Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases

Medicinal Research Reviews, Journal Year: 2021, Volume and Issue: 42(2), P. 946 - 982

Published: Nov. 3, 2021

Abstract Glycogen synthase kinase‐3 (GSK3) is a highly evolutionarily conserved serine/threonine protein kinase first identified as an enzyme that regulates glycogen (GS) in response to insulin stimulation, which involves GSK3 regulation of glucose metabolism and energy homeostasis. Both isoforms GSK3, GSK3α, GSK3β, have been implicated many biological pathophysiological processes. The various functions are indicated by its widespread distribution multiple cell types tissues. studies activity using animal models the observed effects GSK3‐specific inhibitors provide more insights into roles regulating cross‐talk between some important regulators sensors mitochondrial component function further highlight molecular mechanisms involved regulate metabolic activity, beyond classical regulatory effect on GS. In this review, we summarize specific tissues tightly associated with development disorders. We also address impacts function, regulation. application clinical tests will be highlighted too. Interactions GSK3‐mediated responses different stresses related described brief overview previously less‐appreciated diseases through GS other functions.

Language: Английский

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The Pathogenesis of Diabetes

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(8), P. 6978 - 6978

Published: April 10, 2023

Diabetes is the most common metabolic disorder, with an extremely serious effect on health systems worldwide. It has become a severe, chronic, non-communicable disease after cardio-cerebrovascular diseases. Currently, 90% of diabetic patients suffer from type 2 diabetes. Hyperglycemia main hallmark The function pancreatic cells gradually declines before onset clinical hyperglycemia. Understanding molecular processes involved in development diabetes can provide care much-needed updates. This review provides current global state diabetes, mechanisms glucose homeostasis and insulin resistance, long-chain non-coding RNA (lncRNA) associated

Language: Английский

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Advances in Research on Type 2 Diabetes Mellitus Targets and Therapeutic Agents

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(17), P. 13381 - 13381

Published: Aug. 29, 2023

Diabetes mellitus is a chronic multifaceted disease with multiple potential complications, the treatment of which can only delay and prolong terminal stage disease, i.e., type 2 diabetes (T2DM). The World Health Organization predicts that will be seventh leading cause death by 2030. Although many antidiabetic medicines have been successfully developed in recent years, such as GLP-1 receptor agonists SGLT-2 inhibitors, single-target drugs are gradually failing to meet therapeutic requirements owing individual variability, diversity pathogenesis, organismal resistance. Therefore, there remains need investigate pathogenesis T2DM more depth, identify targets, provide improved glycemic control solutions. This review presents an overview mechanisms action development latest agents targeting years. It also discusses emerging target-based therapies new targets emerged within last three aim our theoretical basis for further advancement targeted T2DM.

Language: Английский

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Targeting Tau Protein with Proximity Inducing Modulators: A New Frontier to Combat Tauopathies

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: 8(3), P. 654 - 672

Published: Feb. 10, 2025

Dysregulation of correct protein tau homeostasis represents the seed for development several devastating central nervous system disorders, known as tauopathies, that affect millions people worldwide. Despite massive public and private support to research funding, these diseases still represent unmet medical needs. In fact, tau-targeting tools developed date have failed translate into clinic. Recently, taking advantage modes nature uses mediate flow information in cells, researchers a new class molecules, called proximity-inducing modulators, which exploit spatial proximity modulate function(s) redirect cellular processes. this perspective, after brief discussion about classic approaches, we will discuss different classes modulators so far highlight applications protein's function tau-induced toxicity.

Language: Английский

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The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products

Antioxidants, Journal Year: 2022, Volume and Issue: 11(9), P. 1845 - 1845

Published: Sept. 19, 2022

Oxidative stress and AKT serine-threonine kinase (AKT) are responsible for regulating several cell functions of cancer cells. Several natural products modulate both oxidative anticancer effects. However, the impact product-modulating on lacks systemic understanding. Notably, contribution by downstream effectors is not yet well integrated. This review explores role pathway (AKT/AKT effectors) ten functions, including apoptosis, autophagy, endoplasmic reticulum stress, mitochondrial morphogenesis, ferroptosis, necroptosis, DNA damage response, senescence, migration, cell-cycle progression. The connected to these through function mediators. Moreover, related Based this rationale, with modulating abilities exhibit potential regulate but some were rarely reported, particularly effectors. sheds light understanding roles in providing future directions treatment.

Language: Английский

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The Link between Trace Metal Elements and Glucose Metabolism: Evidence from Zinc, Copper, Iron, and Manganese-Mediated Metabolic Regulation

Metabolites, Journal Year: 2023, Volume and Issue: 13(10), P. 1048 - 1048

Published: Oct. 2, 2023

Trace metal elements are of vital importance for fundamental biological processes. They function in various metabolic pathways after the long evolution living organisms. Glucose is considered to be one main sources energy that supports activities, and its metabolism tightly regulated by trace such as iron, zinc, copper, manganese. However, there still a lack understanding regulation glucose elements. In particular, underlying mechanism action remains elucidated. this review, we summarize current concepts progress linking metabolism, particularly manganese, iron.

Language: Английский

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The metabolic overdrive hypothesis: hyperglycolysis and glutaminolysis in bipolar mania

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(5), P. 1521 - 1527

Published: Jan. 25, 2024

Evidence from diverse areas of research including chronobiology, metabolomics and magnetic resonance spectroscopy indicate that energy dysregulation is a central feature bipolar disorder pathophysiology. In this paper, we propose mania represents condition heightened cerebral metabolism facilitated by hyperglycolysis glutaminolysis. When oxidative glucose becomes impaired in the brain, neurons can utilize glutamate as an alternative substrate to generate through phosphorylation. Glycolysis astrocytes fuels formation denovo glutamate, which be used mitochondrial fuel source via transamination alpha-ketoglutarate subsequent reductive carboxylation replenish tricarboxylic acid cycle intermediates. Upregulation glycolysis glutaminolysis manner causes brain enter state excitatory activity underlie subjective experience mania. Under normal conditions, mechanism serves adaptive function transiently upregulate response acute demand. However, when recruited long term counteract it may become pathological process. article, develop these ideas detail, present supporting evidence novel avenue investigation understand biological basis for

Language: Английский

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GSK3: A potential target and pending issues for treatment of Alzheimer's disease

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(7)

Published: July 1, 2024

Abstract Glycogen synthase kinase‐3 (GSK3), consisting of GSK3α and GSK3β subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains Alzheimer's disease (AD) patients models. AD neurodegenerative disorder with diverse pathogenesis notable cognitive impairments, characterized by Aβ aggregation excessive tau phosphorylation. This article provides an overview GSK3's structure regulation, extensively analyzing its relationship factors. overactivation disrupts neural growth, development, function. It directly promotes phosphorylation, amyloid precursor (APP) cleavage, leading to formation, or indirectly triggers neuroinflammation oxidative damage. We also summarize preclinical research highlighting inhibition activity as primary therapeutic approach for AD. Finally, pending issues like lack highly specific affinity‐driven inhibitors, are raised expected be addressed future research. In conclusion, represents target treatment, filled hope, challenges, opportunities, obstacles.

Language: Английский

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Advanced glycation end products and reactive oxygen species: uncovering the potential role of ferroptosis in diabetic complications

Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(1)

Published: Sept. 9, 2024

Language: Английский

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Liver-X receptor β-selective agonist CE9A215 regulates Alzheimer’s disease-associated pathology in a 3xTg-AD mouse model

Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 184, P. 117895 - 117895

Published: Feb. 6, 2025

Language: Английский

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