The Inhibitory Effects of NCT503 and Exogenous Serine on High-Selenium Induced Insulin Resistance in Mice

Nutrients, Journal Year: 2025, Volume and Issue: 17(2), P. 311 - 311

Published: Jan. 16, 2025

Objective: This study aims to identify whether the development of insulin resistance (IR) induced by high selenium (Se) is related serine deficiency via inhibition de novo synthesis pathway (SSP) administrations 3-phosphoglycerate dehydrogenase (PHGDH) inhibitor (NCT503) or exogenous in mice. Method: forty-eight male C57BL/6J mice were randomly divided into four groups: adequate-Se (0.1 mgSe/kg), high-Se (0.8 +serine (240 mg/kg/day), and +NCT503 (30 mg/kg, twice a week) for 5 months. The glucose tolerance test (GTT) (ITT) used confirm IR with intake, fasting blood levels measured monthly. Se contents plasma tissues detected ICP-MS. (INS), homocysteine (HCY), tested ELISA. Western blot analyses conducted evaluate protein expressions glutathione peroxidase 1 (GPX1), selenoprotein P (SELENOP) PHGDH, PI3K-AKT-mTOR pathway, folate cycle (SHMT1, MTHFR), methionine (MS). Results: An model was developed from group elevated INS levels, impaired tolerance, reduced sensitivity, but not both group. Compared groups, GPX1 SELENOP significantly decreased liver, muscle, pancreas tissues. expression PHGDH higher than that liver (p < 0.05) 0.001). Also, expected effectively inhibited p-AKT (Ser-473) lower pancreas. Conclusions: intake body has been confirmed be partially due deficiency, which led initiation SSP produce endogenous serine. supplementations inhibitors this metabolic could intervention.

Language: Английский

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Glucose Metabolism and Tumor Microenvironment: Mechanistic Insights and Therapeutic Implications

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 1879 - 1879

Published: Feb. 22, 2025

Metabolic reprogramming in cancer cells involves changes glucose metabolism, glutamine utilization, and lipid production, as well promoting increased cell proliferation, survival, immune resistance by altering the tumor microenvironment. Our study analyzes metabolic neoplastically transformed cells, focusing on glutaminolysis, synthesis. Moreover, we discuss therapeutic potential of targeting key enzymes involved glycolysis, pentose phosphate pathway, amino acid including lactate dehydrogenase A, hexokinase, phosphofructokinase others. The review also highlights challenges such heterogeneity, adaptability, need for personalized therapies to overcome minimize adverse effects treatment. This underscores significance comprehending engineer targeted therapies, personalize treatment methodologies, surmount challenges, plasticity resistance.

Language: Английский

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Discovery of RNA-Protein Molecular Clamps Using Proteome-Wide Stability Assays

Journal of Proteome Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

Uncompetitive inhibition is an effective strategy for suppressing dysregulated enzymes and their substrates, but discovery of suitable ligands depends on often-unavailable structural knowledge serendipity. Hence, despite surging interest in mass spectrometry-based target identification, proteomic studies substrate-dependent engagement remain sparse. Herein, we describe a the ligand binding. Using proteome integral solubility alteration (PISA) assays, show that simple biochemical additives can enable detection RNA-protein-small molecule complexes native cell lysates. We apply our approach to rocaglates, molecules specifically clamp RNA eukaryotic translation initiation factor 4A (eIF4A), DEAD-box helicase 3X (DDX3X), potentially other members (DDX) family. To identify unexpected interactions, used class-specific thermal window compared ATP analog base dependencies key rocaglate-DDX interactions. report novel DDX targets high-profile rocaglates-including clinical candidate Zotatifin-and validate findings using limited proteolysis-mass spectrometry fluorescence polarization (FP) experiments. also provide insight into divergent DDX3X affinities between synthetic rocaglates. Taken together, study provides model screening uncompetitive inhibitors chemical proteomics uncovers actionable clamping targets, clearing path toward characterization molecular clamps associated helicases.

Language: Английский

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The role and research progress of serine metabolism in tumor cells

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: April 8, 2025

Serine is crucial for tumor initiation, progression, and adaptive immunity. Metabolic pathways serine synthesis, acquisition, utilization in tumors tumor-associated cells are influenced by various physiological factors the microenvironment, leading to metabolic reprogramming amplification. Excessive metabolism promotes abnormal macromolecule biosynthesis, mitochondrial dysfunction, epigenetic modifications, driving malignant transformation, proliferation, metastasis, immune suppression, drug resistance cells. Restricting dietary intake or reducing expression of synthetic enzymes can effectively slow growth extend patient survival. Consequently, targeting has emerged as a novel promising research focus cancer research. This paper reviews their roles development. It summarizes influencing metabolism. The article explores significance synthesis metabolizing enzymes, along with related biomarkers, diagnosis treatment, providing new insights developing targeted therapies that modulate cancer.

Language: Английский

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Serine metabolism in tumor progression and immunotherapy

Discover Oncology, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 28, 2025

Language: Английский

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Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217512 - 217512

Published: Feb. 1, 2025

Colorectal cancer (CRC) represents a prototypical example of type for which inter- and intra-tumor heterogeneities remain major challenges the clinical management patients. Besides genotype-mediated phenotypic alterations, tumor microenvironment (TME) conditions are increasingly recognized to promote intrinsic diversity plasticity sustain disease progression. In particular, acidosis is common hallmark solid tumors, including CRC, it known induce aggressive cell phenotypes. this study, we report that long-term adaptation acidic pH associated with metabolic glycolysis-to-respiration switch higher reliance on activity phosphoglycerate dehydrogenase (PHGDH), in CRC cells initially displaying molecularly heterogeneous backgrounds. Pharmacological inhibition PHGDH or mitochondrial respiration induces greater growth-inhibitory effects acidosis-exposed 2D 3D culture conditions, patient-derived organoids. These data pave way drugs targeting compartment as "one-size-fits-all" therapeutic approach delay

Language: Английский

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Mevalonate pathway inhibition reduces bladder cancer metastasis by modulating RhoB protein stability and integrin β1 localization

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Nov. 9, 2024

The progression and outcome of bladder cancer (BLCA) are critically affected by the propensity tumor metastasis. Our previous study revealed that activation mevalonate (MVA) pathway promoted migration BLCA cells; however, exact mechanism is unclear. Here we show elevated expression MVA enzymes in cells, correlating with poorer patient prognosis analyzing single-cell bulk-transcriptomic datasets. Inhibition pathway, either through knockdown farnesyl diphosphate synthase (FDPS) or using inhibitors such as zoledronic acid simvastatin, led to a marked reduction cell migration. Notably, this effect was reversed administering geranylgeranyl pyrophosphate (GGPP), not (FPP) cholesterol, indicating specificity geranylgeranylation for motility. Moreover, found RhoB, Rho GTPase family member, identified key effector impact on post-translational modification RhoB GGPP-mediated influenced its protein stability ubiquitin-proteasome pathway. Additionally, overexpression block membrane translocation integrin β1 cells. In summary, our findings underscore role metastasis, providing insights into potential therapeutic targets malignancy.

Language: Английский

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Metabolic functions of misunderstood D-2-hydroxyglutarate

The Innovation Life, Journal Year: 2024, Volume and Issue: unknown, P. 100101 - 100101

Published: Jan. 1, 2024

<p>Isocitrate dehydrogenase mutation-induced D-2-hydroxyglutarate (D-2-HG) accumulation may promote the tumorigenesis of numerous cancers. D-2-HG produced by several promiscuous enzymatic reactions under normal conditions is also toxic to organisms. was thus previously viewed as an abnormal metabolite with no physiological function and conversion 2-ketoglutarate seems be a process repair. However, recent studies have revealed that production not meaningless without purpose. actually participates in many core metabolic processes, disorders these processes reason for some tumors lacking isocitrate mutation. This review summarizes diverse widely distributed involving D-2-HG, highlights functions generation from various precursors, discusses possible applications enzymes related metabolism synthetic biology, diagnosis, treatment accumulation-induced diseases.</p>

Language: Английский

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Genetic heterogeneity and metabolic reprogramming in breast cancer

Acta Medica, Journal Year: 2024, Volume and Issue: 55(4), P. 227 - 246

Published: Dec. 29, 2024

Breast cancer is the most prevalent and leading cause of cancer-related mortality among women. Recent breakthroughs in breast therapeutics have significantly enhanced outcomes for hormone receptor-positive HER2-negative subtypes. However, emergence drug resistance, particularly triple-negative cancer, presents a formidable challenge. The intricate interplay genetic metabolic diversity within cells pivotal to its development. By reprogramming pathways, can adapt thrive, meeting demands survival, growth, invasion. These shifts also play key role development resistance conventional therapies. This review explores complexities emphasizing diverse subtypes their unique profiles. We examine how variations alterations contribute progression, influencing both treatment efficacy resistance. integrating insights into background subtypes, this aims highlight that pathogenesis with vision advancing more precise effective targeted therapies as well discovering novel diagnostic prognostic markers.

Language: Английский

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Metabolic-Modulating Effects of Radiation: Undetectable Yet Deadly—A Review on Radiotherapy

Cancers, Journal Year: 2024, Volume and Issue: 17(1), P. 54 - 54

Published: Dec. 27, 2024

From a cancer-centric perspective, radiotherapy has been primarily viewed as localised treatment modality, targeting cancer tissues with ionising radiation to induce DNA damage and cell death [...]

Language: Английский

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