar
  27. 27.
    Gabrielli M, Bonazzi P, Scarpellini E, Bendia E, Lauritano EC, Fasano A, Ceravolo MG, Capecci M, Rita Bentivoglio A, Provinciali L, Tonali PA, Gasbarrini A (2011) Prevalence of small intestinal bacterial overgrowth in Parkinson's disease. Mov Disord 26(5):889–92. doi: 10.1002/mds.23566 PubMedCrossRefGoogle Scholar
  28. 28.
    Ochoa-Repáraz J, Mielcarz DW, Begum-Haque S, Kasper LH (2011) Gut, bugs, and brain: role of commensal bacteria in the control of central nervous system disease. Ann Neurol 69(2):240–7. doi: 10.1002/ana.22344 PubMedCrossRefGoogle Scholar
  29. 29.
    Geffard M, Bodet D, Martinet Y, Dabadie M-P (2002) Detection of the specific IgM and IgA circulating in sera of multiple sclerosis patients: interest and perspectives. Immuno-Analyse and Biol Spec 17:302–310Google Scholar
  30. 30.
    Shanahan F (1994) Current concepts of the pathogenesis of inflammatory bowel disease. Ir J Med Sci 163(12):544–9PubMedCrossRefGoogle Scholar
  31. 31.
    Krack A, Sharma R, Figulla HR, Anker SD (2005) The importance of the gastrointestinal system in the pathogenesis of heart failure. Eur Heart J 26(22):2368–74PubMedCrossRefGoogle Scholar
  32. 32.
    Sandek A, Bauditz J, Swidsinski A, Buhner S, Weber-Eibel J, von Haehling S, Schroedl W, Karhausen T, Doehner W, Rauchhaus M, Poole-Wilson P, Volk HD, Lochs H, Anker SD (2007) Altered intestinal function in patients with chronic heart failure. J Am CollCardiol 50(16):1561–9CrossRefGoogle Scholar
  33. 33.
    Sandek A, Rauchhaus M, Anker SD, von Haehling S (2008) The emerging role of the gut in chronic heart failure. Curr Opin Clin Nutr Metab Care 11(5):632–9. doi: 10.1097/MCO.0b013e32830a4c6e PubMedCrossRefGoogle Scholar
  34. 34.
    Charalambous BM, Stephens RC, Feavers IM, Montgomery HE (2007) Role of bacterial endotoxin in chronic heart failure: the gut of the matter. Shock 28(1):15–23PubMedCrossRefGoogle Scholar
  35. 35.
    Arai H, Furuya T, Yasuda T, Miura M, Mizuno Y, Mochizuki H (2004) Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1beta, and expression of caspase-11 in mice. J BiolChem 279(49):51647–53Google Scholar
  36. 36.
    Gyurcsovics K, Bertók L (2003) Pathophysiology of psoriasis: coping endotoxins with bile acid therapy. Pathophysiology 10(1):57–61PubMedCrossRefGoogle Scholar
  37. 37.
    Hollingsworth JW, Kleeberger SR, Foster WM (2007) Ozone and pulmonary innate immunity. Proc Am Thorac Soc 4(3):240–6PubMedCrossRefGoogle Scholar
  38. 38.
    Williams AS, Leung SY, Nath P, Khorasani NM, Bhavsar P, Issa R, Mitchell JA, Adcock IM, Chung KF (2007) Role of TLR2, TLR4, and MyD88 in murine ozone-induced airway hyperresponsiveness and neutrophilia. J Appl Physiol 103(4):1189–95PubMedCrossRefGoogle Scholar
  39. 39.
    Oakes JL, O'Connor BP, Warg LA, Burton R, Hock A, Loader J, Laflamme D, Jing J, Hui L, Schwartz DA, Yang IV (2013) Ozone enhances pulmonary innate immune response to a TLR2 agonist. Am J Respir Cell Mol Biol 48(1):27–34PubMedCrossRefGoogle Scholar
  40. 40.
    Connor AJ, Laskin JD, Laskin DL (2012) Ozone-induced lung injury and sterile inflammation. Role of toll-like receptor 4. Exp Mol Pathol 92(2):229–35. doi: 10.1016/j.yexmp.2012.01.004 PubMedCrossRefGoogle Scholar
  41. 41.
    Garantziotis S, Li Z, Potts EN, Lindsey JY, Stober VP, Polosukhin VV, Blackwell TS, Schwartz DA, Foster WM, Hollingsworth JW (2010) TLR4 is necessary for hyaluronan-mediated airway hyperresponsiveness after ozone inhalation. Am J RespirCrit Care Med 181(7):666–75. doi: 10.1164/rccm.200903-0381OC CrossRefGoogle Scholar
  42. 42.
    Li Z, Potts-Kant EN, Garantziotis S, Foster WM, Hollingsworth JW (2011) Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. PLoS One 6(11):e27137. doi: 10.1371/journal.pone.0027137 PubMedCrossRefGoogle Scholar
  43. 43.
    Iuliano L (2011) Pathways of cholesterol oxidation via non-enzymatic mechanisms. ChemPhys Lipids 164(6):457–68. doi: 10.1016/j.chemphyslip.2011.06.006 CrossRefGoogle Scholar
  44. 44.
    Lee C-W, Hsu D-J (2007) Measurements of fine and ultrafine particles formation in photocopy centers in Taiwan. Atmospheric Environment 41(3):6598–09. doi: org/10.1016/j.atmosenv.2007.04.016 CrossRefGoogle Scholar
  45. 45.
    Kampfrath T, Maiseyeu A, Ying Z, Shah Z, Deiuliis JA, Xu X, Kherada N, Brook RD, Reddy KM, Padture NP, Parthasarathy S, Chen LC, Moffatt-Bruce S, Sun Q, Morawietz H, Rajagopalan S (2011) Chronic fine particulate matter exposure induces systemic vascular dysfunction via NADPH oxidase and TLR4 pathways. Circ Res 108(6):716–26. doi: 10.1161/CIRCRESAHA.110.237560 PubMedCrossRefGoogle Scholar
  46. 46.
    US Environmental Protection Agency (2012) National Ambient Air Quality Standards (NAAQS), PM2.5 NAAQS Implementation http://www.epa.gov/ttn/naaqs/pm/pm25_index.html
  47. 47.
    Miyata R, van Eeden SF (2011) The innate and adaptive immune response induced by alveolar macrophages exposed to ambient particulate matter. Toxicol Appl Pharmacol 257(2):209–26. doi: 10.1016/j.taap.2011.09.007 PubMedCrossRefGoogle Scholar
  48. 48.
    Shiraiwa M, Sosedova Y, Rouvière A, Yang H, Zhang Y, Abbatt JP, Ammann M, Pöschl U (2011) The role of long-lived reactive oxygen intermediates in the reaction of ozone with aerosol particles. Nat Chem 3(4):291–5. doi: 10.1038/nchem.988 PubMedCrossRefGoogle Scholar
  49. 49.
    Gruijthuijsen YK, Grieshuber I, Stöcklinger A, Tischler U, Fehrenbach T, Weller MG, Vogel L, Vieths S, Pöschl U, Duschl A (2006) Nitration enhances the allergenic potential of proteins. Int Arch Allergy Immunol 141(3):265–75PubMedCrossRefGoogle Scholar
  50. 50.
    Bermudez E, Mangum JB, Wong BA, Asgharian B, Hext PM, Warheit DB, Everitt JI (2004) Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol Sci 77(2):347–57PubMedCrossRefGoogle Scholar
  51. 51.
    Chen P, Migita S, Kanehira K, Sonezaki S, Taniguchi A (2011) Development of sensor cells using NF-κB pathway activation for detection of nanoparticle-induced inflammation. Sensors (Basel) 11(7):7219–30. doi: 10.3390/s110707219 CrossRefGoogle Scholar
  52. 52.
    Cui Y, Liu H, Zhou M, Duan Y, Li N, Gong X, Hu R, Hong M, Hong F (2011) Signaling pathway of inflammatory responses in the mouse liver caused by TiO2 nanoparticles. J Biomed Mater Res A 96(1):221–9. doi: 10.1002/jbm.a.32976 PubMedGoogle Scholar
  53. 53.
    Dick CA, Brown DM, Donaldson K, Stone V (2003) The role of free radicals in the toxic and inflammatory effects of four different ultrafine particle types. Inhal Toxicol 15(1):39–52PubMedCrossRefGoogle Scholar
  54. 54.
    Reeves JF, Davies SJ, Dodd NJ, Jha AN (2008) Hydroxyl radicals (*OH) are associated with titanium dioxide (TiO(2)) nanoparticle-induced cytotoxicity and oxidative DNA damage in fish cells. Mutat Res 640(1–2):113–22. doi: 10.1016/j.mrfmmm.2007.12.010 PubMedGoogle Scholar
  55. 55.
    Ionita P, Conte M, Gilbert BC, Chechik V (2007) Gold nanoparticle-initiated free radical oxidations and halogen abstractions. Org Biomol Chem 5(21):3504–9PubMedCrossRefGoogle Scholar
  56. 56.
    Xiong D, Fang T, Yu L, Sima X, Zhu W (2011) Effects of nano-scale TiO2, ZnO and their bulk counterparts on zebrafish: acute toxicity, oxidative stress and oxidative damage. Sci Total Environ 409(8):1444–52. doi: 10.1016/j.scitotenv.2011.01.015 PubMedCrossRefGoogle Scholar
  57. 57.
    Long TC, Saleh N, Tilton RD, Lowry GV, Veronesi B (2006) Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity. Environ Sci Technol 40(14):4346–52PubMedCrossRefGoogle Scholar
  58. 58.
    Hu R, Gong X, Duan Y, Li N, Che Y, Cui Y, Zhou M, Liu C, Wang H, Hong F (2010) Neurotoxicological effects and the impairment of spatial recognition memory in mice caused by exposure to TiO2 nanoparticles. Biomaterials 31(31):8043–50. doi: 10.1016/j.biomaterials.2010.07.011 PubMedCrossRefGoogle Scholar
  59. 59.
    Wang J, Chen C, Liu Y, Jiao F, Li W, Lao F, Li Y, Li B, Ge C, Zhou G, Gao Y, Zhao Y, Chai Z (2008) Potential neurological lesion after nasal instillation of TiO(2) nanoparticles in the anatase and rutile crystal phases. Toxicol Lett 183:72–80. doi: 10.1016/j.toxlet.2008.10.001 PubMedCrossRefGoogle Scholar
  60. 60.
    Yang EJ, Kim S, Kim JS, Choi IH (2012) Inflammasome formation and IL-1β release by human blood monocytes in response to silver nanoparticles. Biomaterials 33(28):6858–67. doi: 10.1016/j.biomaterials.2012.06.016 PubMedCrossRefGoogle Scholar
  61. 61.
    Kim AS, Chae CH, Kim J, Choi JY, Kim SG, Băciut G (2012) Silver nanoparticles induce apoptosis through the Toll-like receptor 2 pathway. Oral Surg Oral Med Oral Pathol Oral Radiol 113(6):789–98PubMedCrossRefGoogle Scholar
  62. 62.
    Jang S, Park JW, Cha HR, Jung SY, Lee JE, Jung SS, Kim JO, Kim SY, Lee CS, Park HS (2012) Silver nanoparticles modify VEGF signaling pathway and mucus hypersecretion in allergic airway inflammation. Int J Nanomedicine 7:1329–43. doi: 10.2147/IJN.S27159 PubMedGoogle Scholar
  63. 63.
    Scarino A, Noël A, Renzi PM, Cloutier Y, Vincent R, Truchon G, Tardif R, Charbonneau M (2012) Impact of emerging pollutants on pulmonary inflammation in asthmatic rats: ethanol vapors and agglomerated TiO2 nanoparticles. Inhal Toxicol 24(8):528–38. doi: 10.3109/08958378.2012.696741 PubMedCrossRefGoogle Scholar
  64. 64.
    Chen EY, Garnica M, Wang YC, Chen CS, Chin WC (2011) Mucin secretion induced by titanium dioxide nanoparticles. PLoS One 6(1):e16198. doi: 10.1371/journal.pone.0016198 PubMedCrossRefGoogle Scholar
  65. 65.
    Schmidt M, Raghavan B, Müller V, Vogl T, Fejer G, Tchaptchet S, Keck S, Kalis C, Nielsen PJ, Galanos C, Roth J, Skerra A, Martin SF, Freudenberg MA, Goebeler M (2012) Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol 11(9):814–9. doi: 10.1038/ni.1919 CrossRefGoogle Scholar
  66. 66.
    Raghavan B, Martin SF, Esser PR, Goebeler M, Schmidt M (2012) Metal allergens nickel and cobalt facilitate TLR4 homodimerization independently of MD2. EMBO Rep 13(12):1109–15. doi: 10.1038/embor.2012.155 PubMedCrossRefGoogle Scholar
  67. 67.
    Takahashi H, Kinbara M, Sato N, Sasaki K, Sugawara S, Endo Y (2011) Nickel allergy-promoting effects of microbial or inflammatory substances at the sensitization step in mice. Int Immunopharmacol 11(10):1534–40. doi: 10.1016/j.intimp.2011.05.010 PubMedCrossRefGoogle Scholar
  68. 68.
    Lerner A (2012) Aluminum as an adjuvant in Crohn’s disease induction. Lupus 21(2):231–8. doi: 10.1177/0961203311430090 PubMedCrossRefGoogle Scholar
  69. 69.
    Koedrith P, Seo YR (2011) Advances in carcinogenic metal toxicity and potential molecular markers. Int J Mol Sci 12(12):9576–95. doi: 10.3390/ijms12129576 PubMedCrossRefGoogle Scholar
  70. 70.
    Reiter RJ, Manchester LC, Tan DX (2010) Neurotoxins: free radical mechanisms and melatonin protection. Curr Neuropharmacol 8(3):194–210. doi: 10.2174/157015910792246236 PubMedCrossRefGoogle Scholar
  71. 71.
    Li H, Nookala S, Re F (2007) Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1beta and IL-18 release. J Immunol 178(8):5271–6PubMedGoogle Scholar
  72. 72.
    Didierlaurent AM, Morel S, Lockman L, Giannini SL, Bisteau M, Carlsen H, Kielland A, Vosters O, Vanderheyde N, Schiavetti F, Larocque D, Van Mechelen M, Garçon N (2009) AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol 183(10):6186–97. doi: 10.4049/jimmunol.0901474 PubMedCrossRefGoogle Scholar
  73. 73.
    Poovala VS, Huang H, Salahudeen AK (1999) Role of reactive oxygen metabolites in organophosphate-bidrin-induced renal tubular cytotoxicity. J Am Soc Nephrol 10(8):1746–52PubMedGoogle Scholar
  74. 74.
    Alluwaimi AM, Hussein Y (2007) Diazinon immunotoxicity in mice: modulation of cytokines level and their gene expression. Toxicology 236(1–2):123–31PubMedCrossRefGoogle Scholar
  75. 75.
    Singh AK, Jiang Y (2003) Lipopolysaccharide (LPS) induced activation of the immune system in control rats and rats chronically exposed to a low level of the organothiophosphate insecticide, acephate. Toxicol Ind Health 19(2–6):93–108PubMedCrossRefGoogle Scholar
  76. 76.
    Pestka J, Zhou HR (2006) Toll-like receptor priming sensitizes macrophages to proinflammatory cytokine gene induction by deoxynivalenol and other toxicants. Toxicol Sci 92(2):445–55PubMedCrossRefGoogle Scholar
  77. 77.
    Bohonowych JE, Zhao B, Timme-Laragy A, Jung D, Di Giulio RT, Denison MS (2008) Newspapers and newspaper ink contain agonists for the ah receptor. Toxicol Sci 102(2):278–90. doi: 10.1093/toxsci/kfn011 PubMedCrossRefGoogle Scholar
  78. 78.
    Masuda K, Kimura A, Hanieh H, Nguyen NT, Nakahama T, Chinen I, Otoyo Y, Murotani T, Yamatodani A, Kishimoto T (2011) Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages. Int Immunol 23(10):637–45. doi: 10.1093/intimm/dxr072 PubMedCrossRefGoogle Scholar
  79. 79.
    Zhu BZ, Shan GQ (2009) Potential mechanism for pentachlorophenol-induced carcinogenicity: a novel mechanism for metal-independent production of hydroxyl radicals. Chem Res Toxicol 22(6):969–77. doi: 10.1021/tx900030v PubMedCrossRefGoogle Scholar
  80. 80.
    Ohnishi T, Yoshida T, Igarashi A, Muroi M, Tanamoto K (2008) Effects of possible endocrine disruptors on MyD88-independent TLR4 signaling. FEMS Immunol Med Microbiol 52(2):293–5. doi: 10.1111/j.1574-695X.2007.00355.x PubMedCrossRefGoogle Scholar
  81. 81.
    Sethi G, Sodhi A (2004) In vitro activation of murine peritoneal macrophages by ultraviolet B radiation: upregulation of CD18, production of NO, proinflammatory cytokines and a signal transduction pathway. Mol Immunol 40(18):1315–23PubMedCrossRefGoogle Scholar
  82. 82.
    Yamamoto T, Kimura T, Ueta E, Tatemoto Y, Osaki T (2003) Characteristic cytokine generation patterns in cancer cells and infiltrating lymphocytes in oral squamous cell carcinomas and the influence of chemoradiation combined with immunotherapy on these patterns. Oncology 64(4):407–15PubMedCrossRefGoogle Scholar
  83. 83.
    Shan YX, Jin SZ, Liu XD, Liu Y, Liu SZ (2007) Ionizing radiation stimulates secretion of pro-inflammatory cytokines: dose–response relationship, mechanisms and implications. Radiat Environ Biophys 46(1):21–9PubMedCrossRefGoogle Scholar
  84. 84.
    Hayashi T, Morishita Y, Khattree R, Misumi M, Sasaki K, Hayashi I, Yoshida K, Kajimura J, Kyoizumi S, Imai K, Kusunoki Y, Nakachi K (2012) Evaluation of systemic markers of inflammation in atomic-bomb survivors with special reference to radiation and age effects. FASEB J 26(11):4765–73. doi: 10.1096/fj.12-215228 PubMedCrossRefGoogle Scholar
  85. 85.
    Heyman SN, Rosen S, Khamaisi M, Idée JM, Rosenberger C (2010) Reactive oxygen species and the pathogenesis of radiocontrast-induced nephropathy. Invest Radiol 45(4):188–95. doi: 10.1097/RLI.0b013e3181d2eed8 PubMedCrossRefGoogle Scholar
  86. 86.
    Marquette C, Linard C, Galonnier M, Van Uye A, Mathieu J, Gourmelon P, Clarençon D (2003) IL-1beta, TNFalpha and IL-6 induction in the rat brain after partial-body irradiation: role of vagal afferents. Int J Radiat Biol 79(10):777–85PubMedCrossRefGoogle Scholar
  87. 87.
    Taylor AG, Goehler LE, Galper DI, Innes KE, Bourguignon C (2010) Top-down and bottom-up mechanisms in mind-body medicine: development of an integrative framework for psychophysiological research. Explore (NY) 6(1):29–41. doi: 10.1016/j.explore.2009.10.004 CrossRefGoogle Scholar
  88. 88.
    Goedendorp MM, Gielissen MF, Verhagen CA, Bleijenberg G (2009) Psychosocial interventions for reducing fatigue during cancer treatment in adults. Cochrane Database Syst Rev(1):CD006953. doi: 10.1002/14651858.CD006953.pub2
  89. 89.
    Morris G, Maes M (2012) A neuro-immune model of myalgic encephalomyelitis/chronic fatigue syndrome. Metab Brain Dis doi: 10.1007/s11011-012-9324-8
  90. 90.
    Shakhov AN, Singh VK, Bone F, Cheney A, Kononov Y, Krasnov P, Bratanova-Toshkova TK, Shakhova VV, Young J, Weil MM, Panoskaltsis-Mortari A, Orschell CM, Baker PS, Gudkov A, Feinstein E (2012) Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2). PLoS One 7(3):e33044. doi: 10.1371/journal.pone.0033044 PubMedCrossRefGoogle Scholar
  91. 91.
    Riehl TE, Foster L, Stenson WF (2011) Hyaluronic acid is radioprotective in the intestine through a TLR4 and COX-2-mediated mechanism. Am J Physiol Gastrointest Liver Physiol 302(3):G309–16. doi: 10.1152/ajpgi.00248.2011 PubMedCrossRefGoogle Scholar
  92. 92.
    Borne J, Riascos R, Cuellar H, Vargas D, Rojas R (2005) Neuroimaging in drug and substance abuse part II: opioids and solvents. Top Magn Reson Imaging 16(3):239–45PubMedCrossRefGoogle Scholar
  93. 93.
    Win-Shwe TT, Kunugita N, Yoshida Y, Fujimaki H (2011) Role of hippocampal TLR4 in neurotoxicity in mice following toluene exposure. Neurotoxicol Teratol 33(5):598–602. doi: 10.1016/j.ntt.2011.07.005 PubMedCrossRefGoogle Scholar
  94. 94.
    Martínez-Alfaro M, Cárabez-Trejo A, Gallegos-Corona MA, Pedraza-Aboytes G, Hernández-Chan NG, Leo-Amador GE (2010) Thinner inhalation effects on oxidative stress and DNA repair in a rat model of abuse. J Appl Toxicol 30(3):226–32. doi: 10.1002/jat.1488 PubMedGoogle Scholar
  95. 95.
    Bailey MT, Engler H, Powell ND, Padgett DA, Sheridan JF (2007) Repeated social defeat increases the bactericidal activity of splenic macrophages through a Toll-like receptor-dependent pathway. Am J Physiol Regul Integr Comp Physiol 293(3):R1180–90PubMedCrossRefGoogle Scholar
  96. 96.
    García-Bueno B, Madrigal JL, Pérez-Nievas BG, Leza JC (2008) Stress mediators regulate brain prostaglandin synthesis and peroxisome proliferator-activated receptor-gamma activation after stress in rats. Endocrinology 149(4):1969–78PubMedCrossRefGoogle Scholar
  97. 97.
    Caso JR, Pradillo JM, Hurtado O, Leza JC, Moro MA, Lizasoain I (2008) Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and in the worsening of experimental stroke. Stroke 39(4):1314–20. doi: 10.1161/STROKEAHA.107.498212 PubMedCrossRefGoogle Scholar
  98. 98.
    Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, Schwartz M (2007) Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 9(9):1081–8PubMedCrossRefGoogle Scholar
  99. 99.
    Tancowny BP, Karpov V, Schleimer RP, Kulka M (2010) Substance P primes lipoteichoic acid- and Pam3CysSerLys4-mediated activation of human mast cells by up-regulating Toll-like receptor 2. Immunology 131(2):220–30. doi: 10.1111/j.1365-2567.2010.03296.x PubMedCrossRefGoogle Scholar
  100. 100.
    Hultqvist M, Olofsson P, Holmberg J, Bäckström BT, Tordsson J, Holmdahl R (2004) Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. Proc Natl Acad Sci U S A 101(34):12646–51PubMedCrossRefGoogle Scholar
  101. 101.
    Kadl A, Sharma PR, Chen W, Agrawal R, Meher AK, Rudraiah S, Grubbs N, Sharma R, Leitinger N (2011) Oxidized phospholipid-induced inflammation is mediated by Toll-like receptor 2. Free Radic Biol Med 51(10):1903–9. doi: 10.1016/j.freeradbiomed.2011.08.026 PubMedCrossRefGoogle Scholar
  102. 102.
    Kaconis Y, Kowalski I, Howe J, Brauser A, Richter W, Razquin-Olazarán I, Iñigo-Pestaña M, Garidel P, Rössle M, Martinez de Tejada G, Gutsmann T, Brandenburg K (2011) Biophysical mechanisms of endotoxin neutralization by cationic amphiphilic peptides. Biophys J 100(11):2652–61. doi: 10.1016/j.bpj.2011.04.041 PubMedCrossRefGoogle Scholar
  103. 103.
    Li P, Ho B, Ding JL (2007) Recombinant factor C competes against LBP to bind lipopolysaccharide and neutralizes the endotoxicity. J Endotoxin Res 13(3):150–7PubMedCrossRefGoogle Scholar
  104. 104.
    Lu Z, Zhang X, Li Y, Jin J, Huang Y (2013) TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice. J Endocrinol 216(1):61–71PubMedCrossRefGoogle Scholar
  105. 105.
    Christianson CA, Dumlao DS, Stokes JA, Dennis EA, Svensson CI, Corr M, Yaksh TL (2011) Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain 152(12):2881–91. doi: 10.1016/j.pain.2011.09.020 PubMedCrossRefGoogle Scholar
  106. 106.
    Tidswell M, Tillis W, Larosa SP, Lynn M, Wittek AE, Kao R, Wheeler J, Gogate J, Opal SM; Eritoran Sepsis Study Group (2010) Phase 2 trial of eritorantetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis. Crit Care Med 38(1):72–83. doi: 10.1097/CCM.0b013e3181b07b78 CrossRefGoogle Scholar
  107. 107.
    Macagno A, Molteni M, Rinaldi A, Bertoni F, Lanzavecchia A, Rossetti C, Sallusto F (2006) A cyanobacterial LPS antagonist prevents endotoxin shock and blocks sustained TLR4 stimulation required for cytokine expression. J Exp Med 203(6):1481–92PubMedCrossRefGoogle Scholar
  108. 108.
    Peri F, Piazza M (2012) Therapeutic targeting of innate immunity with Toll-like receptor 4 (TLR4) antagonists. Biotechnol Adv 30(1):251–60. doi: 10.1016/j.biotechadv.2011.05.014 PubMedCrossRefGoogle Scholar
  109. 109.
    Youn HS, Lee JY, Saitoh SI, Miyake K, Kang KW, Choi YJ, Hwang DH (2006) Suppression of MyD88- and TRIF-dependent signaling pathways of Toll-like receptor by (−)-epigallocatechin-3-gallate, a polyphenol component of green tea. Biochem Pharmacol 72(7):850–9PubMedCrossRefGoogle Scholar
  110. 110.
    Kuang X, Huang Y, Gu HF, Zu XY, Zou WY, Song ZB, Guo QL (2012) Effects of intrathecalepigallocatechingallate, an inhibitor of Toll-like receptor 4, on chronic neuropathic pain in rats. Eur J Pharmacol 676(1–3):51–6. doi: 10.1016/j.ejphar.2011.11.037 PubMedCrossRefGoogle Scholar
  111. 111.
    Park SJ, Lee MY, Son BS, Youn HS (2009) TBK1-targeted suppression of TRIF-dependent signaling pathway of Toll-like receptors by 6-shogaol, an active component of ginger. Biosci Biotechnol Biochem 73(7):1474–8PubMedCrossRefGoogle Scholar
  112. 112.
    Liu CL, Xie LX, Li M, Durairajan SS, Goto S, Huang JD (2007) Salvianolic acid B inhibits hydrogen peroxide-induced endothelial cell apoptosis through regulating PI3K/Akt signaling. PLoS One 2(12):e1321PubMedCrossRefGoogle Scholar
  113. 113.
    Wang X, Wang Y, Jiang M, Zhu Y, Hu L, Fan G, Wang Y, Li X, Gao X (2011) Differential cardioprotective effects of salvianolic acid and tanshinone on acute myocardial infarction are mediated by unique signaling pathways. J Ethnopharmacol 135(3):662–71. doi: 10.1016/j.jep.2011.03.070 PubMedCrossRefGoogle Scholar
  114. 114.
    Youn HS, Saitoh SI, Miyake K, Hwang DH (2006) Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem Pharmacol 72(1):62–9PubMedCrossRefGoogle Scholar
  115. 115.
    Kissner TL, Ruthel G, Alam S, Mann E, Ajami D, Rebek M, Larkin E, Fernandez S, Ulrich RG, Ping S, Waugh DS, Rebek J Jr, Saikh KU (2012) Therapeutic inhibition of pro-inflammatory signaling and toxicity to staphylococcal enterotoxin B by a synthetic dimeric BB-loop mimetic of MyD88. PLoS One 7(7):e40773. doi: 10.1371/journal.pone.0040773 PubMedCrossRefGoogle Scholar
  116. 116.
    Hsing CH, Lin MC, Choi PC, Huang WC, Kai JI, Tsai CC, Cheng YL, Hsieh CY, Wang CY, Chang YP, Chen YH, Chen CL, Lin CF (2011) Anesthetic propofol reduces endotoxic inflammation by inhibiting reactive oxygen species-regulated Akt/IKKβ/NF-κB signaling. PLoS One 6(3):e17598. doi: 10.1371/journal.pone.0017598 PubMedCrossRefGoogle Scholar
  117. 117.
    Chiu WT, Lin YL, Chou CW, Chen RM (2009) Propofol inhibits lipoteichoic acid-induced iNOS gene expression in macrophages possibly through downregulation of toll-like receptor 2-mediated activation of Raf-MEK1/2-ERK1/2-IKK-NFkappaB. Chem Biol Interact 181(3):430–9. doi: 10.1016/j.cbi.2009.06.011 PubMedCrossRefGoogle Scholar
  118. 118.
    Wu Y, Li W, Zhou C, Lu F, Gao T, Liu Y, Cao J, Zhang Y, Zhang Y, Zhou C (2012) Ketamine inhibits lipopolysaccharide-induced astrocytes activation by suppressing TLR4/NF-ĸB pathway. Cell Physiol Biochem 30(3):609–17. doi: 10.1159/000341442 PubMedCrossRefGoogle Scholar
  119. 119.
    Montezano AC, Touyz RM (2012) Molecular mechanisms of hypertension-reactive oxygen species and antioxidants: a basic science update for the clinician. Can J Cardiol 28(3):288–95. doi: 10.1016/j.cjca.2012.01.017 PubMedCrossRefGoogle Scholar
  120. 120.
    Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Bush AI (2008) N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry 64(6):468–75. doi: 10.1016/j.biopsych.2008.04.022 PubMedCrossRefGoogle Scholar
  121. 121.
    Magalhães PV, Dean OM, Bush AI, Copolov DL, Malhi GS, Kohlmann K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Berk M (2011) N-acetylcysteine for major depressive episodes in bipolar disorder. Rev Bras Psiquiatr 33(4):374–8PubMedCrossRefGoogle Scholar
  122. 122.
    Smaga I, Pomierny B, Krzyóanowska W, Pomierny-Chamioło L, Miszkiel J, Niedzielska E, Ogórka A, Filip M (2012) N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: behavioral and biochemical analyses in rats. Prog Neuropsychopharmacol Biol Psychiatry 39(2):280–7. doi: 10.1016/j.pnpbp.2012.06.018 PubMedCrossRefGoogle Scholar
  123. 123.
    Hou Y, Wang L, Yi D, Ding B, Yang Z, Li J, Chen X, Qiu Y, Wu G (2013) N-acetylcysteine reduces inflammation in the small intestine by regulating redox, EGF and TLR4 signaling. Amino Acids (in press)Google Scholar
  124. 124.
    Jung TS, Kim SK, Shin HJ, Jeon BT, Hahm JR, Roh GS (2012) α-Lipoic acid prevents non-alcoholic fatty liver disease in OLETF rats. Liver Int 32(10):1565–73. doi: 10.1111/j.1478-3231.2012.02857.x PubMedCrossRefGoogle Scholar
  125. 125.
    Deiuliis JA, Kampfrath T, Ying Z, Maiseyeu A, Rajagopalan S (2011) Lipoic acid attenuates innate immune infiltration and activation in the visceral adipose tissue of obese insulin resistant mice. Lipids 46(11):1021–1032. doi: 10.1007/s11745-011-3603-8 PubMedCrossRefGoogle Scholar
  126. 126.
    Tian YF, Hsieh CH, Hsieh YJ, Chen YT, Peng YJ, Hsieh PS (2012) α-Lipoic acid prevents mild portal endotoxaemia-induced hepatic inflammation and β cell dysfunction. Eur J Clin Invest 42(6):637–48. doi: 10.1111/j.1365-2362.2011.02630.x PubMedCrossRefGoogle Scholar
  127. 127.
    Honda H, Nagai Y, Matsunaga T, Saitoh S, Akashi-Takamura S, Hayashi H, Fujii I, Miyake K, Muraguchi A, Takatsu K (2012) Glycyrrhizin and isoliquiritigenin suppress the LPS sensor toll-like receptor 4/MD-2 complex signaling in a different manner. J Leukoc Biol 91(6):967–76. doi: 10.1189/jlb.0112038 PubMedCrossRefGoogle Scholar
  128. 128.
    Ghanim H, Sia CL, Korzeniewski K, Lohano T, Abuaysheh S, Marumganti A, Chaudhuri A, Dandona P (2011) A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. J Clin Endocrinol Metab 96(5):1409–14. doi: 10.1210/jc.2010-1812 PubMedCrossRefGoogle Scholar
  129. 129.
    Kim SJ, Lee SM (2012) Effect of baicalin on toll-like receptor 4-mediated ischemia/reperfusion inflammatory responses in alcoholic fatty liver condition. Toxicol Appl Pharmacol 258(1):43–50. doi: 10.1016/j.taap.2011.10.005 PubMedCrossRefGoogle Scholar
  130. 130.
    Hao H, Gufu H, Lei F, Dang L, Zhongliang Y (2012) Baicalin suppresses expression of TLR2/4 and NF-κB in Chlamydia trachomatis-infected mice. Immunopharmacol Immunotoxicol 34(1):89–94. doi: 10.3109/08923973.2011.580756 PubMedCrossRefGoogle Scholar
  131. 131.
    Tu XK, Yang WZ, Shi SS, Chen Y, Wang CH, Chen CM, Chen Z (2011) Baicalin inhibits TLR2/4 signaling pathway in rat brain following permanent cerebral ischemia. Inflammation 34(5):463–70. doi: 10.1007/s10753-010-9254-8 PubMedCrossRefGoogle Scholar
  132. 132.
    Ohno K, Ito M, Ichihara M, Ito M (2012) Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. Oxid Med Cell Longev 2012:353152. doi: 10.1155/2012/353152 PubMedCrossRefGoogle Scholar
  133. 133.
    Ito M, Ibi T, Sahashi K, Ichihara M, Ito M, Ohno K (2011) Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. Med Gas Res 1(1):24. doi: 10.1186/2045-9912-1-24 PubMedCrossRefGoogle Scholar
  134. 134.
    Li J, Dong Y, Chen H, Han H, Yu Y, Wang G, Zeng Y, Xie K (2012) Protective effects of hydrogen-rich saline in a rat model of permanent focal cerebral ischemia via reducing oxidative stress and inflammatory cytokines. Brain Res 1486:103–11. doi: 10.1016/j.brainres.2012.09.031 PubMedCrossRefGoogle Scholar
  135. 135.
    Xie K, Yu Y, Huang Y, Zheng L, Li J, Chen H, Han H, Hou L, Gong G, Wang G (2012) Molecular hydrogen ameliorates lipopolysaccharide-induced acute lung injury in mice through reducing inflammation and apoptosis. Shock 37(5):548–55. doi: 10.1097/SHK.0b013e31824ddc81 PubMedGoogle Scholar
  136. 136.
    Taylor KE, Giddings JC, van den Berg CW (2005) C-reactive protein-induced in vitro endothelial cell activation is an artefact caused by azide and lipopolysaccharide. Arterioscler Thromb Vasc Biol 25(6):1225–30PubMedCrossRefGoogle Scholar
  137. 137.
    Kikkert R (2009) Toll-like receptors: tools, assays, and implications for in-vitro pyrogen tests. Thesis, University of Amsterdam, 29 September 2009Google Scholar
  138. 138.
    Józefowski S, Czerkies M, Sobota A, Kwiatkowska K (2011) Determination of cell surface expression of Toll-like receptor 4 by cellular enzyme-linked immunosorbent assay and radiolabeling. Anal Biochem 413(2):185–91. doi: 10.1016/j.ab.2011.02.031 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Sportzenkoppel 54HamburgGermany
  2. 2.Piyavate HospitalBangkokThailand
  3. 3.Department of PsychiatryChulalongkorn UniversityBangkokThailand
  4. 4.International PNI Reference CenterRoosendaalthe Netherlands
  5. 5.Department of PsychiatryDeakin UniversityGeelongAustralia

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