{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:07:38Z","timestamp":1789016858738,"version":"build-2803163510"},"reference-count":169,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006109","name":"Vedeck\u00e1 grantov\u00e1 agent\u00fara M\u0160VVaM SR a SAV","doi-asserted-by":"publisher","award":["VEGA 2\/0079\/24"],"award-info":[{"award-number":["VEGA 2\/0079\/24"]}],"id":[{"id":"10.13039\/501100006109","id-type":"DOI","asserted-by":"publisher"}]},{"award":["VEGA 2\/0079\/24"],"award-info":[{"award-number":["VEGA 2\/0079\/24"]}],"id":[{"id":"https:\/\/ror.org\/02z80ct15","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that represents continuous synovial inflammation, oxidative stress, immune dysregulation, and progressive cartilage degradation and bone erosion. Although disease-modifying antirheumatic drugs (DMARDs), including methotrexate (MTX), have improved clinical outcomes, treatment-limiting adverse effects remain a concern. Increasing evidence suggests that natural bioactive compounds may serve as adjunctive approaches by modulating multiple pathogenic pathways. This review summarizes biomarker-based modulation of inflammatory, oxidative, and immune pathways by plant-derived extracts, nutraceuticals, and biologically derived compounds, with particular emphasis on evidence from adjuvant arthritis (AA). AA is a widely used experimental model that reproduces several inflammatory and oxidative features relevant to RA, including cytokine activation, NF-\u03baB\/MAPK signaling, Th17\/JAK-STAT3 signaling, redox imbalance, and tissue degeneration. Studies in AA indicate that selected natural compounds, alone or in combination with MTX, can reduce inflammatory cytokines (e.g., IL-1\u03b2, IL-6, IL-17A), matrix-remodeling markers (e.g., MMP-9), and oxidative-stress markers (e.g., protein carbonyls and lipid peroxidation) while supporting antioxidant defenses (e.g., HO-1 and CAT). Overall, natural bioactive substances may have potential as adjunctive candidates for further investigation in RA, particularly because of their effects on inflammatory and oxidative pathways. Preclinical studies of MTX combinations have reported additional improvements in selected disease-associated outcomes; however, these findings require confirmation in well-designed clinical studies. This review critically evaluates the preclinical evidence for natural bioactive compounds, with a focus on mechanistic studies in AA and the potential for combination strategies with methotrexate.<\/jats:p>","DOI":"10.3390\/ijms27177968","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:53:28Z","timestamp":1788789208000},"page":"7968","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural Bioactive Compounds in Rheumatoid Arthritis: Experimental Evidence from Adjuvant Arthritis Model Supporting Combination Strategies with Methotrexate"],"prefix":"10.3390","volume":"27","author":[{"given":"Mohammad","family":"Umar","sequence":"first","affiliation":[{"name":"Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"},{"name":"Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waqar","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"},{"name":"Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7863-2142","authenticated-orcid":false,"given":"Katarina","family":"Bauerova","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114929","DOI":"10.1016\/j.bcp.2022.114929","article-title":"Phytochemicals Targeting JAK\/STAT Pathway in the Treatment of Rheumatoid Arthritis: Is There a Future?","volume":"197","author":"Kour","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Damerau, A., and Gaber, T. (2020). Modeling Rheumatoid Arthritis In Vitro: From Experimental Feasibility to Physiological Proximity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217916"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hosseinikhah, S., Barani, M., Rahdar, A., Madry, H., Arshad, R., Mohammadzadeh, V., and Cucchiarini, M. (2021). Nanomaterials for the Diagnosis and Treatment of Inflammatory Arthritis. Int. J. Mol. Sci., 22, Correction in Int. J. Mol. Sci. 2025, 26, 4141.","DOI":"10.3390\/ijms26094141"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lin, Y.-J., Anzaghe, M., and Sch\u00fclke, S. (2020). Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis. Cells, 9.","DOI":"10.3390\/cells9040880"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid Arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00296-020-04731-0","article-title":"The Global Prevalence of Rheumatoid Arthritis: A Meta-Analysis Based on a Systematic Review","volume":"41","author":"Almutairi","year":"2021","journal-title":"Rheumatol. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cca.2016.02.010","article-title":"Understanding the Role of Cytokines in the Pathogenesis of Rheumatoid Arthritis","volume":"455","author":"Mateen","year":"2016","journal-title":"Clin. Chim. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.3390\/cimb45040197","article-title":"Rheumatoid Arthritis and Reactive Oxygen Species: A Review","volume":"45","author":"Kondo","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e19708","DOI":"10.7717\/peerj.19708","article-title":"MAPK\/ERK Signaling Pathway in Rheumatoid Arthritis: Mechanisms and Therapeutic Potential","volume":"13","author":"Xie","year":"2025","journal-title":"PeerJ"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1186\/ar3324","article-title":"Negative Regulation of NF-\u039aB and Its Involvement in Rheumatoid Arthritis","volume":"13","author":"Beyaert","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1007\/s10238-025-01867-w","article-title":"Function of P53 in Angiogenesis and Oxidative Stress in Rheumatoid Arthritis","volume":"25","author":"Farhadi","year":"2025","journal-title":"Clin. Exp. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/j.freeradbiomed.2010.09.006","article-title":"Oxidative Stress, Inflammation, and Cancer: How Are They Linked?","volume":"49","author":"Reuter","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1111\/bph.13544","article-title":"The Oxidative Stress Theory of Disease: Levels of Evidence and Epistemological Aspects","volume":"174","author":"Ghezzi","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1007\/s40265-017-0856-4","article-title":"Baricitinib: A Review in Rheumatoid Arthritis","volume":"78","author":"Scott","year":"2018","journal-title":"Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41584-020-0373-9","article-title":"Methotrexate and Its Mechanisms of Action in Inflammatory Arthritis","volume":"16","author":"Cronstein","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nrrheum.2010.5","article-title":"Methotrexate\u2014How Does It Really Work?","volume":"6","author":"Chan","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"95","DOI":"10.3181\/00379727-91-22179","article-title":"Development of Arthritis, Periarthritis and Periostitis in Rats Given Adjuvants","volume":"91","author":"Pearson","year":"1956","journal-title":"Exp. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/0163-7258(83)90062-1","article-title":"Models of Arthritis and the Search for Anti-Arthritic Drugs","volume":"21","author":"Billingham","year":"1983","journal-title":"Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Marco-Bonilla, M., Fresnadillo, M., de la Riva-Bueno, M., Herrero-Beaumont, G., Gonz\u00e1lez-Gay, M.A., Largo, R., and Mediero, A. (2025). Beyond Joints: The Importance of Animal Models in Exploring Rheumatoid Arthritis Comorbidities. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1693610"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/ptr.4966","article-title":"Animal Studies on Medicinal Herbs: Predictability, Dose Conversion and Potential Value","volume":"28","author":"Wojcikowski","year":"2014","journal-title":"Phytother. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/ddr.21461","article-title":"Dose Translation between Laboratory Animals and Human in Preclinical and Clinical Phases of Drug Development","volume":"79","author":"Nair","year":"2018","journal-title":"Drug Dev. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Peng, Q., Wang, J., Li, K., Xia, C., Yao, C., Guo, Q., Gong, X., Tang, X., and Jiang, Q. (2025). Effects of Plant Active Substances in Rheumatoid Arthritis\u2014A Systematic Review and Network Meta-Analysis. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1536023"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Long, Z., Xiang, W., He, Q., Xiao, W., Wei, H., Li, H., Guo, H., Chen, Y., Yuan, M., and Yuan, X. (2023). Efficacy and Safety of Dietary Polyphenols in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of 47 Randomized Controlled Trials. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1024120"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"157285","DOI":"10.1016\/j.phymed.2025.157285","article-title":"Phytotherapy as an Adjunct to the Treatment of Rheumatoid Arthritis\u2014A Systematic Review of Clinical Trials","volume":"148","author":"Piekarz","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Han, Y., Chen, S., Liu, C., Sun, H., Jia, Z., Shi, J., Li, J., and Chang, Y. (2025). A Comprehensive Review of Natural Products in Rheumatoid Arthritis: Therapeutic Potential and Mechanisms. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1501019"},{"key":"ref_26","first-page":"33","article-title":"Utilization of Adjuvant Arthritis Model for Evaluation of New Approaches in Rheumatoid Arthritis Therapy Focused on Regulation of Immune Processes and Oxidative Stress","volume":"4","year":"2011","journal-title":"Interdiscip. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1056\/NEJMra1004965","article-title":"The Pathogenesis of Rheumatoid Arthritis","volume":"365","author":"McInnes","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Drafi, F., Bauerova, K., Chrastina, M., Taghdisiesfej\u00edr, M., Rocha, J., Direito, R., Figueira, M.E., Sepodes, B., and Ponist, S. (2023). Rhodiola rosea L. Extract, a Known Adaptogen, Evaluated in Experimental Arthritis. Molecules, 28.","DOI":"10.3390\/molecules28135053"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chrastina, M., Dr\u00e1fi, F., Pru\u017einsk\u00e1, K., Poni\u0161t, S., Kamga, K.S., Khademnematolahi, S., Bilka, F., Nov\u00e1k, P., Pa\u0161kov\u00e1, \u013d., and Bauerov\u00e1, K. (2023). Crocus sativus L. Extract (Saffron) Effectively Reduces Arthritic and Inflammatory Parameters in Monotherapy and in Combination with Methotrexate in Adjuvant Arthritis. Nutrients, 15.","DOI":"10.3390\/nu15194108"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Khademnematolahi, S., Ponist, S., Svik, K., Drafi, F., Slovak, L., Muchova, J., Mindang, E.L., Ahmad, W., and Bauerova, K. (2025). Therapeutic Effects of Two Different Molecular Weights of Orally Administered Hyaluronan, Both as Monotherapy and in Combination with Methotrexate in a Rat Model of Arthritis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26093958"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"347","DOI":"10.18388\/abp.2010_2415","article-title":"Combined Methotrexate and Coenzyme Q10 Therapy in Adjuvant-Induced Arthritis Evaluated Using Parameters of Inflammation and Oxidative Stress","volume":"57","author":"Bauerova","year":"2010","journal-title":"Acta Biochim. Pol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.immuni.2017.02.006","article-title":"Immunopathogenesis of Rheumatoid Arthritis","volume":"46","author":"Firestein","year":"2017","journal-title":"Immunity"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nri2094","article-title":"Cytokines in the Pathogenesis of Rheumatoid Arthritis","volume":"7","author":"McInnes","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1146\/annurev.immunol.021908.132710","article-title":"IL-17 and Th17 Cells","volume":"27","author":"Korn","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrrheum.2016.52","article-title":"Family History of Rheumatoid Arthritis: An Old Concept with New Developments","volume":"12","author":"Frisell","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/nrrheum.2009.181","article-title":"Anti-TNF Biologic Agents: Still the Therapy of Choice for Rheumatoid Arthritis","volume":"5","author":"Taylor","year":"2009","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1093\/rheumatology\/kem297","article-title":"MAPKs and Their Relevance to Arthritis and Inflammation","volume":"47","author":"Thalhamer","year":"2007","journal-title":"Rheumatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1089\/ars.2007.1569","article-title":"Rheumatoid Arthritis: The Role of Reactive Oxygen Species in Disease Development and Therapeutic Strategies","volume":"9","author":"Gelderman","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"70539","DOI":"10.1002\/jbt.70539","article-title":"The Nrf2-GPX4 Pathway Provides Protection Against Rheumatoid Arthritis via Inhibition of Macrophage Ferroptosis-Mediated Inflammation and Synovial Fibroblast Proliferation","volume":"39","author":"Liang","year":"2025","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"107686","DOI":"10.1016\/j.phrs.2025.107686","article-title":"A Sinomenine Derivative Alleviates Bone Destruction in Collagen-Induced Arthritis Mice by Suppressing Mitochondrial Dysfunction and Oxidative Stress via the NRF2\/HO-1\/NQO1 Signaling Pathway","volume":"215","author":"Guo","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"479","DOI":"10.2174\/0118715303307608240812114651","article-title":"Activation of the Keap1\/Nrf2\/HO-1 Pathway by \u201cTianyu\u201d Pairing: Implications for Inflammation and Oxidative Stress in Rheumatoid Arthritis","volume":"25","author":"Tang","year":"2025","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"113855","DOI":"10.1016\/j.intimp.2024.113855","article-title":"Regulation of Macrophage Polarization and Pyroptosis by 4-Methylcatechol Alleviates Collagen-Induced Arthritis via Nrf2\/HO-1 and NF-\u039aB\/NLRP3 Signaling Pathways","volume":"146","author":"Zhendong","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s10067-007-0746-3","article-title":"The Interrelation of Glutathione Reductase, Catalase, Glutathione Peroxidase, Superoxide Dismutase, and Glucose-6-Phosphate in the Pathogenesis of Rheumatoid Arthritis","volume":"27","author":"Kalpakcioglu","year":"2008","journal-title":"Clin. Rheumatol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ponist, S., Zloh, M., and Bauerova, K. (2020). Impact of Oxidative Stress on Inflammation in Rheumatoid and Adjuvant Arthritis: Damage to Lipids, Proteins, and Enzymatic Antioxidant Defense in Plasma and Different Tissues. Animal Models in Medicine and Biology, IntechOpen.","DOI":"10.5772\/intechopen.89480"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bauerov\u00e1, K., Glevick\u00e1, M., Mindang, E.L.N., Ahmad, W., Gvozdj\u00e1kov\u00e1, A., and Sumbalov\u00e1, Z. (2024). Mitochondrial Rheumatology. Translational Mitochondrial Medicine, Springer.","DOI":"10.1007\/978-3-031-75741-9_11"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Cui, L., Weiyao, J., Chenghong, S., Limei, L., Xinghua, Z., Bo, Y., Xiaozheng, D., and Haidong, W. (2022). Rheumatoid Arthritis and Mitochondrial Homeostasis: The Crossroads of Metabolism and Immunity. Front. Med., 9.","DOI":"10.3389\/fmed.2022.1017650"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4025","DOI":"10.1002\/cbf.4025","article-title":"Peripheral Blood Mononuclear Cells Show Markers of Mitochondrial Dysfunction in Rheumatoid Arthritis","volume":"42","author":"Abbasifard","year":"2024","journal-title":"Cell Biochem. Funct."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s12276-024-01376-y","article-title":"MtSTAT3 Suppresses Rheumatoid Arthritis by Regulating Th17 and Synovial Fibroblast Inflammatory Cell Death with IL-17-Mediated Autophagy Dysfunction","volume":"57","author":"Lee","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.tibs.2026.02.014","article-title":"Molecular Mechanisms of PINK1\/Parkin-Mediated Mitochondrial Quality Control","volume":"51","author":"Bayne","year":"2026","journal-title":"Trends Biochem. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Stojanovic, S.K., Stamenkovic, B.N., Cvetkovic, J.M., Zivkovic, V.G., and Apostolovic, M.R.A. (2023). Matrix Metalloproteinase-9 Level in Synovial Fluid\u2014Association with Joint Destruction in Early Rheumatoid Arthritis. Medicina, 59.","DOI":"10.3390\/medicina59010167"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Jing, W., Liu, C., Su, C., Liu, L., Chen, P., Li, X., Zhang, X., Yuan, B., Wang, H., and Du, X. (2023). Role of Reactive Oxygen Species and Mitochondrial Damage in Rheumatoid Arthritis and Targeted Drugs. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1107670"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/nrrheum.2009.217","article-title":"Osteoimmunology and the Effects of the Immune System on Bone","volume":"5","author":"Takayanagi","year":"2009","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1210\/endo-123-5-2600","article-title":"Osteoblastic Cells Are Involved in Osteoclast Formation","volume":"123","author":"Takahashi","year":"1988","journal-title":"Endocrinology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00281-003-0128-7","article-title":"Heat Shock Protein 60 and Adjuvant Arthritis: A Model for T Cell Regulation in Human Arthritis","volume":"25","author":"Prakken","year":"2003","journal-title":"Springer Semin. Immunopathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"BSR20182263","DOI":"10.1042\/BSR20182263","article-title":"FM0807 Decelerates Experimental Arthritis Progression by Inhibiting Inflammatory Responses and Joint Destruction via Modulating NF-\u039aB and MAPK Pathways","volume":"39","author":"Zhang","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"78764","DOI":"10.18632\/oncotarget.12853","article-title":"Fasudil, an Inhibitor of Rho-Associated Coiled-Coil Kinase, Improves Cognitive Impairments Induced by Smoke Exposure","volume":"7","author":"Deng","year":"2016","journal-title":"Oncotarget"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.3109\/10715762.2015.1087643","article-title":"Effects of Esculetin on Lipopolysaccharide (LPS)-Induced Acute Lung Injury via Regulation of RhoA\/Rho Kinase\/NF-KB Pathways in Vivo and in Vitro","volume":"49","author":"Chen","year":"2015","journal-title":"Free Radic. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.2147\/DDDT.S190155","article-title":"Effect of Umbelliferone on Adjuvant-Induced Arthritis in Rats by MAPK\/NF-\u03baB Pathway","volume":"13","author":"Ouyang","year":"2019","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"471","DOI":"10.4149\/gpb_2017014","article-title":"Evaluation of Liposomal Carnosine in Adjuvant Arthritis","volume":"36","author":"Fedorova","year":"2017","journal-title":"Gen. Physiol. Biophys."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e509","DOI":"10.1002\/mco2.509","article-title":"Rheumatoid Arthritis: Pathogenesis and Therapeutic Advances","volume":"5","author":"Gao","year":"2024","journal-title":"MedComm"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"104951","DOI":"10.1016\/j.yexmp.2024.104951","article-title":"Modulation of IL-6 Receptor\/STAT3 Downstream Signaling in Rheumatoid Arthritis Patients","volume":"141","author":"Cacciapaglia","year":"2025","journal-title":"Exp. Mol. Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jep.2004.03.052","article-title":"Anti-Metastatic Activity of Acanthopanax Senticosus Extract and Its Possible Immunological Mechanism of Action","volume":"93","author":"Yoon","year":"2004","journal-title":"J. Ethnopharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Wu, Y., Shi, D., Jiang, C., Cao, H., Jiang, F., Bao, X., Shen, Y., and Shi, X. (2024). Acanthopanax Senticosus Improves Cognitive Impairment in Alzheimer\u2019s Disease by Promoting the Phosphorylation of the MAPK Signaling Pathway. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1383464"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1007\/s10753-014-9880-7","article-title":"Eleutheroside E Ameliorates Arthritis Severity in Collagen-Induced Arthritis Mice Model by Suppressing Inflammatory Cytokine Release","volume":"37","author":"He","year":"2014","journal-title":"Inflammation"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/s00393-023-01431-5","article-title":"Salidroside Suppresses Cell Growth and Inflammatory Response of Fibroblast-like Synoviocytes via Inhibition of Phosphoinositol-3 Kinase\/Threonine Kinase Signaling in Rheumatoid Arthritis","volume":"83","author":"Qin","year":"2024","journal-title":"Z. Rheumatol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1016\/j.tiv.2007.04.016","article-title":"(+)-Syringaresinol-Di-O-\u03b2-d-Glucoside, a Phenolic Compound from Acanthopanax Senticosus Harms, Suppresses Proinflammatory Mediators in SW982 Human Synovial Sarcoma Cells by Inhibiting Activating Protein-1 and\/or Nuclear Factor-\u039aB Activities","volume":"21","author":"Yamazaki","year":"2007","journal-title":"Toxicol. Vitr."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Miyazaki, S., Oikawa, H., Takekoshi, H., Hoshizaki, M., Ogata, M., and Fujikawa, T. (2018). Anxiolytic Effects of Acanthopanax Senticosus HARMS Occur via Regulation of Autonomic Function and Activate Hippocampal BDNF\u2013TrkB Signaling. Molecules, 24.","DOI":"10.3390\/molecules24010132"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3335","DOI":"10.1039\/D3BM02129G","article-title":"A Chlorogenic Acid-Conjugated Nanomicelle Attenuates Disease Severity in Experimental Arthritis","volume":"12","author":"Vyawahare","year":"2024","journal-title":"Biomater. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Jain, S., Vaidya, A., Gupta, P.K., Rosenholm, J.M., and Bansal, K.K. (2021). Antiarthritic Activities of Herbal Isolates: A Comprehensive Review. Coatings, 11.","DOI":"10.3390\/coatings11111329"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13020-019-0250-0","article-title":"A Review on the Immunomodulatory Activity of Acanthopanax Senticosus and Its Active Components","volume":"14","author":"Lau","year":"2019","journal-title":"Chin. Med."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Patyra, A., Ko\u0142tun-Jasion, M., Kupniewska, K., Parzonko, A., and Kiss, A.K. (2025). Eleutherococcus Root: A Comprehensive Review of Its Phytochemistry and Pharmacological Potential in the Context of Its Adaptogenic Effect. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1683795"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Qian, Q., Pan, J., Yang, J., Wang, R., Luo, K., Wu, Z., Ma, S., Wang, Y., Li, M., and Gao, Y. (2024). Syringin: A Naturally Occurring Compound with Medicinal Properties. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1435524"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"116681","DOI":"10.1016\/j.intimp.2026.116681","article-title":"Chlorogenic Acid Attenuates Rheumatoid Arthritis by Modulating Immunity via the Gut Microbiota-Derived Metabolite Indolelactic Acid","volume":"180","author":"Zhang","year":"2026","journal-title":"Int. Immunopharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"8042097","DOI":"10.1155\/2019\/8042097","article-title":"Chlorogenic Acid Inhibits BAFF Expression in Collagen-Induced Arthritis and Human Synoviocyte MH7A Cells by Modulating the Activation of the NF- \u03ba B Signaling Pathway","volume":"2019","author":"Fu","year":"2019","journal-title":"J. Immunol. Res."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Kciuk, M., Garg, A., Rohilla, M., Chaudhary, R., Dhankhar, S., Dhiman, S., Bansal, S., Saini, M., Singh, T.G., and Chauhan, S. (2024). Therapeutic Potential of Plant-Derived Compounds and Plant Extracts in Rheumatoid Arthritis\u2014Comprehensive Review. Antioxidants, 13.","DOI":"10.3390\/antiox13070775"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4334","DOI":"10.1002\/ptr.7129","article-title":"Triptolide Promotes the Apoptosis and Attenuates the Inflammation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis by Down-regulating lncRNA ENST00000619282","volume":"35","author":"Wen","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Zhang, M., Ren, H., Li, K., Xie, S., Zhang, R., Zhang, L., Xia, J., Chen, X., Li, X., and Wang, J. (2021). Therapeutic Effect of Various Ginsenosides on Rheumatoid Arthritis. BMC Complement. Med. Ther., 21.","DOI":"10.1186\/s12906-021-03302-5"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.phymed.2018.12.030","article-title":"Comparison of Combination Therapy with Methotrexate and Sinomenine or Leflunomide for Active Rheumatoid Arthritis: A Randomized Controlled Clinical Trial","volume":"57","author":"Huang","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1007\/s10067-018-4080-8","article-title":"Resveratrol as an Effective Adjuvant Therapy in the Management of Rheumatoid Arthritis: A Clinical Study","volume":"37","author":"Khojah","year":"2018","journal-title":"Clin. Rheumatol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.cbi.2009.07.016","article-title":"Apigenin-Induced Apoptosis Is Mediated by Reactive Oxygen Species and Activation of ERK1\/2 in Rheumatoid Fibroblast-like Synoviocytes","volume":"182","author":"Shin","year":"2009","journal-title":"Chem. Biol. Interact."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1016\/j.bcp.2006.02.009","article-title":"Molecular Targets of Dietary Agents for Prevention and Therapy of Cancer","volume":"71","author":"Aggarwal","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1111\/fcp.12085","article-title":"N-feruloylserotonin in Preventive Combination Therapy with Methotrexate Reduced Inflammation in Adjuvant Arthritis","volume":"28","author":"Kuncirova","year":"2014","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.abb.2015.08.008","article-title":"Quercetin Reduced Inflammation and Increased Antioxidant Defense in Rat Adjuvant Arthritis","volume":"583","author":"Gardi","year":"2015","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/j.0105-2896.2009.00859.x","article-title":"Fibroblast-like Synoviocytes: Key Effector Cells in Rheumatoid Arthritis","volume":"233","author":"Bartok","year":"2010","journal-title":"Immunol. Rev."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"111039","DOI":"10.1016\/j.biopha.2020.111039","article-title":"A Mechanistic Insight of Phytoestrogens Used for Rheumatoid Arthritis: An Evidence-Based Review","volume":"133","author":"Chakraborty","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1007\/s00296-012-2657-0","article-title":"Resveratrol Inhibits TNF-\u03b1-Induced IL-1\u03b2, MMP-3 Production in Human Rheumatoid Arthritis Fibroblast-like Synoviocytes via Modulation of PI3kinase\/Akt Pathway","volume":"33","author":"Tian","year":"2013","journal-title":"Rheumatol. Int."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6111","DOI":"10.2147\/DDDT.S527665","article-title":"Pharmacological Mechanisms and Therapeutic Potential of Resveratrol in Rheumatoid Arthritis","volume":"19","author":"Liu","year":"2025","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"114894","DOI":"10.1016\/j.intimp.2025.114894","article-title":"Isorhapontigenin Suppresses Inflammation, Proliferation and Aggressiveness of Rheumatoid Arthritis Fibroblast-like Synoviocytes by Targeting Farnesyl Diphosphate Synthase","volume":"159","author":"Liu","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"355","DOI":"10.3390\/nu2030355","article-title":"Omega-3 Fatty Acids and Inflammatory Processes","volume":"2","author":"Calder","year":"2010","journal-title":"Nutrients"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1017\/S0007114511005460","article-title":"Dietary Factors and Low-Grade Inflammation in Relation to Overweight and Obesity","volume":"106","author":"Calder","year":"2011","journal-title":"Br. J. Nutr."},{"key":"ref_91","first-page":"723","article-title":"Treatment With Coenzyme Q10, \u03c9-3-Polyunsaturated Fatty Acids and Their Combination Improved Bioenergetics and Levels of Coenzyme Q9 and Q10 in Skeletal Muscle Mitochondria in Experimental Model of Arthritis","volume":"70","author":"Taghdisiesfejir","year":"2021","journal-title":"Physiol. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"7432797","DOI":"10.1155\/2016\/7432797","article-title":"Oxidative Stress and Inflammation: What Polyphenols Can Do for Us?","volume":"2016","author":"Hussain","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"13673","DOI":"10.1111\/jfbc.13673","article-title":"Role of Natural Products in Alleviation of Rheumatoid Arthritis\u2014A Review","volume":"45","author":"Sharma","year":"2021","journal-title":"J. Food Biochem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1146\/annurev-pharmtox-011112-140320","article-title":"Role of Nrf2 in Oxidative Stress and Toxicity","volume":"53","author":"Ma","year":"2013","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_95","first-page":"22","article-title":"Effects of Sesame Oil in the Model of Adjuvant Arthritis","volume":"30","author":"Sotnikova","year":"2009","journal-title":"Neuro Endocrinol. Lett."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Pru\u017einsk\u00e1, K., Chrastina, M., Khademnematolahi, S., Vyletelov\u00e1, V., Gajdo\u0161ov\u00e1, L., Pastvov\u00e1, L., Dr\u00e1fi, F., Poni\u0161t, S., Pa\u0161kov\u00e1, \u013d., and Kucharsk\u00e1, J. (2024). Astaxanthin, Compared to Other Carotenoids, Increases the Efficacy of Methotrexate in Rat Adjuvant Arthritis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168710"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Chrastina, M., Poni\u0161t, S., T\u00f3th, J., Czigle, S., Pa\u0161kov\u00e1, \u013d., Vyletelov\u00e1, V., \u0160v\u00edk, K., and Bauerov\u00e1, K. (2022). Combination Therapy of Carnosic Acid and Methotrexate Effectively Suppressed the Inflammatory Markers and Oxidative Stress in Experimental Arthritis. Molecules, 27.","DOI":"10.3390\/molecules27207115"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"100228","DOI":"10.1016\/j.phanu.2020.100228","article-title":"Modulation of Methotrexate Efficacy by Green Tea Polyphenols in Rat Adjuvant Arthritis","volume":"14","author":"Ponist","year":"2020","journal-title":"PharmaNutrition"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Bava, R., Castagna, F., Musella, V., Lupia, C., Palma, E., and Britti, D. (2023). Therapeutic Use of Bee Venom and Potential Applications in Veterinary Medicine. Vet. Sci., 10.","DOI":"10.3390\/vetsci10020119"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1186\/s12951-024-02722-y","article-title":"The Combination of Modified Acupuncture Needle and Melittin Hydrogel as a Novel Therapeutic Approach for Rheumatoid Arthritis Treatment","volume":"22","author":"Liu","year":"2024","journal-title":"J. Nanobiotechnology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"108335","DOI":"10.1016\/j.toxicon.2025.108335","article-title":"Melittin: A Promising Therapeutic Agent for Rheumatoid Arthritis Treatment","volume":"258","author":"Huang","year":"2025","journal-title":"Toxicon"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/s12951-023-02026-7","article-title":"Effective Treatment of Metastatic Sentinel Lymph Nodes by Dual-Targeting Melittin Nanoparticles","volume":"21","author":"Dai","year":"2023","journal-title":"J. Nanobiotechnology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.3390\/toxins7041126","article-title":"Three Valuable Peptides from Bee and Wasp Venoms for Therapeutic and Biotechnological Use: Melittin, Apamin and Mastoparan","volume":"7","author":"Moreno","year":"2015","journal-title":"Toxins"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"113331","DOI":"10.1016\/j.colsurfb.2023.113331","article-title":"In Vitro and in Vivo Antimicrobial Activity of Self-Assembled Melittin Nanoparticles: A Comparative Study with Melittin Peptide","volume":"226","author":"Thankappan","year":"2023","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/nature01320","article-title":"Points of Control in Inflammation","volume":"420","author":"Nathan","year":"2002","journal-title":"Nature"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Sykora, T., Babal, P., Mikus-Kuracinova, K., Drafi, F., Ponist, S., Dvorakova, M., Janega, P., and Bauerova, K. (2021). Hyperbilirubinemia Maintained by Chronic Supplementation of Unconjugated Bilirubin Improves the Clinical Course of Experimental Autoimmune Arthritis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168662"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.bcp.2006.09.023","article-title":"Melittin Inhibits Inflammatory Target Gene Expression and Mediator Generation via Interaction with I\u03baB Kinase","volume":"73","author":"Park","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.3390\/toxins7072413","article-title":"Therapeutic Effects of Bee Venom on Immunological and Neurological Diseases","volume":"7","author":"Hwang","year":"2015","journal-title":"Toxins"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Shi, P., Xie, S., Yang, J., Zhang, Y., Han, S., Su, S., and Yao, H. (2022). Pharmacological Effects and Mechanisms of Bee Venom and Its Main Components: Recent Progress and Perspective. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1001553"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.tips.2008.11.002","article-title":"Pharmacological Basis for the Role of Curcumin in Chronic Diseases: An Age-Old Spice with Modern Targets","volume":"30","author":"Aggarwal","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1039\/c0fo00103a","article-title":"Anti-Inflammatory Activity of Natural Dietary Flavonoids","volume":"1","author":"Pan","year":"2010","journal-title":"Food Funct."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.ejphar.2009.03.080","article-title":"Decreased Activity of Neutrophils in the Presence of Diferuloylmethane (Curcumin) Involves Protein Kinase C Inhibition","volume":"612","year":"2009","journal-title":"Eur. J. Pharmacol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"110822","DOI":"10.1016\/j.cbi.2023.110822","article-title":"Bisdemethoxycurcumin, a Curcumin Derivative, Ameliorates Adjuvant-Induced Arthritis by Suppressing Inflammatory Reactions and Macrophage Migration","volume":"387","author":"Sun","year":"2024","journal-title":"Chem. Biol. Interact."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"8295","DOI":"10.1007\/s00210-025-03897-3","article-title":"Natural and Synthetic Potential Drug Leads for Rheumatoid Arthritis Probing Innovative Target: Mitochondrial Dysfunction and NLRP3 Inflammasome Activation","volume":"398","author":"Iqbal","year":"2025","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1016\/j.biotechadv.2015.08.001","article-title":"Discovery and Resupply of Pharmacologically Active Plant-Derived Natural Products: A Review","volume":"33","author":"Atanasov","year":"2015","journal-title":"Biotechnol. Adv."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"153036","DOI":"10.1016\/j.phymed.2019.153036","article-title":"Genkwanin Ameliorates Adjuvant-Induced Arthritis in Rats through Inhibiting JAK\/STAT and NF-\u039aB Signaling Pathways","volume":"63","author":"Bao","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"4696","DOI":"10.62347\/OEHX5202","article-title":"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","volume":"16","author":"Ahmed","year":"2024","journal-title":"Am. J. Transl. Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1080\/10717544.2020.1818883","article-title":"\u03b2-Sitosterol-Loaded Solid Lipid Nanoparticles Ameliorate Complete Freund\u2019s Adjuvant-Induced Arthritis in Rats: Involvement of NF-KB and HO-1\/Nrf-2 Pathway","volume":"27","author":"Zhang","year":"2020","journal-title":"Drug Deliv."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Tsiklauri, L., \u0160v\u00edk, K., Chrastina, M., Poni\u0161t, S., Dr\u00e1fi, F., Slov\u00e1k, L., Alania, M., Kemertelidze, E., and Bauerova, K. (2021). Bioflavonoid Robinin from Astragalus falcatus Lam. Mildly Improves the Effect of Methotrexate in Rats with Adjuvant Arthritis. Nutrients, 13.","DOI":"10.3390\/nu13041268"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"153926","DOI":"10.1016\/j.phymed.2022.153926","article-title":"Perillyl Alcohol Attenuates Rheumatoid Arthritis via Regulating TLR4\/NF-\u039aB and Keap1\/Nrf2 Signaling Pathways: A Comprehensive Study Onin-Vitro and in-Vivo Experimental Models","volume":"97","author":"Puppala","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.2147\/DDDT.S374827","article-title":"Dehydrozingerone Alleviates Hyperalgesia, Oxidative Stress and Inflammatory Factors in Complete Freund\u2019s Adjuvant-Induced Arthritic Rats","volume":"16","author":"Liu","year":"2022","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1007\/s43440-019-00022-z","article-title":"Astaxanthin Attenuates Oxidative Stress and Inflammatory Responses in Complete Freund-Adjuvant-Induced Arthritis in Rats","volume":"72","author":"Kumar","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.bbrc.2016.05.126","article-title":"Anti-Arthritic Actions of \u03b2-Cryptoxanthin against the Degradation of Articular Cartilage in Vivo and in Vitro","volume":"476","author":"Imada","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"132293","DOI":"10.1016\/j.ijbiomac.2024.132293","article-title":"Amelioration of Melittin on Adjuvant-Induced Rheumatoid Arthritis: Integrated Transcriptome and Metabolome","volume":"270","author":"Yang","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Yang, L., He, X., Zhi, D., Xue, Y., Gong, X., Dong, K., and Tian, Y. (2024). Melittin Promotes Dexamethasone in the Treatment of Adjuvant Rheumatoid Arthritis in Rats. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1338432"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"198","DOI":"10.5606\/ArchRheumatol.2018.6519","article-title":"Bee Venom and Hesperidin Effectively Mitigate Complete Freund\u2019s Adjuvant-Induced Arthritis Via Immunomodulation and Enhancement of Antioxidant Defense System","volume":"33","author":"Ahmed","year":"2018","journal-title":"Arch. Rheumatol."},{"key":"ref_127","first-page":"20","article-title":"Systemic Bee Venom Exerts Anti-Arthritic and Anti-Inflammatory Properties in a Rat Model of Arthritis","volume":"13","author":"Helmy","year":"2020","journal-title":"Biomed. Rep."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Rinkunaite, I., Simoliunas, E., Alksne, M., Dapkute, D., and Bukelskiene, V. (2021). Anti-Inflammatory Effect of Different Curcumin Preparations on Adjuvant-Induced Arthritis in Rats. BMC Complement. Med. Ther., 21.","DOI":"10.1186\/s12906-021-03207-3"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s11010-025-05380-2","article-title":"Exploring the Beneficial Effects of Curcumin-Based Hydrogel Beads in Rats with Rheumatoid Arthritis Induced by Freund\u2019s Complete Adjuvant","volume":"481","author":"Djordjevic","year":"2025","journal-title":"Mol. Cell. Biochem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"8470589","DOI":"10.1155\/2016\/8470589","article-title":"Effect of Carnosine in Experimental Arthritis and on Primary Culture Chondrocytes","volume":"2016","author":"Ponist","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s00011-025-02135-z","article-title":"Effects of Curcumin and Curcuma Longa Extract on Inflammatory Biomarkers in Patients with Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE): A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"75","author":"Liu","year":"2025","journal-title":"Inflamm. Res."},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Fan, Y., Yi, Z., Mao, S., Wen, J., Zhang, J., Zhang, Q., and Liu, R. (2026). Curcumin for the Clinical Treatment of Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Placebo-Controlled Randomized Clinical Trials. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1726157"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1136\/annrheumdis-2013-204145","article-title":"Fish Oil in Recent Onset Rheumatoid Arthritis: A Randomised, Double-Blind Controlled Trial within Algorithm-Based Drug Use","volume":"74","author":"Proudman","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Buondonno, I., Rovera, G., Sassi, F., Rigoni, M.M., Lomater, C., Parisi, S., Pellerito, R., Isaia, G.C., and D\u2019Amelio, P. (2017). Vitamin D and Immunomodulation in Early Rheumatoid Arthritis: A Randomized Double-Blind Placebo-Controlled Study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178463"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1007\/s00296-011-1944-5","article-title":"Efficacy of Vitamin D in Patients with Active Rheumatoid Arthritis Receiving Methotrexate Therapy","volume":"32","author":"Salesi","year":"2012","journal-title":"Rheumatol. Int."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1136\/annrheumdis-2013-204807","article-title":"Comparison of Tripterygium Wilfordii Hook F with Methotrexate in the Treatment of Active Rheumatoid Arthritis (TRIFRA): A Randomised, Controlled Clinical Trial","volume":"74","author":"Lv","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.lfs.2017.01.004","article-title":"Treatment of Rheumatoid Arthritis with Combination of Methotrexate and Tripterygium Wilfordii: A Meta-Analysis","volume":"171","author":"Wang","year":"2017","journal-title":"Life Sci."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.joca.2006.04.008","article-title":"NF-\u039aB as a Potential Therapeutic Target in Osteoarthritis and Rheumatoid Arthritis","volume":"14","author":"Jimenez","year":"2006","journal-title":"Osteoarthr. Cartil."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1136\/ard.2007.074278","article-title":"The P38 Mitogen-Activated Protein Kinase (MAPK) Pathway in Rheumatoid Arthritis","volume":"67","author":"Schett","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"6145810","DOI":"10.1155\/2016\/6145810","article-title":"Enigma of IL-17 and Th17 Cells in Rheumatoid Arthritis and in Autoimmune Animal Models of Arthritis","volume":"2016","author":"Kugyelka","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13075-015-0527-3","article-title":"Non-Canonical NF-\u039aB Signaling in Rheumatoid Arthritis: Dr Jekyll and Mr Hyde?","volume":"17","author":"Noort","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1053\/joca.1999.0226","article-title":"COX-2 in Synovial Tissues","volume":"7","author":"Crofford","year":"1999","journal-title":"Osteoarthr. Cartil."},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Huang, J.-B., Chen, Z.-R., Yang, S.-L., and Hong, F.-F. (2023). Nitric Oxide Synthases in Rheumatoid Arthritis. Molecules, 28.","DOI":"10.3390\/molecules28114414"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1093\/rheumatology\/36.6.651","article-title":"Immunolocalization of Inducible Nitric Oxide Synthase in Synovium and Cartilage in Rheumatoid Arthritis and Osteoarthritis","volume":"36","author":"Grabowski","year":"1997","journal-title":"Rheumatology"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev.pharmtox.46.120604.141046","article-title":"Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway","volume":"47","author":"Kensler","year":"2007","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1016\/S0140-6736(17)31472-1","article-title":"Pathogenetic Insights from the Treatment of Rheumatoid Arthritis","volume":"389","author":"McInnes","year":"2017","journal-title":"Lancet"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"i43","DOI":"10.1093\/rheumatology\/key276","article-title":"JAK-Inhibitors. New Players in the Field of Immune-Mediated Diseases, beyond Rheumatoid Arthritis","volume":"58","author":"Fragoulis","year":"2019","journal-title":"Rheumatology"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41584-021-00726-8","article-title":"Janus Kinase-Targeting Therapies in Rheumatology: A Mechanisms-Based Approach","volume":"18","author":"Tanaka","year":"2022","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"112343","DOI":"10.1016\/j.intimp.2024.112343","article-title":"IL-17A\/IL-17RA Interaction Blockade Sensitizes Synovial Macrophages to Efferocytosis and PD-L1 Signaling via Rewiring STAT-3\/ADAM17\/MERTK Axis in Rheumatoid Arthritis Animal Model","volume":"136","author":"Samarpita","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1080\/08820139.2021.1994589","article-title":"CYT387 Inhibits the Hyperproliferative Potential of Fibroblast-like Synoviocytes via Modulation of IL-6\/JAK1\/STAT3 Signaling in Rheumatoid Arthritis","volume":"51","author":"Srivastava","year":"2022","journal-title":"Immunol. Investig."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1186\/s13075-025-03629-1","article-title":"Brevilin A, a Novel LRRC15 Inhibitor, Exerts Potent Anti-Rheumatoid Arthritis Effects by Inhibiting the LRRC15\/STAT3 Signaling Pathway","volume":"27","author":"Qiao","year":"2025","journal-title":"Arthritis Res. Ther."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nrd.2017.201","article-title":"JAK Inhibition as a Therapeutic Strategy for Immune and Inflammatory Diseases","volume":"16","author":"Schwartz","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/s41584-022-00883-4","article-title":"Busting the Myth of Methotrexate Chronic Hepatotoxicity","volume":"19","author":"Verhoeven","year":"2023","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Bedoui, Y., Guillot, X., S\u00e9lambarom, J., Guiraud, P., Giry, C., Jaffar-Bandjee, M.C., Ralandison, S., and Gasque, P. (2019). Methotrexate an Old Drug with New Tricks. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205023"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/ptr.8379","article-title":"Resveratrol Bioavailability After Oral Administration: A Meta-Analysis of Clinical Trial Data","volume":"39","author":"Szymkowiak","year":"2025","journal-title":"Phytother. Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.ejphar.2011.06.006","article-title":"Synergistic Activity of Curcumin with Methotrexate in Ameliorating Freund\u2019s Complete Adjuvant Induced Arthritis with Reduced Hepatotoxicity in Experimental Animals","volume":"668","author":"Banji","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_157","doi-asserted-by":"crossref","unstructured":"Liu, X., Wang, Z., Qian, H., Tao, W., Zhang, Y., Hu, C., Mao, W., and Guo, Q. (2022). Natural Medicines of Targeted Rheumatoid Arthritis and Its Action Mechanism. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.945129"},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Pru\u017einsk\u00e1, K., Slov\u00e1k, L., Dr\u00e1fi, F., Poni\u0161t, S., Jur\u00e1nek, I., Chrastina, M., \u0160v\u00edk, K., Strojn\u00fd, L., Ambro, \u013d., and Bauerov\u00e1, K. (2022). Enhanced Anti-Inflammatory Effect of the Combination of Lactiplantibacillus Plantarum LS\/07 with Methotrexate Compared to Their Monotherapies Studied in Experimental Arthritis. Molecules, 28.","DOI":"10.3390\/molecules28010297"},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Slov\u00e1k, L., \u0160v\u00edk, K., Mihalov\u00e1, D., T\u00f3th, J., Czigle, S., Pa\u0161kov\u00e1, \u013d., Bilka, F., and Bauerov\u00e1, K. (2017). Ferulaldehyde Improves the Effect of Methotrexate in Experimental Arthritis. Molecules, 22.","DOI":"10.3390\/molecules22111911"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/BF02818800","article-title":"Treatment of Experimental Adjuvant Arthritis with the Combination of Methotrexate and LyophilizedEnterococcus Faecium Enriched with Organic Selenium","volume":"47","author":"Ebringer","year":"2002","journal-title":"Folia Microbiol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s12223-009-0045-2","article-title":"Treatment of Adjuvant-Induced Arthritis with the Combination of Methotrexate and Probiotic Bacteria Escherichia Coli O83 (Colinfant\u00ae)","volume":"54","year":"2009","journal-title":"Folia Microbiol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1136\/ard.2010.132720","article-title":"Role of Oxidative Stress in Rheumatoid Arthritis: Insights from the Nrf2-Knockout Mice","volume":"70","author":"Wruck","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s00296-009-1258-z","article-title":"The Effects of \u03b2-Glucan Isolated from Pleurotus Ostreatus on Methotrexate Treatment in Rats with Adjuvant Arthritis","volume":"31","year":"2011","journal-title":"Rheumatol. Int."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1055\/s-0030-1270904","article-title":"Botanical Drugs, Synergy, and Network Pharmacology: Forth and Back to Intelligent Mixtures","volume":"77","author":"Gertsch","year":"2011","journal-title":"Planta Medica"},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Magini, A., and Datti, A. (2026). Curcumin Between Pleiotropic Potential and Translational Constraints. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27052212"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"70252","DOI":"10.1002\/mco2.70252","article-title":"Resveratrol: Molecular Mechanisms, Health Benefits, and Potential Adverse Effects","volume":"6","author":"Ren","year":"2025","journal-title":"MedComm"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1055\/s-0029-1186153","article-title":"Potent in Vitro Inhibition of CYP3A4 and P-Glycoprotein by Rhodiola Rosea","volume":"76","author":"Hellum","year":"2010","journal-title":"Planta Medica"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"118907","DOI":"10.1016\/j.lfs.2020.118907","article-title":"The Effects of Drug Transporters on the Efficacy of Methotrexate in the Treatment of Rheumatoid Arthritis","volume":"268","author":"Gao","year":"2021","journal-title":"Life Sci."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1017\/S0029665113001031","article-title":"N -3 Fatty Acids, Inflammation and Immunity: New Mechanisms to Explain Old Actions","volume":"72","author":"Calder","year":"2013","journal-title":"Proc. Nutr. Soc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7968\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:23:11Z","timestamp":1789014191000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7968"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":169,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177968"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177968","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,7]]}}}