Rohitukine inhibits in vitro adipogenesis arresting mitotic clonal expansion and improves dyslipidemia in vivo |
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Authors: | Salil Varshney Kripa Shankar Muheeb Beg Vishal M Balaramnavar Sunil Kumar Mishra Pankaj Jagdale Shishir Srivastava Yashpal S Chhonker Vijai Lakshmi Bhushan P Chaudhari Rabi Shankar Bhatta Anil Kumar Saxena Anil Nilkanth Gaikwad |
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Institution: | 2. Medicinal and Process Chemistry Division, Council of Scientific & Industrial Research-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India;4. Regulatory Toxicology Group, Council of Scientific & Industrial Research-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh 226001, India;11. Department of Biochemistry, King George''s Medical University, Chowk Area, Lucknow, Uttar Pradesh 226003, India |
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Abstract: | We developed a common feature pharmacophore model using known antiadipogenic compounds (CFPMA). We identified rohitukine, a reported chromone anticancer alkaloid as a potential hit through in silico mapping of the in-house natural product library on CFPMA. Studies were designed to assess the antiadipogenic potential of rohitukine. Rohitukine was isolated from Dysoxylum binacteriferum Hook. to ⬧95% purity. As predicted by CFPMA, rohitukine was indeed found to be an antiadipogenic molecule. Rohitukine inhibited lipid accumulation and adipogenic differentiation in a concentration- and exposure-time-dependent manner in 3T3-L1 and C3H10T1/2 cells. Rohitukine downregulated expression of PPARγ, CCAAT/enhancer binding protein α, adipocyte protein 2 (aP2), FAS, and glucose transporter 4. It also suppressed mRNA expression of LPL, sterol-regulatory element binding protein (SREBP) 1c, FAS, and aP2, the downstream targets of PPARγ. Rohitukine arrests cells in S phase during mitotic clonal expansion. Rohitukine was bioavailable, and 25.7% of orally administered compound reached systemic circulation. We evaluated the effect of rohitukine on dyslipidemia induced by high-fat diet in the hamster model. Rohitukine increased hepatic expression of liver X receptor α and decreased expression of SREBP-2 and associated targets. Rohitukine decreased hepatic and gonadal lipid accumulation and ameliorated dyslipidemia significantly. In summary, our strategy to identify a novel antiadipogenic molecule using CFPMA successfully resulted in identification of rohitukine, which confirmed antiadipogenic activity and also exhibited in vivo antidyslipidemic activity. |
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Keywords: | S-phase arrest Dysoxylum binacteriferum Hook f 3T3-L1 C3H10T1/2 |
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