Structural characteristics and intestinal flora metabolism mediated immunoregulatory effects of Lactarius deliciosus polysaccharide

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 278, P. 135063 - 135063

Published: Aug. 24, 2024

Language: Английский

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Metabolic reprogramming, sensing, and cancer therapy

Cell Reports, Journal Year: 2024, Volume and Issue: 43(12), P. 115064 - 115064

Published: Dec. 1, 2024

The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- condition-dependent remodeling certain pathways. While it has become increasingly clear that integrate extracellular intracellular signals to adapt proliferate, nutrient metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, changes not only support rapid growth dissemination but promote immune evasion by metabolically "educating" in microenvironment (TME). Recent studies have highlighted profound impact on TME potential targeting pathways as therapeutic strategy, with several enzyme inhibitors showing promising results clinical trials. Thus, understanding how alter remodel proliferation may offer new strategies therapy immunotherapy.

Language: Английский

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Metabolic interplays between the tumour and the host shape the tumour macroenvironment

Nature reviews. Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 20, 2025

Language: Английский

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Cryo-EM structure and regulation of human NAD kinase

Science Advances, Journal Year: 2025, Volume and Issue: 11(4)

Published: Jan. 24, 2025

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is a crucial reducing cofactor for reductive biosynthesis and protection from oxidative stress. To fulfill their heightened anabolic power demands, cancer cells must boost NADPH production. Progrowth mitogenic protein kinases promote the activity of cytosolic NAD kinase (NADK), which produces NADP + , limiting precursor. However, molecular architecture mechanistic regulation human NADK remain undescribed. Here, we report cryo–electron microscopy structure NADK, both in its apo-form complex with substrate (nicotinamide dinucleotide), revealing tetrameric organization distinct structural features. We discover that amino (N)- carboxyl (C)-terminal tails have opposing effects on enzymatic cellular NADP(H) levels. Specifically, C-terminal region critical activity, whereas N-terminal exhibits an inhibitory role. This study highlights insights into vital enzyme governing

Language: Английский

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Uridine-sensitized screening identifies genes and metabolic regulators of nucleotide synthesis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Nucleotides are essential for nucleic acid synthesis, signaling, and metabolism, can be synthesized de novo or through salvage. Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited target cancer therapy. However, resistance frequently emerges, highlighting the need deeper understanding regulation. Here, we harness uridine salvage CRISPR-Cas9 screening to reveal regulators pyrimidine synthesis. We identify several factors report that synthesis continue in absence coenzyme Q (CoQ), canonical electron acceptor further investigate NUDT5 its conserved interaction with PPAT, rate-limiting enzyme purine show NUDT5, hyperactive siphons phosphoribosyl pyrophosphate (PRPP) pool at expense promoting chemotherapy. Intriguingly, between PPAT appears disrupted by PRPP, intricate allosteric Our findings fundamental mechanism maintaining balance position as potential biomarker predicting

Language: Английский

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Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs

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

Published: March 21, 2025

Abstract Activating PIK3CA mutations, present in up to 40% of hormone receptor-positive (HR + ), human epidermal growth factor receptor 2-negative (Her2 − ) breast cancer (BC) patients, can be effectively targeted with the alpha isoform-specific PI3K inhibitor Alpelisib. This treatment significantly improves outcomes for HR , Her2 and -mutated metastatic BC patients. However, acquired resistance, often due aberrant activation mTOR complex 1 (mTORC1) pathway, remains a significant clinical challenge. Our study, using vitro orthotopic xenograft mouse models, demonstrates that constitutively active mTORC1 signaling renders inhibitor-resistant exquisitely sensitive various drugs targeting metabolism. Mechanistically, suppresses induction autophagy during metabolic perturbation, leading energy stress, critical depletion aspartate, ultimately cell death. Supporting this mechanism, cells CRISPR/Cas9-engineered knockouts canonical genes showed similar vulnerability metabolically drugs. In high activity, indicated by 4E-BP1 T37/46 phosphorylation, correlated p62 accumulation, sign impaired autophagy. Together, these markers predicted poor overall survival multiple subgroups. findings reveal signaling, common cause resistance BC, creates druggable suppressing Additionally, combination phosphorylation accumulation serves as biomarker survival, suggesting their potential utility identifying patients who may benefit from therapies.

Language: Английский

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Tissue niche influences immune and metabolic profiles to Staphylococcus aureus biofilm infection

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 17, 2024

Infection is a devastating post-surgical complication, often requiring additional procedures and prolonged antibiotic therapy. This especially relevant for craniotomy prosthetic joint infections (PJI), both of which are characterized by biofilm formation on the bone or implant surface, respectively, with S. aureus representing primary cause. The local tissue microenvironment likely has profound effects immune attributes that can influence treatment efficacy, becomes critical to consider when developing therapeutics infections. However, extent distinct niches function during development remains relatively unknown. To address this, we compare metabolomic, transcriptomic, functional leukocytes in mouse models PJI complemented patient samples from infection modalities, reveals niche-dependent differences nucleic acid, amino lipid metabolism links modulation. These signatures spatially temporally distinct, differing not only between sites but evolving over time within single model. Collectively, this demonstrates biofilms elicit unique metabolic responses heavily influenced microenvironment, will have important implications designing therapeutic approaches targeting these

Language: Английский

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Use of Nicotinamide Mononucleotide as Non-Natural Cofactor

Catalysts, Journal Year: 2025, Volume and Issue: 15(1), P. 37 - 37

Published: Jan. 3, 2025

Nicotinamide mononucleotide (NMN) has emerged as a promising non-natural cofactor with significant potential to transform biocatalysis, synthetic biology, and therapeutic applications. By modulating NAD⁺ metabolism, NMN offers unique advantages in enzymatic reactions, metabolic engineering, regenerative medicine. This review provides comprehensive analysis of NMN’s biochemical properties, mechanisms action, diverse Emphasis is placed on its role addressing challenges multi-enzyme cascades, biofuel production, the synthesis high-value chemicals. The paper also highlights critical research gaps, including need for scalable methods, improved integration into systems, toxicity studies use. Emerging technologies such AI-driven enzyme design CRISPR-based genome engineering are discussed transformative tools optimizing NMN-dependent pathways. Furthermore, synergistic biology innovations, cell-free systems dynamic regulatory networks, explored, paving way precise modular biotechnological solutions. Looking forward, versatility positions it pivotal tool advancing sustainable bioprocessing precision Addressing current limitations through interdisciplinary approaches will enable redefine boundaries innovation. serves roadmap leveraging across scientific industrial domains.

Language: Английский

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Multiomics insights into BMI-related intratumoral microbiota in gastric cancer

Frontiers in Cellular and Infection Microbiology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 18, 2025

Body mass index (BMI) is considered an important factor in tumor prognosis, but its role gastric cancer (GC) remains controversial. There a lack of studies exploring the effect BMI on from perspective intratumoral microbiota. This study aimed to compare and analyze differences functions microbiota among GC patients with varying BMIs, aiming ascertain whether specific microbial features are associated prognosis low-BMI (LBMI) patients. A retrospective analysis clinicopathological 5567 different BMIs was performed between January 2010 December 2019. Tumor tissues 189 were collected for 16S rRNA sequencing, 64 samples selected transcriptome 57 untargeted metabolomic analysis. Clinical cohort revealed that low presented poorer clinical pathological characteristics than those non-low-BMI (NLBMI). LBMI identified as significant independent risk adverse potentially exerting immunosuppressive effects postoperative adjuvant chemotherapy. sequencing no alpha beta diversity two groups However, LEfSe 32 differential NLBMI groups. Notably, genus Abiotrophia significantly enriched group. Further in-depth indicated inversely eosinophils, P2RY12, SCN4B genes, positively linked LGR6 Metabolomic assessments purine metabolites, specifically guanine inosine diphosphate (IDP). In conclusion, poor may have inhibitory Intratumor flora levels differed, immune cell infiltration metabolic characteristics. The promote development progression by regulating eosinophils metabolism pathway, which provides new idea precise treatment cancer.

Language: Английский

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Transcriptomic and Metabolomic Analysis Reveals the Impact of Autophagy Regulation on Purine Content in Mutton

Foods, Journal Year: 2025, Volume and Issue: 14(5), P. 718 - 718

Published: Feb. 20, 2025

Excessive purine intake increases the risk of hyperuricemia and gout. This study investigates relationship between content in mutton meat quality traits explores regulatory mechanism metabolism through transcriptomic metabolomic analyses. Thirty-six-month-old hybrid sheep (Australian White × Small-tail Han) were selected. Purine traits, including inosine monophosphate (IMP), intramuscular fat (IMF), shear force, pH, cooking loss, color, measured. Transcriptomic sequencing analysis performed on muscle samples with high (3895.70 ± 107.03 mg/kg) low (2751.72 175.29 contents (n = 6 per group). Differentially expressed genes validated by quantitative PCR Western blot. In vivo autophagy regulation experiments mice using rapamycin (activator) chloroquine (inhibitor). No significant correlation was found suggesting that reducing does not negatively affect quality. An autophagy-related gene, LAPTM5 (lysosomal-associated protein transmembrane 5), identified as a key gene regulating content. demonstrated affects modulating enzymes such xanthine dehydrogenase (XDH) hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT). reveals role XDH HPRT, providing new insights for improving future.

Language: Английский

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