{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T03:08:07Z","timestamp":1777864087876,"version":"3.51.4"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,5,29]],"date-time":"2019-05-29T00:00:00Z","timestamp":1559088000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,5,29]],"date-time":"2019-05-29T00:00:00Z","timestamp":1559088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Patanjali Research Foundation Trust, Haridwar, India"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that affects joints of hands and feet and introduces injury in secondary organs such as cardiac tissue. In the present study, we induced RA in male Balb\/c mice (CAIA) using collagen-antibody cocktail (C-Ab) and lipopolysaccharide intraperitoneal injections. Induction of RA in the animals was detected through the loss of body weight, food, and water consumption, pedal edema, increased arthritis score of the paw and ankle, increase in radiological and histological lesion score of ankle and knee joints and enhanced pain perception in the C-Ab induced RA animals.\u00a0Ashwashila is a herbo-mineral medicine\u00a0from Indian Ayurvedic system. Human equivalent doses of Ashwashila (ASHW) and standard of care, Methotrexate were given to the CAIA animals for two weeks. ASHW treatment significantly reversed the effect of C-Ab with reduced pedal edema, arthritis score, radiological and histological lesion scores in ankle-joint, knee-joint and articular cartilage, reduced pain perception. These effects were comparable with the Methotrexate treatment. In human monocytic (THP-1) cells, ASHW was found to be biocompatible at <jats:italic>in-vitro<\/jats:italic> test doses. The anti-arthritis mechanism of action for ASHW was established through the suppression of pro-inflammatory cytokines such as IL-1\u03b2, IL-6, TNF-\u03b1; and upstream regulator, NF-\u03baB. Taken together, we show the pre-clinical efficacy of ASHW in reducing RA associated symptoms by controlling inflammation and suggest it as a potential therapeutic candidate for rheumatoid arthritis.<\/jats:p>","DOI":"10.1038\/s41598-019-44485-9","type":"journal-article","created":{"date-parts":[[2019,5,29]],"date-time":"2019-05-29T10:02:24Z","timestamp":1559124144000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Herbo-mineral formulation \u2018Ashwashila\u2019 attenuates rheumatoid arthritis symptoms in collagen-antibody-induced arthritis (CAIA) mice model"],"prefix":"10.1038","volume":"9","author":[{"given":"Acharya","family":"Balkrishna","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sachin Shridhar","family":"Sakat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kheemraj","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandeep","family":"Paudel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepika","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamal","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ravikant","family":"Ranjan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhishek","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunal","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anurag","family":"Varshney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,5,29]]},"reference":[{"key":"44485_CR1","doi-asserted-by":"publisher","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","volume":"4","author":"JS Smolen","year":"2018","unstructured":"Smolen, J. S. et al. Rheumatoid arthritis. Nat Rev Dis Primers 4, 18001, https:\/\/doi.org\/10.1038\/nrdp.2018.1 (2018).","journal-title":"Nat Rev Dis Primers"},{"key":"44485_CR2","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1002\/art.1780380106","volume":"38","author":"JS Smolen","year":"1995","unstructured":"Smolen, J. S. et al. Validity and reliability of the twenty-eight-joint count for the assessment of rheumatoid arthritis activity. Arthritis Rheum 38, 38\u201343 (1995).","journal-title":"Arthritis Rheum"},{"key":"44485_CR3","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1056\/NEJMra1004965","volume":"365","author":"IB McInnes","year":"2011","unstructured":"McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N Engl J Med 365, 2205\u20132219, https:\/\/doi.org\/10.1056\/NEJMra1004965 (2011).","journal-title":"N Engl J Med"},{"key":"44485_CR4","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/nri2094","volume":"7","author":"IB McInnes","year":"2007","unstructured":"McInnes, I. B. & Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7, 429\u2013442, https:\/\/doi.org\/10.1038\/nri2094 (2007).","journal-title":"Nat Rev Immunol"},{"key":"44485_CR5","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1111\/j.0105-2896.2009.00859.x","volume":"233","author":"B Bartok","year":"2010","unstructured":"Bartok, B. & Firestein, G. S. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 233, 233\u2013255, https:\/\/doi.org\/10.1111\/j.0105-2896.2009.00859.x (2010).","journal-title":"Immunol Rev"},{"key":"44485_CR6","doi-asserted-by":"publisher","first-page":"2512","DOI":"10.1038\/nprot.2006.393","volume":"1","author":"LM Khachigian","year":"2006","unstructured":"Khachigian, L. M. Collagen antibody-induced arthritis. Nat Protoc 1, 2512\u20132516, https:\/\/doi.org\/10.1038\/nprot.2006.393 (2006).","journal-title":"Nat Protoc"},{"key":"44485_CR7","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1093\/rheumatology\/33.9.798","volume":"33","author":"NA Staines","year":"1994","unstructured":"Staines, N. A. & Wooley, P. H. Collagen arthritis\u2013what can it teach us? Br J Rheumatol 33, 798\u2013807 (1994).","journal-title":"Br J Rheumatol"},{"key":"44485_CR8","doi-asserted-by":"publisher","first-page":"674142","DOI":"10.1155\/2012\/674142","volume":"2012","author":"C Carrasco-Gallardo","year":"2012","unstructured":"Carrasco-Gallardo, C., Guzman, L. & Maccioni, R. B. Shilajit: a natural phytocomplex with potential procognitive activity. Int J Alzheimers Dis 2012, 674142, https:\/\/doi.org\/10.1155\/2012\/674142 (2012).","journal-title":"Int J Alzheimers Dis"},{"key":"44485_CR9","doi-asserted-by":"publisher","first-page":"308","DOI":"10.3109\/13880209.2013.835325","volume":"52","author":"A Gupta","year":"2014","unstructured":"Gupta, A. & Singh, S. Evaluation of anti-inflammatory effect of Withania somnifera root on collagen-induced arthritis in rats. Pharm Biol 52, 308\u2013320, https:\/\/doi.org\/10.3109\/13880209.2013.835325 (2014).","journal-title":"Pharm Biol"},{"key":"44485_CR10","first-page":"78","volume":"4","author":"KR Giri","year":"2016","unstructured":"Giri, K. R. Comparative study of anti-inflammatory activity of Withania somnifera (Ashwagandha) with hydrocortisone in experimental animals (Albino rats). J Med Plants Studies 4, 78\u201383 (2016).","journal-title":"J Med Plants Studies"},{"key":"44485_CR11","doi-asserted-by":"publisher","first-page":"7661","DOI":"10.1158\/0008-5472.CAN-08-1510","volume":"68","author":"SD Stan","year":"2008","unstructured":"Stan, S. D., Hahm, E. R., Warin, R. & Singh, S. V. Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo. Cancer Res 68, 7661\u20137669, https:\/\/doi.org\/10.1158\/0008-5472.CAN-08-1510 (2008).","journal-title":"Cancer Res"},{"key":"44485_CR12","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/j.bcp.2014.08.004","volume":"91","author":"K Heyninck","year":"2014","unstructured":"Heyninck, K., Lahtela-Kakkonen, M., Van der Veken, P., Haegeman, G. & Vanden Berghe, W. Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKbeta. Biochem Pharmacol 91, 501\u2013509, https:\/\/doi.org\/10.1016\/j.bcp.2014.08.004 (2014).","journal-title":"Biochem Pharmacol"},{"key":"44485_CR13","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1351\/pac199062071285","volume":"62","author":"S Ghosal","year":"1990","unstructured":"Ghosal, S. Chemistry of shilajit, an immunomodulatory Ayurvedic rasayan. Pure and Applied Chemistry 62, 1285\u20131288 (1990).","journal-title":"Pure and Applied Chemistry"},{"key":"44485_CR14","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1111\/j.1439-0396.2010.01023.x","volume":"94","author":"AV Vucskits","year":"2010","unstructured":"Vucskits, A. V. et al. Effect of fulvic and humic acids on performance, immune response and thyroid function in rats. J Anim Physiol Anim Nutr (Berl) 94, 721\u2013728, https:\/\/doi.org\/10.1111\/j.1439-0396.2010.01023.x (2010).","journal-title":"J Anim Physiol Anim Nutr (Berl)"},{"key":"44485_CR15","doi-asserted-by":"publisher","first-page":"143","DOI":"10.3233\/JAD-2011-110623","volume":"27","author":"A Cornejo","year":"2011","unstructured":"Cornejo, A., Jimenez, J. M., Caballero, L., Melo, F. & Maccioni, R. B. Fulvic acid inhibits aggregation and promotes disassembly of tau fibrils associated with Alzheimer\u2019s disease. J Alzheimers Dis 27, 143\u2013153, https:\/\/doi.org\/10.3233\/JAD-2011-110623 (2011).","journal-title":"J Alzheimers Dis"},{"key":"44485_CR16","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1055\/s-0029-1220724","volume":"41","author":"LH Duntas","year":"2009","unstructured":"Duntas, L. H. Selenium and inflammation: underlying anti-inflammatory mechanisms. Horm Metab Res 41, 443\u2013447, https:\/\/doi.org\/10.1055\/s-0029-1220724 (2009).","journal-title":"Horm Metab Res"},{"key":"44485_CR17","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1002\/mnfr.200700346","volume":"52","author":"H Vunta","year":"2008","unstructured":"Vunta, H. et al. Selenium attenuates pro-inflammatory gene expression in macrophages. Mol Nutr Food Res 52, 1316\u20131323, https:\/\/doi.org\/10.1002\/mnfr.200700346 (2008).","journal-title":"Mol Nutr Food Res"},{"key":"44485_CR18","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1053\/joca.2001.0489","volume":"10","author":"B Kurz","year":"2002","unstructured":"Kurz, B., Jost, B. & Schunke, M. Dietary vitamins and selenium diminish the development of mechanically induced osteoarthritis and increase the expression of antioxidative enzymes in the knee joint of STR\/1N mice. Osteoarthritis Cartilage 10, 119\u2013126, https:\/\/doi.org\/10.1053\/joca.2001.0489 (2002).","journal-title":"Osteoarthritis Cartilage"},{"key":"44485_CR19","doi-asserted-by":"publisher","first-page":"S121","DOI":"10.4103\/0973-1296.182170","volume":"12","author":"P Bansal","year":"2016","unstructured":"Bansal, P. & Banerjee, S. Effect of Withinia Somnifera and Shilajit on Alcohol Addiction in Mice. Pharmacogn Mag 12, S121\u2013128, https:\/\/doi.org\/10.4103\/0973-1296.182170 (2016).","journal-title":"Pharmacogn Mag"},{"key":"44485_CR20","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1002\/art.27584","volume":"62","author":"D Aletaha","year":"2010","unstructured":"Aletaha, D. et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology\/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62, 2569\u20132581, https:\/\/doi.org\/10.1002\/art.27584 (2010).","journal-title":"Arthritis Rheum"},{"key":"44485_CR21","doi-asserted-by":"publisher","first-page":"357","DOI":"10.3389\/fnins.2014.00357","volume":"8","author":"NR Fuggle","year":"2014","unstructured":"Fuggle, N. R., Howe, F. A., Allen, R. L. & Sofat, N. New insights into the impact of neuro-inflammation in rheumatoid arthritis. Front Neurosci 8, 357, https:\/\/doi.org\/10.3389\/fnins.2014.00357 (2014).","journal-title":"Front Neurosci"},{"key":"44485_CR22","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/S0304-3959(97)03361-7","volume":"71","author":"VH Morris","year":"1997","unstructured":"Morris, V. H., Cruwys, S. C. & Kidd, B. L. Characterisation of capsaicin-induced mechanical hyperalgesia as a marker for altered nociceptive processing in patients with rheumatoid arthritis. Pain 71, 179\u2013186 (1997).","journal-title":"Pain"},{"key":"44485_CR23","first-page":"166","volume":"66","author":"T Sokka","year":"2008","unstructured":"Sokka, T. Radiographic scoring in rheumatoid arthritis: a short introduction to the methods. Bull NYU Hosp Jt Dis 66, 166\u2013168 (2008).","journal-title":"Bull NYU Hosp Jt Dis"},{"key":"44485_CR24","doi-asserted-by":"publisher","first-page":"7115","DOI":"10.2147\/OTT.S116387","volume":"9","author":"L Xie","year":"2016","unstructured":"Xie, L. et al. Methotrexate induces DNA damage and inhibits homologous recombination repair in choriocarcinoma cells. Onco Targets Ther. 9, 7115\u201371222016 (2016).","journal-title":"Onco Targets Ther."},{"key":"44485_CR25","doi-asserted-by":"publisher","first-page":"319","DOI":"10.4314\/ajtcam.v4i3.31226","volume":"4","author":"B Ravishankar","year":"2007","unstructured":"Ravishankar, B. & Shukla, V. J. Indian systems of medicine: a brief profile. Afr J Tradit Complement Altern Med 4, 319\u2013337 (2007).","journal-title":"Afr J Tradit Complement Altern Med"},{"key":"44485_CR26","doi-asserted-by":"publisher","first-page":"695","DOI":"10.7326\/0003-4819-134-8-200104170-00013","volume":"134","author":"JM Kremer","year":"2001","unstructured":"Kremer, J. M. Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med 134, 695\u2013706 (2001).","journal-title":"Ann Intern Med"},{"key":"44485_CR27","first-page":"27","volume":"4","author":"A Karimi","year":"2015","unstructured":"Karimi, A., Majlesi, M. & Rafieian-Kopaei, M. Herbal versus synthetic drugs; beliefs and facts. J Nephropharmacol 4, 27\u201330 (2015).","journal-title":"J Nephropharmacol"},{"key":"44485_CR28","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.biopha.2004.04.010","volume":"58","author":"I Bohm","year":"2004","unstructured":"Bohm, I. Increased peripheral blood B-cells expressing the CD5 molecules in association to autoantibodies in patients with lupus erythematosus and evidence to selectively down-modulate them. Biomed Pharmacother 58, 338\u2013343, https:\/\/doi.org\/10.1016\/j.biopha.2004.04.010 (2004).","journal-title":"Biomed Pharmacother"},{"key":"44485_CR29","first-page":"667","volume":"31","author":"M Brody","year":"1993","unstructured":"Brody, M., Bohm, I. & Bauer, R. Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells. Eur J Clin Chem Clin Biochem 31, 667\u2013674 (1993).","journal-title":"Eur J Clin Chem Clin Biochem"},{"key":"44485_CR30","doi-asserted-by":"publisher","first-page":"4445","DOI":"10.1007\/s00018-015-2012-1","volume":"72","author":"NJ Dar","year":"2015","unstructured":"Dar, N. J., Hamid, A. & Ahmad, M. Pharmacologic overview of Withania somnifera, the Indian Ginseng. Cell Mol Life Sci 72, 4445\u20134460, https:\/\/doi.org\/10.1007\/s00018-015-2012-1 (2015).","journal-title":"Cell Mol Life Sci"},{"key":"44485_CR31","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/0378-8741(90)90102-Y","volume":"29","author":"RK Goel","year":"1990","unstructured":"Goel, R. K., Banerjee, R. S. & Acharya, S. B. Antiulcerogenic and antiinflammatory studies with shilajit. J Ethnopharmacol 29, 95\u2013103 (1990).","journal-title":"J Ethnopharmacol"},{"key":"44485_CR32","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/j.1472-8206.2006.00461.x","volume":"21","author":"M Rasool","year":"2007","unstructured":"Rasool, M. & Varalakshmi, P. Protective effect of Withania somnifera root powder in relation to lipid peroxidation, antioxidant status, glycoproteins and bone collagen on adjuvant-induced arthritis in rats. Fundam Clin Pharmacol 21, 157\u2013164, https:\/\/doi.org\/10.1111\/j.1472-8206.2006.00461.x (2007).","journal-title":"Fundam Clin Pharmacol"},{"key":"44485_CR33","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1515\/jcim-2014-0075","volume":"12","author":"MA Khan","year":"2015","unstructured":"Khan, M. A., Subramaneyaan, M., Arora, V. K., Banerjee, B. D. & Ahmed, R. S. Effect of Withania somnifera (Ashwagandha) root extract on amelioration of oxidative stress and autoantibodies production in collagen-induced arthritic rats. J Complement Integr Med 12, 117\u2013125, https:\/\/doi.org\/10.1515\/jcim-2014-0075 (2015).","journal-title":"J Complement Integr Med"},{"key":"44485_CR34","doi-asserted-by":"publisher","first-page":"504","DOI":"10.3923\/pjbs.2014.504.510","volume":"17","author":"YS Al-Awthan","year":"2014","unstructured":"Al-Awthan, Y. S., Hezabr, S. M., Al-Zubairi, A. M. & Al-Hemiri, F. A. Effects of aqueous extract of Withania somnifera on some liver biochemical and histopathological parameters in male guinea pigs. Pak J Biol Sci. 17, 504\u201310 (2014).","journal-title":"Pak J Biol Sci."},{"key":"44485_CR35","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1155\/2008\/589394","volume":"5","author":"B Harikrishnan","year":"2008","unstructured":"Harikrishnan, B., Subramanian, P. & Subash, S. Effect of Withania Somnifera Root Powder on the Levels of Circulatory Lipid Peroxidation and Liver Marker Enzymes in Chronic Hyperammonemia. E-Journal of Chemistry. 5, 872\u2013877, https:\/\/doi.org\/10.1155\/2008\/589394 (2008).","journal-title":"E-Journal of Chemistry."},{"key":"44485_CR36","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.toxrep.2014.08.009","volume":"1","author":"M Vedi","year":"2014","unstructured":"Vedi, M., Rasool, M. & Sabina, E. P. Amelioration of bromobenzene hepatotoxicity by Withania somnifera pretreatment: Role of mitochondrial oxidative stress. Toxicol Rep. 1, 629\u2013638, https:\/\/doi.org\/10.1016\/j.toxrep.2014.08.009 (2014).","journal-title":"Toxicol Rep."},{"key":"44485_CR37","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1002\/art.1780380202","volume":"38","author":"WP Arend","year":"1995","unstructured":"Arend, W. P. & Dayer, J. M. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 38, 151\u2013160 (1995).","journal-title":"Arthritis Rheum."},{"key":"44485_CR38","doi-asserted-by":"publisher","first-page":"4030","DOI":"10.12659\/MSM.895116","volume":"21","author":"ST Wei","year":"2015","unstructured":"Wei, S. T., Sun, Y. H., Zong, S. H. & Xiang, Y. B. Serum Levels of IL-6 and TNF-\u03b1 May Correlate with Activity and Severity of Rheumatoid Arthritis. Med Sci Monit. 21, 4030\u20134038 (2015).","journal-title":"Med Sci Monit."},{"key":"44485_CR39","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.coph.2007.03.002","volume":"7","author":"D Khanna","year":"2007","unstructured":"Khanna, D. et al. Natural products as a gold mine for arthritis treatment. Curr Opin Pharmacol 7, 344\u2013351, https:\/\/doi.org\/10.1016\/j.coph.2007.03.002 (2007).","journal-title":"Curr Opin Pharmacol"},{"key":"44485_CR40","first-page":"650","volume":"4","author":"A Rege","year":"2012","unstructured":"Rege, A., Juvekar, P. & Juvekar, A. In vitro and anti-arthritic activities of Shilajit. International Journal of Pharmacy and Pharmaceutical Sciences 4, 650\u2013653 (2012).","journal-title":"International Journal of Pharmacy and Pharmaceutical Sciences"},{"key":"44485_CR41","doi-asserted-by":"publisher","first-page":"100","DOI":"10.4103\/0971-5916.154510","volume":"141","author":"G Kumar","year":"2015","unstructured":"Kumar, G., Srivastava, A., Sharma, S. K., Rao, T. D. & Gupta, Y. K. Efficacy & safety evaluation of Ayurvedic treatment (Ashwagandha powder & Sidh Makardhwaj) in rheumatoid arthritis patients: a pilot prospective study. Indian J Med Res 141, 100\u2013106 (2015).","journal-title":"Indian J Med Res"},{"key":"44485_CR42","doi-asserted-by":"publisher","first-page":"197","DOI":"10.3109\/08916939808995367","volume":"28","author":"Z Han","year":"1998","unstructured":"Han, Z., Boyle, D. L., Manning, A. M. & Firestein, G. S. AP-1 and NF-kappaB regulation in rheumatoid arthritis and murine collagen-induced arthritis. Autoimmunity 28, 197\u2013208 (1998).","journal-title":"Autoimmunity"},{"key":"44485_CR43","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1002\/ptr.2180","volume":"21","author":"D Singh","year":"2007","unstructured":"Singh, D., Aggarwal, A., Maurya, R. & Naik, S. Withania somnifera inhibits NF-kappaB and AP-1 transcription factors in human peripheral blood and synovial fluid mononuclear cells. Phytother Res. 21, 905\u201313 (2007).","journal-title":"Phytother Res."},{"key":"44485_CR44","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1002\/ptr.2498","volume":"22","author":"VN Sumantran","year":"2008","unstructured":"Sumantran, V. N. et al. The relationship between chondroprotective and antiinflammatory effects of Withania somnifera root and glucosamine sulphate on human osteoarthritic cartilage in vitro. Phytother Res 22, 1342\u20131348, https:\/\/doi.org\/10.1002\/ptr.2498 (2008).","journal-title":"Phytother Res"},{"key":"44485_CR45","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1007\/s12038-007-0030-3","volume":"32","author":"VN Sumantran","year":"2007","unstructured":"Sumantran, V. N. et al. Chondroprotective potential of root extracts of Withania somnifera in osteoarthritis. J Biosci 32, 299\u2013307 (2007).","journal-title":"J Biosci"},{"key":"44485_CR46","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1007\/s12017-018-8497-7","volume":"20","author":"M Gupta","year":"2018","unstructured":"Gupta, M. & Kaur, G. Withania somnifera as a Potential Anxiolytic and Anti-inflammatory Candidate Against Systemic Lipopolysaccharide-Induced Neuroinflammation. Neuromolecular Med 20, 343\u2013362, https:\/\/doi.org\/10.1007\/s12017-018-8497-7 (2018).","journal-title":"Neuromolecular Med"},{"key":"44485_CR47","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1093\/bja\/87.1.3","volume":"87","author":"BL Kidd","year":"2001","unstructured":"Kidd, B. L. & Urban, L. A. Mechanisms of inflammatory pain. Br J Anaesth 87, 3\u201311 (2001).","journal-title":"Br J Anaesth"},{"key":"44485_CR48","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.it.2016.10.001","volume":"38","author":"FA Pinho-Ribeiro","year":"2017","unstructured":"Pinho-Ribeiro, F. A., Verri, W. A. Jr. & Chiu, I. M. Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation. Trends Immunol 38, 5\u201319, https:\/\/doi.org\/10.1016\/j.it.2016.10.001 (2017).","journal-title":"Trends Immunol"},{"key":"44485_CR49","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-014-0285-z","volume":"12","author":"AR Moore","year":"2014","unstructured":"Moore, A. R. et al. Collagen II antibody-induced arthritis in Tg1278TNFko mice: optimization of a novel model to assess treatments targeting human TNF\u03b1 in rheumatoid arthritis. J Transl Med 12, 285 (2014).","journal-title":"J Transl Med"},{"key":"44485_CR50","first-page":"409","volume":"4","author":"LO Randall","year":"1957","unstructured":"Randall, L. O. & Sellitto, J. J. A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmaco Ther. 4, 409\u2013419 (1957).","journal-title":"Arch Int Pharmaco Ther."},{"key":"44485_CR51","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1124\/jpet.106.116483","volume":"321","author":"S Anthony","year":"2007","unstructured":"Anthony, S. et al. Characterization of the Antinociceptive Actions of Bicifadine in Models of Acute, Persistent, and Chronic Pain. J of Pharma and Exp Therapeutics. 321, 1208\u20131225, https:\/\/doi.org\/10.1124\/jpet.106.116483 (2007).","journal-title":"J of Pharma and Exp Therapeutics."},{"key":"44485_CR52","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1111\/jphp.12738","volume":"69","author":"PM Chagasa","year":"2017","unstructured":"Chagasa, P. M. et al. Bis(phenylimidazoselenazolyl) diselenide elicits antinociceptive effect by modulating myeloperoxidase activity, NOx and NFkB levels in the collagen-induced arthritis mouse model. J of Pharmacy and Pharmacology. 69, 1022\u20131032 (2017).","journal-title":"J of Pharmacy and Pharmacology."},{"key":"44485_CR53","unstructured":"Eddy, N. B. & Leimbach, D. Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J. Pharmacol. Exp. Ther. 107 (2017)."},{"key":"44485_CR54","doi-asserted-by":"publisher","first-page":"2670","DOI":"10.1002\/art.11227","volume":"48","author":"M Nishikawa","year":"2003","unstructured":"Nishikawa, M. et al. Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum 48, 2670\u20132681 (2003).","journal-title":"Arthritis Rheum"},{"key":"44485_CR55","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1248\/bpb.b15-00566","volume":"38","author":"T Ishimoto","year":"2015","unstructured":"Ishimoto, T., Azechi, K. & Mori, H. Identification of a Novel Protein Kinase A Inhibitor by Bioluminescence Based Screening. Biol. Pharm. Bull. 38, 1969\u20131974 (2015).","journal-title":"Biol. Pharm. Bull."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44485-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44485-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44485-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T10:06:49Z","timestamp":1671271609000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44485-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,29]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["44485"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-44485-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,29]]},"assertion":[{"value":"23 October 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 May 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"8025"}}