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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Altered metabolism in cancer: insights into energy pathways and therapeutic targets

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Sept. 18, 2024

Language: Английский

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Protein neddylation and its role in health and diseases

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

Published: April 4, 2024

Abstract NEDD8 (Neural precursor cell expressed developmentally downregulated protein 8) is an ubiquitin-like that covalently attached to a lysine residue of substrate through process known as neddylation, catalyzed by the enzyme cascade, namely activating (E1), conjugating (E2), and ligase (E3). The substrates neddylation are categorized into cullins non-cullin proteins. Neddylation activates CRLs (cullin RING ligases), largest family E3 ligases, whereas alters their stability activity, well subcellular localization. Significantly, pathway and/or many abnormally activated or over-expressed in various human diseases, such metabolic disorders, liver dysfunction, neurodegenerative cancers, among others. Thus, targeting becomes attractive strategy for treatment these diseases. In this review, we first provide general introduction on its biochemical regulation, crystal structures enzymes complex with cullin substrates; then discuss how governs key biological processes via modification substrates. We further review literature data dysregulated several particularly cancer, followed outline current efforts discovery small molecule inhibitors promising therapeutic approach. Finally, few perspectives were proposed extensive future investigations.

Language: Английский

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Cuprous oxide nanocomposites with photothermal (PTT) and chemical dynamics (CDT) effects induce cuproptosis in breast cancer using the strategy of increasing inflow and reducing outflow

Nano Today, Journal Year: 2024, Volume and Issue: 56, P. 102223 - 102223

Published: March 8, 2024

Chemotherapy is a crucial adjuvant method of treating breast cancer, but it fails to achieve preferable prognosis as the malignant cells eventually develop drug-resistance. Reduced chemotherapeutic sensitivity primarily caused by endogenous and exogenous resistance during treatment. Cuproptosis newly discovered immunogenic cell death (ICD), characterized accumulation copper (Cu) ions inside tumor cells. However, intracellular Cu ion concentrations can hardly reach desired levels induce cuproptosis due limited import via existing ionophores synchronous export ATP-Cu pump. Herein, our research developed an elesclomol (ES) loaded cuprous oxide (Cu2O) nanocomposite, called PEG@Cu2O-ES, solve this dilemma. Our designed PEG@Cu2O-ES could efficiently enter cancer cells, release encapsulated ES Cu2O, while photothermal (PTT) effect Cu2O induced near-infrared II region (NIR-II) radiation in turn accelerate releasing process. discharged substantial amounts cytoplasm, which directly engaged tricarboxylic acid (TCA) cycle mitochondria, resulting some extent. As result PTT-enhanced Fenton-like reactions, generated quantity reactive oxygen species (ROS) that attacked pump on cells' membranes, thereby reducing outflow aggravating cuproptosis. Additionally, free further promoted from microenvironment (TME) exacerbated with higher efficiency. In vivo, nanocomposites showed strong anti-tumor inducing cuproptosis, well ability reprogram TME increase response-sensitivity programmed protein-1 antibody (αPD-1). conclusion, study provides promising strategy combining nano-drug αPD-1 for sensitizing immunotherapy chemotherapy-resistant cancer.

Language: Английский

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Targeting Mitochondrial Dysfunction and Reactive Oxygen Species for Neurodegenerative Disease Treatment

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7952 - 7952

Published: July 21, 2024

Alzheimer's disease (AD) and Parkinson's (PD) are the most common neurodegenerative diseases, they affect millions of people worldwide, particularly older individuals. Therefore, there is a clear need to develop novel drug targets for treatment age-related diseases. Emerging evidence suggests that mitochondrial dysfunction reactive oxygen species (ROS) generation play central roles in onset progression Mitochondria key regulators respiratory function, cellular energy adenosine triphosphate production, maintenance redox homeostasis, which essential cell survival. Mitochondrial morphology function tightly regulated by maintaining balance among fission, fusion, biogenesis, mitophagy. In this review, we provide an overview main functions mitochondria, with focus on recent progress highlighting critical role ROS-induced oxidative stress, dysregulated dynamics, apoptosis, mitochondria-associated inflammation, impaired pathogenesis such as AD PD. We also discuss potential fusion biogenesis enhancers, fission inhibitors, mitochondria-targeted antioxidants drugs these

Language: Английский

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Mitochondrial dynamics and colorectal cancer biology: mechanisms and potential targets

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 1, 2024

Colorectal cancer (CRC) is a significant public health concern, and its development associated with mitochondrial dysfunction. Mitochondria can adapt to the high metabolic demands of cells owing their plasticity dynamic nature. The fusion-fission dynamics mitochondria play crucial role in signal transduction functions CRC cells. Enhanced fission promotes reprogramming cells, leading cell proliferation, metastasis, chemoresistance. Excessive also trigger mitochondria-mediated apoptosis. In contrast, excessive fusion leads adenosine triphosphate (ATP) overproduction abnormal tumor whereas moderate protects intestinal epithelial from oxidative stress-induced damage, thus preventing colitis-associated (CAC). Therefore, an imbalance either promote or inhibit progression. This review provides overview mechanism underlying impact on biology. revealed dual identified potential drug targets. Additionally, this study partially explored immune vascular endothelial microenvironment, suggesting promising prospects for targeting key fusion/fission effector proteins against CRC.

Language: Английский

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S100A8/A9hi neutrophils induce mitochondrial dysfunction and PANoptosis in endothelial cells via mitochondrial complex I deficiency during sepsis

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(6)

Published: June 28, 2024

Abstract S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in variety inflammatory diseases. Although S100a8/a9 has been reported trigger endothelial cell apoptosis, mechanisms S100a8/a9-induced dysfunction during sepsis require in-depth research. We demonstrate that high expression levels suppress Ndufa3 mitochondrial complex I via downregulation Nrf1 expression. Mitochondrial deficiency contributes NAD + -dependent Sirt1 suppression, which induces disorders, including excessive fission blocked mitophagy, mtDNA from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis cells. Moreover, based on comprehensive scRNA-seq bulk RNA-seq analyses, S100A8/A9 hi are closely associated with circulating count (a useful marker damage), S100A8 is an independent risk factor for poor prognosis patients.

Language: Английский

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Energy metabolism in health and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 18, 2025

Language: Английский

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Targeting KRAS: from metabolic regulation to cancer treatment

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 11, 2025

The Kirsten rat sarcoma viral oncogene homolog (KRAS) protein plays a key pathogenic role in oncogenesis, cancer progression, and metastasis. Numerous studies have explored the of metabolic alterations KRAS-driven cancers, providing scientific rationale for targeting metabolism treatment. development KRAS-specific inhibitors has also garnered considerable attention, partly due to challenge acquired treatment resistance. Here, we review reprogramming glucose, glutamine, lipids regulated by oncogenic KRAS, with an emphasis on recent insights into relationship between changes mechanisms driven KRAS mutant related advances targeted therapy. We focus inhibitor discovery strategies colorectal, pancreatic, non-small cell lung cancer, including current clinical trials. Therefore, this provides overview understanding associated mutation therapeutic strategies, aiming facilitate challenges support investigation strategies.

Language: Английский

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Oxidative Stress and Mitochondrial Impairment: Key Drivers in Neurodegenerative Disorders

Ageing Research Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102667 - 102667

Published: Jan. 1, 2025

Language: Английский

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