Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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The Complex Genetic and Epigenetic Regulation of the Nrf2 Pathways: A Review

Antioxidants, Journal Year: 2023, Volume and Issue: 12(2), P. 366 - 366

Published: Feb. 3, 2023

Nrf2 is a major transcription factor that significantly regulates—directly or indirectly—more than 2000 genes. While many of these genes are involved in maintaining redox balance, others balance among metabolic pathways seemingly unrelated to oxidative stress. In the past 25 years, number factors activation, nuclear translocation, and deactivation has continued expand. The purpose this review provide an overview remarkable complexity tortuous sequence stop-and-go signals not only regulate expression repression, but may also modify transcriptional intensity as well specificity promoter recognition, allowing fluidity its gene profile depending on various structural modifications encounters journey DNA. At present, more 45 control points have been identified, which represent sites action so-called activators. pathway synergistic interplay combinations help explain potential advantages seen with phytochemical compositions simultaneously target multiple points, compared traditional pharmaceutical paradigm “one-drug, one-target”.

Language: Английский

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Therapeutic Potential Effect of Glycogen Synthase Kinase 3 Beta (GSK-3β) Inhibitors in Parkinson Disease: Exploring an Overlooked Avenue

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(9), P. 7092 - 7108

Published: Feb. 17, 2024

Abstract Parkinson’s disease (PD) is a progressive neurodegenerative of the brain due to degeneration dopaminergic neurons in substantia nigra (SN). Glycogen synthase kinase 3 beta (GSK-3β) implicated pathogenesis PD. Therefore, purpose present review was revise mechanistic role GSK-3β PD neuropathology, and how inhibitors affect neuropathology. GSK-3 conserved threonine/serine protein that intricate regulation cellular anabolic catabolic pathways by modulating glycogen synthase. Over-expression also interconnected with development different diseases. However, underlying mechanism neuropathology not fully clarified. induces triggering mitochondrial dysfunction oxidative stress SN. NF-κB NLRP3 inflammasome are activated response dysregulated leading neuronal injury. Higher expression early stages might contribute reduction neuroprotective brain-derived neurotrophic factor (BDNF). Thus, may be effective reducing inflammatory disorders which associated

Language: Английский

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Targeting glycogen synthase kinase-3β for Alzheimer's disease: Recent advances and future Prospects

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 265, P. 116065 - 116065

Published: Dec. 20, 2023

Language: Английский

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Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(9), P. 1828 - 1881

Published: April 22, 2024

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a–h), hydrazine monohydrate (NH2NH2•H2O) for regioselective preparation some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a–h). After synthesis characterization mentioned cinnolines (3a–h), in silico multi-targeting inhibitory properties these heterocyclic scaffolds investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2(G2019S), hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, hDHODH, which confirmed their functions roles neurodegenerative (NDs), based on molecular docking studies, obtained results were compared with wide range approved drugs well-known (with IC50, EC50, etc.) compounds. addition, ADMET prediction analysis was performed examine prospective drug synthesized compounds The from studies ADMET-related data demonstrated that series heteroaryl)-5,6-dihydrobenzo[h]cinnolines especially hit ones, can really be turned into potent core new treatment and/or due having reactionable locations, they able further organic reactions (such as cross-coupling reactions), expansion (for example, using other types monohydrates) makes avenue designing novel efficient purpose.

Language: Английский

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Inhibition of GSK-3β Enhances Osteoblast Differentiation of Human Mesenchymal Stem Cells through Wnt Signalling Overexpressing Runx2

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(8), P. 7164 - 7164

Published: April 12, 2023

Small-molecule-inhibitor-based bone differentiation has been recently exploited as a novel approach to regulating osteogenesis-related signaling pathways. In this study, we identified 1-Azakenpaullone, highly selective inhibitor of glycogen synthase kinase-3β (GSK-3β), powerful inducer osteoblastic and mineralization human mesenchymal stem cells (MSCs). GSK-3β is serine-threonine protein kinase that plays major role in different disease development. key regulator Runx2 activity formation. We evaluated alkaline phosphatase staining assays assess osteoblast Alizarin Red the cultured MSCs. Gene expression profiling was assessed using an Agilent microarray platform, bioinformatics were performed Ingenuity Pathway Analysis software. Human MSCs treated with 1-Azakenpaullone showed higher ALP activity, increased vitro mineralized matrix formation, upregulation osteoblast-specific marker gene expression. Global 1-Azakenpaullone-treated 1750 upregulated 2171 downregulated mRNA transcripts compared control cells. It also suggested possible changes various pathways, including Wnt, TGFβ, Hedgehog. Further analysis employing recognized significant enrichment genetic networks involved CAMP, PI3K (Complex), P38 MAPK, HIF1A functional categories associated connective tissue Our results suggest significantly induced mediated by activation Wnt nuclear accumulation β-catenin, leading Runx2, transcription factor ultimately promotes genes. Thus, could be used osteo-promotor engineering.

Language: Английский

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Oxazole-4-carboxamide/butylated hydroxytoluene hybrids with GSK-3β inhibitory and neuroprotective activities against Alzheimer's disease

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 256, P. 115415 - 115415

Published: May 5, 2023

Language: Английский

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Natural compounds from herbs and nutraceuticals as glycogen synthase kinase‐3β inhibitors in Alzheimer's disease treatment

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(8)

Published: Aug. 1, 2024

Abstract Background Alzheimer's disease (AD) pathogenesis is complex. The pathophysiology not fully understood, and safe effective treatments are needed. Glycogen synthase kinase 3β (GSK‐3β) mediates AD progression through several signaling pathways. Recently, studies have found that various natural compounds from herbs nutraceuticals can significantly improve symptoms. Aims This review aims to provide a comprehensive summary of the potential neuroprotective impacts as inhibitors GSK‐3β in treatment AD. Materials Methods We conducted systematic literature search on PubMed, ScienceDirect, Web Science, Google Scholar, focusing vitro vivo investigated Results mechanism may be related activation inhibition regulate amyloid beta production, tau protein hyperphosphorylation, cell apoptosis, cellular inflammation. By reviewing recent phytochemicals intervention, flavonoids including oxyphylla A, quercetin, morin, icariin, linarin, genipin, isoorientin were reported potent for treatment. Polyphenols such schisandrin B, magnolol, dieckol inhibitory effects models, models. Sulforaphene, ginsenoside Rd, gypenoside XVII, falcarindiol, epibrassinolides, 1,8‐Cineole, andrographolide promising inhibitors. Conclusions Natural candidates They qualify derivatives development enhanced pharmacological characteristics.

Language: Английский

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Cross-Talks between Raf Kinase Inhibitor Protein and Programmed Cell Death Ligand 1 Expressions in Cancer: Role in Immune Evasion and Therapeutic Implications

Cells, Journal Year: 2024, Volume and Issue: 13(10), P. 864 - 864

Published: May 17, 2024

Innovations in cancer immunotherapy have resulted the development of several novel immunotherapeutic strategies that can disrupt immunosuppression. One key advancement lies immune checkpoint inhibitors (ICIs), which shown significant clinical efficacy and increased survival rates patients with various therapy-resistant cancers. This intervention consists monoclonal antibodies directed against inhibitory receptors (e.g., PD-1) on cytotoxic CD8 T cells or corresponding ligands PD-L1/PD-L2) overexpressed other tumor microenvironment (TME). However, not all respond—there are still poor responses, immune-related adverse effects, adaptive resistance, vulnerability to ICIs a subset cancer. challenge showcases heterogeneity cancer, emphasizing existence additional immunoregulatory mechanisms many patients. Therefore, it is essential investigate PD-L1’s interaction oncogenic genes pathways further advance targeted therapies address resistance mechanisms. Accordingly, our aim was governing PD-L1 expression cells, given its correlation evasion, uncover for decreasing restoring anti-tumor responses. Numerous studies demonstrated upregulation Raf Kinase Inhibitor Protein (RKIP) cancers contributes suppression hyperactive observed malignant alongside broadening involvement responses modulation TME. We, therefore, hypothesized role surveillance may be inversely correlated low level suppressor cells. hypothesis investigated we found signaling cross-talk between regulations both RKIP expressions. These regulatory factors include MAPK JAK/STAT pathways, GSK3β, cytokines IFN-γ IL-1β, Sox2, transcription YY1 NFκB. The upregulated were vice versa. Bioinformatic analyses human inverse relationship expressions their prognostic roles. suspect direct and/or use inducers combination could result more response—addressing therapeutic challenges related PD-1/PD-L1 monotherapy alone.

Language: Английский

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Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer’s Disease—Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

Molecules, Journal Year: 2024, Volume and Issue: 29(11), P. 2616 - 2616

Published: June 2, 2024

GSK-3β, IKK-β, and ROCK-1 kinases are implicated in the pathomechanism of Alzheimer’s disease due to their involvement misfolding accumulation amyloid β (Aβ) tau proteins, as well inflammatory processes. Among these kinases, GSK-3β plays most crucial role. In this study, we present compound 62, a novel, remarkably potent, competitive inhibitor (IC50 = 8 nM, Ki 2 nM) that also exhibits additional inhibitory activity 2.3 µM) demonstrates anti-inflammatory neuroprotective properties. Compound 62 effectively suppresses production nitric oxide (NO) pro-inflammatory cytokines lipopolysaccharide-induced model inflammation microglial BV-2 cell line. Furthermore, it shows effects an okadaic-acid-induced hyperphosphorylation neurodegeneration. The potential for further development, characterized by its chemical metabolic stability mouse microsomes fair solubility.

Language: Английский

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