scholarly journals Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

2020 ◽  
Vol 21 (4) ◽  
pp. 1289
Author(s):  
Amit Koren-Iton ◽  
Shiran Salomon-Zimri ◽  
Alex Smolar ◽  
Efrat Shavit-Stein ◽  
Amir Dori ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Control Diet ◽  
Fasting Blood Glucose ◽  
Apoe Genotype ◽  
Dependent Manner ◽  
Fiber Density ◽  
Akt Activation ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Gsk 3Β

Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer’s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.

scholarly journals Cell Confluence Regulates Hepatocyte Growth Factor-Stimulated Cell Morphogenesis in a β-Catenin-Dependent Manner

2006 ◽  
Vol 26 (24) ◽  
pp. 9232-9243 ◽  
Author(s):  
Shuta Ishibe ◽  
J. Erika Haydu ◽  
Akashi Togawa ◽  
Arnaud Marlier ◽  
Lloyd G. Cantley
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Glycogen Synthase ◽  
Organ Injury ◽  
Dependent Manner ◽  
Akt Activation ◽  
Nuclear Signaling ◽  
Gsk 3Β ◽  
High Level ◽  
Hepatocyte Growth

ABSTRACT Following organ injury, morphogenic epithelial responses can vary depending on local cell density. In the present study, the role of cell confluence in determining the responsiveness of renal epithelial cells to the dedifferentiating morphogenic signals of hepatocyte growth factor (HGF) was examined. Increasing confluence resulted in a greater tendency of cells to organize into epithelial tubes and a significant decrease in migratory responsiveness to HGF. Analysis of downstream signaling revealed that the HGF receptor c-Met was equally activated in confluent and nonconfluent cells following HGF stimulation but that phosphoinositide 3-kinase-dependent activation of Akt and Rac were selectively diminished in confluent cells. In nonconfluent cells treated with HGF, the high level of Akt activation resulted in inhibitory phosphorylation of glycogen synthase kinase 3β (GSK-3β) and increased β-catenin nuclear signaling. In contrast, confluent cells, in which HGF-stimulated Akt activation was diminished, displayed less inhibitory phosphorylation of GSK-3β and less nuclear signaling by β-catenin. Overexpression of β-catenin (SA), which cannot be phosphorylated by GSK-3β and targeted for ubiquitination, significantly increased migration in fully confluent cells. Thus, cells maintained at high confluence selectively downregulate signaling events such as Rac activation and β-catenin-dependent transcription that would otherwise promote cell dedifferentiation and migration.

Phillyrin ameliorates diabetic nephropathy through the PI3K/Akt/GSK-3β signalling pathway in streptozotocin-induced diabetic mice

2021 ◽  
pp. 096032712110515
Author(s):  
Tianyang Wang ◽  
Xuejiao Wen ◽  
Ziwen Zhang ◽  
Minjuan Xie ◽  
Jie Zhou
Keyword(s):  
Diabetic Nephropathy ◽  
Glycogen Synthase ◽  
Fasting Blood Glucose ◽  
Underlying Mechanism ◽  
Signalling Pathway ◽  
Chinese Herbs ◽  
Diabetic Patients ◽  
Haemoglobin A1c ◽  
Serum Blood Urea Nitrogen ◽  
Gsk 3Β

Diabetic nephropathy is a progressive kidney disease resulting from long-term hyperglycaemia in diabetic patients, and the underlying mechanism is complex and lacks effective treatments. Various active ingredients in Chinese herbs have been shown to alleviate renal injury and improve DN in recent years. Phillyrin, a natural medicinal active compound extracted from the Oleaceae family, has various pharmacological effects, including antioxidative, antiapoptotic and antiobesity effects. However, the role of phillyrin and its underlying mechanism in DN have not yet been explored. To investigate the effects of phillyrin on DN and its potential mechanisms of action, we performed experiments using streptozotocin (STZ)-induced DN mice as models. Phillyrin significantly reduced the levels of fasting blood glucose (FBG) and glycosylated haemoglobin A1c (HbA1c), downregulated the levels of serum blood urea nitrogen (BUN), serum creatinine (Scr), serum and urine β2-microglobulins (β2-MG) and improved the pathological changes of the kidney in a DN mouse model. Phillyrin also increased the level of antioxidants and attenuated oxidative damage in DN model mice. In addition, phillyrin inhibited Glycogen synthase kinase-3β (GSK-3β) activity by activating the PI3K/Akt signalling pathway, increased the Bcl-2/Bax ratio, reduced the release of cytochrome c from the mitochondria to the cytoplasm, subsequently inhibited the activation of caspase-3 and ultimately suppressed renal cell apoptosis. These findings suggested that phillyrin could be a new promising therapeutic strategy for DN, and this protective effect might be related to suppressing oxidative stress and apoptosis via the PI3K/Akt/GSK-3β pathway.

scholarly journals Effect of reduced dietary zinc intake on carbohydrate and Zn metabolism in the genetically diabetic mouse (C57BL/KsJ db+/db+)

1988 ◽  
Vol 60 (3) ◽  
pp. 499-507 ◽  
Author(s):  
Susan Southon ◽  
Z. Kechrid ◽  
A. J. A. Wright ◽  
Susan J. Fairweather-Tait
Keyword(s):  
Blood Glucose ◽  
Control Diet ◽  
Fasting Blood Glucose ◽  
Liver Glycogen ◽  
Diabetic Mouse ◽  
Whole Body ◽  
Diabetic Mice ◽  
Control Groups ◽  
Glucose Levels ◽  
Blood Glucose Levels

1. Male, 4–5-week-old, genetically diabetic mice (C57BL/KsJ db/db) and non-diabetic heterozygote litter-mates (C57BL/KsJ db/+)were fed on a diet containing 1 mg zinc/kg (low-Zn groups) or 54 mg Zn/kg (control groups) for 27 d. Food intakes and body-weight gain were recorded regularly. On day 28, after an overnight fast, animals were killed and blood glucose and insulin concentrations, liver glycogen, and femur and pancreatic Zn concentrations were determined.2. The consumption of the low-Zn diet had only a minimal effect on the Zn status of the mice as indicated by growth rate, food intake and femur and pancreatic Zn concentrations. In fact, diabetic mice fed on the low-Zn diet had a higher total food intake than those fed on the control diet. The low-Zn diabetic mice had higher fasting blood glucose and liver glycogen levels than their control counterparts. Fasting blood insulin concentration was unaffected by dietary regimen.3. A second experiment was performed in which the rate of loss of 65Zn, injected subcutaneously, was measured by whole-body counting in the two mouse genotypes over a 28 d period, from 4 to 5 weeks of age. The influence of feeding low-Zn or control diets was also examined. At the end of the study femur and pancreatic Zn and non-fasting blood glucose levels were determined.4. All mice fed on the low-Zn diet showed a marked reduction in whole-body 65Zn loss compared with those animals fed on the control diet. In the low-Zn groups, the loss of 65Zn from the diabetic mice was significantly greater than that from heterozygote mice. This difference was not observed in the control groups. Blood glucose levels were elevated in the low-Zn groups. Possible reasons for these observations are discussed.5. The present study demonstrates an adverse effect of reduced dietary Zn intake on glucose utilization in the genetically diabetic mouse, which occurred before any significant tissue Zn depletion became apparent.

scholarly journals Xuebijing Protects Against Septic Acute Liver Injury Based on Regulation of GSK-3β Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Liping Cao ◽  
Zhenghong Li ◽  
Yi Ren ◽  
Mengmeng Wang ◽  
Zhizhou Yang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Acute Liver Injury ◽  
Glycogen Synthase ◽  
Binding Protein ◽  
Cecal Ligation ◽  
Inflammatory Factors ◽  
Dependent Manner ◽  
Protective Effects ◽  
Creb Binding Protein ◽  
Gsk 3Β

Xuebijing (XBJ), the only drug approved for the sepsis and multiple organ dysfunction, and its protective effects against acute liver injury (ALI) and its mechanism. The aim of this study was to evaluate the protective effect of XBJ on cecal ligation and perforation (CLP)-induced mouse ALI model and LPS-induced RAW264.7 cell ALI model. Mice were pretreated with XBJ before the CLP model was established, and serum and liver tissues were collected at the end of the experiment to assess the levels of inflammatory factors and liver injury. Results showed that XBJ pretreatment reduced liver/body weight, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in serum, and inhibited levels of pro-inflammatory factors in serum. Cells were treatment with XBJ and modeled by LPS modeling increased cell viability in the XBJ-treated group compared to the model group and XBJ also decreased serum pro-inflammatory factors in a dose-dependent manner. Western blot detected that XBJ also up-regulated the phosphorylated levels of glycogen synthase kinase-3β (p-GSK-3β) and cAMP-response element-binding protein (p-CREB) and down-regulated the phosphorylated level of nuclear factor kappa-B (p-NF-κB) in liver and cell. After overexpression of GSK-3β in cells, the mechanism was further investigated using CO-IP analysis. The binding of p-NF-κB and p-CREB to CREB-binding protein (CBP) was increased and decreased, respectively, indicating that GSK-3β regulated inflammation by regulating the binding of p-NF-κB and p-CREB to CBP. The present studies suggested that the hepatoprotective effect of XBJ may be through up-regulation of GSK-3β (Ser9) and increasing the binding of p-CREB to CBP, thereby alleviating the inflammatory response.

scholarly journals Antidiabetic Effects of Arginyl-Fructosyl-Glucose, a Nonsaponin Fraction from Ginseng Processing in Streptozotocin-Induced Type 2 Diabetic Mice through Regulating the PI3K/AKT/GSK-3β and Bcl-2/Bax Signaling Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Xinglong Liu ◽  
Wencong Liu ◽  
Chuanbo Ding ◽  
Yingchun Zhao ◽  
Xueyan Chen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Inflammatory Responses ◽  
Fasting Blood Glucose ◽  
Organ Damage ◽  
Histological Changes ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Gsk 3Β ◽  
Type 2 Diabetic

Streptozotocin- (STZ-) induced type 2 diabetes mellitus (T2DM) caused insulin secretion disorder and hyperglycemia, further causing tissue and organ damage. In recent years, studies on ginseng (Panax ginseng C. A. Meyer) and its saponins (Ginsenosides) have proved to possess antidiabetic pharmacological activities, but the mechanism of nonsaponins on STZ-induced T2DM is still unclear. Arginyl-fructosyl-glucose (AFG) is a representative nonsaponin component produced in the processing of red ginseng. The present study was designed to assess the possible healing consequence of AFG on STZ-induced T2DM in mice and also to explore its fundamental molecular contrivances. T2DM-related indexes, fasting blood glucose levels, and body weight, histological changes, biochemical considerations, biomarkers, the mRNA countenance intensities of inflammatory facts, and variations in correlated protein manifestation in adipose tissue and liver tissue were calculated. Consequences specified that AFG usage successfully amends STZ-induced insulin conflict and liver grievance in T2DM. Systematically, AFG action diminished STZ-induced oxidative stress and inflammatory responses in the liver. In addition, we demonstrated that AFG also attenuates apoptosis and insulin secretion disorders in T2DM by adjusting the PI3K/AKT/GSK3β signaling pathway. At the end, these discoveries recommend that AFG averts the development of T2DM through numerous types of machinery and proposes that AFG can also be used in order to treat T2DM in the future.

scholarly journals MicroRNA-126 enhances the biological function of endothelial progenitor cells under oxidative stress via PI3K/Akt/GSK-3β and ERK1/2 signaling pathways

2020 ◽  
Author(s):  
Qinqin Wu ◽  
Benling Qi ◽  
Xiaoyu Duan ◽  
Xiaoyan Ming ◽  
Fengqin Yan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Biological Function ◽  
Glycogen Synthase ◽  
Early Stage ◽  
Tube Formation ◽  
Dependent Manner ◽  
Endothelial Progenitor ◽  
H2o2 Treatment ◽  
Reverse Transcription Pcr ◽  
Gsk 3Β

Endothelial progenitor cell (EPC) transplantation is a safe and effective method to treat acute myocardial infarction (AMI). However, oxidative stress leads to the death of a large number of EPCs in the early stage of transplantation, severely weakening the therapeutic effect. Previous studies demonstrated that microRNAs (miRNAs) regulate the biological function of EPCs. The aim of the current study was to investigate the effect of miRNA on the biological function of EPCs under oxidative stress. Quantitative reverse transcription PCR was performed to detect the expression of miR-126, miR-508-5p, miR-150, and miR-16 in EPCs from rats, among which miR-126 showed a relatively higher expression. Treatment with H2O2 decreased miR-126 expression in EPCs in a dose-dependent manner. EPCs were further transfected with miR-126 mimics or inhibitors, followed by H2O2 treatment. Overexpression of miR-126 enhanced the proliferation, migration, and tube formation of H2O2-treated EPCs. MiR-126 overexpression also inhibited reactive oxygen species and malondialdehyde levels and enhanced superoxide dismutase levels, as well as increased angiopoietin (Ang)1 expression and decreased Ang2 expression in H2O2-treated EPCs. Moreover, miR-126 participated in the regulation of phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (Akt)/ glycogen synthase kinase-3β (GSK-3β) and extracellular signal-regulated kinase (ERK)1/2 signaling in EPCs, where both pathways were activated after miR-126 overexpression in H2O2-treated EPCs. Overall, we showed that miR-126 promoted the biological function of EPCs under H2O2-induced oxidative stress by activating the PI3K/Akt/GSK-3β and ERK1/2 signaling pathway, which may serve as a new therapeutic approach to treat AMI.

scholarly journals Effect of Pravastatin on Development of Diabetes Mellitus - A Statement of Review

2020 ◽  
Vol 4 (2) ◽  
pp. 1-4
Author(s):  
Ramu G ◽  
Keyword(s):  
Diabetes Mellitus ◽  
Adipose Tissue ◽  
Plasma Lipids ◽  
Fasting Blood Glucose ◽  
Tissue Perfusion ◽  
Lipid Lowering ◽  
Control Group ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Anti Inflammatory

According to the ADA, diabetes mellitus is defined as having fasting blood glucose levels >= 7.0mmol/l. Statins are the lipid-lowering agents used to treat dyslipidemia and act by inhibiting the HMG Co-A reductase enzyme. Very few studies have reported the results of drugs concerning the profile of blood lipids or which have anti-inflammatory activity behaviour on diabetes. Pravastatin is such a drug that shows inherent beneficial pleiotropic effects on plasma lipids and inflammatory actions. Pravastatin remarkably reduced the increased levels of plasma glucose when compared with the control group, subjecting to no change in body weight or food intake in mice. By performing certain insulin tolerance tests using tracers like 2- [3 H]-deoxy glucose (2DG), they concluded that insulin-induced glucose uptake is increased in adipose tissue. Pravastatin is shown to reduce the circulating concentration of the interleukin-6, cytokines, and TNF-alpha. Pravastatin's anti-inflammatory properties interrupt the natural progression from central obesity to insulin resistance mediated by cytokines from the adipose tissue. Pravastatin can significantly impact selective tissue perfusion through restoring the endothelial function and thus benefit the transportation of glucose and insulin.

β-arrestin-1 mediates the endothelin-1-induced activation of Akt and integrin-linked kinaseThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (8) ◽  
pp. 796-801 ◽  
Author(s):  
Roberta Cianfrocca ◽  
Laura Rosanò ◽  
Francesca Spinella ◽  
Valeriana Di Castro ◽  
Pier Giorgio Natali ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Glycogen Synthase ◽  
Kinase Assay ◽  
Signalling Pathways ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Endothelin 1 ◽  
Gsk 3Β ◽  
Phosphoinositide 3 Kinase

The contribution of the endothelin-1 (ET-1)/ET A receptor (ETAR) axis in tumor growth and progression is investigated in many tumor types, including ovarian carcinoma. In ovarian cancer cells, ET-1 acts as an autocrine growth factor selectively through the ETAR triggering the concomitant activation of multiple pathways. In these cells, the involvement of β-arrestin-1 as signal transducer in ET-1-dependent signalling pathways has been recently highlighted. Because several G protein-coupled receptors have been shown to activate signalling pathways in a β-arrestin-dependent manner, in this study we explored whether β-arrestin-1 is involved in a distinct signalling mechanism linking the ETAR to phosphoinositide 3-kinase (PI3K)/integrin-linked kinase (ILK)/Akt in HEY ovarian cancer cells. The inhibitory effects of ZD4054 (zibotentan), a specific ETAR antagonist, in ET-1-dependent phosphorylation of ILK, Akt, and glycogen synthase kinase (GSK-3β) demonstrated the involvement of the ETAR in these effects. By using a kinase assay, we demonstrate that β-arrestin-1 silencing inhibits the ET-1-induced ILK activity in a time-dependent manner and downstream Akt and GSK-3β phosphorylation. These results reveal that β-arrestin-1 is implicated as an ETAR-transducer in the activation of ILK and Akt and in the inactivation of GSK-3β in response to ET-1 and further support the role of β-arrestin-1 as a multifunctional adaptor facilitating interprotein interactions critically involved in ETAR-mediated signalling that regulate invasive and metastatic behaviour of ovarian cancer.

scholarly journals Silymarin Ameliorates Diabetes-Induced Proangiogenic Response in Brain Endothelial Cells through a GSK-3β Inhibition-Induced Reduction of VEGF Release

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Ahmed Alhusban ◽  
Enaam Alkhazaleh ◽  
Tamam El-Elimat
Keyword(s):  
Endothelial Cells ◽  
Glycogen Synthase ◽  
Antioxidant Properties ◽  
Tube Formation ◽  
Dependent Manner ◽  
Brain Endothelial Cells ◽  
Angiogenic Potential ◽  
Gsk 3Β ◽  
Vegf Release

Diabetes mellitus (DM) is a major risk factor for cardiovascular disease. Additionally, it was found to induce a dysfunctional angiogenic response in the brain that was attributed to oxidative stress. Milk thistle seed extract (silymarin) has potent antioxidant properties, though its potential use in ameliorating diabetes-induced aberrant brain angiogenesis is unknown. Glycogen synthase kinase-3β is a regulator of angiogenesis that is upregulated by diabetes. Its involvement in diabetes-induced angiogenesis is unknown. To evaluate the potential of silymarin to ameliorate diabetes-induced aberrant angiogenesis, human brain endothelial cells (HBEC-5i) were treated with 50 μg/mL advanced glycation end (AGE) products in the presence or absence of silymarin (50, 100 μM). The angiogenic potential of HBEC-5i was evaluated in terms of migration and in vitro tube formation capacities. The involvement of GSK-3β was also evaluated. AGE significantly increased the migration and tube formation rates of HBEC-5i by about onefold (p=0.0001). Silymarin reduced AGE-induced migration in a dose-dependent manner where 50 μM reduced migration by about 50%, whereas the 100 μM completely inhibited AGE-induced migration. Similarly, silymarin 50 μg/mL blunted AGE-induced tube formation (p=0.001). This effect was mediated through a GSK-3β-dependent inhibition of VEGF release. In conclusion, silymarin inhibits AGE-induced aberrant angiogenesis in a GSK-3β-mediated inhibition of VEGF release.

scholarly journals Loss of TSC complex enhances gluconeogenesis via upregulation of Dlk1-Dio3 locus miRNAs

2020 ◽  
Vol 117 (3) ◽  
pp. 1524-1532
Author(s):  
Dritan Liko ◽  
Andrzej Rzepiela ◽  
Vanja Vukojevic ◽  
Mihaela Zavolan ◽  
Michael N. Hall
Keyword(s):  
Glucose Intolerance ◽  
Fasting Blood Glucose ◽  
Metabolic Effects ◽  
Small Rna Sequencing ◽  
Dependent Manner ◽  
Aberrant Expression ◽  
Glucose Levels ◽  
Downstream Effector ◽  
Blood Glucose Levels ◽  
Mtorc1 Signaling

Loss of the tumor suppressor tuberous sclerosis complex 1 (Tsc1) in the liver promotes gluconeogenesis and glucose intolerance. We asked whether this could be attributed to aberrant expression of small RNAs. We performed small-RNA sequencing on liver of Tsc1-knockout mice, and found that miRNAs of the delta-like homolog 1 (Dlk1)–deiodinase iodothyronine type III (Dio3) locus are up-regulated in an mTORC1-dependent manner. Sustained mTORC1 signaling during development prevented CpG methylation and silencing of the Dlk1-Dio3 locus, thereby increasing miRNA transcription. Deletion of miRNAs encoded by the Dlk1-Dio3 locus reduced gluconeogenesis, glucose intolerance, and fasting blood glucose levels. Thus, miRNAs contribute to the metabolic effects observed upon loss of TSC1 and hyperactivation of mTORC1 in the liver. Furthermore, we show that miRNA is a downstream effector of hyperactive mTORC1 signaling.

Sign in / Sign up

Export Citation Format

Share Document