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

• Published in: PloS one 2015-06, Vol.10 (6), p.e0128244
• Main Authors: Dadheech, Nidheesh, Srivastava, Abhay, Paranjape, Neha, Gupta, Shivika, Dave, Arpita, Shah, Girish M, Bhonde, Ramesh R, Gupta, Sarita
• Format: Article
• Language: English
• Subjects: Activin; Animals; Antidiabetics; Apigenin - pharmacology; Basic Helix-Loop-Helix Transcription Factors - metabolism; Beta cells; Biochemistry; Cancer; Cell differentiation; Cell Differentiation - drug effects; Cell growth; Cells (biology); Cells, Cultured; Chemical agents; Diabetes; Diabetes mellitus; Diabetes therapy; Differentiation (biology); Down-Regulation - drug effects; Endocrinology; Gene expression; Gene regulation; Growth factors; Homeobox; Homeodomain Proteins - metabolism; Humans; Hypoglycemic Agents - pharmacology; Imidazoles - pharmacology; Insulin; Intermediate filament proteins; Islet cells; Islets of Langerhans; Islets of Langerhans - cytology; Kinases; Male; MAP kinase; Medical research; Mice; Mice, Inbred BALB C; Mode of action; Molecular chains; Nerve Tissue Proteins - metabolism; Nestin; Neurogenins; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Pancreas; Pharmacology; Phosphorylation; Phosphorylation - drug effects; Progenitor cells; Proteins; Pyridines - pharmacology; Rodents; Signal Transduction - drug effects; Smad protein; Smad Proteins - metabolism; Stem cells; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Studies; Trans-Activators - metabolism; Transcription factors; Transcriptional Activation - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128244

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.