CONTRIBUTION OF TOLL-LIKE RECEPTORS AS A THERAPEUTIC TARGET IN ADJUVANT INDUCED ARTHRITIC RAT MODEL
Main Article Content
Keywords
Pro-inflammatory cytokines, reactive oxygen species, antioxidants, N-(2-hydroxyphenyl) acetamide
Abstract
Background: Rheumatoid arthritis (RA) is an inflammatory joint disease characterized by a variety of abnormal cellular processes. Toll-like receptors (TLRs) have been linked to immunological abnormalities in RA patients.
Objectives: The purpose of this study was to look at the role of TLR2 and TLR4 in progression of arthritis and their modulation by N-(2-hydroxyphenyl) acetamide.
Material and Methods: Arthritis was induced in rats by Heat-killed Mycobacterium tuberculosis (MT37Ra). Progression and impact of disease was observed macroscopically and at molecular level. Reactive oxygen species (ROS) and antioxidants production was estimated in serum to assess the immune response.
Results: We observed over expression of TLRs on bone marrow cells parallel to the severity of arthritis progression in arthritic control group. Over-expression of TLRs triggered ROS expression followed by a decrease in antioxidants resulting in destruction of bones and cartilage in arthritic control group. Treatment with N-(2-hydroxyphenyl) acetamide (NA-2) reduced severity of arthritis by reducing the expression of toll like receptors TLR2 (*P < 0.043) and TLR4 (**P < 0.001) on BMCs in arthritic rats . Production of Reactive oxygen species , a marked increase in the GSH and SOD .
Conclusions
Our findings suggest that TLRs may play a role in the etiology of arthritis by causing direct activation of BMCs. Our data further suggest that NA-2 inhibits TLR-mediated joint inflammation and other arthritis-related symptoms, implying that it could be used to treat arthritis.
References
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18. 26. Pattison DJ, Silman AJ, Goodson NJ, et al. Vitamin C and the risk of developing inflammatory polyarthritis: prospective nested case-control study. Ann RheumDis 2004; 63: 843-847.
19. 27.Asea A, Rehli M, Kabingu E, et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 2002; 277:15028-15034.
20. 28.Bobacz K, Sunk IG, Hofstaetter JG, et al. Toll-like receptors and chondrocytes: the lipopolysaccharide-induced decrease in cartilage matrix synthesis is dependent on the presence of toll-like receptor 4 and antagonized by bone morphogenetic protein 7. Arthritis Rheum 2007; 56: 1880-1893
21. 29. Pedras - Vasconcelos J, Puig M, Verthelyi D. TLRs as therapeutic targets in CNS inflammation and infection. FrontBiosci (Elite Ed) 2009; 1: 476-487
22. 30. Perveen K, Hanif F, Jawed H, et al . Protective efficacy of N-(2-hydroxyphenyl) acetamide against Adjuvant-Induced Arthritis in Rats. Bio Med res intl 2013; 2013:635143.
23. 31.Zimmermann M. Ethical consideration in relation to pain in animal experimentation. Acta Physiol Scand 1986 ; 128(suppl.554): 221-223.
24. 32. Perveen K, Hanif F, Jawed H, et al. N-(2-hydroxy phenyl) acetamide: a novel suppressor of Toll-like receptors (TLR-2 and TLR-4) in adjuvant-induced arthritic rats. Mol Cell Biochem 2014; 394 (1-2): 67-75.
25. 33. Bendele AM. Animal Models of Rheumatoid Arthritis. J Musculoskel Interact 2001; 4: 377– 385.
26. 34. Jawed H, Shah UA, Jamall S, Simjee SU. N-(2-hydroxy phenyl) acetamide inhibits inflammation-related cytokines and ROS in adjuvant-induced arthritic (AIA) rats. IntImmunopharmacol 2010; 10(8): 900-905.
27. 35. Min-Fu. Review: Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors. J Endotoxin Res 2007; 13(1):6-14.
28. 36.Guo-Yun C, Nicholas KB, Wei W, et al., Broad and direct interaction between TLR and Siglec families of pattern recognition receptors and its regulation by Neu1.Elife3 2001; e04066.
29. 37. Gallucci S, Lolkema M, Matzinger P. Natural adjuvants: endogenous activators of dendritic cells. Nat Med 1999; 5(11): 1249-1255.
30. 38 Johnson G L, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298(5600): 1911-1912.
31. 39. Matzinger P. The danger model: a renewed sense of self. Science 2002; 296(5566): 301-305.
32. 40. Schett G, Tohidast-Akrad M, Smolen JS, et al., Activation, differential localization and regulation of the stress‐activated protein kinases, extracellular signal–regulated kinase, c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase, in synovial tissue and cells in rheumatoid arthritis.Arthritis Rheum 2000; 43(11): 2501-2512.
33. 41. Van Lent PL, Van de Loo FA, Holthuysen AE, et al . Major role for interleukin-1 but not tumor necrosis factor in early cartilage damage in immune complex arthritis in mice.J Rheumatol 1995; 22:2250–2258
34. 42.O’Neil, L.J.; Kaplan, M.J. Neutrophils in Rheumatoid Arthritis: Breaking Immune Tolerance and Fueling Disease. Trends Mol. Med. 2019, 25, 215–227. [CrossRef]
35. 43. Mateen, S.; Moin, S.; Khan, A.Q.; Zafar, A.; Fatima, N. Increased Reactive Oxygen Species Formation and Oxidative Stress in Rheumatoid Arthritis. PLoS ONE 2016, 11, e0152925. [CrossRef] [PubMed] .
36. 44. Johnson GB, Brunn GJ, Kodaira Y, et al . Receptor mediated monitoring of tissue well-being via detection of soluble heparin sulfate by Toll-like receptor 4. J Immunol 2002; 68: 5233–5239.
37. 45.Keffer J, Probert L, Cazlaris H, al., Transgenic mice expressing human tumor necrosis factor: a predictive genetic model of arthritis. EMBO J 1991; 10(13): 4025-4031. 36. Schaible HG, Grubb BD. Afferent and spinal mechanisms of joint pain. Pain 1993; 55 (1): 5-54.
38. 46. Kinne RW, Brauer R,Stuhlmuller B, et al .Macrophages in rheumatoid arthritis. .Arth research 2000; 2 (3): 189-202. 47.Bingham CO. The pathogenesis of rheumatoid arthritis: pivotal cytokines involved in bone degradation and inflammation. J Rheumatol 2002; 65: 3-9.
39. 47. Rommel C, Camps M, Ji H. PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 2007; (3): 191-201
40. 48. Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994; 265(5174): 956-959.
41. 49. Farivar RS, Chobanian AV, Brecher P. Salicylate or aspirin inhibits the induction of the inducible nitric oxide synthase in rat cardiac fibroblasts. Circ Res1996; 78(5):759- 768.
42. 50.Aizman E, Blacher E, Ben‐Moshe O, et al .Therapeutic effect of farnesylthiosalicylic acid on adjuvant‐induced arthritis through suppressed release of inflammatory cytokines.Clini & Exp Immunology 2014; 175(3) : 458-467.
43. 51. Joosten LA, Helsen MM, van de Loo FA, et al. Anti-cytokine treatment of established type II collagen induced arthritis in DBA/1 mice: a comparative study using anti-TNF-a anti-IL-1a/ß, and IL-1ra. Arthritis Rheum 1996; 39:797-809.
44. 52 Hoffmann, M.H.; Griffiths, H.R. The dual role of Reactive Oxygen Species in autoimmune and inflammatory diseases: Evidence from preclinical models. Free Radic. Biol. Med. 2018, 125, 62–71. [CrossRef]
45. 53. Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994; 265(5174): 956-959.
46. 54. Farivar RS, Chobanian AV, Brecher P. Salicylate or aspirin inhibits the induction of the inducible nitric oxide synthase in rat cardiac fibroblasts. Circ Res1996; 78(5):759- 768.
47. 55. Khojah, H.M.; Ahmed, S.; Abdel-Rahman, M.S.; Hamza, A.-B. Reactive oxygen and nitrogen species in patients with rheumatoid arthritis as potential biomarkers for disease activity and the role of antioxidants. Free Radic. Biol. Med. 2016, 97, 285–291. [CrossRef]
48. 56.Mahajan A, TandonV R. Antioxidants and rheumatoid arthritis.J Indian Rheumatol Assoc 2004; 12: 139-142.
49. 57. Hrab´ak A, Vercruysse V, Kah´an IL, et al. Indomethacin prevents the induction of inducible nitric oxide synthase in murine peritoneal macrophages and decreases their nitric oxide production. Life Sci 2001; 68(16): 1923–1930.
50. 58. Friman C, Johnston C, Chew C, et al . Effect of diclofenac sodium, tolfenamic acid and indomethacin on the production of superoxide induced by N-formyl methionyl leucyl-phenylalanine in normal human polymorph nuclear leukocytes
51. 59. Pourcyrous M, Leffler CW, Bada HS, et al. Speroxide anion generation in asphyxiatedpiglets and the effect of indomethacin at therapeutic dose. Pediatr Res 1993; 45: 366–369.
52. 60. Aizman E, Blacher E, Ben‐Moshe O, et al. Therapeutic effect of farnesyl thiosalicylic acid on adjuvant‐induced arthritis through suppressed release of inflammatory cytokines.Clini & Exp Immunology 2014; 175(3) : 458-467.
2. McInnes I.B., Schett G. The Pathogenesis of Rheumatoid Arthritis. N. Engl. J. Med. 2011; 365:2205–2219.doi: 10.1056/NEJMra1004965. [PubMed]
3. Wright H.L., Lyon M., Chapman E.A., Moots R.J., Edwards S.W. Rheumatoid Arthritis Synovial Fluid Neutrophils Drive Inflammation Through Production of Chemokines, Reactive Oxygen Species, and Neutrophil Extracellular Traps. Front.Immunol. 2021;11:584116.doi: 10.3389/fimmu.2020.584116. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
1. 4.Trofimenko A.S., Mozgovaya E.E., Bedina S.A., Spasov A.A. Ambiguities in Neutrophil Extracellular Traps. Ongoing Concepts and Potential Biomarkers for Rheumatoid Arthritis: A Narrative Review. Curr.Rheumatol.Rev. 2021;17:283293.doi:
2. 10.2174/1573397116666201221113100. [PubMed] [CrossRef] [Google Scholar]
4. Lee K.H., Kronbichler A., Park D.D.-Y., Park Y., Moon H., Kim H., Choi J.H., Choi Y., Shim S., Lyu I.S., et al. Neutrophil extracellular traps (NETs) in autoimmune diseases:A comprehensive review. Autoimmun. Rev. 2017;16:1160–1173. doi: 10.1016/j.autrev.2017.09.012. [PubMed] [CrossRef] [Google Scholar]
5. Ryan T, Giselle C , Sandra S. Emerging role of endosomal toll-like receptors in rheumatoid arthritis. Front. Immunol 2014; 5: 1.
6. Abdollahi-Roodsaz S, Joosten LA, Koenders MI, et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Invest 2008; 118: 205-216.
7. Akira S, Takeda K. Toll-like receptor signaling. Nat Rev Immunol 2004; 4(7): 499–511.
8. Page TH, Midwood KS.Targeting DAMP activation of toll-like receptors: Novel pathways to treat rheumatoid arthritis?, Rheumatoid Arthritis - Treatment, Dr. Andrew Lemmey (Ed.) 2012; DOI: 10.5772/28110
3. 10.Asea A, Rehli M, Kabingu E, Boch JA, Bare O, et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 2002; 277:15028-15034.
4. 11. Park JS, Svetkauskaite D, He Q, et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box1 protein. J Biol Chem 2004; 279(9): 7370-7377
5. 12. Bobacz K, Sunk IG, Hofstaetter JG, et al. Toll-like receptors and chondrocytes: the lipopolysaccharide-induced decrease in cartilage matrix synthesis is dependent on the presence of toll-like receptor 4 and antagonized by bone morphogenetic protein 7. Arthritis Rheum 2007; 56: 1880-1893
6. 13.Hiratsuka S , Watanabe A, Sakurai Y, et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 2008; 10:1349-1355.
7. 14.Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007; 39(1):44-84
8. 15. Henrotin YE, Bruckner P, Pujol JP. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthr . Cartil. 2003; (10):747-55.
9. 16.Maurice MM, Nakamura H, van der Voort EA , et al. Evidence for the role of an altered redox state in hyporesponsiveness of synovial T cells in rheumatoid arthritis. JImmunol 1997; 158: 1458-1465.
10. 17. Jakubczyk, K.; Dec, K.; Kałdu ´nska, J.; Kawczuga, D.; Kochman, J.; Janda, K. Reactive oxygen species—Sources, functions, oxidative damage. Pol. Merkur. Lek. 2020, 48, 124–127.
11. 18. Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 2002, 82, 47–95. [CrossRef]
12. 19. Sies, H. Oxidative stress: A concept in redox biology and medicine. Redox Biol. 2015, 4, 180–183. [CrossRef]
13. 20. da Fonseca, L.J.S.; Nunes-Souza, V.; Goulart, M.O.F.; Rabelo, L.A. Oxidative Stress in Rheumatoid Arthritis: What the Future Might Hold regarding Novel Biomarkers and Add-On Therapies. Oxid. Med. Cell. Longev. 2019, 2019, 7536805. [CrossRef]
14. 21. Phull, A.-R.; Nasir, B.; Haq, I.U.; Kim, S.J. Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis. Chem. Biol. Interact. 2018, 281, 121–136. [CrossRef] [PubMed]
15. 22. Datta, S.; Kundu, S.; Ghosh, P.; De, S.; Ghosh, A.; Chatterjee, M. Correlation of oxidant status with oxidative tissue damage in patients with rheumatoid arthritis. Clin. Rheumatol. 2014, 33, 1557–1564. [CrossRef] [PubMed]
16. 23. Mateen, S.; Moin, S.; Khan, A.Q.; Zafar, A.; Fatima, N. Increased Reactive Oxygen Species Formation and Oxidative Stress in Rheumatoid Arthritis. PLoS ONE 2016, 11, e0152925. [CrossRef] [PubMed]
17. 24.Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007; 39(1):44-84 25.Maurice MM, Nakamura H, van der Voort EA , et al. Evidence for the role of an altered redox state in hyporesponsiveness of synovial T cells in rheumatoid arthritis. JImmunol 1997; 158: 1458-1465.
18. 26. Pattison DJ, Silman AJ, Goodson NJ, et al. Vitamin C and the risk of developing inflammatory polyarthritis: prospective nested case-control study. Ann RheumDis 2004; 63: 843-847.
19. 27.Asea A, Rehli M, Kabingu E, et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 2002; 277:15028-15034.
20. 28.Bobacz K, Sunk IG, Hofstaetter JG, et al. Toll-like receptors and chondrocytes: the lipopolysaccharide-induced decrease in cartilage matrix synthesis is dependent on the presence of toll-like receptor 4 and antagonized by bone morphogenetic protein 7. Arthritis Rheum 2007; 56: 1880-1893
21. 29. Pedras - Vasconcelos J, Puig M, Verthelyi D. TLRs as therapeutic targets in CNS inflammation and infection. FrontBiosci (Elite Ed) 2009; 1: 476-487
22. 30. Perveen K, Hanif F, Jawed H, et al . Protective efficacy of N-(2-hydroxyphenyl) acetamide against Adjuvant-Induced Arthritis in Rats. Bio Med res intl 2013; 2013:635143.
23. 31.Zimmermann M. Ethical consideration in relation to pain in animal experimentation. Acta Physiol Scand 1986 ; 128(suppl.554): 221-223.
24. 32. Perveen K, Hanif F, Jawed H, et al. N-(2-hydroxy phenyl) acetamide: a novel suppressor of Toll-like receptors (TLR-2 and TLR-4) in adjuvant-induced arthritic rats. Mol Cell Biochem 2014; 394 (1-2): 67-75.
25. 33. Bendele AM. Animal Models of Rheumatoid Arthritis. J Musculoskel Interact 2001; 4: 377– 385.
26. 34. Jawed H, Shah UA, Jamall S, Simjee SU. N-(2-hydroxy phenyl) acetamide inhibits inflammation-related cytokines and ROS in adjuvant-induced arthritic (AIA) rats. IntImmunopharmacol 2010; 10(8): 900-905.
27. 35. Min-Fu. Review: Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors. J Endotoxin Res 2007; 13(1):6-14.
28. 36.Guo-Yun C, Nicholas KB, Wei W, et al., Broad and direct interaction between TLR and Siglec families of pattern recognition receptors and its regulation by Neu1.Elife3 2001; e04066.
29. 37. Gallucci S, Lolkema M, Matzinger P. Natural adjuvants: endogenous activators of dendritic cells. Nat Med 1999; 5(11): 1249-1255.
30. 38 Johnson G L, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298(5600): 1911-1912.
31. 39. Matzinger P. The danger model: a renewed sense of self. Science 2002; 296(5566): 301-305.
32. 40. Schett G, Tohidast-Akrad M, Smolen JS, et al., Activation, differential localization and regulation of the stress‐activated protein kinases, extracellular signal–regulated kinase, c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase, in synovial tissue and cells in rheumatoid arthritis.Arthritis Rheum 2000; 43(11): 2501-2512.
33. 41. Van Lent PL, Van de Loo FA, Holthuysen AE, et al . Major role for interleukin-1 but not tumor necrosis factor in early cartilage damage in immune complex arthritis in mice.J Rheumatol 1995; 22:2250–2258
34. 42.O’Neil, L.J.; Kaplan, M.J. Neutrophils in Rheumatoid Arthritis: Breaking Immune Tolerance and Fueling Disease. Trends Mol. Med. 2019, 25, 215–227. [CrossRef]
35. 43. Mateen, S.; Moin, S.; Khan, A.Q.; Zafar, A.; Fatima, N. Increased Reactive Oxygen Species Formation and Oxidative Stress in Rheumatoid Arthritis. PLoS ONE 2016, 11, e0152925. [CrossRef] [PubMed] .
36. 44. Johnson GB, Brunn GJ, Kodaira Y, et al . Receptor mediated monitoring of tissue well-being via detection of soluble heparin sulfate by Toll-like receptor 4. J Immunol 2002; 68: 5233–5239.
37. 45.Keffer J, Probert L, Cazlaris H, al., Transgenic mice expressing human tumor necrosis factor: a predictive genetic model of arthritis. EMBO J 1991; 10(13): 4025-4031. 36. Schaible HG, Grubb BD. Afferent and spinal mechanisms of joint pain. Pain 1993; 55 (1): 5-54.
38. 46. Kinne RW, Brauer R,Stuhlmuller B, et al .Macrophages in rheumatoid arthritis. .Arth research 2000; 2 (3): 189-202. 47.Bingham CO. The pathogenesis of rheumatoid arthritis: pivotal cytokines involved in bone degradation and inflammation. J Rheumatol 2002; 65: 3-9.
39. 47. Rommel C, Camps M, Ji H. PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 2007; (3): 191-201
40. 48. Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994; 265(5174): 956-959.
41. 49. Farivar RS, Chobanian AV, Brecher P. Salicylate or aspirin inhibits the induction of the inducible nitric oxide synthase in rat cardiac fibroblasts. Circ Res1996; 78(5):759- 768.
42. 50.Aizman E, Blacher E, Ben‐Moshe O, et al .Therapeutic effect of farnesylthiosalicylic acid on adjuvant‐induced arthritis through suppressed release of inflammatory cytokines.Clini & Exp Immunology 2014; 175(3) : 458-467.
43. 51. Joosten LA, Helsen MM, van de Loo FA, et al. Anti-cytokine treatment of established type II collagen induced arthritis in DBA/1 mice: a comparative study using anti-TNF-a anti-IL-1a/ß, and IL-1ra. Arthritis Rheum 1996; 39:797-809.
44. 52 Hoffmann, M.H.; Griffiths, H.R. The dual role of Reactive Oxygen Species in autoimmune and inflammatory diseases: Evidence from preclinical models. Free Radic. Biol. Med. 2018, 125, 62–71. [CrossRef]
45. 53. Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994; 265(5174): 956-959.
46. 54. Farivar RS, Chobanian AV, Brecher P. Salicylate or aspirin inhibits the induction of the inducible nitric oxide synthase in rat cardiac fibroblasts. Circ Res1996; 78(5):759- 768.
47. 55. Khojah, H.M.; Ahmed, S.; Abdel-Rahman, M.S.; Hamza, A.-B. Reactive oxygen and nitrogen species in patients with rheumatoid arthritis as potential biomarkers for disease activity and the role of antioxidants. Free Radic. Biol. Med. 2016, 97, 285–291. [CrossRef]
48. 56.Mahajan A, TandonV R. Antioxidants and rheumatoid arthritis.J Indian Rheumatol Assoc 2004; 12: 139-142.
49. 57. Hrab´ak A, Vercruysse V, Kah´an IL, et al. Indomethacin prevents the induction of inducible nitric oxide synthase in murine peritoneal macrophages and decreases their nitric oxide production. Life Sci 2001; 68(16): 1923–1930.
50. 58. Friman C, Johnston C, Chew C, et al . Effect of diclofenac sodium, tolfenamic acid and indomethacin on the production of superoxide induced by N-formyl methionyl leucyl-phenylalanine in normal human polymorph nuclear leukocytes
51. 59. Pourcyrous M, Leffler CW, Bada HS, et al. Speroxide anion generation in asphyxiatedpiglets and the effect of indomethacin at therapeutic dose. Pediatr Res 1993; 45: 366–369.
52. 60. Aizman E, Blacher E, Ben‐Moshe O, et al. Therapeutic effect of farnesyl thiosalicylic acid on adjuvant‐induced arthritis through suppressed release of inflammatory cytokines.Clini & Exp Immunology 2014; 175(3) : 458-467.
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May 31, 2024
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Kahkashan Perveen, Shabana Usman Simjee, Farina Hanif, & Saima Mahmood Malihi. (2024). CONTRIBUTION OF TOLL-LIKE RECEPTORS AS A THERAPEUTIC TARGET IN ADJUVANT INDUCED ARTHRITIC RAT MODEL. Journal of Population Therapeutics and Clinical Pharmacology, 31(5), 1772-1784. https://doi.org/10.53555/jptcp.v31i5.6424
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Author Biographies
Kahkashan Perveen
Department of Biochemistry, Baqai Medical University, Karachi, Pakistan,
Shabana Usman Simjee
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi. Pakistan, Oric ID:.0000-0001-9675-842x
Farina Hanif
Department of Biochemistry, Dow University of Health Sciences Ojha Campus, Karachi. Pakistan.
Saima Mahmood Malihi
Department of Pharmacology, Dow University of Health Sciences Ojha Campus, Karachi, Pakistan.
How to Cite
Kahkashan Perveen, Shabana Usman Simjee, Farina Hanif, & Saima Mahmood Malihi. (2024). CONTRIBUTION OF TOLL-LIKE RECEPTORS AS A THERAPEUTIC TARGET IN ADJUVANT INDUCED ARTHRITIC RAT MODEL. Journal of Population Therapeutics and Clinical Pharmacology, 31(5), 1772-1784. https://doi.org/10.53555/jptcp.v31i5.6424