scholarly journals Structural-Based Optimizations of the Marine-Originated Meridianin C as Glucose Uptake Agents by Inhibiting GSK-3β

Marine Drugs ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 149
Author(s):  
Shuwen Han ◽  
Chunlin Zhuang ◽  
Wei Zhou ◽  
Fener Chen
Keyword(s):  
Glucose Uptake ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Molecular Target ◽  
Optimization Strategy ◽  
Lead Compounds ◽  
Significant Toxicity ◽  
Treatment Of Diabetes ◽  
Gsk 3Β ◽  
Positive Compound

Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases, and inhibition of GSK-3β activity has become an attractive approach for the treatment of diabetes. Meridianin C, an indole-based natural product isolated from marine Aplidium meridianum, has been reported as a potent GSK-3β inhibitor. In the present study, applying the structural-based optimization strategy, the pyrimidine group of meridianin C was modified by introducing different substituents based on the 2-aminopyrimidines-substituted pyrazolo pyridazine scaffold. Among them, compounds B29 and B30 showed a much higher glucose uptake than meridianin C (<5%) and the positive compound 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8, 16%), with no significant toxicity against HepG2 cells at the same time. Furthermore, they displayed good GSK-3β inhibitory activities (IC50 = 5.85; 24.4 μM). These results suggest that these meridianin C analogues represent novel lead compounds with therapeutic potential for diabetes.

scholarly journals GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 610
Author(s):  
Robin Park ◽  
Andrew L. Coveler ◽  
Ludimila Cavalcante ◽  
Anwaar Saeed
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
In Vivo Models ◽  
Gsk 3Β ◽  
Early Phase Clinical Trials

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

scholarly journals Insulin directly stimulates mitochondrial glucose oxidation in the heart

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Qutuba G. Karwi ◽  
Cory S. Wagg ◽  
Tariq R. Altamimi ◽  
Golam M. Uddin ◽  
Kim L. Ho ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Oxidation ◽  
Glycogen Synthase ◽  
Acid Oxidation ◽  
Mouse Heart ◽  
Insulin Stimulation ◽  
Direct Stimulation ◽  
Gsk 3Β ◽  
Stimulation Of

Abstract Background Glucose oxidation is a major contributor to myocardial energy production and its contribution is orchestrated by insulin. While insulin can increase glucose oxidation indirectly by enhancing glucose uptake and glycolysis, it also directly stimulates mitochondrial glucose oxidation, independent of increasing glucose uptake or glycolysis, through activating mitochondrial pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. However, how insulin directly stimulates PDH is not known. To determine this, we characterized the impacts of modifying mitochondrial insulin signaling kinases, namely protein kinase B (Akt), protein kinase C-delta (PKC-δ) and glycogen synthase kinase-3 beta (GSK-3β), on the direct insulin stimulation of glucose oxidation. Methods We employed an isolated working mouse heart model to measure the effect of insulin on cardiac glycolysis, glucose oxidation and fatty acid oxidation and how that could be affected when mitochondrial Akt, PKC-δ or GSK-3β is disturbed using pharmacological modulators. We also used differential centrifugation to isolate mitochondrial and cytosol fraction to examine the activity of Akt, PKC-δ and GSK-3β between these fractions. Data were analyzed using unpaired t-test and two-way ANOVA. Results Here we show that insulin-stimulated phosphorylation of mitochondrial Akt is a prerequisite for transducing insulin’s direct stimulation of glucose oxidation. Inhibition of mitochondrial Akt completely abolishes insulin-stimulated glucose oxidation, independent of glucose uptake or glycolysis. We also show a novel role of mitochondrial PKC-δ in modulating mitochondrial glucose oxidation. Inhibition of mitochondrial PKC-δ mimics insulin stimulation of glucose oxidation and mitochondrial Akt. We also demonstrate that inhibition of mitochondrial GSK3β phosphorylation does not influence insulin-stimulated glucose oxidation. Conclusion We identify, for the first time, insulin-stimulated mitochondrial Akt as a prerequisite transmitter of the insulin signal that directly stimulates cardiac glucose oxidation. These novel findings suggest that targeting mitochondrial Akt is a potential therapeutic approach to enhance cardiac insulin sensitivity in condition such as heart failure, diabetes and obesity.

Troglitazone ameliorates high glucose-induced EMT and dysfunction of SGLTs through PI3K/Akt, GSK-3β, Snail1, and β-catenin in renal proximal tubule cells

2010 ◽  
Vol 298 (5) ◽  
pp. F1263-F1275 ◽  
Author(s):  
Yu Jin Lee ◽  
Ho Jae Han
Keyword(s):  
Protein Expression ◽  
Glucose Uptake ◽  
Membrane Transport ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Glycogen Synthase ◽  
Mesenchymal Transition ◽  
Pparγ Agonist ◽  
Gsk 3Β ◽  
Tgf Β1

Peroxisome proliferator-activated receptor-γ (PPARγ) agonists ameliorate renal fibrotic lesions in diabetic nephropathy. However, the effects of the agonists on the epithelial-mesenchymal transition (EMT) linked to membrane transport dysfunction are unknown. The present study aimed to verify the effects of the PPARγ agonist troglitazone on high glucose (HG)-induced EMT in primary cultured renal proximal tubular epithelial cells (PTCs). HG (25 mM) as well as hydrogen peroxide (H2O2) and transforming growth factor-β1 (TGF-β1) decreased expression of epithelial cell marker E-cadherin and increased the expression of the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA). HG, H2O2, and TGF-β1 decreased Na+/H+ exchangers (NHEs) or Na+-glucose cotransporters (SGLTs) and glucose uptake, showing membrane transport dysfunction. HG stimulated the production of cellular reactive oxygen species (ROS), and antioxidants blocked the HG-induced increase in phosphatidylinositol 3-kinase (PI3K)/Akt activation. Antioxidants and inhibitors of PI3K/Akt reversed HG-induced EMT protein expression. Inhibition of PI3K/Akt also blocked HG-induced glycogen synthase kinase-3β (GSK-3β) phosphorylation. HG and lithium chloride (GSK-3β inhibitor) blocked Snail1 and β-catenin activation. Moreover, transfection with Snail1 or β-catenin small interfering RNA (siRNA) reversed HG-induced EMT protein expression. Importantly, HG decreased PPARγ activation and troglitazone reversed HG-induced expression of PI3K/Akt, GSK-3β, Snail1, and β-catenin as well as EMT proteins. Finally, inhibitors of PI3K/Akt, Snail1/β-catenin siRNA, and troglitazone blocking the HG-induced EMT restored glucose uptake in PTCs. In conclusion, HG induces EMT through ROS, PI3K/Akt, GSK-3β, Snail, and β-catenin. Subsequently, HG-induced EMT may result in SGLT dysfunction that is restored by the PPARγ agonist troglitazone in primary cultured PTCs.

scholarly journals The Key Roles of GSK-3β in Regulating Mitochondrial Activity

2017 ◽  
Vol 44 (4) ◽  
pp. 1445-1459 ◽  
Author(s):  
Kai Yang ◽  
Zhixi Chen ◽  
Juanjuan Gao ◽  
Weimei Shi ◽  
Linfu Li ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Mitochondrial Activity ◽  
Cell Fates ◽  
Lead Compounds ◽  
Mitochondrial Functions ◽  
Wide Range ◽  
Mitochondrial Motility ◽  
Regulatory Effects ◽  
Gsk 3Β ◽  
Molecular Pathophysiology

Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, has been reported to show essential roles in molecular pathophysiology of many diseases. Mitochondrion is a dynamic organelle for producing cellular energy and determining cell fates. Stress-induced translocated GSK-3β may interact with mitochondrial proteins, including PI3K-Akt, PGC-1α, HK II, PKCε, components of respiratory chain, and subunits of mPTP. Mitochondrial pool of GSK-3β has been implicated in mediation of mitochondrial functions. GSK-3β exhibits the regulatory effects on mitochondrial biogenesis, mitochondrial bioenergetics, mitochondrial permeability, mitochondrial motility, and mitochondrial apoptosis. The versatile functions of GSK-3β might be associated with its wide range of substrates. Accumulative evidence demonstrates that GSK-3β inactivation may be potentially developed as the promising strategy in management of many diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Intensive efforts have been made for exploring GSK-3β inhibitors. Natural products provide us a great source for screening new lead compounds in inactivation of GSK-3β. The key roles of GSK-3β in mediation of mitochondrial functions are discussed in this review.

INTRUSION OF GLYCOGEN SYNTHASE KINASE-3Β TO COPE VARIOUS CARDIAC DISORDERS AT MOLECULAR LEVEL

INDIAN DRUGS ◽  
2020 ◽  
Vol 57 (09) ◽  
pp. 7-18
Author(s):  
Vishal Kumar Vishwakarma ◽  
Tarique Mahmood Ansari ◽  
Anup Maiti ◽  
Ritesh Kumar Srivastav ◽  
Paramdeep Bagga ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Glycogen Synthase ◽  
Cell Signalling ◽  
Mitochondrial Protein ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Cellular Functions ◽  
Lead Compounds ◽  
Cardiac Disorders ◽  
Gsk 3Β

All eukaryotes consist of kinases with a serine/threonine residue called glycogen synthase kinase 3 (GSK-3) which mediates cellular functions by causing phosphorylation of glycogen synthase and regulating glucose metabolism. It establishes disease mechanisms through cell signalling and different transcription factors. Glycogen synthase kinase-3β (GSK-3β) has pharmacological role in cardiac fibrosis, hyperlipidaemia, hyperglycaemia, hyperhomocysteinemia and in case of myocardial reperfusion injury and estrogen deficiency on the heart. The lead compounds were discovered from natural products possessing GSK-3β inhibitory activity. New signalling pathways involving mitochondrion have been investigated for ischemic preconditioning. GSK-3β may bind with mitochondrial protein and mediate mitochondrion function by binding with PI3K-Akt, PGC-1α, HK-II, PKCε subunits of mPTP. The present study explores the structural functionalities of GSK-3β and their contributory role in cardiac disorders and various other diseases. Therefore, GSK-3β is believed to be an imperative target for the discovery and development of newer drugs.

Contraction activates glucose uptake and glycogen synthase normally in muscles from dexamethasone-treated rats

2005 ◽  
Vol 289 (2) ◽  
pp. E241-E250 ◽  
Author(s):  
Jérôme Ruzzin ◽  
Jørgen Jensen
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Skeletal Muscles ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Synthase Kinase 3 ◽  
Dexamethasone Treatment ◽  
Insulin Resistant ◽  
Gsk 3Β

Glucocorticoids cause insulin resistance in skeletal muscle. The aims of the present study were to investigate the effects of contraction on glucose uptake, insulin signaling, and regulation of glycogen synthesis in skeletal muscles from rats treated with the glucocorticoid analog dexamethasone (1 mg·kg−1·day−1 ip for 12 days). Insulin resistance in dexamethasone-treated rats was confirmed by reduced insulin-stimulated glucose uptake (∼35%), glycogen synthesis (∼70%), glycogen synthase activation (∼80%), and PKB Ser473 phosphorylation (∼40%). Chronic dexamethasone treatment did not impair glucose uptake during contraction in soleus or epitrochlearis muscles. In epitrochlearis (but not in soleus), the presence of insulin during contraction enhanced glucose uptake to similar levels in control and dexamethasone-treated rats. Contraction also increased glycogen synthase fractional activity and dephosphorylated glycogen synthase at Ser645, Ser649, Ser653, and Ser657 normally in muscles from dexamethasone-treated rats. After contraction, insulin-stimulated glycogen synthesis was completely restored in epitrochlearis and improved in soleus from dexamethasone-treated rats. Contraction did not increase insulin-stimulated PKB Ser473 or glycogen synthase kinase-3 (GSK-3) phosphorylation. Instead, contraction increased GSK-3β Ser9 phosphorylation in epitrochlearis (but not in soleus) in muscles from control and dexamethasone-treated rats. In conclusion, contraction stimulates glucose uptake normally in dexamethasone-induced insulin resistant muscles. After contraction, insulin's ability to stimulate glycogen synthesis was completely restored in epitrochlearis and improved in soleus from dexamethasone-treated rats.

Role of Akt2 in contraction-stimulated cell signaling and glucose uptake in skeletal muscle

2006 ◽  
Vol 291 (5) ◽  
pp. E1031-E1037 ◽  
Author(s):  
Kei Sakamoto ◽  
David E. Arnolds ◽  
Nobuharu Fujii ◽  
Henning F. Kramer ◽  
Michael F. Hirshman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Intracellular Signaling ◽  
Mammalian Cells ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Metabolism ◽  
Serine Threonine Kinase ◽  
Gsk 3Β

The serine/threonine kinase Akt/PKB plays diverse roles in cells, and genetic studies have indicated distinct roles for the three Akt isoforms expressed in mammalian cells and tissues. Akt2 is a key signaling intermediate for insulin-stimulated glucose uptake and glycogen synthesis in skeletal muscle. Akt2 has also been shown to be activated by exercise and muscle contraction in both rodents and humans. In this study, we used Akt2 knockout mice to explore the role of Akt2 in exercise-stimulated glucose uptake and glycogen synthesis as well as intracellular signaling pathways that regulate glycogen metabolism in skeletal muscle. We found that Akt2 deficiency does not affect basal or exercise-stimulated glucose uptake or intracellular glycogen content in the soleus muscle. In addition, lack of Akt2 did not result in alterations in basal Akt Thr308 or basal and contraction-stimulated glycogen synthase kinase-3β (GSK-3β) Ser9 phosphorylation, glycogen synthase phosphorylation, or glycogen synthase activity. In contrast, in situ contraction failed to elicit normal increases in Akt T-loop Thr308 phosphorylation and GSK-3α Ser21 phosphorylation in tibialis anterior muscles from Akt2-deficient animals. Our data establish a key role for Akt2 in the regulation of GSK-3α Ser21 phosphorylation with contraction and add genetic evidence to support the separation of the intracellular pathways regulated by insulin and exercise that converge on glucose uptake and glycogen synthesis in skeletal muscle.

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.

scholarly journals Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ilandarage Menu Neelaka Molagoda ◽  
Jayasingha Arachchige Chathuranga C Jayasingha ◽  
Yung Hyun Choi ◽  
Rajapaksha Gedara Prasad Tharanga Jayasooriya ◽  
Chang-Hee Kang ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Endotoxic Shock ◽  
Inflammatory Activity ◽  
Prostaglandin E ◽  
Necrosis Factor Alpha ◽  
Zebrafish Larvae ◽  
Proinflammatory Mediators ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Gsk 3Β

AbstractFisetin is a naturally occurring flavonoid that possesses several pharmacological benefits including anti-inflammatory activity. However, its precise anti-inflammatory mechanism is not clear. In the present study, we found that fisetin significantly inhibited the expression of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Additionally, fisetin attenuated LPS-induced mortality and abnormalities in zebrafish larvae and normalized the heart rate. Fisetin decreased the recruitment of macrophages and neutrophils to the LPS-microinjected inflammatory site in zebrafish larvae, concomitant with a significant downregulation of proinflammatory genes, such as inducible NO synthase (iNOS), cyclooxygenase-2a (COX-2a), IL-6, and TNF-α. Fisetin inhibited the nuclear localization of nuclear factor-kappa B (NF-κB), which reduced the expression of pro-inflammatory genes. Further, fisetin inactivated glycogen synthase kinase 3β (GSK-3β) via phosphorylation at Ser9, and inhibited the degradation of β-catenin, which consequently promoted the localization of β-catenin into the nucleus. The pharmacological inhibition of β-catenin with FH535 reversed the fisetin-induced anti-inflammatory activity and restored NF-κB activity, which indicated that fisetin-mediated activation of β-catenin results in the inhibition of LPS-induced NF-κB activity. In LPS-microinjected zebrafish larvae, FH535 promoted the migration of macrophages to the yolk sac and decreased resident neutrophil counts in the posterior blood island and induced high expression of iNOS and COX-2a, which was accompanied by the inhibition of fisetin-induced anti-inflammatory activity. Altogether, the current study confirmed that the dietary flavonoid, fisetin, inhibited LPS-induced inflammation and endotoxic shock through crosstalk between GSK-3β/β-catenin and the NF-κB signaling pathways.

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