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Current Drug Targets


ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

Review Article

Toll-like Receptors as a Novel Therapeutic Target for Natural Products Against Chronic Diseases

Author(s): Arunaksharan Narayanankutty*

Volume 20 , Issue 10 , 2019

Page: [1068 - 1080] Pages: 13

DOI: 10.2174/1389450120666190222181506

Price: $65


Toll-like receptors (TLR) are one among the initial responders of the immune system which participate in the activation inflammatory processes. Several different types of TLR such as TLR2, TLR4, TLR7 and TLR9 have been identified in various cell types, each having distinct ligands like lipids, lipoproteins, nucleic acids and proteins. Though its prime concern is xenobiotic defences, TLR signalling has also recognized as an activator of inflammation and associated development of chronic degenerative disorders (CDDs) including obesity, type 2 diabetes mellitus (T2DM), fatty liver disease, cardiovascular and neurodegenerative disorders as well as various types of cancers. Numerous drugs are in use to prevent these disorders, which specifically inhibit different pathways associated with the development of CDDs. Compared to these drug targets, inhibition of TLR, which specifically responsible for the inflammatory insults has proven to be a better drug target. Several natural products have emerged as inhibitors of CDDs, which specifically targets TLR signalling, among these, many are in the clinical trials. This review is intended to summarize the recent progress on TLR association with CDDs and to list possible use of natural products, their combinations and their synthetic derivative in the prevention of TLR-driven CDD development.

Keywords: Cancer, cardiovascular disorders, inflammation, natural products, toll-like receptors, lipoproteins.

Graphical Abstract
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.
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.
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.
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.
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.
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
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.
Gao D, Li W. Structures and recognition modes of toll-like receptors. Proteins 2017; 85: 3-9.
Botos I, Segal DM, Davies DR. The structural biology of Toll-like receptors Structure (London, England : 1993) 2011; 19: 447-59.
Uematsu S, Akira S. Toll-Like receptors (TLRs) and their ligands. Handb Exp Pharmacol 2008; 183: 1-20.
Gay NJ, Symmons MF, Gangloff M, Bryant CE. Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol 2014; 14: 546.
McGettrick AF, O’Neill LA. Localisation and trafficking of Toll-like receptors: an important mode of regulation. Curr Opin Immunol 2010; 22: 20-7.
Majer O, Liu B, Barton GM. Nucleic acid-sensing TLRs: trafficking and regulation. Curr Opin Immunol 2017; 44: 26-33.
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.
Perales-Linares R, Navas-Martin S. Toll-like receptor 3 in viral pathogenesis: friend or foe? Immunol 2013; 140: 153-67.
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.
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
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.
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.
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.
Tsan MF, Gao B. Endogenous ligands of Toll-like receptors. J Leukoc Biol 2004; 76: 514-9.
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.
Yu L, Wang L, Chen S. Endogenous toll-like receptor ligands and their biological significance. J Cell Mol Med 2010; 14: 2592-603.
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.
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.
Gangloff M. Different dimerisation mode for TLR4 upon endosomal acidification? Trends Biochem Sci 2012; 37: 92-8.
Di Gioia M, Zanoni I. Toll-like receptor co-receptors as master regulators of the immune response. Mol Immunol 2015; 63: 143-52.
Leifer CA, Medvedev AE. Molecular mechanisms of regulation of Toll-like receptor signaling. J Leukoc Biol 2016; 100: 927-41.
Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol 2014; 5: 461.
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.
Gillen JG, Nita-Lazar A. Composition of the myddosome during the innate immune response. J Immunol 2017; 198: (1 Supplement) 75.15;
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.
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.
West AP, Brodsky IE, Rahner C, et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011; 472: 476-80.
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.
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.
Hiscott J. Triggering the Innate Antiviral Response through IRF-3 Activation. J Biol Chem 2007; 282: 15325-9.
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.
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
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.
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.
Moriwaki K, Chan FK. The Inflammatory Signal Adaptor RIPK3: Functions Beyond Necroptosis. Int Rev Cell Mol Biol 2017; 328: 253-75.
Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer 2009; 9: 57-63.
Mishra V, Pathak C. Human Toll-Like Receptor 4 (hTLR4): Structural and functional dynamics in cancer. Int J Biol Macromol 2019; 122: 425-51.
Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer 2008; 9: 57.
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.
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.
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
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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
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.
Ou T, Lilly M, Jiang W. The pathologic role of toll-like receptor 4 in prostate cancer. Front Immunol 2018; 9: 1188.
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.
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.
Khademalhosseini M, Arababadi MK. Toll-like receptor 4 and breast cancer: an updated systematic review. Breast Cancer 2018; 26(3): 265-71.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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
Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol 2017; 9: 715-32.
Asrih M, Jornayvaz FR. Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance. J Endocrinol 2013; 218: 13-0201.
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.
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.
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.
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.
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.
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.
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.
Sharifnia T, Antoun J, Verriere TGC, et al. Hepatic TLR4 signaling in obese NAFLD. Am J Physiol Gastrointest Liver Physiol 2015; 309: G270-8.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
Madan M, Amar S. Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: Proteomic Findings. PLoS One 2008; 3e3204
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
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.
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
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.
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.
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.
Bolos M, Perea JR, Avila J. Alzheimer’s disease as an inflammatory disease. Biomol Concepts 2017; 8: 37-43.
Joshi N, Singh S. Updates on immunity and inflammation in Parkinson disease pathology. J Neurosci Res 2018; 96: 379-90.
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.
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.
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.
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.
Xiang W, Chao ZY, Feng DY. Role of Toll-like receptor/MYD88 signaling in neurodegenerative diseases. Rev Neurosci 2015; 26: 407-14.
Fiebich BL, Batista CRA, Saliba SW, Yousif NM, de Oliveira ACP. Role of Microglia TLRs in Neurodegeneration. Front in Cell Neurosci 2018; 12.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Chen L-C, Hu L-H, Yin M-C. Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury. Biomedicine 2016; 6: 9.
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.
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.
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.
Arslan F, Keogh B, McGuirk P, Parker AE. TLR2 and TLR4 in ischemia reperfusion injury Mediators Inflamm 2010; 2010: 704202-. Epub 2010/06/09.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
Bhagat L, Wang D, Jiang W, Agrawal S. Abstract 2570: IMO-8400, a selective antagonist of TLRs 7, 8 and 9, inhibits MYD88 L265P mutation-driven signaling and cell survival: A potential novel approach for treatment of B-cell lymphomas harboring MYD88 L265P mutation. Cancer Res 2014; 74: 2570.
Wittig B, Schmidt M, Scheithauer W, Schmoll H-J. MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside. Crit Rev in Oncol Hematol 2015; 94: 31-44.

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