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 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 Regulation of thymocyte β-selection, development and positive selection by glycogen synthase kinase-3

2019 ◽  
Author(s):  
Michael J. Parsons ◽  
Satish Patel ◽  
Bradley W. Doble ◽  
Pamela S. Ohashi ◽  
James R. Woodgett
Keyword(s):  
Positive Selection ◽  
Glycogen Synthase ◽  
Functional Expression ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Phosphatidylinositol 3 Kinase ◽  
Double Positive ◽  
Serine Threonine Kinase ◽  
Gsk 3Β ◽  
Knockout Animals

AbstractGlycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase, that exists as two isoforms in mammals, GSK-3α and GSK-3β, that are key downstream mediators of the phosphatidylinositol 3’ kinase, Wnt, Notch and other pathways. Here, we report that simultaneous inactivation of both GSK-3α and GSK-3β during early thymocyte ontogeny has profound effects on both β-selection and positive selection, key checkpoints essential to producing functionally mature αβ T cells. Conditional GSK-3α/β knockout animals (LckCre+ GSK-3αβfl/fl) possessed pre-double positive (pre-DP) thymocytes (CD4−CD8−CD117−CD25−) with compromised TCRβ chain expression along with elevated levels of β-catenin and reduced Notch activity. β-selection was impaired allowing pre-DP thymocytes to differentiate to DP thymocytes (CD4+CD8+) while bypassing strict requirements for productive TCRβ chain rearrangements and functional expression. Also impaired was the requisite pre-TCR and Notch-mediated expansion that normally precedes differentiation to the DP stage. Consequently, LckCre+ GSK-3αβfl/fl mice initially generated fewer DP thymocytes that expressed significantly reduced levels of mature TCR. The aberrant DP thymocytes expressed high levels of the pro-survival Bcl-2 family member Mcl-1, failed positive selection and accumulated as CD4hiCD8lo positive selection intermediates resulting in loss of both mature CD4 and CD8 lineages. LckCre+ GSK-3αβfl/fl mice succumbed to oligoclonal peripheral lymphomas with high penetrance. These data reveal essential roles for GSK-3 in several checkpoints of early T cell development.

In vivo regulation of protein-serine kinases by insulin in skeletal muscle of fructose-hypertensive rats

1999 ◽  
Vol 277 (2) ◽  
pp. E299-E307 ◽  
Author(s):  
Sanjay Bhanot ◽  
Baljinder S. Salh ◽  
Subodh Verma ◽  
John H. McNeill ◽  
Steven L. Pelech
Keyword(s):  
Skeletal Muscle ◽  
Glycogen Synthase ◽  
Insulin Injection ◽  
Glycogen Synthase Kinase 3 ◽  
Phosphatidylinositol 3 Kinase ◽  
S6 Kinase ◽  
Serine Kinases ◽  
Gsk 3Β

The effects of tail-vein insulin injection (2 U/kg) on the regulation of protein-serine kinases in hindlimb skeletal muscle were investigated in hyperinsulinemic hypertensive fructose-fed (FF) animals that had been fasted overnight. Basal protein kinase B (PKB) activity was elevated about twofold in FF rats and was not further stimulated by insulin. Phosphatidylinositol 3-kinase (PI3K), which lies upstream of PKB, was increased ∼3.5-fold within 2–5 min by insulin in control rats. Basal and insulin-activated PI3K activities were further enhanced up to 2-fold and 1.3-fold, respectively, in FF rats. The 70-kDa S6 kinase (S6K) was stimulated about twofold by insulin in control rats. Both basal and insulin-stimulated S6K activity was further enhanced up to 1.5-fold and 3.5-fold, respectively, in FF rats. In control rats, insulin caused a 40–50% reduction of the phosphotransferase activity of the β-isoform of glycogen synthase kinase 3 (GSK-3β), which is a PKB target in vitro. Basal GSK-3β activity was decreased by ∼40% in FF rats and remained unchanged after insulin treatment. In summary, 1) the PI3K → PKB → S6K pathway was upregulated under basal conditions, and 2) insulin stimulation of PI3K and S6K activities was enhanced, but both PKB and GSK-3 were refractory to the effects of insulin in FF rats.

scholarly journals PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Rui Liu ◽  
Youwen Chen ◽  
Guangzhi Liu ◽  
Chenxi Li ◽  
Yurong Song ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Lipid Kinase ◽  
Cellular Processes ◽  
Nuclear Factor Kappa Beta ◽  
Apoptosis Related Protein ◽  
Gsk 3Β

Abstract Multidrug resistance (MDR) is the dominant challenge in the failure of chemotherapy in cancers. Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that spreads intracellular signal cascades and regulates a variety of cellular processes. PI3Ks are considered significant causes of chemoresistance in cancer therapy. Protein kinase B (AKT) is also a significant downstream effecter of PI3K signaling, and it modulates several pathways, including inhibition of apoptosis, stimulation of cell growth, and modulation of cellular metabolism. This review highlights the aberrant activation of PI3K/AKT as a key link that modulates MDR. We summarize the regulation of numerous major targets correlated with the PI3K/AKT pathway, which is further related to MDR, including the expression of apoptosis-related protein, ABC transport and glycogen synthase kinase-3 beta (GSK-3β), synergism with nuclear factor kappa beta (NF-κB) and mammalian target of rapamycin (mTOR), and the regulation of glycolysis.

scholarly journals Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen–glucose deprivation-induced apoptosis in primary rat cortical neuronal cells

2008 ◽  
Vol 198 (3) ◽  
pp. 511-521 ◽  
Author(s):  
Hyunju Chung ◽  
Sanghee Seo ◽  
Minho Moon ◽  
Seungjoon Park
Keyword(s):  
Glycogen Synthase ◽  
Glucose Deprivation ◽  
Glycogen Synthase Kinase ◽  
Protective Effects ◽  
Glycogen Synthase Kinase 3Β ◽  
Phosphatidylinositol 3 Kinase ◽  
Unacylated Ghrelin ◽  
Gsk 3Β ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Only acylated ghrelin (AG) binds GH secretagog receptor 1a (GHS-R1a) and has central endocrine activities. An anti-apoptotic effect of AG in neuronal cells has recently been reported. However, whether there is a neuroprotective effect of unacylated ghrelin (UAG), the most abundant form of ghrelin in plasma, is still unknown. Therefore, we investigated whether UAG was neuroprotective against ischemic neuronal injury using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD). Both AG and UAG inhibited OGD-induced apoptosis. Exposure of cells to the receptor-specific antagonist d-Lys-3-GHRH-6 abolished the protective effects of AG against OGD, whereas those of UAG were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. Chemical inhibition of MAPK and phosphatidylinositol-3-kinase (PI3K) blocked the anti-apoptotic effects of AG and UAG. Ghrelin siRNA enhanced apoptosis either during OGD or even in normoxic conditions. The protective effects of AG and UAG were accompanied by an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3β (GSK-3β). Furthermore, treatment of cells with AG or UAG resulted in nuclear translocation of β-catenin. In addition, both AG and UAG increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. The data indicate that, independent of acylation, ghrelin can function as a neuroprotective agent that inhibits apoptotic pathways. These effects may be mediated via activation of the MAPK and PI3K/Akt pathways. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3β and stabilization of β-catenin contribute to the anti-apoptotic effects of ghrelin.

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 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 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.

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