scholarly journals Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer

2020 ◽  
Vol 8 (2) ◽  
pp. e001458
Author(s):  
Amal Ashour ◽  
Mingzhan Xue ◽  
Maryam Al-Motawa ◽  
Paul J Thornalley ◽  
Naila Rabbani
Keyword(s):  
Glucose Metabolism ◽  
High Glucose ◽  
Glucose Concentration ◽  
Periodontal Ligament ◽  
High Glucose Concentration ◽  
Periodontal Ligament Fibroblasts ◽  
Unfolded Protein ◽  
Increased Risk ◽  
The Unfolded Protein Response ◽  
Protein Response

IntroductionPatients with diabetes have increased risk of periodontal disease, with increased risk of weakening of periodontal ligament and tooth loss. Periodontal ligament is produced and maintained by periodontal ligament fibroblasts (PDLFs). We hypothesized that metabolic dysfunction of PDLFs in hyperglycemia produces an accumulation of the reactive glycating agent, methylglyoxal (MG), leading to increased formation of the major advanced glycation endproduct, MG-H1 and PDLF dysfunction. The aim of this study was to assess if there is dicarbonyl stress and functional impairment of human PDLFs in primary culture in high glucose concentration—a model of hyperglycemia, to characterize the metabolic drivers of it and explore remedial intervention by the glyoxalase 1 inducer dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP).Research design and methodsHuman PDLFs were incubated in low and high glucose concentration in vitro. Metabolic and enzymatic markers of MG and glucose control were quantified and related changes in the cytoplasmic proteome and cell function—binding to collagen-I, assessed. Reversal of PDLF dysfunction by tRES-HESP was explored.ResultsIn high glucose concentration cultures, there was a ca. twofold increase in cellular MG, cellular protein MG-H1 content and decreased attachment of PDLFs to collagen-I. This was driven by increased hexokinase-2 linked glucose metabolism and related increased MG formation. Proteomics analysis revealed increased abundance of chaperonins, heat shock proteins (HSPs), Golgi-to-endoplasmic reticulum transport and ubiquitin E3 ligases involved in misfolded protein degradation in high glucose concentration, consistent with activation of the unfolded protein response by increased misfolded MG-modified proteins. PDLF dysfunction was corrected by tRES-HESP.ConclusionsIncreased hexokinase-2 linked glucose metabolism produces dicarbonyl stress, increased MG-modified protein, activation of the unfolded protein response and functional impairment of PDLFs in high glucose concentration. tRES-HESP resolves this at source by correcting increased glucose metabolism and may be of benefit in prevention of diabetic periodontal disease.

Author response for "A high glucose concentration during early stages of in vitro equine embryo development alters expression of genes involved in glucose metabolism"

2020 ◽  
Author(s):  
María Jesús Sánchez‐Calabuig ◽  
Raúl Fernández‐González ◽  
Meriem Hamdi ◽  
Katrien Smits ◽  
Angela Patricia López‐Cardona ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Embryo Development ◽  
High Glucose ◽  
Glucose Concentration ◽  
Author Response ◽  
High Glucose Concentration ◽  
Early Stages ◽  
Expression Of Genes

scholarly journals Activation of the unfolded protein response in high glucose treated endothelial cells is mediated by methylglyoxal

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zehra Irshad ◽  
Mingzhan Xue ◽  
Amal Ashour ◽  
James R. Larkin ◽  
Paul J. Thornalley ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Unfolded Protein Response ◽  
High Glucose ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract MP110: Inhibition of the Unfolded Protein Response Reduces Arrhythmic Risk After Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Man Liu ◽  
Hong Liu ◽  
Preethy Parthiban ◽  
guangbin shi ◽  
Gyeoung-Jin Kang ◽  
...  
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Ion Channel ◽  
Unfolded Protein Response ◽  
Coronary Artery Ligation ◽  
Unfolded Protein ◽  
Cardiac Ion Channels ◽  
Increased Risk ◽  
The Unfolded Protein Response ◽  
Protein Response

Background: Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels and transporters. When activated, the protein kinase-like ER kinase (PERK) arm of the unfolded protein response (UPR) reduces protein translation and abundance. We hypothesize that inhibition of PERK could prevent cardiac ion channel downregulation and reduce arrhythmic risk after myocardial infarct (MI). Methods: The MI mouse model was induced by a left anterior descending coronary artery ligation. Pharmacological inhibition of PERK was achieved with a specific inhibitor, GSK2606414. Genetic inhibition of PERK was achieved by cardiac-specific PERK knockout in C57BL/6J mice (PERKKO). Echocardiography, telemetry, and electrophysiological measurements were performed to monitor cardiac function and arrhythmias. Results: Three weeks after surgery, the wild type MI mice exhibited decreased ejection fraction (EF%), ventricular tachycardia (VT) and prolonged QTc intervals. The UPR effectors (phospho-PERK, phospho-IRE1, and ATF6N) were elevated significantly (1.7- to 5.9-fold) at protein levels, and all major cardiac ion channels showed decreased protein expression in MI hearts. MI cardiomyocytes showed decreased currents for all major channels (I Na , I CaL , I to , I K1 , and I Kur : 60±6%, 53±9%, 27±6%, 55±7%, and 40±7% of sham, respectively, P<0.05 vs. sham) with significantly prolonged action potential duration (APD 90 : 291±43 ms of MI vs. 100±12 ms of sham, P<0.05) and decreased maximum upstroke velocity (dV/dt max : 95±4 V/s of MI vs. 132±6 ms of sham, P<0.05) of the action potential phase 0. GSK treatment restored I Na and I to , shortened APD, and increased dV/dt max . PERKKO mice exhibited reduced electrical remodeling in response to MI with shortened QTc intervals, less VT episodes, and higher survival rates. Conclusion: PERK is activated during MI and contributes to arrhythmic risk by downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmic risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmic mechanism and maintaining ion channel levels is antiarrhythmic.

Glucose, dexamethasone, and the unfolded protein response regulate TRB3 mRNA expression in 3T3-L1 adipocytes and L6 myotubes

2006 ◽  
Vol 291 (6) ◽  
pp. E1274-E1280 ◽  
Author(s):  
Sherif Z. Yacoub Wasef ◽  
Katherine A. Robinson ◽  
Mary N. Berkaw ◽  
Maria G. Buse
Keyword(s):  
Insulin Resistance ◽  
Cell Survival ◽  
Mrna Expression ◽  
Unfolded Protein Response ◽  
High Glucose ◽  
Glucose Deprivation ◽  
Unfolded Protein ◽  
L6 Myotubes ◽  
The Unfolded Protein Response ◽  
Protein Response

Tribbles 3 (TRB3) is a recently recognized atypical inactive kinase that negatively regulates Akt activity in hepatocytes, resulting in insulin resistance. Recent reports link TRB3 to nutrient sensing and regulation of cell survival under stressful conditions. We studied the regulation of TRB3 by glucose, insulin, dexamethasone (Dex), and the unfolded protein response (UPR) in 3T3-L1 adipocytes and in L6 myotubes. In 3T3-L1 adipocytes, incubation in high glucose with insulin did not increase TRB3 mRNA expression. Rather, TRB3 mRNA increased fourfold with glucose deprivation and two- to threefold after incubation with tunicamcyin (an inducer of the UPR). Incubation of cells in no glucose or in tunicamcyin stimulated the expression of CCAAT/enhancer-binding protein homologous protein. In L6 myotubes, absent or low glucose induced TRB3 mRNA expression by six- and twofold, respectively. The addition of Dex to 5 mM glucose increased TRB3 mRNA expression twofold in 3T3-L1 adipocytes but decreased it 16% in L6 cells. In conclusion, TRB3 is not the mediator of high glucose or glucocorticoid-induced insulin resistance in 3T3-L1 adipocytes or L6 myotubes. TRB3 is induced by glucose deprivation in both cell types as a part of the UPR, where it may be involved in regulation of cell survival in response to glucose depletion.

Author response for "A high glucose concentration during early stages of in vitro equine embryo development alters expression of genes involved in glucose metabolism"

2020 ◽  
Author(s):  
María Jesús Sánchez‐Calabuig ◽  
Raúl Fernández‐González ◽  
Meriem Hamdi ◽  
Katrien Smits ◽  
Angela Patricia López‐Cardona ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Embryo Development ◽  
High Glucose ◽  
Glucose Concentration ◽  
Author Response ◽  
High Glucose Concentration ◽  
Early Stages ◽  
Expression Of Genes
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