Amorphous solid dispersion of Berberine mitigates apoptosis via iPLA₂β/Cardiolipin/Opa1 pathway in db/db mice and in Palmitate-treated MIN6 β-cells

Abstract

Aims : Berberine (BBR) improves beta-cell function in Type 2 diabetes (T2D) because of its anti-apoptotic activity, and our laboratory developed a new preparation named Huang-Gui Solid Dispersion (HGSD) to improve the oral bioavailability of BBR. However, the mechanism by which BBR inhibits beta-cell apoptosis is unclear. We hypothesized that the Group VIA Ca 2+ -Independent Phospholipase A 2 (iPLA 2 β)/Cardiolipin(CL)/Opa1 signaling pathway could exert a protective role in T2D by regulating beta-cell apoptosis and that HGSD could inhibit β-cell apoptosis through iPLA 2 β/CL/Opa1 upregulation. Methods : We examined how iPLA 2 β and BBR regulated apoptosis and insulin secretion through CL/Opa1 in vivo and in vitro . In in vitro studies, we developed Palmitate(PA)-induced apoptotic cell death model in mouse insulinoma cells (MIN6). iPLA 2 β overexpression and silencing technology were used to examine how the iPLA 2 β/CL/Opa1 interaction may play an important role in BBR treatment. In in vivo studies, db/db mice were used as a diabetic animal model. The pancreatic islet function and morphology, beta-cell apoptosis and mitochondrial injury were examined to explore the effects of HGSD. The expression of iPLA 2 β/CL/Opa1 was measured to explore whether the signaling pathway was damaged in T2D and was involved in HGSD treatment. Results : The overexpression of iPLA 2 β and BBR treatment significantly attenuated Palmitate- induced mitochondrial injury and apoptotic death compared with Palmitate-treated MIN6 cell. In addition, iPLA 2 β silencing could simultaneously partly abolish the anti-apoptotic effect of BBR and decrease CL/Opa1 signaling in MIN6 cells. Moreover, HGSD treatment significantly decreased beta-cell apoptosis and resulted in the upregulation of iPLA 2 β/CL/Opa1 compared to those of the db/db mice. Conclusion : The results indicated that the regulation of iPLA 2 β/CL/Opa1 by HGSD may prevent beta-cell apoptosis and may improve islet beta-cell function in Type 2 diabetic mice and in palmitate-treated MIN6 cells.

<p>Berberine-Loaded Thiolated Pluronic F127 Polymeric Micelles for Improving Skin Permeation and Retention</p>

“…The crystalline nature of berberine was indicated by two sharp, narrow, diffraction peaks with the highest intensities at 19.1º and 25.3º. 51,52 Cysteine conjugated pluronic F127 exhibited two sharp peaks at 18.4º and 23.9º. Additionally, the diffraction patterns of berberine were different from those of the lyophilised BTFM.…”

Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis

“…Therefore, Mfn1 and 2 direct β-cell function, at least in part, through the regulation of Tfammediated mtDNA copy number control.Mitofusin agonists restore mtDNA content and improve GSIS in a mouse model of T2DMitochondrial structural and functional defects have been previously reported in islets of human T2D donors(4,5), yet it is unknown if defects in the mitochondrial fusion machinery contribute to β-cell dysfunction in T2D. Thus, we first evaluated the expression of Mfn1 and 2 in islets isolated from the leptin receptor deficient db/db model of T2D, which develops obesity, progressive β-cell mitochondrial and insulin secretory dysfunction, and eventual β-cell failure(41)(42)(43)(44)(45). We observed that Mfn2, but not Mfn1, protein levels were reduced in islets of 10-12 week old db/db mice when compared to db/+ controls (Figures 8A-B), measured at an age prior to β-cell failure(41,42).To determine if targeting mitofusins could attenuate β-cell dysfunction in T2D, we treated db/db islets with recently described pharmacological tandem mitofusin agonists, (2-{2-[(5cyclopropyl-4-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propanamido}-4H,5H,6H-cyclopenta [b]thiophene-3-carboxamide and 1-[2-(benzylsulfanyl)ethyl]-3-(2-methylcyclohexyl)urea (hereafter called Mfn agonists), which together mimic an open Mfn2 conformation favoring mitochondrial fusion but require some residual mitofusin levels to be effective (46).…”

Berberine Alleviates Adiposity and Cardiac Dysfunction in Offspring Exposed to Gestational Diabetes Mellitus

“…For example, CL binds directly to subunits of complex 1 which promotes global conformational changes and subsequently modulates activity (Jussupow et al, 2019). Cell signaling pathways which depend on CL (Dudek & Maack, 2017) may additionally be altered by BBR treatment (Li et al, 2019). Together, these studies indicate that dietary BBR effectively attenuates the development of cardiac dysfunction in GDM exposed offspring by improving mitochondrial respiratory function.…”