Abstract
Background/Objectives: Anti-inflammatory agents play a crucial role in controlling inflammatory diseases such as Inflammatory Bowel Disease (IBD) but their use is restricted due to their vast side effects. M2000 (β-D-mannuronic acid) is a new immunomodulatory drug. According to the capacity of M2000 in suppressing some molecules involved in Toll Like Receptors (TLRs) signaling and reducing oxidative stress we hypothesize that, this molecule may have a potential role in decreasing inflammatory responses in IBD. The aim of this study was to evaluate the cytotoxicity of M2000 and its effect on the gene expression of TLR2 and TLR4.
Methods: HEK293 cell line was grown and divided into 96-well cell plate and MTT assay was performed. HT29 cells were cultured and treated with low and high doses of M2000. Total RNA was extracted and cDNA synthesized and quantitative real-time PCR was done to quantify the TLR2 and TLR4 mRNA expression.
Results: We found that M2000 at the concentration of ≤ 1000µg/ml had no obvious cytotoxicity effect on the HEK293 cells. Also, low and high doses of M2000 could significantly down-regulate both TLR2 and TLR4 mRNA expression. Moreover, a significant reduction in gene expression of TLR2 and TLR4 in an inflammatory condition resulted in high doses of M2000 in the presence of LPS.
Conclusion: Our study which was conducted in colonic epithelial cell model, shows that M2000 can be considered as a new anti-inflammatory agent in IBD. However, more comprehensive experimental and clinical studies are required to recognize the molecular mechanism of M2000 and also its safety and efficacy.
Keywords: HT29, IBD, M2000, β-D-Mannuronic acid, TLR2, TLR4.
[1]
Tian TZ. Wang, Zhang J. Pathomechanisms of oxidative stress in inflammatory bowel disease and potential antioxidant therapies. Oxid Med Cell Longev 2017; 20174535194
[2]
Molodecky NA, Soon S, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142(1): 46-54.
[3]
Loftus EV, Sandborn WJ. Epidemiology of inflammatory bowel disease. Gastroenterol Clin North Am 2002; 31(1): 1-20.
[4]
Ng SC, Tang W, Ching JY, Wong M, Chow CM, Hui AJ, et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn’s and colitis epidemiology study. Gastroenterology 2013; 145(1): 158-65.
[5]
Zeng Z, Zhu Z, Yang Y, Ruan W, Peng X, Su Y, et al. Incidence and clinical characteristics of inflammatory bowel disease in a developed region of Guangdong Province China: A prospective population-based study. J Gastroenterol Hepatol 2013; 28(7): 1148-53.
[6]
Goyette P, Labbé C, Trinh TT, Xavier RJ, Rioux JD. Molecular pathogenesis of inflammatory bowel disease: Genotypes, phenotypes and personalized medicine. Ann Med 2007; 39(3): 177-99.
[7]
Fukata M, Arditi M. The role of pattern recognition receptors in intestinal inflammation. Mucosal Immunol 2013; 6(3): 451-63.
[8]
Pastorelli L, De Salvo C, Mercado JR, Vecchi M, Pizarro TT. Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: Lessons learned from animal models and human genetics. Front Immunol 2013; 4: 280-7.
[9]
Moossavi S, Rezaei N. Toll-like receptor signalling and their therapeutic targeting in colorectal cancer. Int Immunopharmacol 2013; 16(2): 199-209.
[10]
Price AE, Shamardani K, Lugo KA, Deguine J, Roberts AW, Lee BL, et al. A map of toll-like receptor expression in the intestinal epithelium reveals distinct spatial, cell type-specific, and temporal patterns. Immunity 2018; 49(3): 560-75.
[12]
Akira S, Takeda K. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011; 34(5): 637-50.
[15]
Heidemann J, Domschke W, Kucharzik T, Maaser C. Intestinal microvascular endothelium and innate immunity in inflammatory bowel disease: A second line of defense? Infect Immun 2006; 74(10): 5425-32.
[16]
De Jager PL, Franchimont D, Waliszewska A, Bitton A, Cohen A, Langelier D, et al. The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes Immun 2007; 8(5): 387-97.
[17]
Liu Y, Yin H, Zhao M, Lu Q. TLR2 and TLR4 in autoimmune diseases: a comprehensive review. Clin Rev Allergy Immunol 2014; 47(2): 136-47.
[18]
Takahashi K, Sugi Y, Hosono A, Kaminogawa S. Epigenetic regulation of TLR4 gene expression in intestinal epithelial cells for the maintenance of intestinal homeostasis. J Immunol 2009; 183(10): 6522-9.
[19]
Dahan A, Amidon GL, Zimmermann EM. Drug targeting strategies for the treatment of inflammatory bowel disease: A mechanistic update. Expert Rev Clin Immunol 2010; 6(4): 543-50.
[21]
Mirshafiey A, Cuzzocrea S, Rehm B, Mazzon E, Saadat F, Sotoude M. Treatment of experimental arthritis with M2000, a novel designed non-steroidal anti-inflammatory drug. Scand J Immunol 2005; 61(5): 435-41.
[22]
Mirshafiey A, Cuzzocrea S, Rehm B, Matsuo H. M2000: A revolution in pharmacology. Med Sci Monit 2005; 11(8): I53-63.
[23]
Mirshafiey A, Matsuo H, Nakane S, Rehm BH, Koh CS, Miyoshi S. Novel immunosuppressive therapy by M2000 in experimental multiple sclerosis. Immunopharmacol Immunotoxicol 2005; 27(2): 255-65.
[24]
Fattahi MJ, Abdollahi M, Agha Mohammadi A, Rastkari N, Khorasani R, Ahmadi H. Preclinical assessment of beta-D-mannuronic acid (M2000) as a non-steroidal anti-inflammatory drug. Immunopharmacol Immunotoxicol 2015; 37(6): 535-40.
[25]
Hosseini S, Abdollahi M, Azizi G, Fattahi MJ, Rastkari N, Zavareh FT, et al. Anti-aging effects of M2000 (beta-D-mannuronic acid) as a novel immunosuppressive drug on the enzymatic and non-enzymatic oxidative stress parameters in an experimental model. J Basic Clin Physiol Pharmacol 2017; 28(3): 249-55.
[26]
Ahmadi H. A Phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of beta-D-mannuronic acid in rheumatoid arthritis patients. Inflammopharm 2018; 26(3): 737-45.
[27]
Fattahi MJ, Jamshidi AR, Mahmoudi M, Vojdanian M, Yekaninejad MS, Jafarnezhad-Ansariha F, et al. Evaluation of the efficacy and safety of beta-D-mannuronic acid in patients with ankylosing spondylitis: A 12-week randomized, placebo-controlled, Phase I/II clinical trial. Int Immunopharmacol 2018; 54: 112-7.
[28]
Aletaha S, Haddad L, Roozbehkia M, Bigdeli R, Asgary V, Mahmoudi M, et al. M2000 (beta-D-mannuronic acid) as a novel antagonist for blocking the TLR2 and TLR4 downstream signalling pathway. Scand J Immunol 2017; 85(2): 122-9.
[29]
Mortazavi-Jahromi S, Jamshidi MM, Farazmand A, Aghazadeh Z, Yousefi M, Mirshafiey A. Pharmacological effects of beta-d-mannuronic acid (M2000) on miR-146a, IRAK1, TRAF6 and NF-kappaB gene expression, as target molecules in inflammatory reactions. Pharmacol Rep 2017; 69(3): 479-84.
[30]
Sharifi L, Mirshafiey A. Immunomodulatory effect of G2013 (a-L-guluronic acid) on theTLR2 and TLR4 in human mononuclear cells. Curr Drug Discov Technol 2017; 143-9.
[31]
Sharifi L, Aghamohammadi A, Mohsenzadegan M, Rezaei N, Tofighi Zavareh F, Moshiri M, et al. Immunomodulation of TLR2 and TLR4 by G2013 (alpha-L-guluronic acid) in CVID Patients. Int J Pediatr 2017; 5(7): 5327-37.
[32]
Mirshafiey A, Hosseini S, Afraei S, Rastkari N, Zavareh F, Azizi G. Anti-aging property of G2013 molecule as a novel immunosuppressive agent on enzymatic and non-enzymatic oxidative stress determinants in Rat model. Curr Drug Discov Technol 2016; 13(1): 25-33.
[33]
Böcker U, Yezerskyy O, Feick P, Manigold T, Panja A, Kalina U, et al. Responsiveness of intestinal epithelial cell lines to lipopolysaccharide is correlated with Toll-like receptor 4 but not Toll-like receptor 2 or CD14 expression. Int J Colorectal Dis 2003; 18(1): 25-32.
[34]
Böcker U. Influence of Therapeutic Intervention with Interleukins on Epithelial Cell Function.In: Andus T (ed) Cytokines and Cell Homeostasis in the Gastrointestinal Tract Kluwer, Lancaster,. 61-71.
[35]
Danese S, Colombel JF, Peyrin‐Biroulet L, Rutgeerts P, Reinisch W. The role of anti-TNF in the management of ulcerative colitis: Past, present and future. Aliment Pharmacol Ther 2013; 37(9): 855-66.
[36]
Sidiropoulos PI, Hatemi G, Song IH, Avouac J, Collantes E, Hamuryudan V, et al. Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practising rheumatologists. Rheumatology 2008; 47(3): 355-61.
[37]
Wheat CL, Ko CW, Clark-Snustad K, Grembowski D, Thornton TA, Devine B. Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis. BMC Gastroenterol 2017; 17(1): 52-67.
[38]
McDaniel DK, Eden K, Ringel VM, Allen IC. Emerging Roles for Noncanonical NF-kappaB Signaling in the Modulation of Inflammatory Bowel Disease Pathobiology. Inflamm Bowel Dis 2016; 22(9): 2265-79.
[39]
Kim JY, Morgan M, Kim DG, Lee JY, Bai L, Lin Y, et al. TNFalpha induced noncanonical NF-kappaB activation is attenuated by RIP1 through stabilization of TRAF2. J Cell Sci 2011; 124(Pt 4): 647-56.
[40]
Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353(23): 2462-76.
[41]
van Heel DA, Udalova IA, De Silva AP, McGovern DP, Kinouchi Y, Hull J, et al. Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-Kappa)B transcription factors. Hum Mol Genet 2002; 11(11): 1281-9.
[42]
Hennessy EJ, Parker AE, O’neill LA. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov 2010; 9(4): 293-307.Trichuris suis soluble products induce
Rab7b expression and limit TLR4 responses in human dendritic
cells. Genes Immun. 2015; 16(6): 378-07.
[43]
Klaver EJ, van der Pouw Kraan TC, Laan LC, Kringel H, Cummings RD, Bouma G, et al. Trichuris suis soluble products induce Rab7b expression and limit TLR4 responses in human dendritic cells. Genes Immun 2015; 16(6): 378-87.
[44]
Ottow MK, Klaver EJ, van der Pouw Kraan TC, Heijnen PD, Laan LC, Kringel H, et al. The helminth Trichuris suis suppresses TLR4-induced inflammatory responses in human macrophages. Genes Immun 2014; 15(7): 477-86.
[45]
Garg SK, Croft AM, Bager P. Helminth therapy (worms) for induction of remission in inflammatory bowel disease. Cochrane Database Syst Rev 2014; (1): CD009400
[46]
Fleming JO, Isaak A, Lee JE, Luzzio CC, Carrithers MD, Cook TD, et al. Probiotic helminth administration in relapsing-remitting multiple sclerosis: A Phase 1 study. Mult Scler 2011; 17(6): 743-54.
[47]
Summers RW. Trichuris suis therapy for active ulcerative colitis: A randomized controlled trial. Gastroenterology 2005; 128(4): 825-32.
[48]
Summers RW, Elliott DE, Urban JF, Thompson R, Weinstock JV. Trichuris suis therapy in Crohn’s disease. Gut 2005; 54(1): 87-90.
[49]
Sun S, Wang X, Wu X, Zhao Y, Wang F, Liu X, et al. Toll-like receptor activation by helminths or helminth products to alleviate inflammatory bowel disease. Parasit Vectors 2011; 4: 186-92.
[50]
Gao W, Xiong Y, Li Q, Yang H. Inhibition of Toll-like receptor signaling as a promising therapy for inflammatory diseases: A journey from molecular to nano therapeutics. Front Physiol 2017; 8: 508-17.
[51]
Danese S, Colombel JF, Peyrin‐Biroulet L, Rutgeerts P, Reinisch W. TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol 2011; 79(1): 34-41.
[52]
Yang J, Jiang H, Yang J, Ding JW, Chen LH, Li S, et al. Valsartan preconditioning protects against myocardial ischemia-reperfusion injury through TLR4/NF-kappaB signaling pathway. Mol Cell Biochem 2009; 330(1-2): 39-46.
[53]
Dasu MR, Riosvelasco AC, Jialal I. Candesartan inhibits Toll-like receptor expression and activity both in vitro and in vivo. Atherosclerosis 2009; 202(1): 76-83.
[54]
Földes G, von Haehling S, Okonko DO, Jankowska EA, Poole-Wilson PA, Anker SD. Fluvastatin reduces increased blood monocyte Toll-like receptor 4 expression in whole blood from patients with chronic heart failure. Int J Cardiol 2008; 124(1): 80-5.
[55]
Fang D, Yang S, Quan W, Jia H, Quan Z, Qu Z. Atorvastatin suppresses Toll-like receptor 4 expression and NF-kappaB activation in rabbit atherosclerotic plaques. Eur Rev Med Pharmacol Sci 2014; 18(2): 242-6.
[56]
Methe H, Kim JO, Kofler S, Nabauer M, Weis M. Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes. Arterioscler Thromb Vasc Biol 2005; 25(7): 1439-45.
[57]
Suzuki M, Kato C, Kato A. Therapeutic antibodies: Their mechanisms of action and the pathological findings they induce in toxicity studies. J Toxicol Pathol 2015; 28(3): 133-9.
[58]
Spiller S, Elson G, Ferstl R, Dreher S, Mueller T, Freudenberg M, et al. TLR4-induced IFN-gamma production increases TLR2 sensitivity and drives gram-negative sepsis in mice. J Exp Med 2008; 205(8): 1747-54.
[59]
Lima CX, Souza DG, Amaral FA, Fagundes CT, Rodrigues IP, Alves-Filho JC, et al. Therapeutic effects of treatment with anti-tlr2 and anti-tlr4 monoclonal antibodies in polymicrobial sepsis. PLoS One 2015; 10(7)e0132336
[60]
Ungaro R, Fukata M, Hsu D, Hernandez Y, Breglio K, Chen A, et al. A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. Am J Physiol Gastrointest Liver Physiol 2009; 296(6): G1167-79.
[61]
Monnet E, Shang L, Lapeyre G, Hatterer E, Buatois V, Elson G, et al. AB0451 NI-0101, a monoclonal antibody targeting toll like receptor 4 (TLR4) being developed for rheumatoid arthritis (RA) treatment with a potential for personalized medicine. Annals Rheumatic Diseases 2015; 74(Suppl. 2): 1046-53.
[62]
Hatterer E, Shang L, Simonet P, Herren S, Daubeuf B, Teixeira S, et al. A specific anti-citrullinated protein antibody profile identifies a group of rheumatoid arthritis patients with a toll-like receptor 4-mediated disease. Arthritis Res Ther 2016; 18(1): 224-9.
[63]
Monnet E, Lapeyre G, van Poelgeest E, et al. Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized Phase I dose escalation study in healthy volunteers receiving LPS. Clin Pharmacol Ther 2017; 101(2): 200-8.
[64]
Barrat FJ, Meeker T, Gregorio J, Chan JH, Uematsu S, Akira S, et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 2005; 202(8): 1131-9.
[65]
Suárez-Fariñas M, Arbeit R, Jiang W, Ortenzio FS, Sullivan T, Krueger JG. Suppression of molecular inflammatory pathways by Toll-like receptor 7, 8, and 9 antagonists in a model of IL-23-induced skin inflammation. PLoS One 2013; 8(12)e84634
[66]
Zhu FG, Jiang W, Bhagat L, et al. A novel antagonist of Toll-like receptors 7, 8 and 9 suppresses lupus disease-associated parameters in NZBW/F1 mice. Autoimmunity 2013; 46(7): 419-28.
[67]
Gao W, Xiong Y, Li Q, Yang H. Inhibition of Toll-like receptor signaling as a promising therapy for inflammatory diseases: A journey from molecular to nano therapeutics. Front Physiol 2017; 8: 508-13.
[68]
Römmler F, Jurk M, Uhlmann E, Hammel M, Waldhuber A, Pfeiffer L, et al. Guanine modification of inhibitory oligonucleotides potentiates their suppressive function. J Immunol 2013; 191(6): 3240-53.
[69]
Jiang W, Zhu FG, Bhagat L, Yu D, Tang JX, Kandimalla ER, et al. A Toll-like receptor 7, 8, and 9 antagonist inhibits Th1 and Th17 responses and inflammasome activation in a model of IL-23-induced psoriasis. J Invest Dermatol 2013; 133(7): 1777-84.
[70]
Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, et al. Bacterial endotoxin: molecular relationships of structure to activity and function. FASEB J 1994; 8(2): 217-25.
[71]
Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 2009; 458(7242): 1191-5.
[72]
Tidswell M, Tillis W, LaRosa SP, Lynn M, Wittek AE, Kao R. Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis. Crit Care Med 2010; 38(1): 72-83.
[73]
Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: The ACCESS randomized trial. JAMA 2013; 309(11): 1154-62.
[74]
Liu B, Li J, Cairns MJ. Identifying miRNAs, targets and functions. Brief Bioinform 2014; 15(1): 1-19.
[75]
He X, Jing Z, Cheng G. MicroRNAs: new regulators of Toll-like receptor signalling pathways. BioMed Res Int 2014; 2014945169
[76]
Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 2006; 103(33): 12481-6.
[77]
Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 2011; 208(6): 1189-201.
[78]
Sheedy FJ, Palsson-McDermott E, Hennessy EJ, Martin C, O’leary JJ, Ruan Q, et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol 2010; 11(2): 141-7.
[79]
Ceppi M, Pereira PM, Dunand-Sauthier I, Barras E, Reith W, Santos MA, et al. MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci USA 2009; 106(8): 2735-40.
[80]
O’connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 2010; 33(4): 607-19.
[81]
Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B, et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 2007; 179(8): 5082-9.
[82]
Barker KR, Lu Z, Kim H, et al. miR-155 modifies inflammation, endothelial activation and blood-brain barrier dysfunction in cerebral malaria. Mol Med 2017; 23: 24-33.
[83]
He C, Hu Y, Yin L, Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 2010; 31(13): 3657-66.
[84]
Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol 2015; 33(9): 941-51.
[85]
Babazada H, Yamashita F, Hashida M. Suppression of experimental arthritis with self-assembling glycol-split heparin nanoparticles via inhibition of TLR4-NF-kappaB signaling. J Control Release 2014; 194: 295-300.
[86]
Pedrosa P. Gold Nanotheranostics: Proof-of-concept or clinical tool? Nanomat (Basel) 2015; 5(4): 1853-79.
[87]
Foit L, Thaxton CS. Synthetic high-density lipoprotein-like nanoparticles potently inhibit cell signaling and production of inflammatory mediators induced by lipopolysaccharide binding Toll-like receptor 4. Biomaterials 2016; 100: 67-75.
[88]
Pereira DV. Effects of gold nanoparticles on endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci 2012; 53(13): 8036-41.
[89]
Rodriguez Lavado J, Sestito SE, Cighetti R, Aguilar Moncayo EM, Oblak A, et al. Trehalose- and glucose-derived glycoamphiphiles: small-molecule and nanoparticle Toll-like receptor 4 (TLR4) modulators. J Med Chem 2014; 57(21): 9105-23.
[90]
Mirshafiey A, Rehm BH, Sahmani AA, Naji A, Razavi A. M-2000, as a new anti-inflammatory molecule in treatment of experimental nephrosis. Immunopharmacol Immunotoxicol 2004; 26(4): 611-9.
[91]
Ahmadi H, Jamshidi AR, Mahmoudi M, Cuzzocrea S, Fattahi MJ, Barati A. The potent inhibitory effect of beta-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property on anti-cyclic citrullinated peptide antibodies, rheumatoid factor and anti-dsDNA antibodies in patients with rheumatoid arthritis. Curr Drug Discov Technol 2017; 14(3): 206-14.
[92]
Barati A, Jamshidi AR, Ahmadi H, Aghazadeh Z, Mirshafiey A. Effects of beta-D-mannuronic acid, as a novel non-steroidal anti-inflammatory medication within immunosuppressive properties, on IL17, ROR gamma T, IL4 and GATA3 gene expressions in rheumatoid arthritis patients. Drug Des Devel Ther 2017; 11: 1027-33.
Related Journals
Current Medicinal Chemistry
Current Pharmaceutical Design
Current Topics in Medicinal Chemistry
Current Respiratory Medicine Reviews
Infectious Disorders - Drug Targets
Endocrine, Metabolic & Immune Disorders - Drug Targets
Anti-Infective Agents
Coronaviruses
Recent Advances in Inflammation & Allergy Drug Discovery
Current Probiotics
Related Books
The NLRP3 Inflammasome: An Attentive Arbiter of Inflammatory Response
Natural Immunomodulators: Promising Therapy for Disease Management
Herbal Immunity Boosters Against COVID-19
Mitochondrial DNA and the Immuno-inflammatory Response: New Frontiers to Control Specific Microbial Diseases
Frontiers in Clinical Drug Research – Anti Allergy Agents
Frontiers in Inflammation
Article Metrics
17
3
1
1