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Mahmoud Aghaei - One of the best experts on this subject based on the ideXlab platform.
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a2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 Cell Line through protein kinase a protein kinase b cyclic adenosine monophosphate response element binding protein and growth arrest and dna damage inducible 34 eukaryotic initiation factor 2α pathways
Journal of Cellular Physiology, 2019Co-Authors: Fatemeh Panahi Arasi, Mohammad Keyvanloo Shahrestanaki, Mahmoud AghaeiAbstract:Endoplasmic reticulum (ER) stress is one of the main molecular events underlying pancreatic beta Cell (PBC) failure, apoptosis, and a decrease in insulin secretion. Recent studies have highlighted the fundamental role of A2a adenosine receptor (A2aR) in potentiation of insulin secretion and proliferation of PBCs. However, possible protective effects of A2aR signaling against ER stress have not been elucidated yet. Thus, in the present study, we aimed to investigate the effects of A2aR activation in MIN6 beta Cells undergoing tunicamycin (TM)-mediated ER stress. A2aR expression and activity were evaluated using real-time polymerase chain reaction and measurement of the cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), phospho-protein kinase B or Akt (p-Akt)/Akt, and phospho-Cyclic adenosine monophosphate response element-binding protein/CREB levels in response to a specific agonist (CGS 21680). Survival and proliferation in TM and CGS 21680 cotreated Cells were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), annexin V-fluorescein isothiocyanate (FITC)/propidium iodide staining, colony formation, and 5-bromo-2'-deoxyuridine (Brdu) assays. In addition, the effects of A2aR stimulation on insulin secretion were evaluated using the enzyme-linked immunosorbent assay. B-Cell lymphoma 2 (Bcl-2), phospho-eukaryotic Initiation Factor 2α (p-eIF2α)/eIF2α, growth arrest and DNA-damage-inducible 34 (GADD34), X-box binding protein 1 (XBP-1), spliced X-box binding protein 1 (XBP-1s), immunoglobulin heavy-chain-binding protein (BIP), and CCAAT-enhancer-binding protein homologous protein (CHOP) levels were evaluated using western blotting. Our results showed a decrease in A2aR expression and p-Akt/Akt and p-CREB/CREB levels in TM-pretreated Cells. We also mentioned that CGS 21680 effectively increased Cell survival, proliferation, and insulin secretion in TM-treated Cells. The antiapoptotic effects were possibly mediated through Bcl-2 upregulation. Our western blotting results indicated that A2aR effectively downregulated p-eIF2α/eIF2α, XBP-1, XBP-1s, BIP, and CHOP levels, whereas GADD34 was upregulated. Altogether, the present study revealed that A2aR signaling through PKA/Akt/CREB mediators alleviated TM cytotoxicity effects in MIN6 beta Cells. Thus, the stimulation of this receptor was seen as a new approach to control ER stress in the PBC Cells.
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ipp 1 controls akt creb phosphorylation extension in a2a adenosine receptor signaling cascade in MIN6 pancreatic β Cell Line
European Journal of Pharmacology, 2019Co-Authors: Mohammad Keyvanloo Shahrestanaki, Fatemeh Panahi Arasi, Mahmoud AghaeiAbstract:Abstract Signaling through A2a adenosine receptor specifically prevent pancreatic β-Cells (PBCs) loses under diabetogenic conditions. However, signaling mediators of this receptor in PBCs remained unidentified. Thus, we aimed to investigate the possible involvement of PKA/Akt/IPP-1/CREB pathway in MIN6 β-Cells. In addition, we investigated IPP-1 role in A2a receptor signaling pathway. The expression of A2a receptor in MIN6 Cell Line was evaluated by RT-PCR and its functionality confirmed by quantification of cAMP in response to the CGS 21680, an A2a receptor agonist. MTT and Brdu assays were used to evaluate Cell viability and proliferation, respectively. PKA activity and insulin release were evaluated using ELISA methods. P-Akt/Akt, p-IPP-1/IPP-1, and p-CREB/CREB levels were assessed using western blotting. IPP-1 knock down assessments was performed using specific siRNA. Our result revealed that MIN6 Cells express A2a receptor which actively increased cAMP levels (with EC50 = 2.41 µM) and PKA activity. Activation of this receptor increased Cell viability, proliferation and insulin release. Moreover, we mentioned A2a receptor stimulation increased p-Akt, p-IPP-1, and p-CREB levels in dose (max at 10 µM of CGS 21680) and time (max at 30 min after CGS 21680 treatment) dependent manner. Interestingly, herein, we found in IPP-1 knocked down Cells, A2a receptor failed to activate Akt and CREB. Altogether, we mentioned that in MIN6 Cells A2a receptor increase Cell viability, proliferation and insulin release through PKA/Akt/IPP-1/CREB signaling pathway. In addition, we conclude A2a receptor signaling through this pathway is dependent to activation of IPP-1.
D. Bataille - One of the best experts on this subject based on the ideXlab platform.
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glucagon promotes camp response element binding protein phosphorylation via activation of erk1 2 in MIN6 Cell Line and isolated islets of langerhans
Journal of Biological Chemistry, 2004Co-Authors: Stephane Dalle, Christine Longuet, Safia Costes, Christophe Broca, Omar Faruque, Ghislaine Fontes, El Habib Hani, D. BatailleAbstract:Abstract By using the MIN6 Cell Line and pancreatic islets, we show that in the presence of a low glucose concentration, corresponding to physiological glucagon release from α Cells, glucagon treatment of the β Cell caused a rapid, time-dependent phosphorylation and activation of p44/p42 mitogen-activated protein kinase (ERK1/2) independently from extraCellular calcium influx. Inhibition of either cAMP-dependent protein kinase (PKA) or MEK completely blocked ERK1/2 activation by glucagon. However, no significant activation of several upstream activators of MEK, including Shc-p21Ras and phosphatidylinositol 3-kinase, was observed in response to glucagon treatment. Chelation of intraCellular calcium (intraCellular [Ca2+]) reduced glucagon-mediated ERK1/2 activation. In addition, internalization of glucagon receptors through clathrin-coated pits formation is required for ERK1/2 activation. Remarkably, glucagon promotes the nuclear translocation of ERK1/2 and induces the phosphorylation of cAMP-response element-binding protein (CREB). Miniglucagon, produced from glucagon and released together with the mother hormone from the α Cells in low glucose situations, blocks the insulinotropic effect of glucagon, whereas it does not inhibit the glucagon-induced PKA/ERK1/2/CREB pathway. We conclude that glucagon-induced ERK1/2 activation is mediated by PKA and that an increase in [Ca2+]i is required for maximal ERK activation. Our results uncover a novel mechanism by which the PKA/ERK1/2 signaling network engaged by glucagon, in situation of low glucose concentration, regulates phosphorylation of CREB, a transcription factor crucial for normal β Cell function and survival.
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stimulation of insulin release from the MIN6 Cell Line by a new imidazoLine compound s 21663 evidence for the existence of a novel imidazoLine site in β Cells
British Journal of Pharmacology, 1997Co-Authors: Laurence Le Brigand, Anne Virsolvy, Karine Peyrollier, Dominique Manechez, Jeanjacques Godfroid, Beatrice Guardiolalemaitre, D. BatailleAbstract:1 The MIN6 Cell Line derived from in vivo immortalized insulin-secreting pancreatic β Cells was used to study the insulin-releasing capacity and the Cellular mode of action of S-21663, a newly synthesized imadizoLine compound known for its antidiabetic effect in vivo and its ability to release insulin from perfused pancreas. 2 S-21663, at concentrations ranging from 10−5 M to 10−3 M was able to release insulin from MIN6 Cells; its activity peaked at 10−4 M, a drop in the stimulant factor being noted between 10−4 and 10−3 M. Its efficacy, which did not differ whatever the glucose concentration (stimulant or not), was higher than that of the other secretagogues tested, glucose, sulphonylureas or the peptide tGLP-1. 3 In contrast to tGLP-1, S-21663 did not change the cyclic AMP content, whereas it increased Ca2+ influx via verapamil- and nifedipine-sensitive voltage-dependent calcium channels, the insulin release being a direct consequence of this Ca2+ entry. The S-21663-induced Ca2+ influx appears to be essentially the consequence of closure of K+ channels which differ from the ATP-dependent K+ (K-ATP) channels as determined by measurement of 86Rb efflux and use of a K-ATP channel opener. 4 Comparison of the effects of S-21663 to that of efaroxan, another imidazoLine compound shown to act on insulin release in a glucose-dependent way via binding sites distinct from the imidazoLine I1 and I2 sites, suggested that S-21663 acts through a novel site which displays a remarkably stable expression along the Cell culture. 5 It is concluded that S-21663 is a very efficient, glucose-independent insulin secretagogue acting through a novel imidazoLine site, linked to K+ channels, distinct from the I1, I2 and ‘efaroxan’ binding sites. In vitro and in vivo features of S-21663 indicate that this compound, or new drugs drived from it, might be the basis for a new pharmacological approach to the mangement of type II (non insulin-dependent) diabetes. British Journal of Pharmacology (1997) 122, 786–791; doi:10.1038/sj.bjp.0701449
Fatemeh Panahi Arasi - One of the best experts on this subject based on the ideXlab platform.
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a2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 Cell Line through protein kinase a protein kinase b cyclic adenosine monophosphate response element binding protein and growth arrest and dna damage inducible 34 eukaryotic initiation factor 2α pathways
Journal of Cellular Physiology, 2019Co-Authors: Fatemeh Panahi Arasi, Mohammad Keyvanloo Shahrestanaki, Mahmoud AghaeiAbstract:Endoplasmic reticulum (ER) stress is one of the main molecular events underlying pancreatic beta Cell (PBC) failure, apoptosis, and a decrease in insulin secretion. Recent studies have highlighted the fundamental role of A2a adenosine receptor (A2aR) in potentiation of insulin secretion and proliferation of PBCs. However, possible protective effects of A2aR signaling against ER stress have not been elucidated yet. Thus, in the present study, we aimed to investigate the effects of A2aR activation in MIN6 beta Cells undergoing tunicamycin (TM)-mediated ER stress. A2aR expression and activity were evaluated using real-time polymerase chain reaction and measurement of the cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), phospho-protein kinase B or Akt (p-Akt)/Akt, and phospho-Cyclic adenosine monophosphate response element-binding protein/CREB levels in response to a specific agonist (CGS 21680). Survival and proliferation in TM and CGS 21680 cotreated Cells were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), annexin V-fluorescein isothiocyanate (FITC)/propidium iodide staining, colony formation, and 5-bromo-2'-deoxyuridine (Brdu) assays. In addition, the effects of A2aR stimulation on insulin secretion were evaluated using the enzyme-linked immunosorbent assay. B-Cell lymphoma 2 (Bcl-2), phospho-eukaryotic Initiation Factor 2α (p-eIF2α)/eIF2α, growth arrest and DNA-damage-inducible 34 (GADD34), X-box binding protein 1 (XBP-1), spliced X-box binding protein 1 (XBP-1s), immunoglobulin heavy-chain-binding protein (BIP), and CCAAT-enhancer-binding protein homologous protein (CHOP) levels were evaluated using western blotting. Our results showed a decrease in A2aR expression and p-Akt/Akt and p-CREB/CREB levels in TM-pretreated Cells. We also mentioned that CGS 21680 effectively increased Cell survival, proliferation, and insulin secretion in TM-treated Cells. The antiapoptotic effects were possibly mediated through Bcl-2 upregulation. Our western blotting results indicated that A2aR effectively downregulated p-eIF2α/eIF2α, XBP-1, XBP-1s, BIP, and CHOP levels, whereas GADD34 was upregulated. Altogether, the present study revealed that A2aR signaling through PKA/Akt/CREB mediators alleviated TM cytotoxicity effects in MIN6 beta Cells. Thus, the stimulation of this receptor was seen as a new approach to control ER stress in the PBC Cells.
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ipp 1 controls akt creb phosphorylation extension in a2a adenosine receptor signaling cascade in MIN6 pancreatic β Cell Line
European Journal of Pharmacology, 2019Co-Authors: Mohammad Keyvanloo Shahrestanaki, Fatemeh Panahi Arasi, Mahmoud AghaeiAbstract:Abstract Signaling through A2a adenosine receptor specifically prevent pancreatic β-Cells (PBCs) loses under diabetogenic conditions. However, signaling mediators of this receptor in PBCs remained unidentified. Thus, we aimed to investigate the possible involvement of PKA/Akt/IPP-1/CREB pathway in MIN6 β-Cells. In addition, we investigated IPP-1 role in A2a receptor signaling pathway. The expression of A2a receptor in MIN6 Cell Line was evaluated by RT-PCR and its functionality confirmed by quantification of cAMP in response to the CGS 21680, an A2a receptor agonist. MTT and Brdu assays were used to evaluate Cell viability and proliferation, respectively. PKA activity and insulin release were evaluated using ELISA methods. P-Akt/Akt, p-IPP-1/IPP-1, and p-CREB/CREB levels were assessed using western blotting. IPP-1 knock down assessments was performed using specific siRNA. Our result revealed that MIN6 Cells express A2a receptor which actively increased cAMP levels (with EC50 = 2.41 µM) and PKA activity. Activation of this receptor increased Cell viability, proliferation and insulin release. Moreover, we mentioned A2a receptor stimulation increased p-Akt, p-IPP-1, and p-CREB levels in dose (max at 10 µM of CGS 21680) and time (max at 30 min after CGS 21680 treatment) dependent manner. Interestingly, herein, we found in IPP-1 knocked down Cells, A2a receptor failed to activate Akt and CREB. Altogether, we mentioned that in MIN6 Cells A2a receptor increase Cell viability, proliferation and insulin release through PKA/Akt/IPP-1/CREB signaling pathway. In addition, we conclude A2a receptor signaling through this pathway is dependent to activation of IPP-1.
Mohammad Keyvanloo Shahrestanaki - One of the best experts on this subject based on the ideXlab platform.
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a2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 Cell Line through protein kinase a protein kinase b cyclic adenosine monophosphate response element binding protein and growth arrest and dna damage inducible 34 eukaryotic initiation factor 2α pathways
Journal of Cellular Physiology, 2019Co-Authors: Fatemeh Panahi Arasi, Mohammad Keyvanloo Shahrestanaki, Mahmoud AghaeiAbstract:Endoplasmic reticulum (ER) stress is one of the main molecular events underlying pancreatic beta Cell (PBC) failure, apoptosis, and a decrease in insulin secretion. Recent studies have highlighted the fundamental role of A2a adenosine receptor (A2aR) in potentiation of insulin secretion and proliferation of PBCs. However, possible protective effects of A2aR signaling against ER stress have not been elucidated yet. Thus, in the present study, we aimed to investigate the effects of A2aR activation in MIN6 beta Cells undergoing tunicamycin (TM)-mediated ER stress. A2aR expression and activity were evaluated using real-time polymerase chain reaction and measurement of the cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), phospho-protein kinase B or Akt (p-Akt)/Akt, and phospho-Cyclic adenosine monophosphate response element-binding protein/CREB levels in response to a specific agonist (CGS 21680). Survival and proliferation in TM and CGS 21680 cotreated Cells were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), annexin V-fluorescein isothiocyanate (FITC)/propidium iodide staining, colony formation, and 5-bromo-2'-deoxyuridine (Brdu) assays. In addition, the effects of A2aR stimulation on insulin secretion were evaluated using the enzyme-linked immunosorbent assay. B-Cell lymphoma 2 (Bcl-2), phospho-eukaryotic Initiation Factor 2α (p-eIF2α)/eIF2α, growth arrest and DNA-damage-inducible 34 (GADD34), X-box binding protein 1 (XBP-1), spliced X-box binding protein 1 (XBP-1s), immunoglobulin heavy-chain-binding protein (BIP), and CCAAT-enhancer-binding protein homologous protein (CHOP) levels were evaluated using western blotting. Our results showed a decrease in A2aR expression and p-Akt/Akt and p-CREB/CREB levels in TM-pretreated Cells. We also mentioned that CGS 21680 effectively increased Cell survival, proliferation, and insulin secretion in TM-treated Cells. The antiapoptotic effects were possibly mediated through Bcl-2 upregulation. Our western blotting results indicated that A2aR effectively downregulated p-eIF2α/eIF2α, XBP-1, XBP-1s, BIP, and CHOP levels, whereas GADD34 was upregulated. Altogether, the present study revealed that A2aR signaling through PKA/Akt/CREB mediators alleviated TM cytotoxicity effects in MIN6 beta Cells. Thus, the stimulation of this receptor was seen as a new approach to control ER stress in the PBC Cells.
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ipp 1 controls akt creb phosphorylation extension in a2a adenosine receptor signaling cascade in MIN6 pancreatic β Cell Line
European Journal of Pharmacology, 2019Co-Authors: Mohammad Keyvanloo Shahrestanaki, Fatemeh Panahi Arasi, Mahmoud AghaeiAbstract:Abstract Signaling through A2a adenosine receptor specifically prevent pancreatic β-Cells (PBCs) loses under diabetogenic conditions. However, signaling mediators of this receptor in PBCs remained unidentified. Thus, we aimed to investigate the possible involvement of PKA/Akt/IPP-1/CREB pathway in MIN6 β-Cells. In addition, we investigated IPP-1 role in A2a receptor signaling pathway. The expression of A2a receptor in MIN6 Cell Line was evaluated by RT-PCR and its functionality confirmed by quantification of cAMP in response to the CGS 21680, an A2a receptor agonist. MTT and Brdu assays were used to evaluate Cell viability and proliferation, respectively. PKA activity and insulin release were evaluated using ELISA methods. P-Akt/Akt, p-IPP-1/IPP-1, and p-CREB/CREB levels were assessed using western blotting. IPP-1 knock down assessments was performed using specific siRNA. Our result revealed that MIN6 Cells express A2a receptor which actively increased cAMP levels (with EC50 = 2.41 µM) and PKA activity. Activation of this receptor increased Cell viability, proliferation and insulin release. Moreover, we mentioned A2a receptor stimulation increased p-Akt, p-IPP-1, and p-CREB levels in dose (max at 10 µM of CGS 21680) and time (max at 30 min after CGS 21680 treatment) dependent manner. Interestingly, herein, we found in IPP-1 knocked down Cells, A2a receptor failed to activate Akt and CREB. Altogether, we mentioned that in MIN6 Cells A2a receptor increase Cell viability, proliferation and insulin release through PKA/Akt/IPP-1/CREB signaling pathway. In addition, we conclude A2a receptor signaling through this pathway is dependent to activation of IPP-1.
Shahid Hameed - One of the best experts on this subject based on the ideXlab platform.
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synthesis of new arylsulfonylspiroimidazolidine 2 4 diones and study of their effect on stimulation of insulin release from MIN6 Cell Line inhibition of human aldose reductase sorbitol accumulations in various tissues and oxidative stress
European Journal of Medicinal Chemistry, 2019Co-Authors: Zafar Iqbal, Grant Morahan, Mahreen Arooj, Alexandre N Sobolev, Shahid HameedAbstract:A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 Cell Line derived from in-vivo immortalized insulin-secreting pancreatic Cells. The MIN6 Cells represent an important model of beta Cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited exCellent insulin release activity from MIN6 Cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess exCellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney Cell Lines 293 (HEK293).