DR DIVYA SINGH
 
.. Senior Scientist
Endocrinology Division
Central Drug Research Institute
Lucknow-226 031
 
Educational Qualifications M.Sc. (Lucknow University), Ph.D. (JNU)
Date of Birth 21.03.1975
Phone +91-522-2772450 Ext. 4395
Fax +91-522-2771941
E-Mail [email protected]
 
CURRENT AREAS OF INTEREST
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 Identification and characterization of novel targets for osteoporosis therapy
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To study the role of T cell, B cells and cytokine network in pathogenesis of osteoporosis

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 To characterize novel miRNA candidates which positively or negatively regulate osteoblast functions
 
Some Important Research Contributions from Lab
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 immunoprotective effects by anti-IL17 antibody translates to improved skeletal parameters under estrogen deficiency compared to anti-RANKL and anti-TNFα antibodies
  Our studies have shown that neutralization of pro-inflammatory cytokine IL-17 in estrogen deficient mice model protects against Ovx-induced bone loss by suppressing osteoclast function and promoting osteoblast survival and differentiation. Additionally, anti-IL17 antibody administration to osteopenic mice reversed detrimental pro-inflammatory changes triggered by Ovx. All these effects were better with anti-IL17 when compared to other therapeutic strategies like anti-RANKL and anti-TNFα therapy. This study forms a strong case for using a humanized antibody against IL-17 cytokine towards the treatment of postmenopausal osteoporosis.

                         Improved trabecular microarchitectural restoration by Anti-IL17 treatment in Ovx mice model
   
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miR-542-3p suppresses osteoblast cell proliferation and differentiation, targets BMP-7 signaling and inhibits bone formation

  MicroRNAs are 15-22 nucleotides, single-stranded non-coding RNAs which have emerged as important post-transcriptional regulators of gene expression. They play key role in the regulation of various biological processes, including cellular differentiation, proliferation, apoptosis and cancer development. Studies by our group identified osteogenic efficacy in medicarpin, a natural pterocarpan. MiRNA microarray profiling in medicarpin induced osteoblast cultures resulted in differential regulation of various miRNA candidates. Our studies identified an uncharacterized function of miR-542-3p, a known tumor suppressor, in osteoblast. It was found that miR-542-3p functions as a negative regulator of osteogenesis. Functional inhibition of miR-542-3p accelerates osteoblast proliferation and differentiation and leads to increased bone formation.

                                             Inhibition of miR-542-3p protects against bone loss in Ovx mice model
   
Present Lab Members
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Mrs. Kamini Srivastava, SRF
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Ms. Jyoti Kureel, SRF
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 Mohd. Nizam Mansoori, JRF
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 Ms. Manisha Dixit, JRF
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 Ms. Priyanka Shukla, JRF
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 Mr. Aijaz Ahmad John Bhat, JRF
Alumni
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Dr. Abnish K Gautam
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Dr. Abdul M Tyagi
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 Dr. Rashmi Pandey
SELECTED PUBLICATIONS
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 Tyagi AM, Mansoori MN, Srivastava K, Khan MP, Kureel J, Dixit M, Shukla P, Trivedi R, Chattopadhyay N, Singh D. Enhanced Immunoprotective Effects by Anti-IL17 Antibody Translates to Improved Skeletal Parameters Under Estrogen Deficiency Compared to Anti-RANKL and Anti-TNFα Antibodies. J Bone Miner Res. 2014 Mar 28. doi: 10.1002/jbmr.2228. [Epub ahead of print].
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 Kureel J, Dixit M, Tyagi AM, Mansoori MN, Srivastava K, Raghuvanshi A, Maurya R, Trivedi R, Goel A, Singh D. miR-542-3p suppresses osteoblast cell proliferation and differentiation, targets BMP-7 signaling and inhibits bone formation. Cell Death Dis. 2014 Feb 6;5:e1050. doi: 10.1038/cddis.2014.4.
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 Gautam J, Choudhary D, Khedgikar V, Kushwaha P, Singh RS, Singh D, Tiwari S, Trivedi R. Micro-architectural changes in cancellous bone differ in female and male C57BL/6 mice with high-fat diet-induced low bone mineral density. Br J Nutr. 2014 Feb 10:1-11. [Epub ahead of print].
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 Khedgikar V, Kushwaha P, Gautam J, Verma A, Changkija B, Kumar A, Sharma S, Nagar GK, Singh D, Trivedi PK, Sangwan NS, Mishra PR, Trivedi R. Withaferin A: a proteasomal inhibitor promotes healing after injury and exerts anabolic effect on osteoporotic bone. Cell Death Dis. 2013 Aug 22;4:e778. doi: 10.1038/cddis.2013.294.
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Srivastava K, Khan K, Tyagi AM, Khan MP, Yadav DK, Trivedi R, Maurya R, Singh D, Chattopadhyay N. Greater Skeletal Gains in Ovary Intact Rats at Maturity Are Achieved by Supplementing a Standardized Extract of Butea monosperma Stem Bark that Confers Better Bone Conserving Effect following Ovariectomy and Concurrent Treatment Withdrawal. Evid Based Complement Alternat Med. 2013; 2013:519387. doi: 10.1155/2013/519387. Epub 2013 Apr 27.

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 Srivastava K, Tyagi AM, Khan K, Dixit M, Lahiri S, Kumar A, Changkija B, Khan MP, Nagar GK, Yadav DK, Maurya R, Singh SP, Jain GK, Wahajuddin, Trivedi R, Chattopadhyay N, Singh D. Isoformononetin, a methoxydaidzein present in medicinal plants, reverses bone loss in osteopenic rats and exerts bone anabolic action by preventing osteoblast apoptosis. Phytomedicine. 2013 Apr 15;20(6):470-80. doi: 10.1016/j.phymed.2012.12.021. Epub 2013 Feb 8.
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 Sashidhara KV, Kumar M, Khedgikar V, Kushwaha P, Modukuri RK, Kumar A, Gautam J, Singh D, Sridhar B, Trivedi R. Discovery of coumarin-dihydropyridine hybrids as bone anabolic agents. J Med Chem. 2013 Jan 10;56(1):109-22. doi: 10.1021/jm301281e. Epub 2012 Dec 18.
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 Tyagi AM, Srivastava K, Mansoori MN, Trivedi R, Chattopadhyay N, Singh D. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS One. 2012;7(9):e44552. doi: 10.1371/journal.pone.0044552. Epub 2012 Sep 10.
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Goel A, Kumar A, Hemberger Y, Raghuvanshi A, Jeet R, Tiwari G, Knauer M, Kureel J, Singh AK, Gautam A, Trivedi R, Singh D, Bringmann G. Synthesis, optical resolution, absolute configuration, and osteogenic activity of cis-pterocarpans. Org Biomol Chem. 2012 Dec 28;10(48):9583-92. doi: 10.1039/c2ob25722j. Epub 2012 Sep 6.

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 Gautam J, Kushwaha P, Swarnkar G, Khedgikar V, Nagar GK, Singh D, Singh V, Jain M, Barthwal M, Trivedi R. EGb 761 promotes osteoblastogenesis, lowers bone marrow adipogenesis and atherosclerotic plaque formation. Phytomedicine. 2012 Sep 15;19(12):1134-42. doi: 10.1016/j.phymed.2012.07.005. Epub 2012 Aug 27.
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 Khedgikar V, Gautam J, Kushwaha P, Kumar A, Nagar GK, Dixit P, Chillara R, Voruganti S, Singh SP, Uddin W, Jain GK, Singh D, Maurya R, Chattopadhyay N, Trivedi R. A standardized phytopreparation from an Indian medicinal plant (Dalbergia sissoo) has antiresorptive and bone-forming effects on a postmenopausal osteoporosis model of rat. Menopause. 2012 Dec;19(12):1336-46. doi: 10.1097/gme.0b013e318256b6ae.
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 Tyagi AM, Srivastava K, Singh AK, Kumar A, Changkija B, Pandey R, Lahiri S, Nagar GK, Yadav DK, Maurya R, Trivedi R, Singh D. Formononetin reverses established osteopenia in adult ovariectomized rats. Menopause. 2012 Aug;19(8):856-63. doi: 10.1097/gme.0b013e31824f9306.
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 Dixit P, Chillara R, Khedgikar V, Gautam J, Kushwaha P, Kumar A, Singh D, Trivedi R, Maurya R. Constituents of Dalbergia sissoo Roxb. leaves with osteogenic activity. Bioorg Med Chem Lett. 2012 Jan 15;22(2):890-7. doi: 10.1016/j.bmcl.2011.12.036. Epub 2011 Dec 13.
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 Tyagi AM, Srivastava K, Sharan K, Yadav D, Maurya R, Singh D. Daidzein prevents the increase in CD4+CD28null T cells and B lymphopoesis in ovariectomized mice: a key mechanism for anti-osteoclastogenic effect. PLoS One. 2011;6(6):e21216. doi: 10.1371/journal.pone.0021216. Epub 2011 Jun 22.
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 Tyagi AM, Srivastava K, Kureel J, Kumar A, Raghuvanshi A, Yadav D, Maurya R, Goel A, Singh D. Premature T cell senescence in Ovx mice is inhibited by repletion of estrogen and medicarpin: a possible mechanism for alleviating bone loss. Osteoporos Int. 2012 Mar;23(3):1151-61. doi: 10.1007/s00198-011-1650-x. Epub 2011 May 12.
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 Bhargavan B, Singh D, Gautam AK, Mishra JS, Kumar A, Goel A, Dixit M, Pandey R, Manickavasagam L, Dwivedi SD, Chakravarti B, Jain GK, Ramachandran R, Maurya R, Trivedi A, Chattopadhyay N, Sanyal S. Medicarpin, a legume phytoalexin, stimulates osteoblast differentiation and promotes peak bone mass achievement in rats: evidence for estrogen receptor β-mediated osteogenic action of medicarpin. J Nutr Biochem. 2012 Jan;23(1):27-38. doi: 10.1016/j.jnutbio.2010.11.002. Epub 2011 Feb 18.
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 Kumar M, Rawat P, Kureel J, Singh AK, Singh D, Maurya R. One step synthesis of 2-hydroxymethylisoflavone and their osteogenic activity. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1706-9. doi: 10.1016/j.bmcl.2011.01.095. Epub 2011 Jan 26.
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 Yadav DK, Gautam AK, Kureel J, Srivastava K, Sahai M, Singh D, Chattopadhyay N, Maurya R. Synthetic analogs of daidzein, having more potent osteoblast stimulating effect. Bioorg Med Chem Lett. 2011 Jan 15;21(2):677-81. doi: 10.1016/j.bmcl.2010.12.008. Epub 2010 Dec 8.
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 Manickavasagam L, Gupta S, Mishra S, Kumar A, Raghuvanshi A, Goel A, Singh D, Jain GK. Determination of 3-hydroxy pterocarpan, a novel osteogenic compound in rat plasma by liquid chromatography-tandem mass spectrometry: application to pharmacokinetics study. Biomed Chromatogr. 2011 Jul;25(7):843-50. doi: 10.1002/bmc.1527. Epub 2010 Oct 20.
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 Gautam AK, Bhargavan B, Tyagi AM, Srivastava K, Yadav DK, Kumar M, Singh A, Mishra JS, Singh AB, Sanyal S, Maurya R, Manickavasagam L, Singh SP, Wahajuddin W, Jain GK, Chattopadhyay N, Singh D. Differential effects of formononetin and cladrin on osteoblast function, peak bone mass achievement and bioavailability in rats. J Nutr Biochem. 2011 Apr;22(4):318-27. doi: 10.1016/j.jnutbio.2010.02.010. Epub 2010 Jun 25.
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 Tyagi AM, Gautam AK, Kumar A, Srivastava K, Bhargavan B, Trivedi R, Saravanan S, Yadav DK, Singh N, Pollet C, Brazier M, Mentaverri R, Maurya R, Chattopadhyay N, Goel A, Singh D. Medicarpin inhibits osteoclastogenesis and has nonestrogenic bone conserving effect in ovariectomized mice. Mol Cell Endocrinol. 2010 Aug 30;325(1-2):101-9. doi: 10.1016/j.mce.2010.05.016. Epub 2010 Jun 4.
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 Kumar M, Rawat P, Dixit P, Mishra D, Gautam AK, Pandey R, Singh D, Chattopadhyay N, Maurya R. Anti-osteoporotic constituents from Indian medicinal plants. Phytomedicine. 2010 Nov;17(13):993-9. doi: 10.1016/j.phymed.2010.03.014. Epub 2010 May 31.
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 Pandey R, Gautam AK, Bhargavan B, Trivedi R, Swarnkar G, Nagar GK, Yadav DK, Kumar M, Rawat P, Manickavasagam L, Kumar A, Maurya R, Goel A, Jain GK, Chattopadhyay N, Singh D. Total extract and standardized fraction from the stem bark of Butea monosperma have osteoprotective action: evidence for the nonestrogenic osteogenic effect of the standardized fraction. Menopause. 2010 May-Jun;17(3):602-10. doi: 10.1097/gme.0b013e3181d0f7f0.
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 Kumar A, Singh AK, Gautam AK, Chandra D, Singh D, Changkija B, Singh MP, Trivedi R. Identification of kaempferol-regulated proteins in rat calvarial osteoblasts during mineralization by proteomics. Proteomics. 2010 May;10(9):1730-9. doi: 10.1002/pmic.200900666.
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 Bhargavan B, Gautam AK, Singh D, Kumar A, Chaurasia S, Tyagi AM, Yadav DK, Mishra JS, Singh AB, Sanyal S, Goel A, Maurya R, Chattopadhyay N. Methoxylated isoflavones, cajanin and isoformononetin, have non-estrogenic bone forming effect via differential mitogen activated protein kinase (MAPK) signaling. J Cell Biochem. 2009 Oct 1;108(2):388-99. doi: 10.1002/jcb.22264.
 
Students Achievement
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 Dr. Abdul M Tyagi
Dr MM Dhar Memorial Distinguished Career Achievement Award-2014 for best thesis
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 Ms. Jyoti Kureel
IOF Young investigator award-2014 at IOF-Orlando, USA