Article
Biochemistry & Molecular Biology
Davoud Ghazanfari, Mahboubeh S. Noori, Stephen C. Bergmeier, Jennifer Hines, Kelly D. McCall, Douglas J. Goetz
Summary: COB-187 inhibits GSK3 beta via a specific, reversible, time and Cys-199-dependent mechanism, demonstrating high selectivity and potent activity against the target enzyme.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Davoud Ghazanfari, Maria Cecilia Courreges, Lydia Belinski, Stephen C. Bergmeier, Kelly D. McCall, Douglas J. Goetz
Summary: This study found that SARS-CoV-2 proteins can induce cytokine storm by triggering the secretion of pro inflammatory cytokines. Inhibitors of glycogen synthase kinase-3 (GSK-3) can attenuate this cytokine expression, providing a potential therapeutic approach for severe COVID-19.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Neurosciences
Shaohui Wang, Yao Jiang, Yabo Liu, Qianhui Liu, Hongwei Sun, Mengjie Mei, Xiaomei Liao
Summary: This study demonstrates that ferroptosis promotes abnormal aggregation of tau protein and may serve as a promising therapeutic target for tauopathies.
MOLECULAR NEUROBIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Prachi Umbarkar, Sulivette Y. Ruiz Ramirez, Angelica Toro Cora, Sultan Tousif, Hind Lal
Summary: This article focuses on the isoform-specific roles of GSK-3 in the pathophysiology of cardiometabolic disorders. GSK-3α plays a critical role in promoting adverse fibrotic remodeling and deterioration of cardiac function, while GSK-3β has the opposite effect in cardiac fibrosis. Inhibition of both GSK-3 isoforms shows benefits against obesity-associated cardiometabolic pathologies, and the molecular interactions with other signaling pathways are discussed. The article also reviews the limitations and potential applications of small molecule inhibitors targeting GSK-3 for the treatment of metabolic disorders.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Review
Medicine, Research & Experimental
Xiong Dong, Hongxiang Hong, Zhiming Cui
Summary: Spinal cord injury (SCI) is a significant social problem that involves glial scar formation and irreversible neuron loss. The GSK-3 signaling pathway plays an important role in controlling neurite growth and functional recovery from SCI. Understanding the role of GSK-3 signaling in the pathogenesis of SCI is crucial for the development of effective treatments.
EXPERIMENTAL AND THERAPEUTIC MEDICINE
(2023)
Article
Multidisciplinary Sciences
Samuel M. Law, Jie J. Zheng
Summary: Wnt signaling pathways play a significant role in various diseases. β-catenin is central to the canonical Wnt signaling pathway. CHIR-99021, a GSK-3β inhibitor, is widely used for studying this pathway. However, caution is needed when using CHIR-99021 at certain concentrations.
Article
Cell Biology
S. Grace Herod, Annie Dyatel, Stefanie Hodapp, Marko Jovanovic, Luke E. Berchowitz
Summary: Amyloids play important roles in age-related diseases. Some cells use reversible amyloid-like structures for translational control. Yeast 14-3-3 proteins bind to amyloid-like assemblies and facilitate their clearance, contributing to global protein aggregate homeostasis. These findings suggest that 14-3-3 proteins may protect against pathological protein aggregates.
Article
Pharmacology & Pharmacy
Heba Al-Hussaini, Rawan Sharhabeel Kittaneh, Narayana Kilarkaje
Summary: Microvascular changes and retinal degeneration precede diabetic retinopathy. Oxidative stress alters intracellular signaling pathways, forming the basis for diabetic retinopathy. Many antioxidants have been studied for their potential in preventing and treating diabetic retinopathy. In a study on rats, trans-resveratrol was found to modulate gene expressions of apoptosis-related proteins and MAPKs, showing potential protective effects against diabetic retinopathy.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Yuko Nagao, Kikuko Amo-Shiinoki, Hiroko Nakabayashi, Masayuki Hatanaka, Manabu Kondo, Kimie Matsunaga, Masahiro Emoto, Shigeru Okuya, Yukio Tanizawa, Katsuya Tanabe
Summary: Endoplasmic reticulum stress is a key pathogenic factor in type 1 and 2 diabetes. Gsk-3 inhibition prevents proteasomal degradation of ATF4 and alleviates apoptosis by regulating phosphorylation of ATF4-S214. Mechanistically, Gsk-3 inhibition modulates transcription targets of ATF4 and facilitates dephosphorylation of eIF2 alpha under ER stress.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Xueyang Jiang, Junting Zhou, Yang Wang, Xin Liu, Kaiying Xu, Jian Xu, Feng Feng, Haopeng Sun
Summary: A series of heterobifunctional small molecule PROTACs based on CRBN were designed and synthesized to effectively degrade GSK-3β protein and protect against cell death, showing potential for further investigation in the biological function of GSK-3β protein and its association with diseases.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Veerabahu Subbukutti, Ethirajulu Sailatha, Sethu Gunasekaran, Subramaniyan Manibalan, Kumba Janarthanan Uma Devi, Koteeswaran Bhuvaneshwari, Rajendran Suvedha
Summary: The wound-healing process can be accelerated by inhibiting proteins that slow down the healing pathway. Catnenin, an active protein, is involved in enhancing healing at the nuclear level and in gene expression. A medicated wound dressing transdermal patch with fusion of bio wastes was analyzed against GSK3 beta to enhance healing. The stability and efficiency of the patch in accelerating wound healing process were confirmed through molecular dynamics simulation studies.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
Francesco Cinetto, Jessica Ceccato, Ilaria Caputo, Daniela Cangiano, Barbara Montini, Francesca Lunardi, Maria Piazza, Carlo Agostini, Fiorella Calabrese, Gianpietro Semenzato, Marcello Rattazzi, Carmela Gurrieri, Riccardo Scarpa, Carla Felice, Fabrizio Vianello
Summary: The inhibition of GSK-3 can modulate the expression of MMP-9 and -2 in a mouse model of lung fibrosis and different cell lines, reducing MMP activity in inflammatory cells and fibroblasts, suggesting a potential therapeutic strategy for IPF.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Review
Oncology
Alberto M. Martelli, Camilla Evangelisti, Francesca Paganelli, Francesca Chiarini, James A. McCubrey
Summary: GSK-3 consists of two isoforms, alpha and beta, that are constitutively active but can be inactivated through phosphorylation by upstream kinases. It was initially considered a tumor suppressor, but it has also been found to have oncogenic properties in promoting pathways critical for cancer cell proliferation, survival, and drug-resistance.
Article
Biochemistry & Molecular Biology
David Cabezas, Guido Mellado, Nicolas Espinoza, Jose Antonio Garate, Cesar Morales, Alejandro Castro-Alvarez, Maria J. Matos, Marco Mellado, Jaime Mella
Summary: Glycogen synthase kinase 3 (GSK-3) plays a role in various diseases and inhibiting GSK-3 could have pro-insulin effects. Aminopyrimidine derivatives have already proven to be promising GSK-3 inhibitors. In this study, CoMFA and CoMSIA models were developed to design new compounds with antidiabetic activity.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Review
Chemistry, Medicinal
Neha Chauhan, Swati Paliwal, Smita Jain, Kanika Verma, Sarvesh Paliwal, Swapnil Sharma
Summary: Alzheimer's disease is a major health and socioeconomic burden worldwide, characterized by neuronal loss, memory loss, and cognitive impairment. GSK-3 beta plays a significant role in the molecular mechanisms of AD progression, making it a potential therapeutic target for the disease.
MINI-REVIEWS IN MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
William P. Miller, Siddharth Sunilkumar, Michael D. Dennis
Summary: Diabetic Retinopathy (DR) is primarily caused by oxidative stress, with the stress response protein REDD1 playing a key role by regulating the cell's response through mTORC1. Additionally, REDD1 acts independently of mTORC1 to promote oxidative stress by enhancing reactive oxygen species production and suppressing antioxidant responses. Early clinical trials targeting REDD1 mRNA with siRNA have shown some success in combating ischemic retinal disease, indicating the potential for novel therapies targeting the underlying molecular mechanisms of DR.
FREE RADICAL BIOLOGY AND MEDICINE
(2021)
Article
Cell Biology
Siddharth Sunilkumar, Scot R. Kimball, Michael D. Dennis
Summary: Insulin enhances mTORC1 phosphorylation, while the effect of glucagon on mTORC1 is biphasic, first increasing phosphorylation levels and then suppressing them. Glucagon induces a transient activation of mTORC1/2 through an EPAC-dependent increase in Rap1GTP.
CELLULAR SIGNALLING
(2021)
Meeting Abstract
Endocrinology & Metabolism
William P. Miller, Allyson Toro, Siddharth Sunilkumar, Joseph Giordano, Michael D. Dennis
Article
Biochemistry & Molecular Biology
Rohan Reddy Nagavally, Siddharth Sunilkumar, Mumtaz Akhtar, Louis D. Trombetta, Sue M. Ford
Summary: Chrysin demonstrates nephroprotective effects against CsA-induced renal dysfunction and fibrosis by inhibiting TGF-beta(1)-dependent EMT in proximal tubule cells through modulation of Smad-dependent and independent signaling pathways.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Endocrinology & Metabolism
William P. Miller, Allyson L. Toro, Siddharth Sunilkumar, Shaunaci A. Stevens, Ashley M. VanCleave, David L. Williamson, Alistair J. Barber, Michael D. Dennis
Summary: Clinical studies support the role of REDD1 protein in ischemic retinal complications caused by diabetes. The study found that REDD1 expression specifically in Muller glia contributes to diabetes-induced retinal pathology, including gliosis, neurodegeneration, and impaired vision.
Meeting Abstract
Biochemistry & Molecular Biology
Siddharth Sunilkumar, William P. Miller, Allyson Toro, Esma Yerlikaya, Michael D. Dennis
Article
Endocrinology & Metabolism
William P. Miller, Congzhou M. Sha, Siddharth Sunilkumar, Allyson L. Toro, Ashley M. VanCleave, Scot R. Kimball, Nikolay V. Dokholyan, Michael D. Dennis
Summary: The stress response protein REDD1 is implicated in visual deficits in diabetic patients. Increased REDD1 protein expression in diabetic mice retina was found, which was suppressed by oral antioxidant supplementation. Hyperglycemic conditions enhance REDD1 expression and inhibit its degradation through a redox-sensitive disulfide bond at C150/C157.
Article
Endocrinology & Metabolism
Siddharth Sunilkumar, Esma I. Yerlikaya, Allyson L. Toro, William P. Miller, Han Chen, Kebin Hu, Scot R. Kimball, Michael D. Dennis
Summary: Chronic hyperglycemia promotes the expression of REDD1 in the kidney, leading to oxidative stress and renal injury. Deletion of REDD1 reduces reactive oxygen species and prevents podocyte loss, indicating its role in diabetes-induced renal complications.
Article
Biochemistry & Molecular Biology
Siddharth Sunilkumar, Allyson L. Toro, Christopher M. McCurry, Ashley M. VanCleave, Shaunaci A. Stevens, William P. Miller, Scot R. Kimball, Michael D. Dennis
Summary: The study revealed that REDD1 plays a crucial role in diabetes-induced retinal inflammation by enhancing the activation of the NF-KB signaling pathway to increase the expression of inflammatory cytokines.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Endocrinology & Metabolism
Shaunaci A. Stevens, Maria K. Gonzalez Aguiar, Allyson L. Toro, Esma I. Yerlikaya, Siddharth Sunilkumar, Ashley M. VanCleave, Jessica Pfleger, Elisa A. Bradley, Scot R. Kimball, Michael D. Dennis
Summary: The interplay between endoplasmic reticulum stress and inflammation contributes to cardiovascular disease progression. This study identifies REDD1, a stress response protein, as a missing link that connects the development of endoplasmic reticulum stress with increased production of proinflammatory cytokines in the hearts of obese mice.
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
(2022)
Article
Ophthalmology
Esma Yerlikaya, Allyson L. Toro, Siddharth Sunilkumar, Ashley M. VanCleave, Ming Leung, Yuka Imamura Kawasawa, Scot R. Kimball, Michael D. Dennis
Summary: In diabetic retinopathy, neuroglial dysfunction occurs early and Muller glia play a significant role in disease progression. This study investigates the common signaling pathways activated in Muller glia by both type 1 and pre-/type 2 diabetes. The findings suggest that the TREM2/DAP12 receptor-adaptor complex signals via SYK to promote HIF1a stabilization and increased angiogenic cytokine production by Muller glia.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2022)
Meeting Abstract
Ophthalmology
Michael D. Dennis, Siddharth Sunilkumar, Allyson Toro, Christopher McCurry, William Miller
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2022)
Meeting Abstract
Ophthalmology
William Miller, Amason Toro, Siddharth Sunilkumar, David Williamson, Michael Dennis
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2021)
Meeting Abstract
Biochemistry & Molecular Biology
Siddharth Sunilkumar, Scott Kimball, Michael Dennis