Cecropia pachystachya protection against preproIAPP cytotoxicity is independent of Ca2+ homeostasis: lessons learned using a novel yeast model of preproIAPP-induced Ca2+ intracellular dysregulation

Abstract

Despite the progresses in therapeutics, type 2 diabetes is still an epidemic with alarming numbers worldwide. New strategies for prevention and treatments are imperative. A venue of research with potential is the aggregation of Islet Amyloid PolyPeptide (IAPP), a contributor to pancreatic β-cell dysfunction. To address the impact of IAPP on calcium (Ca2+) signalling, we developed a dual reporter yeast model independently expressing preproIAPP-GFP (ppIAPP) and encoding the lacZ gene under the control of Crz1-recognition elements. In this reporter system, ppIAPP induced Crz1 hyperactivation, a yeast transcription factor activated by the Ca2+/calmodulin/calcineurin pathway, which was followed by the increase in β-galactosidase activity. Encouraged by the reported healthy effects of Urticaceae plants against metabolic disturbances, we tested the protective potential of Cecropia pachystachya against IAPP-induced cytotoxicity using the newly designed yeast model. Although C. pachystachya extract exerted no beneficial effects towards the prevention of ppIAPP cytotoxicity, treatment with C. pachystachya enriched C-glycosyl flavonoid fraction (EFF-Cp) significantly improved viability of ppIAPP-expressing cells. Potential bioactivities of C. pachystachya extract and EFF-Cp towards the restoration of Ca2+ homeostasis disrupted by ppIAPP expression were also assessed. Neither prevented Crz1 hyperactivation, suggesting that the EFF-Cp-induced protection against ppIAPP toxicity was mediated by Ca2+-independent mechanisms. Keywords: Amylin, Calcium signaling; Cecropia pachystachya; Diabetes; Islet Amyloid Polypeptide (IAPP)