title: A Small Molecule Swertisin from Enicostemma littorale Differentiates NIH3T3 Cells into Islet-Like Clusters and Restores Normoglycemia upon Transplantation in Diabetic Balb/c Mice.
abstract: Aim. Stem cell therapy is one of the upcoming therapies for the treatment of diabetes. Discovery of potent differentiating agents is a prerequisite for increasing islet mass. The present study is an attempt to screen the potential of novel small biomolecules for their differentiating property into pancreatic islet cells using NIH3T3, as representative of extra pancreatic stem cells/progenitors. Methods. To identify new agents that stimulate islet differentiation, we screened various compounds isolated from Enicostemma littorale using NIH3T3 cells and morphological changes were observed. Characterization was performed by semiquantitative RT-PCR, Q-PCR, immunocytochemistry, immunoblotting, and insulin secretion assay for functional response in newly generated islet-like cell clusters (ILCC). Reversal of hyperglycemia was monitored after transplanting ILCC in STZ-induced diabetic mice. Results. Among various compounds tested, swertisin, an isolated flavonoid, was the most effective in differentiating NIH3T3 into endocrine cells. Swertisin efficiently changed the morphology of NIH3T3 cells from fibroblastic to round aggregate cell cluster in huge numbers. Dithizone (DTZ) stain primarily confirmed differentiation and gene expression studies signified rapid onset of differentiation signaling cascade in swertisin-induced ILCC. Molecular imaging and immunoblotting further confirmed presence of islet specific proteins. Moreover, glucose induced insulin release (in vitro) and decreased fasting blood glucose (FBG) (in vivo) in transplanted diabetic BALB/c mice depicted functional maturity of ILCC. Insulin and glucagon expression in excised islet grafts illustrated survival and functional integrity. Conclusions. Rapid induction for islet differentiation by swertisin, a novel herbal biomolecule, provides low cost and readily available differentiating agent that can be translated as a therapeutic tool for effective treatment in diabetes.
authors: Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara Gujarat, 390 002, India.
authors: Nidheesh
authors: N
authors: Dadheech
authors: Sanket
authors: S
authors: Soni
authors: Abhay
authors: A
authors: Srivastava
authors: Sucheta
authors: S
authors: Dadheech
authors: Shivika
authors: S
authors: Gupta
authors: Renjitha
authors: R
authors: Gopurappilly
authors: Ramesh R
authors: RR
authors: Bhonde
authors: Sarita
authors: S
authors: Gupta
references: Mol Aspects Med. 2006 Feb;27(1):1-93
references: 16105678
references: J Mol Med (Berl). 1999 Jan;77(1):62-6
references: 9930929
references: Diabetes. 2004 Jul;53(7):1721-32
references: 15220196
references: Arch Med Res. 2012 Jan;43(1):83-8
references: 22374243
references: Mol Cell Endocrinol. 2012 Jul 6;358(1):69-80
references: 22429991
references: Curr Med Chem. 2006;13(10):1203-18
references: 16719780
references: Chin Med J (Engl). 2011 May;124(10):1534-9
references: 21740812
references: J Clin Invest. 2009 Jul;119(7):1888-98
references: 19487809
references: Lancet. 2001 Jul 21;358(9277):221-9
references: 11476858
references: Indian J Exp Biol. 2000 Aug;38(8):781-4
references: 12557910
references: Exp Mol Med. 2012 Jan 31;44(1):26-35
references: 22020533
references: Differentiation. 2009 Feb;77(2):135-47
references: 19281773
references: Int J Biochem Cell Biol. 2006;38(5-6):923-30
references: 16337165
references: Evid Based Complement Alternat Med. 2012;2012:260467
references: 22474495
references: Phytother Res. 2004 Mar;18(3):233-5
references: 15103671
references: Nat Biotechnol. 2006 Nov;24(11):1392-401
references: 17053790
references: Stem Cell Rev Rep. 2009 Jun;5(2):159-73
references: 19263252
references: Diabetologia. 2001 Oct;44(10):1203-14
references: 11692168
references: PLoS One. 2012;7(5):e37055
references: 22606327
references: J Nucl Med. 2008 Sep;49(9):1512-9
references: 18703596
references: Nature. 2002 Jul 4;418(6893):41-9
references: 12077603
references: Indian J Exp Biol. 2010 Jan;48(1):26-30
references: 20358863
references: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1364-9
references: 12538864
references: J Pharm Sci. 1974 Aug;63(8):1286-90
references: 4527698
references: F1000 Biol Rep. 2010;2:17
references: 20445833
references: World J Gastroenterol. 2005 May 21;11(19):2906-11
references: 15902726
references: J Ethnopharmacol. 2002 Aug;81(3):317-20
references: 12127231
references: PLoS One. 2011;6(6):e20615
references: 21687731
references: Asian Pac J Trop Biomed. 2012 Apr;2(4):320-30
references: 23569923
references: World J Surg. 1996 Oct;20(8):1016-22; discussion 1022-3
references: 8798359
references: Dev Growth Differ. 2011 Apr;53(3):357-65
references: 21477161
references: Stem Cells Dev. 2010 Jun;19(6):887-902
references: 19686050
references: Development. 2007 Feb;134(3):427-38
references: 17185316
references: Evid Based Complement Alternat Med. 2011;2011:852720
references: 21785636
references: Diabetologia. 1999 Jun;42(6):719-27
references: 10382592
references: N Engl J Med. 2000 Jul 27;343(4):230-8
references: 10911004
references: Methods Mol Biol. 2012;879:291-313
references: 22610566
references: Int J Biochem Cell Biol. 2011 Mar;43(3):286-9
references: 21147252
references: Semin Cell Dev Biol. 2000 Aug;11(4):253-66
references: 10966859
references: BMJ. 2011 Jan 21;342:d217
references: 21257658