title: Allylpyrocatechol Attenuates Collagen-Induced Arthritis via Attenuation of Oxidative Stress Secondary to Modulation of the MAPK, JAK/STAT, and Nrf2/HO-1 Pathways.
abstract: Rheumatoid arthritis (RA), an inflammatory autoimmune disorder, is characterized by synovial hyperplasia and bony destruction. The pathogenesis of RA includes redox dysregulation, concomitant with increased levels of proinflammatory mediators. As the ability of allylpyrocatechol (APC), a phytoconstituent of Piper betle leaves, to alleviate oxidative stress has been demonstrated in patients with RA, its antiarthritic activity was evaluated in an animal model of arthritis, and the underlying mechanism(s) of action clarified. The animal model was established by immunizing rats with bovine collagen type II (CII) followed by lipopolysaccharide, along with a booster dose of CII on day 15. Rats were treated with APC or methotrexate (MTX) from days 11 to 27, when paw edema, radiography, histopathology, and markers of inflammation were evaluated. The pro/antiinflammatory signaling pathways were studied in a RAW264.7 macrophage cell line. Allylpyrocatechol (APC) prevented the progression of arthritis as was evident from the reduction in paw edema, and attenuation of damage to bones and cartilage shown by radiography and histopathology. Additionally, there was reduction in the levels of proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] and restoration of the redox balance. Importantly, MTX ameliorated the features of arthritis but not the associated oxidative stress. In RAW264.7, APC inhibited generation of nitric oxide and proinflammatory cytokines (TNF-α, IL-6, and IL-12p40), and modulated the phosphorylation of proinflammatory (extracellular signal-regulated kinase 1/2, stress-activated protein kinase/c-Jun N-terminal protein kinase, and Janus kinase/signal transducers and activators of transcription) and cytoprotective (nuclear factor erythroid 2-related factor 2, heme oxygenase-1) signaling pathways. Taken together, APC controlled the development of arthritis, possibly via modulation of signaling pathways, and deserves further consideration as a therapy for RA.
authors.affiliation: Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, India (S.D., A.M., S.K., S.D.S., M.C.); Department of Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India (U.C.); School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India (T.S.); Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India (S.C.).
authors.forename: Soumita
authors.initials: S
authors.lastname: De
authors.affiliation: Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, India (S.D., A.M., S.K., S.D.S., M.C.); Department of Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India (U.C.); School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India (T.S.); Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India (S.C.).
authors.forename: Alak
authors.initials: A
authors.lastname: Manna
authors.affiliation: Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, India (S.D., A.M., S.K., S.D.S., M.C.); Department of Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India (U.C.); School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India (T.S.); Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India (S.C.).
authors.forename: Sunanda
authors.initials: S
authors.lastname: Kundu
authors.affiliation: Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, India (S.D., A.M., S.K., S.D.S., M.C.); Department of Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India (U.C.); School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India (T.S.); Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India (S.C.).
authors.forename: Sritama
authors.initials: S
authors.lastname: De Sarkar
authors.affiliation: Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, India (S.D., A.M., S.K., S.D.S., M.C.); Department of Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India (U.C.); School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India (T.S.); Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India (S.C.).
authors.forename: Uttara
authors.initials: U
authors.lastname: Chatterjee
authors.affiliation: Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, India (S.D., A.M., S.K., S.D.S., M.C.); Department of Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India (U.C.); School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India (T.S.); Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India (S.C.).
authors.forename: Tuhinadri
authors.initials: T
authors.lastname: Sen
authors.affiliation: Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, India (S.D., A.M., S.K., S.D.S., M.C.); Department of Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India (U.C.); School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India (T.S.); Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India (S.C.).
authors.forename: Subrata
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, India (S.D., A.M., S.K., S.D.S., M.C.); Department of Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India (U.C.); School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India (T.S.); Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India (S.C.) ilatim@vsnl.net ilatimc@gmail.com.
authors.forename: Mitali
authors.initials: M
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002396:Catechols / Q000494:pharmacology* / Q000627:therapeutic use; D002417:Cattle; D003094:Collagen / Q000009:adverse effects*; D018450:Disease Progression; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D000067996:RAW 264.7 Cells; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000187:drug effects; D050791:STAT Transcription Factors / Q000378:metabolism
chemical_list: D002396:Catechols; D018836:Inflammation Mediators; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C557704:PTD4-apoptin protein; D011993:Recombinant Fusion Proteins; D050791:STAT Transcription Factors; C523074:allylpyrocatechol; D003094:Collagen; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D053612:Janus Kinases; D020928:Mitogen-Activated Protein Kinases