Tectorigenin enhances PDX1 expression and protects pancreatic β-cells by activating ERK and reducing ER stress

Abstract

Pancreas/duodenum homeobox protein 1 (PDX1) is an important transcription factor that regulates islet β-cell proliferation, differentiation, and function. Reduced expression of PDX1 is thought to contribute to β-cell loss and dysfunction in diabetes. Thus, promoting PDX1 expression can be an effective strategy to preserve β-cell mass and function. Previously, we established a PDX1 promoter-dependent luciferase system to screen agents that can promote PDX1 expression. Natural compound tectorigenin (TG) was identified as a promising candidate that could enhance the activity of the promoter for PDX1 gene. In this study, we first demonstrated that TG could promote the expression of PDX1 in β-cells via activating extracellular signal-related kinase (ERK), as indicated by increased phosphorylation of ERK; this effect was observed under either normal or glucotoxic/lipotoxic conditions. We then found that TG could suppress induced apoptosis and improved the viability of β-cells under glucotoxicity and lipotoxicity by activation of ERK and reduction of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. These effects held true in vivo as well: prophylactic or therapeutic use of TG could obviously inhibit ER stress and decrease islet β-cell apoptosis in the pancreas of mice given a high-fat/high-sucrose diet (HFHSD), thus dramatically maintaining or restoring β-cell mass and islet size respectively. Accordingly, both prophylactic and therapeutic use of TG improved HFHSD impaired glucose metabolism in mice, as evidenced by ameliorating hyperglycemia and glucose intolerance. Taken together, TG, as an agent promoting PDX1 expression exhibits strong protective effects on islet β-cells both in vitro and in vivo.

Accelerated Generation of Extra-Islet Insulin-Producing Cells in Diabetic Rats, Treated with Sodium Phthalhydrazide

“…Promoting Pdx1 expression is suggested to be an effective strategy to preserve the mass and function of IPCs, both intra- and extra-islet. For instance, Yao et al demonstrated that the natural compound tectorigenin can enhance the activity of the promotor for the Pdx1 gene via activating extracellular signal-related kinase, and this effect was observed under either normal or glucotoxic/lipotoxic conditions [ 25 ].…”

Development of approach for flavonoid profiling of biotechnological raw materials Iris sibirica L. by HPLC with high‐resolution tandem mass spectrometry

“…Identified compounds has wide range of medicinal perspectives. For example, tectorigenin has antioxidant, 43–45 antiplatelet, 46 anticancer 47 and receptor modulating activities 48,49 ; iristectorigenin A demonstrates hepatoprotective 50 activity, iristectorigenin B is cholinesterase inhibitor 51 . Genistein is useful for treating Alzheimer 52 and other age‐related diseases 53–56 .…”

Regulation of Pdx1 by oxidative stress and Nrf2 in pancreatic beta-cells

“…Beta-cells express a unique set of key marker genes that define their identity and function by contributing to the expression and secretion of insulin (12). One of these genes is the duodenal homeobox 1 (Pdx1), a protein that plays many distinct roles in the life of a beta-cell, including involvement in beta-cell differentiation, beta-cell function, beta-cell survival and beta-cell proliferation (13)(14)(15)(16)(17)(18). To do so, PDX1 controls the expression of other genes that play important roles in the betacell fate.…”