PMID- 25466667 OWN - NLM STAT- MEDLINE DCOM- 20160111 LR - 20161125 IS - 1873-1244 (Electronic) IS - 0899-9007 (Linking) VI - 31 IP - 1 DP - 2015 Jan TI - Preventive effects of withaferin A isolated from the leaves of an Indian medicinal plant Withania somnifera (L.): comparisons with 17-beta-estradiol and alendronate. PG - 205-13 LID - S0899-9007(14)00277-9 [pii] LID - 10.1016/j.nut.2014.05.010 [doi] AB - OBJECTIVE: Bone protective effects of withaferin A (WFA) from leaves of Withania somnifera (L.) were evaluated in preventive model of Balb/c mice with 17 beta-estradiol (E2) and alendronate (ALD). METHODS: Adult female Balb/c mice, 7 to 9 wk, were bilaterally ovariectomized (OVx) to mimic the state of E2 deficiency. Immediately after surgery mice were administrated WFA at doses of 1, 5, 10 mg/kg/d while other two OVx groups received ALD or E2 for 2 mo. Sham and OVx groups with vehicle and no treatment served as controls. RESULTS: WFA administration increased new bone formation, as well as improving microarchitecture and biomechanical strength of the bones. It prevented bone loss by reducing expression of osteoclastic genes tartrate resistant acid phosphatase (TRAP) and receptor activator of nuclear factor kappa B (RANK). Increase in bone turnover marker, osteocalcin (OCN) and inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) because of ovariectomy were reduced with WFA treatment, with effects comparable to E2 administration. Histomorphometric analysis of uterus shows that WFA was not fraught with estrogenic or antiestrogenic effects. At cellular level, WFA promoted differentiation of bone marrow cells (BMCs) and increased mineralization by inducing expression of osteogenic genes. WFA has bone protective potential as its treatment prevents bone loss that is comparable to ALD and E2. CONCLUSIONS: It is surmised that WFA in preclinical setting is effective in preserving bone loss by both inhibition of resorption and stimulation of new bone formation before onset of osteoporosis with no uterine hyperplasia. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Khedgikar, Vikram AU - Khedgikar V AD - Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India; Jawaharlal Nehru University, New Delhi, India. FAU - Ahmad, Naseer AU - Ahmad N AD - Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India. FAU - Kushwaha, Priyanka AU - Kushwaha P AD - Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India; Academy of Scientific and Innovation Research, New Delhi, India. FAU - Gautam, Jyoti AU - Gautam J AD - Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India; Jawaharlal Nehru University, New Delhi, India. FAU - Nagar, Geet K AU - Nagar GK AD - Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India. FAU - Singh, Divya AU - Singh D AD - Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India. FAU - Trivedi, Prabodh K AU - Trivedi PK AD - Plant Gene Expression Laboratory, Council of Scientific and Industrial Research-National Botanic Research Institute, Lucknow, India. FAU - Mishra, Prabhat R AU - Mishra PR AD - Division of Pharmaceutics Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India. FAU - Sangwan, Neelam S AU - Sangwan NS AD - Council of Scientific and Industrial Research-Central Institute of Medicinal and Aromatic Plants, Lucknow, India. FAU - Trivedi, Ritu AU - Trivedi R AD - Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India. Electronic address: Ritu_trivedi@cdri.res.in. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140610 PL - United States TA - Nutrition JT - Nutrition (Burbank, Los Angeles County, Calif.) JID - 8802712 RN - 0 (Biomarkers) RN - 0 (Isoenzymes) RN - 0 (Receptor Activator of Nuclear Factor-kappa B) RN - 0 (Tnfrsf11a protein, mouse) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (Withanolides) RN - 104982-03-8 (Osteocalcin) RN - 4TI98Z838E (Estradiol) RN - EC 3.1.3.2 (Acid Phosphatase) RN - EC 3.1.3.2 (Acp5 protein, mouse) RN - EC 3.1.3.2 (Tartrate-Resistant Acid Phosphatase) RN - L6DO3QW4K5 (withaferin A) RN - X1J18R4W8P (Alendronate) SB - IM MH - Acid Phosphatase/genetics/metabolism MH - Alendronate/*pharmacology MH - Animals MH - Biomarkers/blood MH - Bone and Bones/drug effects MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Drug Evaluation, Preclinical MH - Estradiol/*pharmacology MH - Female MH - Isoenzymes/genetics/metabolism MH - Mice MH - Mice, Inbred BALB C MH - Osteocalcin/blood MH - Osteoclasts/drug effects/metabolism MH - Osteoporosis/*prevention & control MH - Ovariectomy MH - Plant Leaves/chemistry MH - Plants, Medicinal/*chemistry MH - Receptor Activator of Nuclear Factor-kappa B/genetics/metabolism MH - Tartrate-Resistant Acid Phosphatase MH - Tumor Necrosis Factor-alpha/blood MH - Withania/*chemistry MH - Withanolides/*pharmacology OTO - NOTNLM OT - Antiresorptive OT - Microcomputed tomography OT - Osteogenic OT - Premenopausal OT - Trabecular microarchitecture EDAT- 2014/12/04 06:00 MHDA- 2016/01/12 06:00 CRDT- 2014/12/04 06:00 PHST- 2013/12/06 00:00 [received] PHST- 2014/04/21 00:00 [revised] PHST- 2014/05/06 00:00 [accepted] PHST- 2014/12/04 06:00 [entrez] PHST- 2014/12/04 06:00 [pubmed] PHST- 2016/01/12 06:00 [medline] AID - S0899-9007(14)00277-9 [pii] AID - 10.1016/j.nut.2014.05.010 [doi] PST - ppublish SO - Nutrition. 2015 Jan;31(1):205-13. doi: 10.1016/j.nut.2014.05.010. Epub 2014 Jun 10.