Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice

Abstract

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by β cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice. PEDF levels are significantly elevated in pancreas, in parallel with pancreatic TNF levels in NOD mice. To identify experimental therapeutics, we screened 2,327 compounds in two chemical libraries (the NIH Clinical Collection and Pharmakon-1600) for leads that inhibit PEDF mediated TNF release in macrophage cultures. The lead molecule selected, "emetine" is a widely used emetic. It inhibited PEDF-mediated macrophage activation with an EC50 or 146 nmol/L. Administration of emetine to NOD mice and to C57Bl6 mice subjected to streptozotocin significantly attenuated hyperglycemia, reduced TNF levels in pancreas and attenuated insulitis. Together, these results suggest that targeting PEDF with emetine may attenuate TNF release and hyperglycemia in murine diabetes models. This suggests that further investigation of PEDF and emetine in the pathogenesis of human diabetes is warranted.

Identification of a Novel Immune Landscape Signature for Predicting Prognosis and Response of Endometrial Carcinoma to Immunotherapy and Chemotherapy

“…Carbenoxolone can also act as the inhibitor of Pannexin 1 (Panx-1) and suppress the migration and invasion of testicular cancer cells to counter cancer progression and metastasis (Penuela et al, 2012;Furlow et al, 2015;Jankowski et al, 2018;Liu et al, 2019). Emetine, a potent anti-protozoal and emetic drug, recent evidence has verified its anti-malarial, anti-bacterial and anti-amoebic effects (Matthews et al, 2013;Hudson et al, 2016;Khandelwal et al, 2017;Yang et al, 2018). Over the past decades, emetine has been reported to have anti-tumor effects on leukemia, ovarian cancer, bladder cancer and lung cancer by inhibiting tumor growth by regulating multiple mechanisms such as apoptosis and autophagy Kim et al, 2015;Sun et al, 2015).…”

Unveiling FOS as a Potential Diagnostic Biomarker and Emetine as a Prospective Therapeutic Agent for Diabetic Nephropathy

“…Previous research indicated that the application of emetine restrained TNF level and insulitis in diabetes mellitus mouse. 22 However, the role of emetine in DN has not been clearly clarified.…”