Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancer

Pharmacological Research, Год журнала: 2025, Номер 213, С. 107636 - 107636

Опубликована: Фев. 1, 2025

FOLFOX (5-Fluorouracil, Calcium Folinate combined with Oxaliplatin) is a preferred chemotherapy regimen for colon cancer, but its limited efficacy remains major challenge, significantly impairs patient outcomes. There an urgent need to identify strategies improve therapeutic effectiveness. Our previous studies have suggested that gut microbiota-derived bile acids may be involved in the anticancer effect of vitro, however, underlying mechanism unclear. In this study, we investigated role modulating and related mechanisms. We first demonstrated depletion (cholestyramine treatment) enhanced orthotopic cancer mouse model, suggesting play key FOLFOX's effects. Further, based on system screen 15 via MTT, colony formation flow cytometry assay, Deoxycholic Acid (DCA) Glycodeoxycholic (GDCA) were annotated as potential modulators efficacy. Among these, DCA was further validated enhance anti-colon effects vivo. Transcriptomic analysis subsequent biological experiments revealed Ugt1a6b. conclusion, our findings establish enhances potentially Ugt1a6b mediated enterohepatic circulation, providing novel insights into synergistic strategy improving treatment.

Язык: Английский

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Metabolic Crosstalk between Liver and Brain: From Diseases to Mechanisms

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(14), С. 7621 - 7621

Опубликована: Июль 11, 2024

Multiple organs and tissues coordinate to respond dietary environmental challenges. It is interorgan crosstalk that contributes systemic metabolic homeostasis. The liver brain, as key organs, have their unique dialogue transmit messages. interconnected pathogenesis of brain implicated in numerous neurodegenerative disorders. Recent insights positioned the not only a central hub but also an endocrine organ, capable secreting hepatokines signals throughout body via bloodstream. Metabolites from or gut microbiota facilitate complex between brain. In parallel humoral factors, neural pathways, particularly hypothalamic nuclei autonomic nervous system, are pivotal modulating bilateral interplay cerebral hepatic compartments. term “liver–brain axis” vividly portrays this interaction. At end review, we summarize cutting-edge technical advancements enabled observation manipulation these signals, including genetic engineering, molecular tracing, delivery technologies. These innovations paving way for deeper understanding liver–brain axis its role

Язык: Английский

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Nanobilosome as custom-tailored modality in addressing Alzheimer’s disease: advancements and translational glitches

Journal of Dispersion Science and Technology, Год журнала: 2025, Номер unknown, С. 1 - 32

Опубликована: Апрель 11, 2025

Язык: Английский

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Metabolomic Profiling of Three Body Fluids Differentiates UWS and MCS in Disorders of Consciousness

Biomedical Chromatography, Год журнала: 2025, Номер 39(5)

Опубликована: Апрель 11, 2025

ABSTRACT Disorders of consciousness (DOC), including unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), are complex brain dysfunctions with various causes. Misdiagnosis is common when relying solely on neurological exams, highlighting the need for accurate differentiation to guide clinical rehabilitation. This study explores metabolomic differences between UWS MCS across cerebrospinal fluid (CSF), serum, urine samples identify biomarkers metabolic pathways. Fifty‐one subjects were categorized into ( n = 35) 16) based coma recovery scale‐revised (CRS‐R) scores. Ultraperformance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) was used analyze samples, statistical methods identified 14, 24, 22 differential metabolites in CSF, urine, respectively. CSF linked necrosis, apoptosis, neuroprotection; serum lipid metabolism immune response; cell signaling neural function. Metabolomic panels showed AUC values 0.85 (95% CI: 0.73–0.96) 0.86–1.00), 0.94 0.93 0.79–1.00) distinguishing from MCS. profiling offers valuable insights DOC pathophysiology aids these states.

Язык: Английский

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Multiple Enzymes Expressed by the Gut Microbiota Can Transform Typhaneoside and Are Associated with Improving Hyperlipidemia

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Abstract The mechanism of multiple enzymes mediated drug metabolism in gut microbiota is still unclear. This study explores enzyme interaction process typhactyloside (TYP) with and its lipid‐lowering pharmacological activity. TYP, bioavailability only 2.78%, an active component Typha angustifolia L . Pushen capsules which clinically treated for hyperlipidemia. metabolic TYP identified, key involved are validated through gene knockout overexpression techniques. Through overexpressing α‐rhamnosidase (Rha) Escherichia coli , verified to metabolize into isorhamnetin‐3‐ O ‐neohesperidin (M1) ‐glucoside (M2) after removing rhamnose Rha. Besides, β‐glucosidase (Glu) confirms that generates M3 Glu glucose. Combined molecular docking, transformed generate 3,4‐dihydroxyphenylacetic acid (M4), protocatechuic (M5), 3‐hydroxyphenylacetic (M6) flavonoid reductase (Flr) chalcone isomerase (Chi). In conclusion, (Rha/Glu→Flr→Chi) identified. vivo experiments, combined use M5 also shows excellent anti‐hyperlipidemia efficacy. the first on complex activity natural flavonoids by enzymes, provide insight investigate analogous products.

Язык: Английский

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The role of the gut microbiome in Alzheimer's disease pathophysiology

Current Opinion in Neurology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 7, 2025

Purpose of review The present aims to provide an overview the existing understanding role gut microbiome in Alzheimer's disease pathophysiology. Recent findings research has highlighted significant pathogenesis via gut-brain axis. However, precise mechanisms by which and its microbial metabolites influence brain function are not clearly understood. Various factors, such as diet, drugs, lifestyle, stress, infections can provoke imbalance homeostasis, known dysbiosis. This dysbiosis impacts intestinal blood-brain barrier permeability, elevating pro-inflammatory cytokines contributing neurodegeneration. Moreover, generates neurotransmitters, amyloids, neurotoxins, metabolites, may play a systemic inflammation disruption physiological barriers. Summary In past decade, advancements analysis technologies bioinformatics have significantly enhanced our disease. plays pivotal regulatory progression disease, closely interacts with pathogenesis, encompassing inflammation, amyloidosis, neurodegeneration, tauopathy, co-pathologies.

Язык: Английский

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A panel of altered blood oxysterols in patients with mild cognitive impairment: A novel combined diagnostic marker

Pharmacological Research, Год журнала: 2025, Номер 213, С. 107661 - 107661

Опубликована: Фев. 20, 2025

Perturbed cholesterol metabolism may play an important role in the development of dementia and its preclinical stage, mild cognitive impairment (MCI). Oxysterols, metabolites generated during oxidation, also appear to be risk factors for MCI. Therefore, we aimed investigate if metabolic profile blood oxysterols could used characterize MCI risk. This cross-sectional study incorporated 501 participants-253 patients with 248 cognitively normal controls. Serum levels 22 free were measured, a set 27 oxysterol-related gene polymorphisms was genotyped. Five [27-hydroxycholesterol (27-OHC), 27-OHC periphery-derived metabolite 3β-hydroxy-5-cholestenoic acid (27-CA) brain-derived 7α-hydroxy-3-oxo-4-cholestenoic (7-HOCA), 4β-hydroxycholesterol (4β-OHC); 4α-hydroxycholesterol (4α-OHC)] twenty-two detected serum significantly differed between controls, greatly distinguishing from control individuals (AUC=0.834, 95% CI: 0.804-0.866). Association analyses demonstrated significant correlations these candidate oxysterol biomarkers younger age, higher lipids, worse performance, monounsaturated fatty intake. panel as highlighted essential pathogenesis early prevention. (The registered Chinese Clinical Trial Registry ChiCTR-OOC-17011882).

Язык: Английский

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Bile acid signaling in skeletal muscle homeostasis: from molecular mechanisms to clinical applications

Frontiers in Endocrinology, Год журнала: 2025, Номер 16

Опубликована: Март 12, 2025

The intricate relationship between bile acid metabolism and skeletal muscle function has emerged as a crucial area of research in metabolic health. This review synthesizes current evidence highlighting the fundamental role acids key signaling molecules homeostasis their therapeutic potential muscle-related disorders. Recent advances molecular biology metabolomics have revealed that acids, beyond classical lipid absorption, essential regulators mass through multiple pathways, particularly via nuclear receptor FXR membrane TGR5. Clinical studies demonstrated significant associations altered profiles wasting conditions, while experimental elucidated underlying mechanisms linking to protein synthesis, energy metabolism, regeneration capacity. We critically examine emerging strategies targeting including receptor-specific agonists, microbiome modulators, personalized interventions based on individual profiles. Additionally, we discuss novel diagnostic approaches utilizing acid-based biomarkers early detection monitoring also addresses challenges standardization clinical translation promising future directions this rapidly evolving field. Understanding acid-muscle axis may provide new opportunities for developing targeted therapies age-related loss diseases.

Язык: Английский

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The bile acid profile

Clinica Chimica Acta, Год журнала: 2024, Номер 565, С. 120004 - 120004

Опубликована: Окт. 16, 2024

Язык: Английский

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Emerging Roles of Bile Acids and TGR5 in the Central Nervous System: Molecular Functions and Therapeutic Implications

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(17), С. 9279 - 9279

Опубликована: Авг. 27, 2024

Bile acids (BAs) are cholesterol derivatives synthesized in the liver and released into digestive tract to facilitate lipid uptake during digestion process. Most of these BAs reabsorbed recycled back liver. Some progress other tissues through bloodstream. The presence central nervous system (CNS) has been related their capacity cross blood–brain barrier (BBB) from systemic circulation. However, expression enzymes receptors involved synthesis signaling, respectively, support hypothesis that there is an endogenous source with a specific function CNS. Over last decades, have tested as treatments for many CNS pathologies, beneficial effects. Although they were initially reported neuroprotective substances, also known reduce inflammatory processes. effects activation Takeda G protein-coupled receptor 5 (TGR5). This review addresses new challenges face BA research neuroscience, focusing on molecular functions. We discuss exogenous sources CNS, signaling TGR5 receptor, mechanisms action potential therapeutics neuropathologies.

Язык: Английский

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