摘要
Toll样受体（TLR）是参与激活炎症过程的免疫系统的初始应答者之一。已经在各种细胞类型中鉴定了几种不同类型的TLR，例如TLR2，TLR4，TLR7和TLR9，每种细胞类型具有不同的配体，如脂质，脂蛋白，核酸和蛋白质。虽然它的主要关注点是异生素防御，但TLR信号传导也被认为是炎症的激活因子和慢性退行性疾病（CDDs）的相关发展，包括肥胖，2型糖尿病（T2DM），脂肪肝疾病，心血管和神经退行性疾病以及各种类型的癌症。许多药物用于预防这些疾病，这些疾病特异性地抑制与CDD发展相关的不同途径。与这些药物靶标相比，特异性负责炎症损伤的TLR的抑制已被证明是更好的药物靶标。已经出现了几种天然产物作为CDD的抑制剂，其特异性地靶向TLR信号传导，其中许多是在临床试验中。本综述旨在总结TLR与CDD相关的最新进展，并列出天然产物，其组合及其合成衍生物在预防TLR驱动的CDD发展中的可能用途。
关键词: 癌症，心血管疾病，炎症，天然产物，Toll样受体，脂蛋白。
图形摘要
[1]
Hashimoto C, Hudson KL, Anderson KV. The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 1988; 52: 269-79.
[2]
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997; 388: 394-7.
[3]
Hoshino K, Takeuchi O, Kawai T, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999; 162: 3749-52.
[4]
Kumar VG, Sejian V, Bagath M, Krishnan G, Bhatta R. Toll-like receptors: Significance, ligands, signaling pathways, and functions in mammals AU - Vidya, Mallenahally Kusha. Int Rev Immunol 2018; 37: 20-36.
[5]
Yu L, Wang L, Chen S. Exogenous or endogenous Toll-like receptor ligands: which is the MVP in tumorigenesis? Cell Mol Life Sci 2012; 69: 935-49.
[6]
Samadi R, Nazemalhosseini Mojarad E, Molaei M, et al. Clinical Value of Human Leucocyte Antigen G (HLA-G) Expression in the Prognosis of Colorectal Cancer. Int J Cancer Manag 2017; 10e9346
[7]
Wlasiuk P, Tomczak W, Zajac M, Dmoszynska A, Giannopoulos K. Total expression of HLA-G and TLR-9 in chronic lymphocytic leukemia patients. Hum Immunol 2013; 74: 1592-7.
[9]
Botos I, Segal DM, Davies DR. The structural biology of Toll-like receptors Structure (London, England : 1993) 2011; 19: 447-59.
[10]
Uematsu S, Akira S. Toll-Like receptors (TLRs) and their ligands. Handb Exp Pharmacol 2008; 183: 1-20.
[11]
Gay NJ, Symmons MF, Gangloff M, Bryant CE. Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol 2014; 14: 546.
[12]
McGettrick AF, O’Neill LA. Localisation and trafficking of Toll-like receptors: an important mode of regulation. Curr Opin Immunol 2010; 22: 20-7.
[13]
Majer O, Liu B, Barton GM. Nucleic acid-sensing TLRs: trafficking and regulation. Curr Opin Immunol 2017; 44: 26-33.
[14]
Chattopadhyay S, Sen GC. dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects. J Interferon Cytokine Res 2014; 34: 427-36.
[15]
Perales-Linares R, Navas-Martin S. Toll-like receptor 3 in viral pathogenesis: friend or foe? Immunol 2013; 140: 153-67.
[16]
Shukla NM, Mutz CA, Malladi SS, et al. Toll-like receptor (TLR)-7 and -8 modulatory activities of dimeric imidazoquinolines. J Med Chem 2012; 55: 1106-16.
[17]
Ganapathi L, Van Haren S, Dowling DJ, et al. The Imidazoquinoline toll-like receptor-7/8 agonist hybrid-2 potently induces cytokine production by human newborn and adult leukocytes. PLoS One 2015; 10e0134640
[18]
Zhang Z, Ohto U, Shibata T, et al. Structural analysis reveals that toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA. Immunity 2016; 45: 737-48.
[19]
Takeshita F, Leifer CA, Gursel I, et al. Cutting Edge: Role of toll-like receptor 9 in cpg dna-induced activation of human cells. J Immunol 2001; 167: 3555.
[20]
Gao M, Ha T, Zhang X, et al. The Toll-like receptor 9 ligand, CpG oligodeoxynucleotide, attenuates cardiac dysfunction in polymicrobial sepsis, involving activation of both phosphoinositide 3 kinase/ Akt and extracellular-signal-related kinase signaling. J Infect Dis 2013; 207: 1471-9.
[22]
Valenty LM, Longo CM, Horzempa C, et al. TLR4 ligands selectively synergize to induce expression of IL-8. Adv Wound Care 2017; 6: 309-19.
[23]
Yu L, Wang L, Chen S. Endogenous toll-like receptor ligands and their biological significance. J Cell Mol Med 2010; 14: 2592-603.
[24]
Lefebvre JS, Lévesque T, Picard S, et al. Extra domain A of fibronectin primes leukotriene biosynthesis and stimulates neutrophil migration through activation of Toll-like receptor 4. Arthritis Rheum 2011; 63: 1527-33.
[25]
Matsumoto C, Oda T, Yokoyama S, et al. Toll-like receptor 2 heterodimers, TLR2/6 and TLR2/1 induce prostaglandin E production by osteoblasts, osteoclast formation and inflammatory periodontitis. Biochem Biophys Res Commun 2012; 428: 110-5.
[26]
Gangloff M. Different dimerisation mode for TLR4 upon endosomal acidification? Trends Biochem Sci 2012; 37: 92-8.
[27]
Di Gioia M, Zanoni I. Toll-like receptor co-receptors as master regulators of the immune response. Mol Immunol 2015; 63: 143-52.
[28]
Leifer CA, Medvedev AE. Molecular mechanisms of regulation of Toll-like receptor signaling. J Leukoc Biol 2016; 100: 927-41.
[30]
De Nardo D, Balka KR, Cardona Gloria Y, et al. Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a dual role in myddosome formation and Toll-like receptor signaling. J Biol Chem 2018; 293: 15195-207.
[31]
Gillen JG, Nita-Lazar A. Composition of the myddosome during the innate immune response. J Immunol 2017; 198: (1 Supplement) 75.15;
[32]
Walsh MC, Kim GK, Maurizio PL, Molnar EE, Choi Y. TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL. PLoS One 2008; 3: e4064-e.
[33]
Zhao W, Wang L, Zhang M, Yuan C, Gao C. E3 ubiquitin ligase tripartite motif 38 negatively regulates TLR-mediated immune responses by proteasomal degradation of TNF receptor-associated factor 6 in macrophages. J Immunol 2012; 188: 2567-74.
[34]
West AP, Brodsky IE, Rahner C, et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011; 472: 476-80.
[35]
Ahmed S, Maratha A, Butt AQ, Shevlin E, Miggin SM. TRIF-mediated TLR3 and TLR4 signaling is negatively regulated by ADAM15. J Immunol 2013; 190: 2217-28.
[36]
Ullah MO, Sweet MJ, Mansell A, Kellie S, Kobe B. TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target. J Leukoc Biol 2016; 100: 27-45.
[37]
Hiscott J. Triggering the Innate Antiviral Response through IRF-3 Activation. J Biol Chem 2007; 282: 15325-9.
[38]
Kim SS, Lee KG, Chin CS, et al. DOK3 is required for IFN-beta production by enabling TRAF3/TBK1 complex formation and IRF3 activation. J Immunol 2014; 193: 840-8.
[39]
Aziz N, Son Y-J, Cho JY. Thymoquinone Suppresses IRF-3-Mediated Expression of Type I Interferons via Suppression of TBK1. Int J Mol Sci 2018; 19E1355
[40]
Kondylis V, Kumari S, Vlantis K, Pasparakis M. The interplay of IKK, NF-kappaB and RIPK1 signaling in the regulation of cell death, tissue homeostasis and inflammation. Immunol Rev 2017; 277: 113-27.
[41]
Yatim N, Jusforgues-Saklani H, Orozco S, et al. RIPK1 and NF-kappaB signaling in dying cells determines cross-priming of CD8(+) T cells. Science 2015; 350: 328-34.
[42]
Moriwaki K, Chan FK. The Inflammatory Signal Adaptor RIPK3: Functions Beyond Necroptosis. Int Rev Cell Mol Biol 2017; 328: 253-75.
[44]
Mishra V, Pathak C. Human Toll-Like Receptor 4 (hTLR4): Structural and functional dynamics in cancer. Int J Biol Macromol 2019; 122: 425-51.
[46]
Tongtawee T, Simawaranon T, Wattanawongdon W, Dechsukhum C, Leeanansaksiri W. Toll-like receptor 2 and 4 polymorphisms associated with Helicobacter pylori susceptibility and gastric cancer. Turk J Gastroenterol 2019; 30(1): 15-20.
[47]
Chen J, Hu S, Liang S, et al. Associations between the four toll-like receptor polymorphisms and the risk of gastric cancer: a meta-analysis. Cancer Biother Radiopharm 2013; 28: 674-81.
[48]
Zhou Q, Wang C, Wang X, et al. Association between TLR4 (+896A/G and +1196C/T) polymorphisms and gastric cancer risk: an updated meta-analysis. PLoS One 2014; 9E109605
[49]
Castano-Rodriguez N, Kaakoush NO, Goh KL, Fock KM, Mitchell HM. The role of TLR2, TLR4 and CD14 genetic polymorphisms in gastric carcinogenesis: a case-control study and meta-analysis. PLoS One 2013; 8: 2: e60327.
[50]
Tian S, Zhang L, Yang T, et al. The Associations between Toll-Like Receptor 9 Gene Polymorphisms and Cervical Cancer Susceptibility. Mediators Inflamm 2018; 20189127146
[51]
Sheng WY, Yong Z, Yun Z, Hong H, Hai LL. Toll-like receptor 4 gene polymorphisms and susceptibility to colorectal cancer: a meta-analysis and review. Arch Med Sci 2015; 11: 699-707.
[52]
Sun M, Geng D, Li S, Chen Z, Zhao W. LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells. Biol Chem 2018; 399: 387-95.
[53]
Wang W, Wang J. Toll-Like Receptor 4 (TLR4)/Cyclooxygenase-2 (COX-2) regulates prostate cancer cell proliferation, migration, and invasion by nf-kappab activation. Med Sci Monit 2018; 24: 5588-97.
[54]
Wang L, Zhu R, Huang Z, Li H, Zhu H. Lipopolysaccharide-induced toll-like receptor 4 signaling in cancer cells promotes cell survival and proliferation in hepatocellular carcinoma. Dig Dis Sci 2013; 58: 2223-36.
[55]
Zu Y, Ping W, Deng T, Zhang N, Fu X, Sun W. Lipopolysaccharide-induced toll-like receptor 4 signaling in esophageal squamous cell carcinoma promotes tumor proliferation and regulates inflammatory cytokines expression. Dis Esophagus 2017; 30: 1-8.
[56]
Min R, Zun Z, Siyi L, et al. Increased expression of Toll-like receptor-9 has close relation with tumour cell proliferation in oral squamous cell carcinoma. Arch Oral Biol 2011; 56: 877-84.
[57]
Song IJ, Yang YM, Inokuchi-Shimizu S, et al. The contribution of toll-like receptor signaling to the development of liver fibrosis and cancer in hepatocyte-specific TAK1-deleted mice. Int J Cancer 2018; 142: 81-91.
[58]
Bao H, Lu P, Li Y, et al. Triggering of toll-like receptor-4 in human multiple myeloma cells promotes proliferation and alters cell responses to immune and chemotherapy drug attack. Cancer Biol Ther 2011; 11: 58-67.
[59]
Zheng Q, Xu J, Lin Z, et al. Inflammatory factor receptor Toll-like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell. J Cell Mol Med 2018; 22: 3246-58.
[60]
Terawaki K, Kashiwase Y, Uzu M, et al. Leukemia inhibitory factor via the Toll-like receptor 5 signaling pathway involves aggravation of cachexia induced by human gastric cancer-derived 85As2 cells in rats. Oncotarget 2018; 9: 34748-64.
[61]
Yuan S, Qiao T, Li X, et al. Toll-like receptor 9 activation by CpG oligodeoxynucleotide 7909 enhances the radiosensitivity of A549 lung cancer cells via the p53 signaling pathway. Oncol Lett 2018; 15: 5271-9.
[62]
Semlali A, Parine NR, Al-Numair NS, et al. Potential role of Toll-like receptor 2 expression and polymorphisms in colon cancer susceptibility in the Saudi Arabian population. OncoTargets Ther 2018; 11: 8127-41.
[63]
Moradi-Marjaneh R, Hassanian SM, Fiuji H, et al. Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer. J Cell Physiol 2018; 233: 5613-22.
[64]
Liu YD, Ji CB, Li SB, et al. Toll-like receptor 2 stimulation promotes colorectal cancer cell growth via PI3K/Akt and NF-kappaB signaling pathways. Int Immunopharmacol 2018; 59: 375-83.
[65]
Quan XQ, Xie ZL, Ding Y, et al. miR-198 regulated the tumorigenesis of gastric cancer by targeting Toll-like receptor 4 (TLR4). Eur Rev Med Pharmacol Sci 2018; 22: 2287-96.
[66]
Chen G, Xu M, Chen J, et al. Clinicopathological features and increased expression of toll-like receptor 4 of gastric cardia cancer in a high-risk chinese population. J Immunol Res 2018; 20187132868
[67]
Yue Y, Zhou T, Gao Y, et al. High mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling promotes progression of gastric cancer. Tumour Biol 2017; 391010428317694312
[68]
Peyret V, Nazar M, Martin M, et al. Functional toll-like receptor 4 overexpression in papillary thyroid cancer by mapk/erk-induced ets1 transcriptional activity. Mol Cancer Res 2018; 16: 833-45.
[69]
Ou T, Lilly M, Jiang W. The pathologic role of toll-like receptor 4 in prostate cancer. Front Immunol 2018; 9: 1188.
[70]
Liu YD, Yu L, Ying L, et al. Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2. Int J Cancer 2019; 144(12): 3056-69.
[71]
Huang J, Hang JJ, Qin XR, Wang XY. Interaction of H. pylori with toll-like receptor 2-196 to -174 ins/del polymorphism is associated with gastric cancer susceptibility in southern China. Int J Clin Oncol 2018.
[72]
Khademalhosseini M, Arababadi MK. Toll-like receptor 4 and breast cancer: an updated systematic review. Breast Cancer 2018; 26(3): 265-71.
[73]
Gao XL, Yang JJ, Wang SJ, et al. Effects of RNA interference-mediated silencing of toll-like receptor 4 gene on proliferation and apoptosis of human breast cancer MCF-7 and MDA-MB-231 cells: An in vitro study. J Cell Physiol 2018; 234: 433-42.
[74]
Semlali A, Jalouli M, Parine NR, et al. Toll-like receptor 4 as a predictor of clinical outcomes of estrogen receptor-negative breast cancer in Saudi women. OncoTargets Ther 2017; 10: 1207-16.
[75]
Shuang C, Weiguang Y, Zhenkun F, et al. Toll-like receptor 5 gene polymorphism is associated with breast cancer susceptibility. Oncotarget 2017; 8: 88622-9.
[76]
Shahriari S, Rezaeifard S, Moghimi HR, Khorramizadeh MR, Faghih Z. Cell membrane and intracellular expression of toll-like receptor 9 (TLR9) in colorectal cancer and breast cancer cell-lines. Cancer Biomark 2017; 18: 375-80.
[77]
Sandholm J, Lehtimaki J, Ishizu T, et al. Toll-like receptor 9 expression is associated with breast cancer sensitivity to the growth inhibitory effects of bisphosphonates in vitro and in vivo. Oncotarget 2016; 7: 87373-89.
[78]
Matijevic Glavan T, Cipak Gasparovic A, Verillaud B, Busson P, Pavelic J. Toll-like receptor 3 stimulation triggers metabolic reprogramming in pharyngeal cancer cell line through Myc, MAPK, and HIF. Mol Carcinog 2017; 56: 1214-26.
[79]
Maitra R, Augustine T, Dayan Y, et al. Toll like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer. Oncotarget 2017; 8: 35138-53.
[80]
Jin Y, Qiu S, Shao N, Zheng J. Association of toll-like receptor gene polymorphisms and its interaction with HPV infection in determining the susceptibility of cervical cancer in Chinese Han population. Mamm Genome 2017; 28: 213-9.
[81]
Jiang N, Xie F, Guo Q, et al. Toll-like receptor 4 promotes proliferation and apoptosis resistance in human papillomavirus-related cervical cancer cells through the Toll-like receptor 4/nuclear factor-kappaB pathway. Tumour Biol 2017; 391010428317710586
[82]
de Barros Gallo C, Marichalar-Mendia X, Setien-Olarra A, Acha-Sagredo A, Bediaga NG, Gainza-Cirauqui ML, et al. Toll-like receptor 2 rs4696480 polymorphism and risk of oral cancer and oral potentially malignant disorder. Arch Oral Biol 2017; 82: 109-14.
[83]
Wang F, Jin R, Zou BB, et al. Activation of Toll-like receptor 7 regulates the expression of IFN-lambda1, p53, PTEN, VEGF, TIMP-1 and MMP-9 in pancreatic cancer cells. Mol Med Rep 2016; 13: 1807-12.
[84]
Sun Y, Wu C, Ma J, et al. Toll-like receptor 4 promotes angiogenesis in pancreatic cancer via PI3K/AKT signaling. Exp Cell Res 2016; 347: 274-82.
[85]
Semlali A, Reddy Parine N, Arafah M, et al. Expression and polymorphism of toll-like receptor 4 and effect on nf-kappab mediated inflammation in colon cancer patients. PLoS One 2016; 11e0146333
[86]
Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol 2017; 9: 715-32.
[87]
Asrih M, Jornayvaz FR. Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance. J Endocrinol 2013; 218: 13-0201.
[88]
Narayanankutty A, Anil A, Illam SP, Kandiyil SP, Raghavamenon AC. Non-polar lipid carbonyls of thermally oxidized coconut oil induce hepatotoxicity mediated by redox imbalance. Prostaglandins Leukot Essent Fatty Acids 2018; 138: 45-51.
[89]
Narayanankutty A, Manalil JJ, Suseela IM, et al. Deep fried edible oils disturb hepatic redox equilibrium and heightens lipotoxicity and hepatosteatosis in male Wistar rats. Hum Exp Toxicol 2017; 36: 919-30.
[90]
Soto-Alarcon SA, Valenzuela R, Valenzuela A, Videla LA. Liver Protective Effects of Extra Virgin Olive Oil: Interaction between Its Chemical Composition and the Cell-signaling Pathways Involved in Protection. Endocr Metab Immune Disord Drug Targets 2018; 18: 75-84.
[91]
Narayanankutty A, Illam SP, Raghavamenon AC. Health impacts of different edible oils prepared from coconut (Cocos nucifera): A comprehensive review. Trends Food Sci Technol 2018; 80: 1-7.
[92]
Narayanankutty A, Mukesh RK, Ayoob SK, et al. Virgin coconut oil maintains redox status and improves glycemic conditions in high fructose fed rats. J Food Sci Technol 2016; 53: 895-901.
[93]
Narayanankutty A, Palliyil DM, Kuruvilla K, Raghavamenon AC. Virgin coconut oil reverses hepatic steatosis by restoring redox homeostasis and lipid metabolism in male Wistar rats. J Sci Food Agric 2018; 98: 1757-64.
[94]
Valenzuela R, Videla LA. The importance of the long-chain polyunsaturated fatty acid n-6/n-3 ratio in development of non-alcoholic fatty liver associated with obesity. Food Funct 2011; 2: 644-8.
[95]
Sharifnia T, Antoun J, Verriere TGC, et al. Hepatic TLR4 signaling in obese NAFLD. Am J Physiol Gastrointest Liver Physiol 2015; 309: G270-8.
[96]
Jia L, Chang X, Qian S, et al. Hepatocyte toll-like receptor 4 deficiency protects against alcohol-induced fatty liver disease. Mol Metab 2018; 14: 121-9.
[97]
Roh YS, Park S, Kim JW, et al. Toll-like receptor 7-mediated type I interferon signaling prevents cholestasis- and hepatotoxin-induced liver fibrosis. Hepatol 2014; 60: 237-49.
[98]
Roh YS, Kim JW, Park S, et al. Toll-Like Receptor-7 signaling promotes nonalcoholic steatohepatitis by inhibiting regulatory t cells in mice. Am J Pathol 2018; 188: 2574-88.
[99]
Matsumoto H, Yang C, Sugimoto K. Role of TLR7 in development of alcoholic fatty liver disease: a new target for prevention of alcoholic fatty liver disease FASEB J 2016; 30: 516.8-.8.
[100]
Yang L, Miura K, Zhang B, et al. TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in Mice. Cell Mol Gastroenterol Hepatol 2017; 3: 469-83.
[101]
Pang S, Tang H, Zhuo S, Zang YQ, Le Y. Regulation of fasting fuel metabolism by toll-like receptor 4. Diabetes 2010; 59: 3041-8.
[102]
Kim S, Park S, Kim B, Kwon J. Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease. Sci Rep 2016; 6: 27849.
[103]
Etienne-Mesmin L, Vijay-Kumar M, Gewirtz AT, Chassaing B. Hepatocyte toll-like receptor 5 promotes bacterial clearance and protects mice against high-fat diet-induced liver disease. Cell Mol Gastroenterol Hepatol 2016; 2(5): 584-604.
[104]
Rafieian-Kopaei M, Setorki M, Doudi M, Baradaran A, Nasri H. Atherosclerosis: process, indicators, risk factors and new hopes. Int J Prev Med 2014; 5: 927-46.
[105]
Fava C, Montagnana M. Atherosclerosis is an inflammatory disease which lacks a common anti-inflammatory therapy: How human genetics can help to this issue. A Narrative Review. Front Pharmacol 2018; 9: 55.
[106]
Seyed Mostafa P, Maryam G, Motahareh H-M, et al. Toll-like receptors signaling pathways as a potential therapeutic target in cardiovascular disease. Curr Pharm Des 2018; 24: 1887-98.
[107]
De Meyer I, Martinet W, Schrijvers DM, et al. Toll-like receptor 7 stimulation by imiquimod induces macrophage autophagy and inflammation in atherosclerotic plaques Basic Res Cardiol 2012; 107: 012-0269.
[108]
Ellenbroek GHJM, van Puijvelde GHM, Anas AA, et al. Leukocyte TLR5 deficiency inhibits atherosclerosis by reduced macrophage recruitment and defective T-cell responsiveness. Sci Rep 2017; 7: 42688.
[109]
Tang YL, Jiang JH, Wang S, et al. TLR4/NF-κB signaling contributes to chronic unpredictable mild stress-induced atherosclerosis in ApoE-/- Mice. PLoS One 2015; 10e0123685
[110]
Yang S, Li R, Tang L, et al. TLR4-mediated anti-atherosclerosis mechanisms of angiotensin-converting enzyme inhibitor – Fosinopril. Cell Immunol 2013; 285: 38-41.
[111]
Madan M, Amar S. Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: Proteomic Findings. PLoS One 2008; 3e3204
[112]
Mellal K, Zoccal K, Mulumba M, et al. Modulation of TLR2-mediated inflammation by azapeptides as selective ligands of cd36 in atherosclerosis. Atherosclerosis 2015; 241e53
[113]
Ma C, Ouyang Q, Huang Z, et al. Toll-Like Receptor 9 inactivation alleviated atherosclerotic progression and inhibited macrophage polarized to m1 phenotype in apoe−/− mice. Dis Markers 2015; 2015: 9.
[114]
Krogmann AO, Lüsebrink E, Steinmetz M, et al. Proinflammatory stimulation of toll-like receptor 9 with high dose cpg odn 1826 impairs endothelial regeneration and promotes atherosclerosis in mice. PLoS One 2016; 11e0146326
[115]
Salagianni M, Galani IE, Lundberg AM, et al. Toll-like receptor 7 protects from atherosclerosis by constraining “inflammatory” macrophage activation. Circulation 2012; 126: 952-62.
[116]
Koulis C, Chen Y-C, Hausding C, Ahrens I, Kyaw Tin S, Tay C, et al. Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice. Arterioscler Thromb Vasc Biol 2014; 34: 516-25.
[117]
Ardura-Fabregat A, Boddeke EWGM, Boza-Serrano A, Brioschi S, Castro-Gomez S, Ceyzériat K, et al. Targeting Neuroinflammation to Treat Alzheimer’s Disease. CNS Drugs 2017; 31: 1057-82. Epub 2017/12/19.
[118]
Bolos M, Perea JR, Avila J. Alzheimer’s disease as an inflammatory disease. Biomol Concepts 2017; 8: 37-43.
[119]
Joshi N, Singh S. Updates on immunity and inflammation in Parkinson disease pathology. J Neurosci Res 2018; 96: 379-90.
[120]
Chiang P-L, Chen H-L, Lu C-H, Chen P-C, Chen M-H, Yang IH, et al. White matter damage and systemic inflammation in Parkinson’s disease. BMC Neurosci 2017; 18: 48.
[121]
Yang H-M, Yang S, Huang S-S, Tang B-S, Guo J-F. Microglial Activation in the Pathogenesis of Huntington’s Disease. Front in Aging Neurosci 2017; 9: 193.
[122]
Colpo GD, Stimming EF, Rocha NP, Teixeira AL. Promises and pitfalls of immune-based strategies for Huntington’s disease. Neural Regen Res 2017; 12: 1422-5.
[123]
Rocha NP, Ribeiro FM, Furr-Stimming E, Teixeira AL. Neuroimmunology of Huntington's Disease: Revisiting Evidence from Human Studies. Mediators Inflamm 2016; 2016: 8653132-. Epub 2016/08/08.
[124]
Xiang W, Chao ZY, Feng DY. Role of Toll-like receptor/MYD88 signaling in neurodegenerative diseases. Rev Neurosci 2015; 26: 407-14.
[125]
Fiebich BL, Batista CRA, Saliba SW, Yousif NM, de Oliveira ACP. Role of Microglia TLRs in Neurodegeneration. Front in Cell Neurosci 2018; 12.
[126]
Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, et al. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer’s disease. Cell Physiol Biochem 2007; 20: 947-56.
[127]
Song M, Jin J, Lim JE, Kou J, Pattanayak A, Rehman JA, et al. TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation 2011; 8: 1742-2094.
[128]
Qin Y, Liu Y, Hao W, Decker Y, Tomic I, Menger MD, et al. Stimulation of TLR4 Attenuates Alzheimer’s Disease-Related Symptoms and Pathology in Tau-Transgenic Mice. J Immunol 2016; 197: 3281-92.
[129]
Huang NQ, Jin H, Zhou SY, Shi JS, Jin F. TLR4 is a link between diabetes and Alzheimer’s disease. Behav Brain Res 2017; 316: 234-44.
[130]
Shmuel-Galia L, Klug Y, Porat Z, Charni M, Zarmi B, Shai Y. Intramembrane attenuation of the TLR4-TLR6 dimer impairs receptor assembly and reduces microglia-mediated neurodegeneration. J Biol Chem 2017; 292: 13415-27.
[131]
McDonald CL, Hennessy E, Rubio-Araiz A, Keogh B, McCormack W, McGuirk P, et al. Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer’s disease. Brain Behav Immun 2016; 58: 191-200.
[132]
Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, et al. TLR2 is a primary receptor for Alzheimer’s amyloid beta peptide to trigger neuroinflammatory activation. J Immunol 2012; 188: 1098-107.
[133]
Jana M, Palencia CA, Pahan K. Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease. Journal of immunology (Baltimore, Md : 1950) 2008; 181: 7254-62.
[134]
Chakrabarty P, Li A, Ladd TB, Strickland MR, Koller EJ, Burgess JD, et al. TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease. J Exp Med 2018; 215: 2247-64.
[135]
Scholtzova H, Chianchiano P, Pan J, Sun Y, Goni F, Mehta PD, et al. Amyloid beta and Tau Alzheimer's disease related pathology is reduced by Toll-like receptor 9 stimulation Acta Neuropathol Commun 2014; 2: 014-0101.
[136]
Scholtzova H, Do E, Dhakal S, Sun Y, Liu S, Mehta PD, et al. Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits. J Neurosci 2017; 37: 936-59.
[137]
Scholtzova H, Kascsak RJ, Bates KA, Boutajangout A, Kerr DJ, Meeker HC, et al. Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer’s disease-related pathology. The Journal of neuroscience : the official journal of the Society for Neuroscience 2009; 29: 1846-54.
[138]
Zhu K, Teng J, Zhao J, Liu H, Xie A. Association of TLR9 polymorphisms with sporadic Parkinson’s disease in Chinese Han population. Int J Neurosci 2016; 126: 612-6.
[139]
Maatouk L, Compagnion A-C. Sauvage M-AC-d, Bemelmans A-P, Leclere-Turbant S, Cirotteau V, et al. TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons. Nat Commun 2018; 9: 2450.
[140]
Dzamko N, Gysbers A, Perera G, Bahar A, Shankar A, Gao J, et al. Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol 2017; 133: 303-19. Epub 2016/11/25.
[141]
Doorn KJ, Moors T, Drukarch B, van de Berg W, Lucassen PJ, van Dam AM. Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson's disease patients Acta Neuropathol Commun 2014; 2: 014-0090.
[142]
Zhao X-D, Wang F-X, Cao W-F, Zhang Y-H, Li Y. TLR4 signaling mediates AP-1 activation in an MPTP-induced mouse model of Parkinson’s disease. Int Immunopharmacol 2016; 32: 96-102.
[143]
Mariucci G, Pagiotti R, Galli F, Romani L, Conte C. The Potential Role of Toll-Like Receptor 4 in Mediating Dopaminergic Cell Loss and Alpha-Synuclein Expression in the Acute MPTP Mouse Model of Parkinson’s Disease. J Mol Neurosci 2018; 64: 611-8.
[144]
Chahal DS, Sivamani RK, Isseroff RR, Dasu MR. Plant-based modulation of Toll-like receptors: an emerging therapeutic model. Phytother Res 2013; 27: 1423-38.
[145]
Illam SP, Narayanankutty A, Mathew SE, Valsalakumari R, Jacob RM, Raghavamenon AC. Epithelial Mesenchymal Transition in Cancer Progression: Prev entive Phytochemicals. Recent Patents Anticancer Drug Discov 2017; 12: 234-46. Epub 2017/04/26.
[146]
Rana M, Maurya P, Reddy SS, Singh V, Ahmad H, Dwivedi AK, et al. A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates Cytotoxicity. Front Pharmacol 2016; 7.
[147]
Li PM, Li YL, Liu B, Wang WJ, Wang YZ, Li Z. Curcumin inhibits MHCC97H liver cancer cells by activating ROS/TLR-4/caspase signaling pathway. Asian Pac J Cancer Prev 2014; 15: 2329-34.
[148]
Chen X, Chang L, Qu Y, Liang J, Jin W, Xia X. Tea polyphenols inhibit the proliferation, migration, and invasion of melanoma cells through the down-regulation of TLR4 International Journal of Immunopathology and Pharmacology 2018; 31: 0394632017739 531.
[149]
Mukherjee S, Siddiqui MA, Dayal S, Ayoub YZ, Malathi K. Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells. J Inflamm Res 2014; 7: 89-101. Epub 2014/06/28.
[150]
Zhu J, Ghosh A, Coyle EM, Lee J, Hahm ER, Singh SV, et al. Differential effects of phenethyl isothiocyanate and D,L-sulforaphane on TLR3 signaling. J Immunol 2013; 190: 4400-7.
[151]
Lu H, Yang Y, Gad E, Wenner CA, Chang A, Larson ER, et al. Polysaccharide krestin is a novel TLR2 agonist that mediates inhibition of tumor growth via stimulation of CD8 T cells and NK cells. Clin Cancer Res 2011; 17: 67-76. Epub 2010/11/10.
[152]
Plummer S, Manning T, Baker T, McGreggor T, Patel M, Wylie G, et al. Isolation, analytical measurements, and cell line studies of the iron-bryostatin-1 complex. Bioorg Med Chem Lett 2016; 26: 2489-97.
[153]
Ariza ME, Ramakrishnan R, Singh NP, Chauhan A, Nagarkatti PS, Nagarkatti M. Bryostatin-1, a naturally occurring antineoplastic agent, acts as a Toll-like receptor 4 (TLR-4) ligand and induces unique cytokines and chemokines in dendritic cells. J Biol Chem 2011; 286: 24-34.
[154]
Koizumi S-i, Masuko K, Wakita D, Tanaka S, Mitamura R, Kato Y, et al. Extracts of Larix Leptolepis effectively augments the generation of tumor antigen-specific cytotoxic T lymphocytes via activation of dendritic cells in TLR-2 and TLR-4-dependent manner. Cell Immunol 2012; 276: 153-61.
[155]
Tu CT, Yao QY, Xu BL, Wang JY, Zhou CH, Zhang SC. Protective effects of curcumin against hepatic fibrosis induced by carbon tetrachloride: modulation of high-mobility group box 1, Toll-like receptor 4 and 2 expression. Food Chem Toxicol 2012; 50: 3343-51. Epub 2012/06/12.
[156]
Tu CT, Han B, Yao QY, Zhang YA, Liu HC, Zhang SC. Curcumin attenuates Concanavalin A-induced liver injury in mice by inhibition of Toll-like receptor (TLR) 2, TLR4 and TLR9 expression. Int Immunopharmacol 2012; 12: 151-7. Epub 2011/12/06.
[157]
Afrin R, Arumugam S, Rahman A, Wahed MI, Karuppagounder V, Harima M, et al. Curcumin ameliorates liver damage and progression of NASH in NASH-HCC mouse model possibly by modulating HMGB1-NF-kappaB translocation. Int Immunopharmacol 2017; 44: 174-82.
[158]
Shi H, Dong L, Jiang J, Zhao J, Zhao G, Dang X, et al. Chlorogenic acid reduces liver inflammation and fibrosis through inhibition of toll-like receptor 4 signaling pathway. Toxicology 2013; 303: 107-14.
[159]
Li X, Jin Q, Yao Q, Xu B, Li Z, Tu C. Quercetin attenuates the activation of hepatic stellate cells and liver fibrosis in mice through modulation of HMGB1-TLR2/4-NF-kappaB signaling pathways. Toxicol Lett 2016; 261: 1-12.
[160]
Li J, Sapper TN, Mah E, Moller MV, Kim JB, Chitchumroonchokchai C, et al. Green tea extract treatment reduces NFkappaB activation in mice with diet-induced nonalcoholic steatohepatitis by lowering TNFR1 and TLR4 expression and ligand availability. J Nutr Biochem 2017; 41: 34-41.
[161]
Li J, Sasaki GY, Dey P, Chitchumroonchokchai C, Labyk AN, McDonald JD, et al. Green tea extract protects against hepatic NFκB activation along the gut-liver axis in diet-induced obese mice with nonalcoholic steatohepatitis by reducing endotoxin and TLR4/MyD88 signaling. J Nutr Biochem 2018; 53: 58-65.
[162]
Bao S, Cao Y, Fan C, Fan Y, Bai S, Teng W, et al. Epigallocatechin gallate improves insulin signaling by decreasing toll-like receptor 4 (TLR4) activity in adipose tissues of high-fat diet rats. Mol Nutr Food Res 2014; 58: 677-86. Epub 2013/11/22.
[163]
Kumazoe M, Nakamura Y, Yamashita M, Suzuki T, Takamatsu K, Huang Y, et al. Green Tea Polyphenol Epigallocatechin-3-gallate Suppresses Toll-like Receptor 4 Expression via Up-regulation of E3 Ubiquitin-protein Ligase RNF216. J Biol Chem 2017; 292: 4077-88. Epub 2017/02/06.
[164]
Han L-P, Sun B, Li C-J, Xie Y, Chen L-M. Effect of celastrol on toll-like receptor 4-mediated inflammatory response in free fatty acid-induced HepG2 cells. Int J Mol Med 2018; 42: 2053-61. Epub 2018/07/12.
[165]
Wan Y, Jiang S, Lian LH, Bai T, Cui PH, Sun XT, et al. Betulinic acid and betulin ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro. Int Immunopharmacol 2013; 17: 184-90.
[166]
Chen L-C, Hu L-H, Yin M-C. Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury. Biomedicine 2016; 6: 9.
[167]
Yuan J, Ge K, Mu J, Rong J, Zhang L, Wang B, et al. Ferulic acid attenuated acetaminophen-induced hepatotoxicity though down-regulating the cytochrome P 2E1 and inhibiting toll-like receptor 4 signaling-mediated inflammation in mice. Am J Transl Res 2016; 8: 4205-14. Epub 2016/11/11.
[168]
He D, Guo Z, Pu JL, Zheng DF, Wei XF, Liu R, et al. Resveratrol preconditioning protects hepatocytes against hepatic ischemia reperfusion injury via Toll-like receptor 4/nuclear factor-kappaB signaling pathway in vitro and in vivo. Int Immunopharmacol 2016; 35: 201-9. Epub 2016/04/12.
[169]
Fang J, Sun X, Xue B, Fang N, Zhou M. Dahuang Zexie Decoction Protects against High-Fat Diet-Induced NAFLD by Modulating Gut Microbiota-Mediated Toll-Like Receptor 4 Signaling Activation and Loss of Intestinal Barrier. Evidence-based complementary and alternative medicine : eCAM 2017; 2017: 2945803-. Epub 2017/11/12.
[170]
Arslan F, Keogh B, McGuirk P, Parker AE. TLR2 and TLR4 in ischemia reperfusion injury Mediators Inflamm 2010; 2010: 704202-. Epub 2010/06/09.
[171]
Kim YS, Kwon JS, Cho YK, Jeong MH, Cho JG, Park JC, et al. Curcumin reduces the cardiac ischemia-reperfusion injury: involvement of the toll-like receptor 2 in cardiomyocytes. J Nutr Biochem 2012; 23: 1514-23. Epub 2012/03/10.
[172]
Zhang Y, Tao X, Jin G, Jin H, Wang N, Hu F, et al. A Targetable Molecular Chaperone Hsp27 Confers Aggressiveness in Hepatocellular Carcinoma. Theranostics 2016; 6: 558-70.
[173]
Bhaskar S, Helen A. Quercetin modulates toll-like receptor-mediated protein kinase signaling pathways in oxLDL-challenged human PBMCs and regulates TLR-activated atherosclerotic inflammation in hypercholesterolemic rats. Mol Cell Biochem 2016; 423: 53-65.
[174]
Bhaskar S, Sudhakaran PR, Helen A. Quercetin attenuates atherosclerotic inflammation and adhesion molecule expression by modulating TLR-NF-kappaB signaling pathway. Cell Immunol 2016; 310: 131-40.
[175]
Bhaskar S, Shalini V, Helen A. Quercetin regulates oxidized LDL induced inflammatory changes in human PBMCs by modulating the TLR-NF-kappaB signaling pathway. Immunobiology 2011; 216: 367-73.
[176]
Mathew LE, Rajagopal VAH. Betulinic acid and fluvastatin exhibits synergistic effect on toll-like receptor-4 mediated anti-atherogenic mechanism in type II collagen induced arthritis. Biomed Pharmacother 2017; 93: 681-94.
[177]
Kuang X, Huang Y, Gu HF, Zu XY, Zou WY, Song ZB, et al. Effects of intrathecal epigallocatechin gallate, an inhibitor of Toll-like receptor 4, on chronic neuropathic pain in rats. Eur J Pharmacol 2012; 676: 51-6. Epub 2011/12/17.
[178]
Jiwrajka M, Phillips A, Butler M, Rossi M, Pocock JM. The Plant-Derived Chalcone 2,2′,5′-Trihydroxychalcone Provides Neuroprotection against Toll-Like Receptor 4 Triggered Inflammation in Microglia. Oxid Med Cell Longev 2016; 20166301712 Epub 2016/01/23.
[179]
Ding G, Feng C, Jiang H, Ding Q, Zhang L, Na R, et al. Combination of Rapamycin, CI-1040, and 17-AAG Inhibits Metastatic Capacity of Prostate Cancer via Slug Inhibition. PLoS One 2013; 8e77400
[180]
Brenner L, Arbeit RD, Sullivan T. IMO-8400, an Antagonist of Toll-like Receptors 7, 8, and 9, in Development for Genetically Defined B-Cell Lymphomas: Safety and Activity in Phase 1 and Phase 2 Clinical Trials. Blood 2014; 124: 3101.
Article Metrics
67
9