Cucurbita ficifolia Bouché increases insulin secretion in RINm5F cells through an influx of Ca2+ from the endoplasmic reticulum

2016 ◽  
Vol 188 ◽  
pp. 159-166 ◽  
Author(s):  
Maria Elizabeth Miranda-Perez ◽  
Clara Ortega-Camarillo ◽  
Maria Del Carmen Escobar-Villanueva ◽  
Gerardo Blancas-Flores ◽  
Francisco Javier Alarcon-Aguilar
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Rinm5f Cells ◽  
Cucurbita Ficifolia

scholarly journals Alternative redox forms of ASNA-1 separate insulin signaling from tail-anchored protein targeting and cisplatin resistance in C. elegans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dorota Raj ◽  
Ola Billing ◽  
Agnieszka Podraza-Farhanieh ◽  
Bashar Kraish ◽  
Oskar Hemmingsson ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Protein Targeting ◽  
Cisplatin Resistance ◽  
Acquired Resistance ◽  
Endoplasmic Reticulum Membrane ◽  
C Elegans ◽  
Cisplatin Sensitivity ◽  
Tumor Environment ◽  
The One

AbstractCisplatin is a frontline cancer therapeutic, but intrinsic or acquired resistance is common. We previously showed that cisplatin sensitivity can be achieved by inactivation of ASNA-1/TRC40 in mammalian cancer cells and in Caenorhabditis elegans. ASNA-1 has two more conserved functions: in promoting tail-anchored protein (TAP) targeting to the endoplasmic reticulum membrane and in promoting insulin secretion. However, the relation between its different functions has remained unknown. Here, we show that ASNA-1 exists in two redox states that promote TAP-targeting and insulin secretion separately. The reduced state is the one required for cisplatin resistance: an ASNA-1 point mutant, in which the protein preferentially was found in the oxidized state, was sensitive to cisplatin and defective for TAP targeting but had no insulin secretion defect. The same was true for mutants in wrb-1, which we identify as the C. elegans homolog of WRB, the ASNA1/TRC40 receptor. Finally, we uncover a previously unknown action of cisplatin induced reactive oxygen species: cisplatin induced ROS drives ASNA-1 into the oxidized form, and selectively prevents an ASNA-1-dependent TAP substrate from reaching the endoplasmic reticulum. Our work suggests that ASNA-1 acts as a redox-sensitive target for cisplatin cytotoxicity and that cisplatin resistance is likely mediated by ASNA-1-dependent TAP substrates. Treatments that promote an oxidizing tumor environment should be explored as possible means to combat cisplatin resistance.

scholarly journals A Phenolic Fraction from Catharanthus roseus L. Stems Decreases Glycemia and Stimulates Insulin Secretion

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Janet Alejandra Espejel-Nava ◽  
Elisa Vega-Avila ◽  
Francisco Alarcon-Aguilar ◽  
Alejandra Contreras-Ramos ◽  
Guadalupe Díaz-Rosas ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Phenolic Compounds ◽  
Chlorogenic Acid ◽  
Gallic Acid ◽  
Catharanthus Roseus ◽  
Chromatographic Analysis ◽  
Hypoglycemic Effect ◽  
Diabetic Mice ◽  
Rinm5f Cells ◽  
Phenolic Fraction

Catharanthus roseus (L.) G. (C. roseus) is a medicinal plant used traditionally for diabetes mellitus control. Several compounds of an alkaloidal nature have been proposed as hypoglycemic principles. However, little attention has been paid to other compounds in this plant that could also participate in this hypoglycemic activity. This study aimed to analyze the hypoglycemic effect of a polyphenolic fraction from C. roseus, as well as its action on insulin secretion and expression in RINm5F cells. Methods. An alkaloid-free aqueous extract was obtained from C. roseus stems. The hypoglycemic effect of different doses of this extract was evaluated in normal and streptozotocin-induced diabetic mice. This extract was fractionated by bipartition, and the resultant fractions were assessed by their hypoglycemic effects. Subsequently, the fraction with the greater hypoglycemic activity was added to the RINm5F cells, and the expression and secretion of insulin were analyzed. The antioxidant activity was determined by the DPPH method and through chromatographic analysis of the most active fraction by HPLC, using an Econosphere C18 column. Results. The aqueous alkaloid-free extract of C. roseus stems significantly reduced blood glucose in normal and diabetic mice. The fractionation of this extract provided three fractions, one of which (a precipitate) showed significant reductions in glycemia at 6 h (48.1 and 64.5% in normal and diabetic mice, respectively). This precipitate contained phenolic compounds and saponins. Its chromatographic analysis showed that it is formed by several phenolic compounds; gallic acid (0.053%) and chlorogenic acid (0.216%) were identified and quantified. Conclusion. The phenolic fraction of C. roseus containing gallic acid and chlorogenic acid had a hypoglycemic effect that may be explained by an increase in insulin secretion.

scholarly journals The endoplasmic reticulum-plasma membrane tethering protein TMEM24 is a regulator of cellular Ca2+ homeostasis

2021 ◽  
Author(s):  
Beichen Xie ◽  
Styliani Panagiotou ◽  
Jing Cen ◽  
Patrick Gilon ◽  
Peter Bergsten ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Insulin Secretion ◽  
Lipid Transfer Protein ◽  
Underlying Mechanism ◽  
Lipid Transfer ◽  
Β Cells ◽  
Transfer Protein ◽  
Lipid Exchange ◽  
Membrane Tethering

Endoplasmic reticulum (ER) - plasma membrane (PM) contacts are sites of lipid exchange and Ca2+ transport, and both lipid transport proteins and Ca2+ channels specifically accumulate at these locations. In pancreatic β-cells, both lipid- and Ca2+ signaling are essential for insulin secretion. The recently characterized lipid transfer protein TMEM24 dynamically localize to ER-PM contact sites and provide phosphatidylinositol, a precursor of PI(4)P and PI(4,5)P2, to the plasma membrane. β-cells lacking TMEM24 exhibit markedly suppressed glucose-induced Ca2+ oscillations and insulin secretion but the underlying mechanism is not known. We now show that TMEM24 only weakly interact with the PM, and dissociates in response to both diacylglycerol and nanomolar elevations of cytosolic Ca2+. Release of TMEM24 into the bulk ER membrane also enables direct interactions with mitochondria, and we report that loss of TMEM24 results in excessive accumulation of Ca2+ in both the ER and mitochondria and in impaired mitochondria function.

Regulation of exocytosis in electrically permeabilized insulin-secreting cells. Evidence for Ca2+ dependent and independent secretion

1987 ◽  
Vol 7 (5) ◽  
pp. 443-454 ◽  
Author(s):  
Claes B. Wollheim ◽  
Susanne Ullrich ◽  
Paolo Meda ◽  
Lucia Vallar
Keyword(s):  
Arachidonic Acid ◽  
Insulin Secretion ◽  
Cyclic Amp ◽  
Phospholipase C ◽  
Guanine Nucleotide ◽  
Rinm5f Cells ◽  
Enzyme Systems ◽  
Enhanced Secretion ◽  
Insulin Secreting Cells ◽  
High Voltage Discharge

The regulation of insulin secretion from RINm5F cells exposed to high voltage discharge has been investigated. Electron microscopy revealed that the overall structure of the cells was preserved after permeabilization. In this preparation insulin release was stimulated by Ca2+ (EC50=2.4 μM). The stable GTP analogue GTPγS enhanced secretion both at intermediate (nano- to micromolar) and vanishingly low (<10 pM) Ca2+ concentrations. At optimal Ca2+ (10 μM) the effect of GTPγS was greatly reduced. We investigated whether the secretory response to GTP analogues was mediated by any of three enzyme systems regulated by GTP-binding proteins, i.e. generation of cyclic AMP by adenylate cyclase, of diacylglycerol by phospholipase C and of arachidonic acid by phospholipase A2. The involvement of these messenger systems could be excluded as (i) cyclic AMP only had minor, Ca2+ dependent effects, (ii) phospholipase C was not activated in the absence of Ca2+ and insulin secretion due to the phorbol ester TPA displayed a different Ca2+ dependency, (iii) arachidonic acid did not elicit Ca2+ independent insulin secretion. These results, taken together with the finding that insulin secretion due to Ca2+ or TPA is attenuated by the inhibitory guanine nucleotide GDPβS, suggest the existence of a regulatory site in exocytosis which is sensitive to guanine nucleotides.

scholarly journals Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

2008 ◽  
Vol 199 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Ernest Sargsyan ◽  
Henrik Ortsäter ◽  
Kristofer Thorn ◽  
Peter Bergsten
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Eukaryotic Translation ◽  
Β Cell Function ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response

Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of β-cell function and impaired insulin secretion observed in these individuals. A strategy to improve β-cell function in individuals with T2DM has been intermittent administration of KATP channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of KATP channels improve β-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in β-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic β-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the ERN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and β-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves β-cell function.

scholarly journals Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function

2015 ◽  
Vol 55 (1) ◽  
pp. 21-29 ◽  
Author(s):  
S Lortz ◽  
S Lenzen ◽  
I Mehmeti
Keyword(s):  
Gene Expression ◽  
Hydrogen Peroxide ◽  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
Insulin Gene ◽  
Insulin Content ◽  
Insulin Biosynthesis ◽  
Β Cell ◽  
Insulin Gene Expression

Oxidative folding of nascent proteins in the endoplasmic reticulum (ER), catalysed by one or more members of the protein disulfide isomerase family and the sulfhydryl oxidase ER oxidoreductin 1 (ERO1), is accompanied by generation of hydrogen peroxide (H2O2). Because of the high rate of insulin biosynthesis and the low expression of H2O2-inactivating enzymes in pancreatic β cells, it has been proposed that the luminal H2O2concentration might be very high. As the role of this H2O2in ER stress and proinsulin processing is still unsolved, an ER-targeted and luminal-active catalase variant, ER-Catalase N244, was expressed in insulin-secreting INS-1E cells. In these cells, the influence of ER-specific H2O2removal on cytokine-mediated cytotoxicity and ER stress, insulin gene expression, insulin content and secretion was analysed. The expression of ER-Catalase N244 reduced the toxicity of exogenously added H2O2significantly with a threefold increase of the EC50value for H2O2. However, the expression of cytokine-induced ER stress genes and viability after incubation with β cell toxic cytokines (IL1β alone or together with TNFα+IFNγ) was not affected by ER-Catalase N244. In control and ER-Catalase N244 expressing cells, insulin secretion and proinsulin content was identical, while removal of luminal H2O2reduced insulin gene expression and insulin content in ER-Catalase N244 expressing cells. These data show that ER-Catalase N244 reduced H2O2toxicity but did not provide protection against pro-inflammatory cytokine-mediated toxicity and ER stress. Insulin secretion was not affected by decreasing H2O2in the ER in spite of a reduced insulin transcription and processing.

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