Skip to content
2000
image of Chrysin and Bone Marrow-derived Mesenchymal Stem Cells Restrain Complete Freund’s Adjuvant-induced Arthritis in Wistar Rats via Subsiding Inflammation and Oxidative Stress

Abstract

Introduction

Rheumatoid arthritis (RA) is an inflammatory disease that causes significant disability and persistent inflammation. Currently, there are no appropriate treatments for RA other than systemic immunosuppressants, which have a variety of undesirable effects after long-term use. Thus, this study aims to determine the anti-arthritis effect of chrysin (5,7-dihydroxyflavone) and/or bone marrow-derived mesenchymal stem cells (BM-MSCs), separately and combined, on CFA (complete Freund’s adjuvant)-induced arthritis in rats as an animal model of RA.

Methods

Male Wistar rats were subcutaneously injected with 100 μL of CFA/rat/day in the paw of the right hind limb for two consecutive days to induce RA. Arthritic rats received chrysin in an oral dose of 100 mg/kg bw each day, BM-MSCs at 1 × 106 cells/rat once per week in DMEM (Dulbecco’s modified Eagle’s medium) into the lateral tail vein, and a combination for 21 days.

Results

The oral administration of chrysin and intravenous injection of BM-MSCs significantly reduced the increased anteroposterior thickness, volume, and circumference of the right hind paw, as well as serum levels of RF, IL-1β, TNF-α, and IL-17, as well as serum MDA level, besides augmenting serum levels of GPx, GST, GSH, and SOD. The arthritic rats treated with chrysin and/or BM-MSCs exhibited a significant improvement in the elevated expression levels of IκBα, NF-κB p50, and NF-κB p65 proteins in ankle joint articular tissue. Similarly, the histopathological score and histological sections provided additional evidence of the improvement in arthritic lesions.

Discussion

The treatment with chrysin and BM-MSCs has potential anti-arthritic effects, which may be attributed to their abilities to suppress the inflammation and oxidative stress and enhance the antioxidant defense system. The combinatory effect of chrysin and BM-MSCs was found to be the most effective. However, further clinical studies are required to assess their safety and efficacy in patients with arthritis.

Conclusion

Due to their strong antioxidant and anti-inflammatory properties, the combined administration of chrysin and BM-MSCs was found to be more effective in treating arthritis than either treatment alone in Wistar rats.

Loading

Article metrics loading...

/content/journals/cscr/10.2174/011574888X367150250701071144
2025-07-15
2025-09-15
Loading full text...

Full text loading...

References

  1. Smolen J.S. Aletaha D. McInnes I.B. Artritis reumatoide. Lancet 2016 388 10055 2023 2038 10.1016/S0140‑6736(16)30173‑8 27156434
    [Google Scholar]
  2. Zhu L. Zhang Z. Xia N. Anti-arthritic activity of ferulic acid in complete Freund’s adjuvant (CFA)-induced arthritis in rats: JAK2 inhibition. Inflammopharmacology 2020 28 2 463 473 10.1007/s10787‑019‑00642‑0 31562605
    [Google Scholar]
  3. Okada Y. Eyre S. Suzuki A. Kochi Y. Yamamoto K. Genetics of rheumatoid arthritis: 2018 status. Ann. Rheum. Dis. 2019 78 4 446 453 10.1136/annrheumdis‑2018‑213678 30530827
    [Google Scholar]
  4. Mbiantcha M. Almas J. Shabana S.U. Nida D. Aisha F. Anti-arthritic property of crude extracts of Piptadeniastrum africanum (Mimosaceae) in complete Freund’s adjuvant-induced arthritis in rats. BMC Complement. Altern. Med. 2017 17 1 111 10.1186/s12906‑017‑1623‑5 28202019
    [Google Scholar]
  5. Nielen M.M.J. van Schaardenburg D. Reesink H.W. Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis Rheum. 2004 50 2 380 386 10.1002/art.20018 14872479
    [Google Scholar]
  6. Avina-Zubieta J.A. Thomas J. Sadatsafavi M. Lehman A.J. Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: A meta-analysis of observational studies. Ann. Rheum. Dis. 2012 71 9 1524 1529 10.1136/annrheumdis‑2011‑200726 22425941
    [Google Scholar]
  7. Gözel N. Çakirer M. Karataş A. Sorafenib reveals anti-arthritic potentials in collagen induced experimental arthritis model. Arch. Rheumatol. 2018 33 3 309 315 10.5606/ArchRheumatol.2018.6652 30632530
    [Google Scholar]
  8. Edrees A.F. Misra S.N. Abdou N.I. Anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis: Correlation of TNF-alpha serum level with clinical response and benefit from changing dose or frequency of infliximab infusions. Clin. Exp. Rheumatol. 2005 23 4 469 474 [PMID: 16095114
    [Google Scholar]
  9. Luisa Corvo M. Jorge J.C.S. van’t Hof R. Cruz M.E.M. Crommelin D.J.A. Storm G. Superoxide dismutase entrapped in long-circulating liposomes: Formulation design and therapeutic activity in rat adjuvant arthritis. Biochim. Biophys. Acta Biomembr. 2002 1564 1 227 236 10.1016/S0005‑2736(02)00457‑1
    [Google Scholar]
  10. Ahmed O.M. Curcumin ameliorative efficacy on type 1 diabetes mellitus coexisted with rheumatoid arthritis in Wistar rats. Merit Res J Med Med Sci 2015 3 7 256 270
    [Google Scholar]
  11. Gaffo A. Saag K.G. Curtis J.R. Treatment of rheumatoid arthritis. Am. J. Health Syst. Pharm. 2006 63 24 2451 2465 10.2146/ajhp050514 17158693
    [Google Scholar]
  12. Bevaart L. Vervoordeldonk M.J. Tak P.P. Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis? Arthritis Rheum. 2010 62 8 2192 2205 10.1002/art.27503 20506322
    [Google Scholar]
  13. Ahmed O. Khalifa M.M. Atia T. The Anti-arthritic role of naringenin through modulating different T helper cells’ cytokines, inflammatory mediators, oxidative stress and anti-oxidant defense system. J. Biol. Regul. Homeost. Agents 2024 38 7 5393 5405
    [Google Scholar]
  14. Nasuti C. Fedeli D. Bordoni L. Anti-inflammatory, anti-arthritic and anti-nociceptive activities of Nigella sativa oil in a rat model of arthritis. Antioxidants 2019 8 9 342 10.3390/antiox8090342 31450670
    [Google Scholar]
  15. Jalil J. Attiq A. Hui C.C. Yao L.J. Zakaria N.A. Modulation of inflammatory pathways, medicinal uses and toxicities of Uvaria species: Potential role in the prevention and treatment of inflammation. Inflammopharmacology 2020 28 5 1195 1218 10.1007/s10787‑020‑00734‑2 32617790
    [Google Scholar]
  16. Ahmed O.M. Ahmed R.R. Abdel-Hafeez D.A. Navel orange peel ethanolic extract and naringin ameliorate CFA-induced arthritis in Wistar rats through their modulatory effects on Th1/Th2/Th17 cytokines and oxidative stress. Am. J. Transl. Res. 2024 16 9 4696 4713 10.62347/OEHX5202 39398602
    [Google Scholar]
  17. Mobashar A. Shabbir A. Shahzad M. Gobe G. Preclinical rodent models of arthritis and acute inflammation indicate Immunomodulatory and Anti-Inflammatory Properties of Juglans regia Extracts. Evid. Based Complement. Alternat. Med. 2022 2022 1 10 10.1155/2022/1695701 35422870
    [Google Scholar]
  18. Mani R. Natesan V. Chrysin: Sources, beneficial pharmacological activities, and molecular mechanism of action. Phytochemistry 2018 145 187 196 10.1016/j.phytochem.2017.09.016 29161583
    [Google Scholar]
  19. Zullkiflee N. Taha H. Usman A. Propolis: Its role and efficacy in human health and diseases. Molecules 2022 27 18 6120 10.3390/molecules27186120 36144852
    [Google Scholar]
  20. Spencer J.P.E. Vafeiadou K. Williams R.J. Vauzour D. Neuroinflammation: Modulation by flavonoids and mechanisms of action. Mol. Aspects Med. 2012 33 1 83 97 10.1016/j.mam.2011.10.016 22107709
    [Google Scholar]
  21. Lee J.H. Park J.H. Cho M.H. Lee J. Flavone reduces the production of virulence factors, staphyloxanthin and α-hemolysin, in Staphylococcus aureus. Curr. Microbiol. 2012 65 6 726 732 10.1007/s00284‑012‑0229‑x 22965624
    [Google Scholar]
  22. Rashid S. Ali N. Nafees S. Alleviation of doxorubicin-induced nephrotoxicity and hepatotoxicity by chrysin in Wistar rats. Toxicol. Mech. Methods 2013 23 5 337 345 10.3109/15376516.2012.759306 23256457
    [Google Scholar]
  23. Al-Hatamleh M.A.I. Hatmal M.M. Sattar K. Antiviral and immunomodulatory effects of phytochemicals from honey against COVID-19: Potential mechanisms of action and future directions. Molecules 2020 25 21 5017 10.3390/molecules25215017 33138197
    [Google Scholar]
  24. Pick A. Müller H. Mayer R. Structure–activity relationships of flavonoids as inhibitors of breast cancer resistance protein (BCRP). Bioorg. Med. Chem. 2011 19 6 2090 2102 10.1016/j.bmc.2010.12.043 21354800
    [Google Scholar]
  25. Talebi M. Talebi M. Farkhondeh T. An updated review on the versatile role of chrysin in neurological diseases: Chemistry, pharmacology, and drug delivery approaches. Biomed. Pharmacother. 2021 141 111906 10.1016/j.biopha.2021.111906 34328092
    [Google Scholar]
  26. Jiang Y. Gong F.L. Zhao G.B. Li J. Chrysin suppressed inflammatory responses and the inducible nitric oxide synthase pathway after spinal cord injury in rats. Int. J. Mol. Sci. 2014 15 7 12270 12279 10.3390/ijms150712270 25014398
    [Google Scholar]
  27. Du Q. Gu X. Cai J. Huang M. Su M. Chrysin attenuates allergic airway inflammation by modulating the transcription factors T-bet and GATA-3 in mice. Mol. Med. Rep. 2012 6 1 100 104 10.3892/mmr.2012.893 22552848
    [Google Scholar]
  28. Shen Y. Tian P. Li D. Chrysin suppresses cigarette smoke-induced airway inflammation in mice. Int. J. Clin. Exp. Med. 2015 8 2 2001 2008 [PMID: 25932129
    [Google Scholar]
  29. Vishnu R. Krishnan R. Histopathological and x-ray based evaluation of anti-rheumatoid effect of chrysin in freund’s induced arthritis in wistar albino rats. Inter J Resn Pharma Pharmacoth 2021 6 4 421 426
    [Google Scholar]
  30. Darwish H.A. Arab H.H. Abdelsalam R.M. Chrysin alleviates testicular dysfunction in adjuvant arthritic rats via suppression of inflammation and apoptosis: Comparison with celecoxib. Toxicol. Appl. Pharmacol. 2014 279 2 129 140 10.1016/j.taap.2014.05.018 24932515
    [Google Scholar]
  31. Liu H. Li R. Liu T. Yang L. Yin G. Xie Q. Immunomodulatory effects of mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles in rheumatoid arthritis. Front. Immunol. 2020 11 1912 10.3389/fimmu.2020.01912 32973792
    [Google Scholar]
  32. Sayed H.M. Awaad A.S. Abdel Rahman F.E.Z.S. Al-Dossari M. Abd El-Gawaad N.S. Ahmed O.M. Combinatory effect and modes of action of chrysin and bone marrow-derived mesenchymal stem cells on streptozotocin/nicotinamide-induced diabetic rats. Pharmaceuticals 2022 16 1 34 10.3390/ph16010034 36678531
    [Google Scholar]
  33. Deans R.J. Moseley A.B. Mesenchymal stem cells. Exp. Hematol. 2000 28 8 875 884 10.1016/S0301‑472X(00)00482‑3 10989188
    [Google Scholar]
  34. Jiang W. Xu J. Immune modulation by mesenchymal stem cells. Cell Prolif. 2020 53 1 12712 10.1111/cpr.12712 31730279
    [Google Scholar]
  35. Galipeau J. Sensébé L. Mesenchymal stromal cells: Clinical challenges and therapeutic opportunities. Cell Stem Cell 2018 22 6 824 833 10.1016/j.stem.2018.05.004 29859173
    [Google Scholar]
  36. Lopez-Santalla M. Bueren J.A. Garin M.I. Mesenchymal stem/stromal cell-based therapy for the treatment of rheumatoid arthritis: An update on preclinical studies. EBioMedicine 2021 69 103427 10.1016/j.ebiom.2021.103427 34161884
    [Google Scholar]
  37. Berthelot J.M. Le Goff B. Maugars Y. Bone marrow mesenchymal stem cells in rheumatoid arthritis, spondyloarthritis, and ankylosing spondylitis: Problems rather than solutions? Arthritis Res. Ther. 2019 21 1 239 10.1186/s13075‑019‑2014‑8 31722720
    [Google Scholar]
  38. Contreras R.A. Figueroa F.E. Djouad F. Luz-Crawford P. Mesenchymal stem cells regulate the innate and adaptive immune responses dampening arthritis progression. Stem Cells Int. 2016 2016 1 3162743 10.1155/2016/3162743 27847522
    [Google Scholar]
  39. Cagliani J. Grande D. Molmenti E.P. Miller E.J. Rilo H.L. Immunomodulation by mesenchymal stromal cells and their clinical applications. J Stem Cell Regen Biol 2017 3 2 10.15436/2471‑0598.17.022
    [Google Scholar]
  40. Chahal J. Gómez-Aristizábal A. Shestopaloff K. Bone marrow mesenchymal stromal cell treatment in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation. Stem Cells Transl. Med. 2019 8 8 746 757 10.1002/sctm.18‑0183 30964245
    [Google Scholar]
  41. Zappia E. Casazza S. Pedemonte E. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005 106 5 1755 1761 10.1182/blood‑2005‑04‑1496 15905186
    [Google Scholar]
  42. Ishida T. Inaba M. Hisha H. Requirement of donor-derived stromal cells in the bone marrow for successful allogeneic bone marrow transplantation. Complete prevention of recurrence of autoimmune diseases in MRL/MP-Ipr/Ipr mice by transplantation of bone marrow plus bones (stromal cells) from the same donor. J. Immunol. 1994 152 6 3119 3127
    [Google Scholar]
  43. Ahmed E.A. Ahmed O.M. Fahim H.I. Combinatory effects of bone marrow-derived mesenchymal stem cells and indomethacin on adjuvant-induced arthritis in Wistar rats: Roles of IL-1β, IL-4, Nrf-2, and oxidative stress. Evid. Based Complement. Alternat. Med. 2021 2021 1 15 10.1155/2021/8899143
    [Google Scholar]
  44. Ahmed E.A. Ahmed O.M. Fahim H.I. Ali T.M. Elesawy B.H. Ashour M.B. Potency of bone marrow-derived mesenchymal stem cells and indomethacin in complete Freund’s adjuvant-induced arthritic rats: Roles of TNF-α, IL-10, iNOS, MMP-9, and TGF-β1. Stem Cells Int. 2021 2021 1 11 10.1155/2021/6665601 33884000
    [Google Scholar]
  45. Sun X. Jiang H. Yang H. In vitro culture of bone marrow mesenchymal stem cells in rats and differentiation into retinal neural-like cells. J. Huazhong Univ. Sci. Technolog. Med. Sci. 2007 27 5 598 600 10.1007/s11596‑007‑0531‑1 18060645
    [Google Scholar]
  46. Ahmed O.M. Hassan M.A. Saleh A.S. Combinatory effect of hesperetin and mesenchymal stem cells on the deteriorated lipid profile, heart and kidney functions and antioxidant activity in STZ-induced diabetic rats. Biocell 2020 44 1 27 10.32604/biocell.2020.08040
    [Google Scholar]
  47. Chaudhary J.K. Rath P.C. A simple method for isolation, propagation, characterization, and differentiation of adult mouse bone marrow-derived multipotent mesenchymal stem cells. J. Cell Sci. Ther. 2017 8 1 1 10
    [Google Scholar]
  48. Ahmed R.H. Galaly S.R. Moustafa N. Curcumin and mesenchymal stem cells ameliorate ankle, testis, and ovary deleterious histological changes in arthritic rats via suppression of oxidative stress and inflammation. Stem Cells Int. 2021 2021 1 20 10.1155/2021/3516834 34795765
    [Google Scholar]
  49. Snekhalatha U. Anburajan M. Venkatraman B. Menaka M. Evaluation of complete Freund’s adjuvant-induced arthritis in a Wistar rat model. Z. Rheumatol. 2013 72 4 375 382 10.1007/s00393‑012‑1083‑8 23208192
    [Google Scholar]
  50. Faheem M.A. Akhtar T. Naseem N. Chrysin is immunomodulatory and anti-inflammatory against complete freund’s adjuvant-induced arthritis in a pre-clinical rodent model. Pharmaceutics 2023 15 4 1225 10.3390/pharmaceutics15041225 37111711
    [Google Scholar]
  51. Afnan A. Saleem A. Akhtar M.F. Chrysin, a 5,7-dihydroxyflavone restrains inflammatory arthritis in rats via subsiding oxidative stress biomarkers and inflammatory cytokines. Inflammopharmacology 2023 31 4 1863 1878 10.1007/s10787‑023‑01229‑6 37083920
    [Google Scholar]
  52. Chaudhari S.S. Chaudhari S.R. Chavan M.J. Analgesic, anti-inflammatory and anti-arthritic activity of Cassia uniflora Mill. Asian Pac. J. Trop. Biomed. 2012 2 1 S181 S186 10.1016/S2221‑1691(12)60155‑5
    [Google Scholar]
  53. Ahmed O.M. Soliman H.A. Mahmoud B. Gheryany R.R. Ulva lactuca hydroethanolic extract suppresses experimental arthritis via its anti-inflammatory and antioxidant activities. Beni. Suef Univ. J. Basic Appl. Sci. 2017 6 4 394 408 10.1016/j.bjbas.2017.04.013
    [Google Scholar]
  54. Olajide O.A. Ajayi A.M. Wright C.W. Anti‐inflammatory properties of cryptolepine. Phytother. Res. 2009 23 10 1421 1425 10.1002/ptr.2794 19288476
    [Google Scholar]
  55. Sancho D. Gómez M. Viedma F. CD69 downregulates autoimmune reactivity through active transforming growth factor-β production in collagen-induced arthritis. J. Clin. Invest. 2003 112 6 872 882 10.1172/JCI200319112 12975472
    [Google Scholar]
  56. Ahmed O. Fahim H. Mahmoud A. Eman Ahmed E.A. Bee venom and hesperidin effectively mitigate complete Freund’s adjuvant-induced arthritis via immunomodulation and enhancement of antioxidant defense system. Arch. Rheumatol. 2018 33 2 198 212 10.5606/ArchRheumatol.2018.6519 30207564
    [Google Scholar]
  57. Preuss H.G. Jarrell S.T. Scheckenbach R. Lieberman S. Anderson R.A. Comparative effects of chromium, vanadium and gymnema sylvestre on sugar-induced blood pressure elevations in SHR. J. Am. Coll. Nutr. 1998 17 2 116 123 10.1080/07315724.1998.10718736 9550454
    [Google Scholar]
  58. Beutler E. Duron O. Kelly B.M. Improved method for the determination of blood glutathione. J. Lab. Clin. Med. 1963 61 882 888 [PMID: 13967893
    [Google Scholar]
  59. Matkovics B. Kotorman M. Varga I.S. Hai D.Q. Varga C. Oxidative stress in experimental diabetes induced by streptozotocin. Acta Physiol. Hung. 1997 85 1 29 38 [PMID: 9530434
    [Google Scholar]
  60. Mannervik B. Guthenberg C. Glutathione transferase (human placenta). Methods Enzymol. 1981 77 231 235 10.1016/S0076‑6879(81)77030‑7 7329301
    [Google Scholar]
  61. Marklund S. Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur. J. Biochem. 1974 47 3 469 474 10.1111/j.1432‑1033.1974.tb03714.x 4215654
    [Google Scholar]
  62. Rao K.G. Rao Y.T. Satishchandra A. Protective role of tridax procumbens against adjuvant induced arthritis in a murine model. Int. J. Life Sci. Pharma Res. 2021 11 2 29 34
    [Google Scholar]
  63. Nagai N. Fukuhata T. Ito Y. Usui S. Hirano K. Involvement of interleukin 18 in indomethacin-induced lesions of the gastric mucosa in adjuvant-induced arthritis rat. Toxicology 2009 255 3 124 130 10.1016/j.tox.2008.10.005 18996434
    [Google Scholar]
  64. Tatiya A.U. Saluja A.K. Further studies on membrane stabilizing, anti-inflammatory and FCA induced arthritic activity of various fractions of bark of Machilus macrantha in rats. Rev. Bras. Farmacogn. 2011 21 6 1052 1064 10.1590/S0102‑695X2011005000152
    [Google Scholar]
  65. Cai X. Wong Y.F. Zhou H. The comparative study of sprague–dawley and lewis rats in adjuvant-induced arthritis. Naunyn Schmiedebergs Arch. Pharmacol. 2006 373 2 140 147 10.1007/s00210‑006‑0062‑5 16703402
    [Google Scholar]
  66. Shaaban H.H. Hozayen W.G. Khaliefa A.K. El-Kenawy A.E. Ali T.M. Ahmed O.M. Diosmin and trolox have anti-arthritic, anti-inflammatory and antioxidant potencies in complete Freund’s adjuvant-induced arthritic male wistar rats: Roles of NF-κB, iNOS, Nrf2 and MMPs. Antioxidants 2022 11 9 1721 10.3390/antiox11091721 36139795
    [Google Scholar]
  67. Franch A. Castellote C. Castell M. Blood lymphocyte subsets in rats with adjuvant arthritis. Ann. Rheum. Dis. 1994 53 7 461 466 10.1136/ard.53.7.461 7944619
    [Google Scholar]
  68. Pinal P. Dharmik P. Natvarlal P. Experimental investigation of anti-rheumatoid activity of Pleurotus sajorcaju in adjuvant-induced arthritic rats. Chin. J. Nat. Med. 2012 10 4 269 274 10.3724/SP.J.1009.2012.00269
    [Google Scholar]
  69. El-fatah A. Reduction of some extra-articular complications associated with arthritis development in rats by low dose γ-irradiation. Arab J Nucl Sci Applicat 2020 53 1 172 181
    [Google Scholar]
  70. El-Tanbouly G.S. Abdelrahman R.S. Novel anti-arthritic mechanisms of trans-cinnamaldehyde against complete Freund’s adjuvant-induced arthritis in mice: Involvement of NF-кB/TNF-α and IL-6/IL-23/ IL-17 pathways in the immuno-inflammatory responses. Inflammopharmacology 2022 30 5 1769 1780 10.1007/s10787‑022‑01005‑y 35648328
    [Google Scholar]
  71. Saleem A. Saleem M. Akhtar M.F. Shahzad M. Jahan S. Polystichum braunii extracts inhibit Complete Freund’s adjuvant-induced arthritis via upregulation of I-κB, IL-4, and IL-10, downregulation of COX-2, PGE2, IL-1β, IL-6, NF-κB, and TNF-α, and subsiding oxidative stress. Inflammopharmacology 2020 28 6 1633 1648 10.1007/s10787‑020‑00688‑5 32162074
    [Google Scholar]
  72. Kugyelka R. Kohl Z. Olasz K. Enigma of IL-17 and Th17 cells in rheumatoid arthritis and in autoimmune animal models of arthritis. Mediators Inflamm. 2016 2016 1 11 10.1155/2016/6145810 26903711
    [Google Scholar]
  73. Gaffen S.L. The role of interleukin-17 in the pathogenesis of rheumatoid arthritis. Curr. Rheumatol. Rep. 2009 11 5 365 370 10.1007/s11926‑009‑0052‑y 19772832
    [Google Scholar]
  74. Mills K.H.G. IL-17 and IL-17-producing cells in protection versus pathology. Nat. Rev. Immunol. 2023 23 1 38 54 10.1038/s41577‑022‑00746‑9 35790881
    [Google Scholar]
  75. Ullah A. Munir S. Badshah S.L. Important flavonoids and their role as a therapeutic agent. Molecules 2020 25 22 5243 10.3390/molecules25225243 33187049
    [Google Scholar]
  76. Oršolić N. Nemrava J. Jeleč Ž. Antioxidative and anti-inflammatory activities of chrysin and naringenin in a drug-induced bone loss model in rats. Int. J. Mol. Sci. 2022 23 5 2872 10.3390/ijms23052872 35270014
    [Google Scholar]
  77. Rodríguez-Landa J.F. German-Ponciano L.J. Puga-Olguín A. Olmos-Vázquez O.J. Pharmacological, neurochemical, and behavioral mechanisms underlying the anxiolytic-and antidepressant-like effects of flavonoid chrysin. Molecules 2022 27 11 3551 10.3390/molecules27113551 35684488
    [Google Scholar]
  78. Haque R. Lei F. Xiong X. Song J. Stem cell-based cellular therapy in rheumatoid arthritis. In:Autoimmune Diseases - Contributing Factors, Specific Cases of Autoimmune Diseases, and Stem Cell and Other Therapies. London, UK IntechOpen 2012 10.5772/47804
    [Google Scholar]
  79. El-Jawhari J.J. El-Sherbiny Y.M. Jones E.A. McGonagle D. Mesenchymal stem cells, autoimmunity and rheumatoid arthritis. QJM 2014 107 7 505 514 10.1093/qjmed/hcu033 24518000
    [Google Scholar]
  80. Spaggiari G.M. Capobianco A. Abdelrazik H. Becchetti F. Mingari M.C. Moretta L. Mesenchymal stem cells inhibit natural killer–cell proliferation, cytotoxicity, and cytokine production: Role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 2008 111 3 1327 1333 10.1182/blood‑2007‑02‑074997 17951526
    [Google Scholar]
  81. Jiang X.X. Zhang Y. Liu B. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005 105 10 4120 4126 10.1182/blood‑2004‑02‑0586 15692068
    [Google Scholar]
  82. Aggarwal S. Pittenger M.F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005 105 4 1815 1822 10.1182/blood‑2004‑04‑1559 15494428
    [Google Scholar]
  83. Beyth S. Borovsky Z. Mevorach D. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 2005 105 5 2214 2219 10.1182/blood‑2004‑07‑2921 15514012
    [Google Scholar]
  84. Zhou B. Yuan J. Zhou Y. Administering human adipose-derived mesenchymal stem cells to prevent and treat experimental arthritis. Clin. Immunol. 2011 141 3 328 337 10.1016/j.clim.2011.08.014 21944669
    [Google Scholar]
  85. Yu Y. Yoon K.A. Kang T.W. Therapeutic effect of long-interval repeated intravenous administration of human umbilical cord blood-derived mesenchymal stem cells in DBA/1 mice with collagen-induced arthritis. J. Tissue Eng. Regen. Med. 2019 13 7 1241 1252 10.1002/term.2861 30959558
    [Google Scholar]
  86. Vasilev G. Ivanova M. Ivanova-Todorova E. Secretory factors produced by adipose mesenchymal stem cells downregulate Th17 and increase Treg cells in peripheral blood mononuclear cells from rheumatoid arthritis patients. Rheumatol. Int. 2019 39 5 819 826 10.1007/s00296‑019‑04296‑7 30944956
    [Google Scholar]
  87. Luz-Crawford P. Hernandez J. Djouad F. Mesenchymal stem cell repression of Th17 cells is triggered by mitochondrial transfer. Stem Cell Res. Ther. 2019 10 1 232 10.1186/s13287‑019‑1307‑9 31370879
    [Google Scholar]
  88. Sen R. Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 1986 46 5 705 716 10.1016/0092‑8674(86)90346‑6
    [Google Scholar]
  89. Ahmed Sahabuddin Mundhe N. Borgohain M. Diosmin modulates the NF-kB signal transduction pathways and downregulation of various oxidative stress markers in alloxan-induced diabetic nephropathy. Inflammation 2016 39 5 1783 1797 10.1007/s10753‑016‑0413‑4
    [Google Scholar]
  90. Hartung J.E. Eskew O. Wong T. Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation. Brain Behav. Immun. 2015 50 196 202 10.1016/j.bbi.2015.07.014 26187567
    [Google Scholar]
  91. Berköz M. Diosmin suppresses the proinflammatory mediators in lipopolysaccharide-induced RAW264.7 macrophages via NF-κB and MAPKs signal pathways. Gen. Physiol. Biophys. 2019 38 4 315 324 10.4149/gpb_2019010 31241043
    [Google Scholar]
  92. Li J. Tang R.S. Shi Z. Li J.Q. Nuclear factor‐κB in rheumatoid arthritis. Int. J. Rheum. Dis. 2020 23 12 1627 1635 10.1111/1756‑185X.13958 32965792
    [Google Scholar]
  93. Wu Z. Li C. Chen Y. Chrysin protects against titanium particle-induced osteolysis by attenuating osteoclast formation and function by inhibiting NF-KB and MAPK signaling. Front. Pharmacol. 2022 13 793087 10.3389/fphar.2022.793087 35401243
    [Google Scholar]
  94. Hamdalla H.M. Ahmed R.R. Galaly S.R. Assessment of the efficacy of bone marrow-derived mesenchymal stem cells against a monoiodoacetate-induced osteoarthritis model in Wistar rats. Stem Cells Int. 2022 2022 1 14 10.1155/2022/1900403 36017131
    [Google Scholar]
  95. Weng W. Wang F. He X. Zhou K. Wu X. Wu X. Protective effect of Corynoline on the CFA induced Rheumatoid arthritis via attenuation of oxidative and inflammatory mediators. Mol. Cell. Biochem. 2021 476 2 831 839 10.1007/s11010‑020‑03948‑8 33174074
    [Google Scholar]
  96. El-Masry H. Mahmoud A.E.A. Free radicals and antioxidants in diseased neonates. Ann Neonat J 2021 3 1 8 23
    [Google Scholar]
  97. Walker A.F. Bundy R. Hicks S.M. Middleton R.W. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults. Phytomedicine 2002 9 8 681 686 10.1078/094471102321621269 12587686
    [Google Scholar]
  98. Suresh P. Kavitha C.N. Babu S.M. Reddy V.P. Latha A.K. Effect of ethanol extract of Trigonella foenum graecum (Fenugreek) seeds on Freund’s adjuvant-induced arthritis in albino rats. Inflammation 2012 35 4 1314 1321 10.1007/s10753‑012‑9444‑7 22395729
    [Google Scholar]
  99. Okabe T. Hamaguchi K. Inafuku T. Hara M. Aging and superoxide dismutase activity in cerebrospinal fluid. J. Neurol. Sci. 1996 141 1-2 100 104 10.1016/0022‑510X(96)00160‑8 8880700
    [Google Scholar]
  100. Walz D.T. DiMARTINO MJ, Misher A. Adjuvant-induced arthritis in rats. II. Drug effects on physiologic, biochemical and immunologic parameters. J. Pharmacol. Exp. Ther. 1971 178 1 223 231 10.1016/S0022‑3565(25)28953‑4 5087400
    [Google Scholar]
  101. Nicotera P. Orrenius S. Role of thiols in protection against biological reactive intermediates. In:Biological Reactive Intermediates III: Mechanisms of Action in Animal Models and Human Disease. Boston, MA Springer US 1986 41 51 10.1007/978‑1‑4684‑5134‑4_4
    [Google Scholar]
  102. Sindhu G. Ratheesh M. Shyni G.L. Nambisan B. Helen A. Anti-inflammatory and antioxidative effects of mucilage of Trigonella foenum graecum (Fenugreek) on adjuvant induced arthritic rats. Int. Immunopharmacol. 2012 12 1 205 211 10.1016/j.intimp.2011.11.012 22155102
    [Google Scholar]
  103. Guo Q. Wang Y. Xu D. Nossent J. Pavlos N.J. Xu J. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018 6 1 15 10.1038/s41413‑018‑0016‑9 29736302
    [Google Scholar]
  104. Usher K.M. Zhu S. Mavropalias G. Carrino J.A. Zhao J. Xu J. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Res. 2019 7 1 9 10.1038/s41413‑019‑0047‑x 30937213
    [Google Scholar]
/content/journals/cscr/10.2174/011574888X367150250701071144
Loading
/content/journals/cscr/10.2174/011574888X367150250701071144
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test