Lithium and Therapeutic Targeting of GSK-3

Cells, Journal Year: 2021, Volume and Issue: 10(2), P. 255 - 255

Published: Jan. 28, 2021

Lithium salts have been in the therapeutic toolbox for better or worse since 19th century, with purported benefit gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, remarkable effects of reported by John Cade subsequently Mogens Schou revolutionized treatment bipolar disorder. The known molecular targets are surprisingly few include signaling kinase glycogen synthase kinase-3 (GSK-3), a group structurally related phosphomonoesterases includes inositol monophosphatases, phosphoglucomutase. Here we present brief history uses then focus on GSK-3 as target diverse diseases, including disorder, cancer, coronavirus infections.

Language: Английский

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GSK3β as a novel promising target to overcome chemoresistance in pancreatic cancer

Drug Resistance Updates, Journal Year: 2021, Volume and Issue: 58, P. 100779 - 100779

Published: Aug. 12, 2021

Pancreatic cancer is an aggressive malignancy with increasing incidence and poor prognosis due to its late diagnosis intrinsic chemoresistance. Most pancreatic patients present locally advanced or metastatic disease characterized by inherent resistance chemotherapy. These features pose a series of therapeutic challenges new targets are urgently needed. Glycogen synthase kinase 3 beta (GSK3β) conserved serine/threonine kinase, which regulates key cellular processes including cell proliferation, DNA repair, cycle progression, signaling metabolic pathways. GSK3β implicated in non-malignant malignant diseases inflammation, neurodegenerative diseases, diabetes cancer. recently emerged among the factors involved onset progression cancer, as well acquisition Intensive research has been conducted on oncogenic functions potential druggable target; currently developed inhibitors display promising results preclinical models distinct tumor types, Here, we review latest findings about GSK-3β biology role development Moreover, discuss agents targeting that could be administered monotherapy combination other drugs surmount Several studies also defining gene signatures identify who might benefit from GSK3β-based intervention. This detailed overview emphasizes urgent need additional molecular impact inhibition structural analysis novel compounds omics predictive biomarkers.

Language: Английский

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High Throughput Confined Migration Microfluidic Device for Drug Screening

Small, Journal Year: 2023, Volume and Issue: 19(16)

Published: Jan. 12, 2023

Abstract Cancer metastasis is the major cause of cancer‐related death. Excessive extracellular matrix deposition and increased stiffness are typical features solid tumors, creating confined spaces for tumor cell migration metastasis. Confined involved in all steps. However, unconfined inhibitors different drugs available to inhibit rare. The main challenges modeling migration, suffering low throughput, others. Microfluidic device has advantage reduce reagent consumption enhance throughput. Here, a microfluidic chip that can achieve multi‐function drug screening against collective cancer cells under environment designed. This applied screen out effective on among novel mechanoreceptors compound library (166 compounds) hepatocellular carcinoma, non‐small lung cancer, breast pancreatic ductal adenocarcinoma cells. Three compounds significantly pan‐cancer: mitochonic acid 5 (MA‐5), SB‐705498, diphenyleneiodonium chloride found. Finally, it elucidated these targeted mitochondria, actin polymerization, viability, respectively. In sum, high‐throughput platform targeting established three multiple types identified.

Language: Английский

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Nobiletin Induces Ferroptosis in Human Skin Melanoma Cells Through the GSK3β-Mediated Keap1/Nrf2/HO-1 Signalling Pathway

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: March 8, 2022

Melanoma is an aggressive malignant skin tumour with increasing global incidence. However, current treatments have limitations owing to the acquired drug resistance. Ferroptosis a recently discovered form of programmed cell death characterised by iron accumulation and lipid peroxidation plays critical role in growth inhibition. Recently, ferroptosis inducers been regarded as promising therapeutic strategy overcome apoptosis resistance cells. In this study, we reported that nobiletin, natural product isolated from citrus peel, exhibited antitumour activity inducing melanoma Subsequently, further explored potential mechanism nobiletin-induced ferroptosis, found expression level glycogen synthase kinase 3β (GSK3β) tissue patients was significantly reduced compared normal tissue. Additionally, nobiletin increased GSK3β Moreover, Kelch-like Ech-associated protein-1 (Keap1) increased, while nuclear factor erythroid 2-related 2 (Nrf2), haem oxygenase-1 (HO-1) decreased nobiletin-treated cells, suggesting antioxidant defence system downregulated. Furthermore, knockdown upregulated Keap1/Nrf2/HO-1 signalling pathway, opposite observed cells overexpressing GSK3β. addition, molecular docking assay results indicated showed strong binding affinities for GSK3β, Keap1, Nrf2, HO-1. Taken together, our demonstrated could induce regulating GSK3β-mediated pathway human Hence, stands candidate treatment development prospects.

Language: Английский

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Molecular docking, molecular dynamics simulations and in vitro screening reveal cefixime and ceftriaxone as GSK3β covalent inhibitors

RSC Advances, Journal Year: 2023, Volume and Issue: 13(17), P. 11278 - 11290

Published: Jan. 1, 2023

Cefixime and ceftriaxone covalently inhibit GSK3β.

Language: Английский

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Exploring gene-patient association to identify personalized cancer driver genes by linear neighborhood propagation

BMC Bioinformatics, Journal Year: 2024, Volume and Issue: 25(1)

Published: Jan. 22, 2024

Abstract Background Driver genes play a vital role in the development of cancer. Identifying driver is critical for diagnosing and understanding However, challenges remain identifying personalized due to tumor heterogeneity Although many computational methods have been developed solve this problem, few efforts undertaken explore gene-patient associations identify genes. Results Here we propose method called LPDriver cancer by employing linear neighborhood propagation model on individual genetic data. builds gene network based data patients, extracts from bipartite graph utilizes mine detect The experimental results demonstrate that as compared existing methods, our shows competitive performance can predict more accurate way. Furthermore, these also show besides revealing novel reported be related with cancer, able patients their characteristics even if mutation are hidden. Conclusions provide an effective approach genes, which could promote diagnosis treatment source code freely available at https://github.com/hyr0771/LPDriver .

Language: Английский

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Capivasertib combines with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer

British Journal of Cancer, Journal Year: 2024, Volume and Issue: 130(8), P. 1377 - 1387

Published: Feb. 23, 2024

Abstract Background/objective To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null WT prostate tumours. Methods Mechanisms associated with capivasertib treatment cancer were examined using a panel vivo tumour models cell lines. Results Combining had increased vivo. In vitro short-term caused cycle arrest majority cells. However, sub-population docetaxel-persister cells did not undergo G2/M but upregulated phosphorylation PI3K/AKT pathway effectors GSK3β, p70S6K, 4E-BP1, to lesser extent AKT. acute induced p70S6K 4E-BP1 phosphorylation. Treating reduced activation progression. it proliferation apoptosis or DNA damage though effects more marked Docetaxel-persister partly reliant on GSK3β as inhibitor AZD2858 reversed capivasertib-induced damage. Conclusion Capivasertib can enhance by targeting residual cells, independent status, induce part through GSK3β.

Language: Английский

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Systems pharmacology of phytochemical anacardic acid in the chemoprevention of hepatocellular carcinoma

Drug Metabolism and Personalized Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

Abstract Objectives Hepatocellular carcinoma (HCC) is a common type of liver cancer that progresses quickly and has limited treatment options. Nutraceutical anacardic acid (AA), bioactive compound derived from cashew nut shell, emerged as potential candidate for HCC owing to its reported anti-inflammatory, anticancer diverse pharmacological properties. In the present study, we investigate AA an inhibitor using molecular docking, gene ontology, network pharmacology. Methods The pharmacokinetic physicochemical properties were assessed Swiss ADME. SuperPred, Similarity Ensemble Approach, ChEMBL Target Prediction online tools used determining targets AA. addition, GeneCards, NCBI, DisGeNET UniProt ID search top 25 hub genes determined Cytohubba plugin. A protein interaction (PPI) was constructed through STRING database. Gene Ontology (GO) biological process Kyoto Encyclopaedia Genes (KEGG) pathway enrichment analysis performed FunRich ShinyGO 0.77. Moreover, docking studies on NF-κB GSK-3β. expression levels also validated by western blotting. Results Comprehensive data identified 375 11,333 HCC, with 264 in common. Network key targets, including caspase-3, NF-κB. ontology topology highlighted essential pathways implicated progression such renin-angiotensin system, VEGF signalling, apoptosis. Molecular revealed strong binding affinity proteins Upregulation p-NRF2 p-GSK-3β, downregulation p-NF-κB caspase-1 Conclusions Taken together, our study highlights promising chemopreventive agent because significant modulatory effects important regulatory linked cell division, inflammation, apoptosis, antioxidant response.

Language: Английский

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Development of inhibitors targeting glycogen synthase kinase-3β for human diseases: Strategies to improve selectivity

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 236, P. 114301 - 114301

Published: March 31, 2022

Language: Английский

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Combination Approaches to Target PD-1 Signaling in Cancer

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 14, 2022

Cancer remains the second leading cause of death in US, accounting for 25% all deaths nationwide. Immunotherapy techniques bolster immune cells' ability to target malignant cancer cells and have brought immense improvements field treatments. One important inhibitory protein T cells, programmed cell 1 (PD-1), has become an invaluable immunotherapy. While anti-PD-1 antibody therapy is extremely successful some patients, others it fails or even causes further complications, including hyper-progression immune-related adverse events. Along with countless translational studies PD-1 signaling pathway, there are currently close 5,000 clinical trials antibodies against its ligand, PD-L1, around 80% which investigate combinations other therapies. Nevertheless, more work needed better understand pathway facilitate new improved evidence-based combination strategies. In this work, we consolidate recent discoveries mediators their therapeutic potential anti-PD-1/PD-L1 agents. We focus on phosphatases SHP2 PTPN2; kinases ITK, VRK2, GSK-3, CDK4/6; adaptor PAG. discuss biology both a role relation determine combinations. The literature discussed here was obtained from search published ClinicalTrials.gov following key terms: checkpoint inhibition, immunotherapy, PD-1, SHP2, PTPN2, CDK4/6, Together, find that these proteins logical promising targets therapy, deeper mechanistic understanding they improve response rate decrease events when thoughtfully used inhibitors.

Language: Английский

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