scholarly journals Effect of Epigallocatechin Gallate and Catechin on Overexpression of GSK-3β and IR Genes Induced by Streptozotocin in Rat Brain

2019 ◽  
Vol 5 (4) ◽  
pp. 161-167 ◽  
Author(s):  
Marzieh Zamani ◽  
◽  
Kambiz Rohampour ◽  
Samira Rashtiani ◽  
Masoume Dolati ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Significant Risk ◽  
Epigallocatechin Gallate ◽  
Suppressive Effect ◽  
Neuroprotective Activity ◽  
Male Wistar Rats ◽  
Polymerase Chain ◽  
Gsk 3Β ◽  
Ir Genes

Background: Type 2 diabetes mellitus (T2DM) is one of the significant risk factors for Alzheimer disease (AD). Defects in insulin signaling pathway induce AD hallmarks mainly through activation of glycogen synthase kinase-3β (GSK-3β) pathway. Objectives: In this study, we investigated the expression of GSK-3β and insulin receptor (IR) genes in the hippocampi of an animal model of sporadic AD and assessed the preventive effect of Catechin (CAT) and epigallocatechin gallate (EGCG) on their expression. Materials & Methods: Adult male Wistar rats were treated by intracerebroventricular streptozotocin (STZ) injection (3 mg/kg) at day 1 and 3 after cannulation. CAT was administered at a dose of 40 mg/kg for 10 days per gavage, and EGCG was administered at a dose of 3 mg/kg for 14 days into drinking water. Then the animals were decapitated, and their hippocampi were removed. Real-time Polymerase Chain Reaction (PCR) was used to evaluate the alteration in gene expression. Results: There was overexpression in GSK-3β gene in STZ-treated rats (P≤0.05), which was brought back to normalcy by EGCG (P≤0.01). The IR gene also increased after STZ treatment, but CAT reduced IR expression (P≤0.05). However, the suppressive effect of EGCG on IR expression was stronger (P≤0.01). Conclusion: The neuroprotective activity of EGCG might be due to its influence on IR and GSK-3β expression.

scholarly journals Acute elevation of circulating fatty acids impairs downstream insulin signalling in rat skeletal muscle in vivo independent of effects on stress signalling

2008 ◽  
Vol 197 (2) ◽  
pp. 277-285 ◽  
Author(s):  
Georgia Frangioudakis ◽  
Gregory J Cooney
Keyword(s):  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Insulin Signalling ◽  
Plasma Free Fatty Acid ◽  
Nuclear Factor Κb ◽  
Quadriceps Muscle ◽  
Male Wistar Rats ◽  
Gsk 3Β ◽  
Stress Signalling

The aim of this study was to examine the effect of an acute, physiological increase in plasma free fatty acid (FFA) on initial signalling events in rat red quadriceps muscle (RQ). Male Wistar rats received a 7% glycerol (GLYC) or 7% Intralipid/heparin (LIP) infusion for 3 h, after which they were either killed or infused with insulin at a rate of 0.5 U/kg per h for 5 min, before RQ collection. Plasma FFAs were elevated to ∼2 mM in the LIP rats only. Insulin-stimulated insulin receptor (IR) Tyr1162/Tyr1163 phosphorylation and IR substrate (IRS)-1 Tyr612 phosphorylation were increased at least twofold over basal in GLYC rats with insulin and this increase was not significantly impaired in the LIP rats. However, there was no insulin-stimulated protein kinase B (PKB) Ser473 or glycogen synthase kinase (GSK)-3β Ser9 phosphorylation in the LIP rats, compared with at least a twofold increase over basal in GLYC rats for both proteins. c-Jun N-terminal kinase, inhibitor of κ kinase β and inhibitor of nuclear factor-κB phosphorylation and total protein expression, as well as Ser307-IRS-1 phosphorylation, were not altered by lipid infusion compared with GLYC infusion. These data indicate that acute, physiological elevation in FFA has a greater impact on insulin signalling downstream of IR and IRS-1, at the level of PKB and GSK-3β, and that under these conditions stress signalling pathways are not significantly stimulated. Decreased PKB and GSK-3β phosphorylation in RQ may therefore be primary determinants of the reduced insulin action observed in situations of acute FFA oversupply.

scholarly journals Dietary Supplementation with Curcumin Reduce Circulating Levels of Glycogen Synthase Kinase-3β and Islet Amyloid Polypeptide in Adults with High Risk of Type 2 Diabetes and Alzheimer’s Disease

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1032 ◽  
Author(s):  
Rohith N Thota ◽  
Jessica I Rosato ◽  
Cintia B Dias ◽  
Tracy L Burrows ◽  
Ralph N Martins ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Placebo Group ◽  
Glycogen Synthase ◽  
Islet Amyloid Polypeptide ◽  
Dietary Supplementation ◽  
Islet Amyloid ◽  
Gsk 3Β ◽  
Circulating Levels

Dietary supplementation with curcumin has been previously reported to have beneficial effects in people with insulin resistance, type 2 diabetes (T2D) and Alzheimer’s disease (AD). This study investigated the effects of dietary supplementation with curcumin on key peptides implicated in insulin resistance in individuals with high risk of developing T2D. Plasma samples from participants recruited for a randomised controlled trial with curcumin (180 mg/day) for 12 weeks were analysed for circulating glycogen synthase kinase-3 β (GSK-3β) and islet amyloid polypeptide (IAPP). Outcome measures were determined using ELISA kits. The homeostasis model for assessment of insulin resistance (HOMA-IR) was measured as parameters of glycaemic control. Curcumin supplementation significantly reduced circulating GSK-3β (−2.4 ± 0.4 ng/mL vs. −0.3 ± 0.6, p = 0.0068) and IAPP (−2.0 ± 0.7 ng/mL vs. 0.4 ± 0.6, p = 0.0163) levels compared with the placebo group. Curcumin supplementation significantly reduced insulin resistance (−0.3 ± 0.1 vs. 0.01 ± 0.05, p = 0.0142) compared with placebo group. Dietary supplementation with curcumin reduced circulating levels of IAPP and GSK-3β, thus suggesting a novel mechanism through which curcumin could potentially be used for alleviating insulin resistance related markers for reducing the risk of T2D and AD.

scholarly journals Characterization and Hypoglycemic Activity of a Rhamnan-Type Sulfated Polysaccharide Derivative

Marine Drugs ◽  
2019 ◽  
Vol 17 (1) ◽  
pp. 21 ◽  
Author(s):  
Jie-Fen Cui ◽  
Han Ye ◽  
Yu-Jie Zhu ◽  
Yin-Ping Li ◽  
Jing-Feng Wang ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Lethal Dose ◽  
Insulin Receptors ◽  
Sulfated Polysaccharide ◽  
Phosphatidylinositol 3 Kinase ◽  
Pharmaceutical Development ◽  
Hypoglycemic Agent ◽  
Gsk 3Β ◽  
Polysaccharide Derivative

Polysaccharide chromium (III) derivatives are gaining increasing attention in improving type 2 diabetes. In this study, the sulfated polysaccharide from Enteromorpha prolifera (SPE) with 4.8 kDa was prepared by specific enzymatic hydrolysis. The obtained SPE was used to prepare a rhamnan-type sulfated polysaccharide derivative (SPED). Results indicated that O-H, C=O, and S=O were effectively involved in the chelation of SPED (chromium content 20.26%). Acute (half lethal dose > 2.38 g/kg) and sub-acute toxicity showed that SPED had no damaging effects on mice. Anti-diabetic experiment demonstrated that SPED improved glucose metabolism. Moreover, SPED promoted the PI3K/PKB/GSK-3β signaling pathway by regulating mRNA expression of insulin receptors (IR), insulin receptor substrate 2 (IRS-2), phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB), and glycogen synthase kinase 3β (GSK-3β). In conclusion, the SPED might represent a novel marine-derived candidate against hyperglycemia, which may undergo further pharmaceutical development as a hypoglycemic agent.

scholarly journals Lithium Chloride Suppresses Colorectal Cancer Cell Survival and Proliferation through ROS/GSK-3β/NF-κB Signaling Pathway

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Huili Li ◽  
Kun Huang ◽  
Xinghua Liu ◽  
Jinlin Liu ◽  
Xiaoming Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase 3 ◽  
Potential Therapeutic Target ◽  
Colorectal Cancer Cells ◽  
Cancer Cell Survival ◽  
Polymerase Chain ◽  
Cancer Intervention ◽  
Underlying Mechanisms ◽  
Gsk 3Β

Glycogen synthase kinase-3β(GSK-3β), a serine/threonine protein kinase, has been regarded as a potential therapeutic target for multiple human cancers. In addition, oxidative stress is closely related to all aspects of cancer. We sought to determine the biological function of lithium, one kind of GSK-3βinhibitors, in the process of reactive oxygen species (ROS) production in colorectal cancer. In this study, we analyzed the cell apoptosis and proliferation by cell viability, EdU, and flow cytometry assays through administration of LiCl. We used polymerase chain reaction and Western blotting to establish the effect of GSK-3βinhibition on the nuclear factor-κB (NF-κB) pathway. Results showed administration of LiCl increased apoptosis and the level of ROS in colorectal cancer cells. Furthermore, the underlying mechanisms could be mediated by the reduction of NF-κB expression and NF-κB-mediated transcription. Taken together, our results demonstrated that therapeutic targeting of ROS/GSK-3β/NF-κB pathways may be an effective way for colorectal cancer intervention, although further preclinical and clinical testing are desirable.

scholarly journals Fisiopatologia e desenvolvimento do diabetes mellitus tipo 3 e sua relação com a doença de Alzheimer

2021 ◽  
Vol 4 (35) ◽  
pp. 421-426
Author(s):  
Giúlia Jäger Maximowicz de Oliveira ◽  
Camila Luisa Roda Cichacewski ◽  
Carolina Fantin Carneiro ◽  
Leticia Fuganti Campos ◽  
Antônio Carlos Ligocki Campos
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glycogen Synthase ◽  
Dietary Interventions ◽  
Cortical Function ◽  
Insulin Metabolism ◽  
Gsk 3Β ◽  
Type 3

Introduction: Alzheimer’s disease (AD) is characterized by a progressive and persistent deterioration of the whole cognitive function, which results in an impaired cortical function. Some years ago, the connection between AD and type 2 diabetes has been studied, resulting in the term type 3 diabetes (T3D). Methods: This is a literature review, a search for articles published in the last 5 years in the Medline and PubMed databases was performed, using the descriptor: Alzheimer disease, diabetes, insulin resistance. Results: For analysis, 12 articles were selected, with 10 literature reviews and 2 original studies. Among those who explored the cellular and molecular relationship between AD and insulin resistance, possible pathogenic mechanisms, the role of insulin in the brain, environmental factors linked to AD and dietary interventions to prevent neurodegeneration. Conclusion: The relation between AD and type 2 diabetes is due several mechanisms such as lipid metabolism, insulin metabolism and agents related to its functioning, like the ApoEε4, C-peptide, the glycogen synthase kinase 3β (GSK-3β) and the amyloid-beta (Aβ). It is suggested that several changes, mainly in insulin metabolism, can impair neurocognitive function and trigger AD. Future studies are needed to analyze the context of T3D and find possible treatments that attenuate the AD progression and promote quality of life for the patients.

scholarly journals Sulforaphane prevents type 2 diabetes-induced nephropathy via AMPK-mediated activation of lipid metabolic pathways and Nrf2 antioxidative function

2020 ◽  
Vol 134 (18) ◽  
pp. 2469-2487
Author(s):  
Zhuo Li ◽  
Hua Guo ◽  
Jia Li ◽  
Tianjiao Ma ◽  
Shanshan Zhou ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Lipid Metabolism ◽  
Glycogen Synthase ◽  
Normal Diet ◽  
Renal Hypertrophy ◽  
Antioxidative Function ◽  
Urine Albumin ◽  
Induce Insulin Resistance ◽  
Gsk 3Β

Abstract Sulforaphane (SFN) prevents diabetic nephropathy (DN) in type 2 diabetes (T2D) by up-regulating nuclear factor (erythroid-derived 2)-like 2 (Nrf2). AMP-activated protein kinase (AMPK) can attenuate the pathogenesis of DN by improving renal lipotoxicity along with the activation of Nrf2-mediated antioxidative signaling. Therefore, we investigated whether AMPKα2, the central subunit of AMPK in energy metabolism, is required for SFN protection against DN in T2D, and whether potential cross-talk occurs between AMPKα2 and Nrf2. AMPKα2 knockout (Ampkα2−/−) mice and wildtype (WT) mice were fed a high-fat diet (HFD) or a normal diet (ND) to induce insulin resistance, followed by streptozotocin (STZ) injection to induce hyperglycemia, as a T2D model. Both T2D and control mice were treated with SFN or vehicle for 3 months. At the end of the 3-month treatment, all mice were maintained only on HFD or ND for an additional 3 months without SFN treatment. Mice were killed at sixth month after T2D onset. Twenty-four-hour urine albumin at third and sixth months was significantly increased as renal dysfunction, along with significant renal pathological changes and biochemical changes including renal hypertrophy, oxidative damage, inflammation, and fibrosis in WT T2D mice, which were prevented by SFN in certain contexts, but not in Ampkα2−/− T2D mice. SFN prevention of T2D-induced renal lipotoxicity was associated with AMPK-mediated activation of lipid metabolism and Nrf2-dependent antioxidative function in WT mice, but not in SFN-treated Ampkα2−/− mice. Therefore, SFN prevention of DN is AMPKα2-mediated activation of probably both lipid metabolism and Nrf2 via AMPK/AKT/glycogen synthase kinase (GSK)-3β/Src family tyrosine kinase (Fyn) pathways.

Strong Association of Serum GSK-3β/BDNF Ratio with Mild Cognitive Impairment in Elderly Type 2 Diabetic Patients

2020 ◽  
Vol 16 (12) ◽  
pp. 1151-1160
Author(s):  
Bingying Du ◽  
Yongjie Lian ◽  
Chao Chen ◽  
Hailing Zhang ◽  
Yueping Bi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Function ◽  
Glycogen Synthase ◽  
Diabetic Patients ◽  
Diagnostic Biomarker ◽  
Gsk 3Β ◽  
And Oxidative Stress

Background: Glycogen Synthase Kinase (GSK)-3β and Brain-derived Neurotrophic Factor (BDNF) play vital roles in both Mild Cognitive Impairment (MCI) and Type 2 Diabetes Mellitus (T2DM). The underlying mechanisms may involve inflammation and oxidative stress. Objectives: To investigate the association of the GSK-3β/BDNF ratio with MCI in elderly patients with T2DM and whether GSK-3β/BDNF ratio can serve as a new diagnostic biomarker for MCI in comorbid with T2DM (MD). Methods: A total of 326 old Chinese T2DM patients were included and stratified according to cognition and GSK-3β/BDNF ratio quartiles. MCI was diagnosed according to the National Institute on Aging Alzheimer’s Association workgroups criteria. In addition to routine hematuria and biochemical examinations, Montreal Cognitive Assessment (MoCA) scale was also used to evaluate the cognitive function, and ELISA method was used to measure GSK-3β activity and the serum levels of BDNF, interleukin 1β (IL-1β), high mobility group box-1 (HMGB1) protein, Malonaldehyde (MDA) and 8-isoprostaglandinF2α (8-iso-PGF2α). Results: We found that GSK-3β activity was negatively correlated with BDNF (r=-0.270, P=0.008), and patients with higher GSK-3β/BDNF ratio had lower MoCA scores (P=0.001). When compared with T2DM patients without MCI (nMD), MD patients had higher GSK-3β activity and GSK-3β/BDNF ratio, but lower BDNF levels. As for inflammation and oxidative stress, IL-1β was inversely correlated with GSK-3β activity, while 8-isoPGF2α was positively correlated with GSK-3β activity and GSK-3β/BDNF ratio. The odds ratio for MCI increased gradually when GSK-3β/BDNF ratio quartile rose from the lowest to the highest (6.90, 95% CI 3.22-14.78). MoCA score was conversely related to GSK-3β/BDNF ratio, age and fast blood glucose (FBG), with GSK-3β/BDNF ratio having the most significant influence on cognition (β=-0.199, P<0.001). Conclusion: Our data provide evidence for a strong link between GSK-3β/BDNF ratio and MCI. GSK- 3β/BDNF ratio may serve as a better diagnostic biomarker for MD than either GSK-3β or BDNF alone and increased GSK-3β/BDNF ratio indicates a worse cognitive function.

Molecular analysis of FVIII gene in severe HA patients of Costa Rica

2010 ◽  
Vol 30 (S 01) ◽  
pp. S150-S152
Author(s):  
G. Jiménez-Cruz ◽  
M. Mendez ◽  
P. Chaverri ◽  
P. Alvarado ◽  
W. Schröder ◽  
...  
Keyword(s):  
Factor Viii ◽  
Coagulation Factor ◽  
Costa Rican ◽  
Factor Viii Gene ◽  
Intron 22 Inversion ◽  
Intron 1 ◽  
Polymerase Chain ◽  
Inversion Analysis

SummaryHaemophilia A (HA) is X-chromosome linked bleeding disorders caused by deficiency of the coagulation factor VIII (FVIII). It is caused by FVIII gene intron 22 inversion (Inv22) in approximately 45% and by intron 1 inversion (Inv1) in 5% of the patients. Both inversions occur as a result of intrachromosomal recombination between homologous regions, in intron 1 or 22 and their extragenic copy located telomeric to the FVIII gene. The aim of this study was to analyze the presence of these mutations in 25 HA Costa Rican families. Patients, methods: We studied 34 HA patients and 110 unrelated obligate members and possible carriers for the presence of Inv22or Inv1. Standard analyses of the factor VIII gene were used incl. Southern blot and long-range polymerase chain reaction for inversion analysis. Results: We found altered Inv22 restriction profiles in 21 patients and 37 carriers. It was found type 1 and type 2 of the inversion of Inv22. During the screening for Inv1 among the HA patient, who were Inv22 negative, we did not found this mutation. Discussion: Our data highlight the importance of the analysis of Inv22 for their association with development of inhibitors in the HA patients and we are continuous searching of Inv1 mutation. This knowledge represents a step for genetic counseling and prevention of the inhibitor development.

Synthesis of Coumarin Derivatives as Versatile Scaffolds for GSK-3β Enzyme Inhibition

2020 ◽  
Vol 20 (2) ◽  
pp. 153-160 ◽  
Author(s):  
Carla S. Francisco ◽  
Clara L. Javarini ◽  
Iatahanderson de S. Barcelos ◽  
Pedro A.B. Morais ◽  
Heberth de Paula ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Glycogen Synthase ◽  
Synthetic Methods ◽  
Kinase Assay ◽  
Crystallographic Structure ◽  
Coumarin Derivatives ◽  
Enzymatic Production ◽  
Docking Simulations ◽  
In Silico Studies ◽  
Gsk 3Β

Background: Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3β isoforms is likely to represent an effective strategy against AD. Objective: The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3β kinase inhibitors. Method: The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3β activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3β complex [Protein Data Bank (PDB) code: 1Q3D]. Results: The eleven coumarin derivatives were obtained and evaluated as potential GSK-3β inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3β enzymatic activity by 38.97–49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224–6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. Conclusion: The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3β inhibitors.

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