title: Swertiamarin attenuates inflammation mediators via modulating NF-κB/I κB and JAK2/STAT3 transcription factors in adjuvant induced arthritis.
abstract: Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease that leads to pannus formation followed by severe joint destruction, characterized by synovial hyperplasia, inflammation and angiogenesis. Swertiamarin is a secoiridoid glycoside that is used as an anti-inflammatory compound, mainly found in Enicostema axillare (Lam) A. Raynal, a medicinal plant used in Indian system of traditional medicine. In the present study, the effect of swertiamarin was evlauated in experimental adjuvant arthritis animal model by the estimation of biochemical (paw thickness, lysosomal enzymes, and urinary degradative products) parameters, proinflammatory cytokines and enzymes along with histopathological and radiographic observations. The proteins of phosphorylated NF-κB/IκB and JAK2/STAT3 transcription factors were also quantified from experimental animals as well as LPS induced RAW 264.7 macrophage cells. In in silico analysis, swertiamarin was docked with proinflammatory enzymes to confirm its potential. The administration of swertiamarin (2, 5, 10mg/kg bw) significantly (P⩽0.05) inhibited the levels of paw thickness, lysosomal enzymes and increased the body weight of experimental animals in a dose dependent manner. In molecular analysis, the treatment decreased the release of proinflammatory cytokines (IL1, TNF, IL-6) and proangiogenic enzymes (MMPs, iNOS, PGE2, PPARγ and COX-2); and also significantly (P⩽0.05) increased the levels of antiinflammatory proteins (IL-10, IL-4) when compared to the disease groups. The swertiamarin treatment significantly (P⩽0.05) inhibited the release of NF-κB p65, p-IκBα, p-JAK2 and p-STAT3 signaling proteins levels on both experimental animals and LPS induced cells. Histopathological and radiological analysis evidenced the curative effect of swertiamarin on bone destruction. The docking studies of swertiamarin on proinflammatory enzymes supported the results from the in vivo experiments. Thus the swertiamarin inhibited the development of arthritis by modulating NF-κB/IκB and JAK2/STAT3 signaling. These findings suggested that swertiamarin acted as an anti-rheumatic agent.
authors.affiliation: Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India.
authors.forename: S
authors.initials: S
authors.lastname: Saravanan
authors.affiliation: Division of Microbiology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India; Pondicherry Centre for Biological Sciences, Pondicherry 605 005, Pondicherry, India.
authors.forename: V I Hairul
authors.initials: VI
authors.lastname: Islam
authors.affiliation: Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India.
authors.forename: N Prakash
authors.initials: NP
authors.lastname: Babu
authors.affiliation: Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India.
authors.forename: P
authors.initials: P
authors.lastname: Pandikumar
authors.affiliation: Pondicherry Centre for Biological Sciences, Pondicherry 605 005, Pondicherry, India.
authors.forename: K
authors.initials: K
authors.lastname: Thirugnanasambantham
authors.affiliation: Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India.
authors.forename: M
authors.initials: M
authors.lastname: Chellappandian
authors.affiliation: Department of Pathology, Sri Ramachandra Medical College and Research Institute, Porur, Chennai 600 116, Tamil Nadu, India.
authors.forename: C Simon Durai
authors.initials: CS
authors.lastname: Raj
authors.affiliation: Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India.
authors.forename: M Gabriel
authors.initials: MG
authors.lastname: Paulraj
authors.affiliation: Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India; Division of Microbiology, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India; Department of Botany and Microbiology, College of Science, King Saud University, P.O.Box 2455, Riyadh, 1145, Saudi Arabia. Electronic address: entolc@hotmail.com.
authors.forename: S
authors.initials: S
authors.lastname: Ignacimuthu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001798:Blood Proteins / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics; D016207:Cytokines / Q000097:blood; D015232:Dinoprostone / Q000235:genetics; D005260:Female; D005528:Foot / Q000473:pathology; D020672:I-kappa B Proteins / Q000378:metabolism; D057888:Iridoid Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D053614:Janus Kinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D011753:Pyrones / Q000494:pharmacology* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001798:Blood Proteins; D016207:Cytokines; D020672:I-kappa B Proteins; D057888:Iridoid Glucosides; D016328:NF-kappa B; D047495:PPAR gamma; D011753:Pyrones; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C013270:swertiamarin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D015232:Dinoprostone
keywords: Adjuvant induced animals; Antiarthritic activity; JAK2/STAT3; NF-κB/IκB; Proinflammatory cytokines; Swertiamarin