Abstract
Rheumatoid arthritis (RA) is a multifactorial disease which is complicated by apoptosis resistance. Autophagy is one of the key mechanisms which are involved in the development of resistance to apoptosis as well as to the standard therapies against RA. Aberration in autophagy and apoptosis homeostasis results in the development of oxidative stress thus complicates the pathogenesis of RA. In the given study, tomorou, an indigenous herb of Hunza-Nagar Valley, has been evaluated for its pro-apoptotic, anti-inflammatory, and anti-rheumatic activity. Several major classes of bioactive phytochemicals including steroids, terpenoids, phenols, flavonoids, and essential oils have been detected in the aqueous and ethyl acetate extracts of tomorou through phytochemical analysis. Plant extracts depicted enhanced free radical scavenging activity through di-phenyl-2-picryl hydrazyl hydrate (DPPH) assay and ameliorated the symptoms of arthritis in collagen induced arthritic (CIA) mice model. Moreover, the 6 week extract treatment resulted in the reduction of IL-6 serum levels thus making it an effective anti-inflammatory agent. Upregulation of microtubule-associated proteins light chain 3b (LC3b) and downregulation of UNC51-like kinase 1 (ULK-1) in arthritic mice proposed a ULK-1 independent non-canonical autophagy pathway. Treatment with extracts upregulated the expression of caspase 3 which in turn inhibited the activity of LC3b thus altering the autophagy pathway. However, ULK-1 expression was restored to normal in aqueous extract treated group whereas it was upregulated in ethyl acetate extract treated group. On the other hand, a novel LC3b-independent autophagy pathway was observed in mice treated with ethyl acetate extract due to ULK-1 upregulation. Despite of significantly high IL-6 levels, the arthritic symptoms waned off which suggested the participation of IL-6 in LC3b-independent autophagy pathway in the extract prepared in ethyl acetate. Conclusively, the study established pro-apoptotic, antioxidant, anti-inflammatory and anti-rheumatic activity of tomorou and suggested an intricate autophagy pathway shift.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease of obscure etiology that is delineated by hyperplasic synovium, bone erosion, and disrupted joint architecture due to the presence of citrulinated proteins-autoantibody complexes[1,2]
RA is a multifactorial disorder with mysterious pathophysiology that is classified through bone erosion and modifications in joint architecture[1,2]
Results signify that treatment with extracts altered the expression of UNC51-like kinase 1 (ULK-1), caspase 3, light chain 3b (LC3b), and IL6 which is generally attributed to the presence of high phytochemical content
Summary
Rheumatoid arthritis (RA) is an autoimmune disease of obscure etiology that is delineated by hyperplasic synovium, bone erosion, and disrupted joint architecture due to the presence of citrulinated proteins-autoantibody complexes[1,2]. Cellular proliferation, angiogenesis and altered glucose metabolism causes hypoxia generating oxidative stress through reactive oxygen species (ROS) and augment the production of citrulinated proteins[9,10]. Hyper-activation of autophagy is involved in increased production of cirtulinated proteins, osteoclastogenesis, and survival of lymphocytes in RA synovium[16,17,18]. Studies show that inhibition of autophagy ameliorate synovial hyperplasia, inflammation, and pannus growth[15,21,22]. This attenuation of synovial inflammation can be either due to reduced hypoxia and initiation of PI3K/AKT pathway mediated apoptosis or culmination of UNC51-like kinase 1 (ULK-1) mediated autophagy initiation complex by the action of mTOR18,23,24
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