title: Swertisin an Anti-Diabetic Compound Facilitate Islet Neogenesis from Pancreatic Stem/Progenitor Cells via p-38 MAP Kinase-SMAD Pathway: An In-Vitro and In-Vivo Study.
abstract: Transplanting islets serves best option for restoring lost beta cell mass and function. Small bio-chemical agents do have the potential to generate new islets mass, however lack of understanding about mechanistic action of these small molecules eventually restricts their use in cell-based therapies for diabetes. We recently reported "Swertisin" as a novel islet differentiation inducer, generating new beta cells mass more effectively. Henceforth, in the present study we attempted to investigate the molecular signals that Swertisin generate for promoting differentiation of pancreatic progenitors into islet cells. To begin with, both human pancreatic progenitors (PANC-1 cells) and primary cultured mouse intra-islet progenitor cells (mIPC) were used and tested for Swertisin induced islet neogenesis mechanism, by monitoring immunoblot profile of key transcription factors in time dependent manner. We observed Swertisin follow Activin-A mediated MEPK-TKK pathway involving role of p38 MAPK via activating Neurogenin-3 (Ngn-3) and Smad Proteins cascade. This MAP Kinase intervention in differentiation of cells was confirmed using strong pharmacological inhibitor of p38 MAPK (SB203580), which effectively abrogated this process. We further confirmed this mechanism in-vivo in partial pancreatectomised (PPx) mice model, where we could show Swertisin exerted potential increase in insulin transcript levels with persistent down-regulation of progenitor markers like Nestin, Ngn-3 and Pancreatic Duodenal Homeobox Gene-1 (PDX-1) expression, within three days post PPx. With detailed molecular investigations here in, we first time report the molecular mode of action of Swertisin for islet neogenesis mediated through MAP Kinase (MEPK-TKK) pathway involving Ngn-3 and Smad transcriptional regulation. These findings held importance for developing Swertisin as potent pharmacological drug candidate for effective and endogenous differentiation of islets in cell based therapy for diabetes.
authors.affiliation: Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The M S University of Baroda, Vadodara, Gujarat, India.
authors.forename: Nidheesh
authors.initials: N
authors.lastname: Dadheech
authors.affiliation: Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The M S University of Baroda, Vadodara, Gujarat, India.
authors.forename: Abhay
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Hislope College of Biotechnology, Nagpur, Maharashtra, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Paranjape
authors.affiliation: Hislope College of Biotechnology, Nagpur, Maharashtra, India.
authors.forename: Shivika
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The M S University of Baroda, Vadodara, Gujarat, India.
authors.forename: Arpita
authors.initials: A
authors.lastname: Dave
authors.affiliation: Skin Cancer Research Laboratory, Centre de Recherche du CHUL, CHUQ, Univerisity Laval, Quebec City, Quebec, Canada.
authors.forename: Girish M
authors.initials: GM
authors.lastname: Shah
authors.affiliation: Manipal Hospital and Regenerative Medicine Centre, Manipal Hospital, Manipal, Karnataka, India.
authors.forename: Ramesh R
authors.initials: RR
authors.lastname: Bhonde
authors.affiliation: Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The M S University of Baroda, Vadodara, Gujarat, India.
authors.forename: Sarita
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000818:Animals; D047310:Apigenin / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047310:Apigenin; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D011725:Pyridines; D051785:Smad Proteins; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; C407737:Neurog3 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C556941:swertisin; C093642:SB 203580