The tryptophan metabolic pathway of the microbiome and host cells in health and disease

International Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: June 13, 2024

Abstract The intricate and dynamic tryptophan (Trp) metabolic pathway in both the microbiome host cells highlights its profound implications for health disease. This involves complex interactions between cellular bacteria processes, producing bioactive compounds such as 5-hydroxytryptamine (5-HT) kynurenine derivatives. Immune responses to Trp metabolites through specific receptors have been explored, highlighting role of aryl hydrocarbon receptor inflammation modulation. Dysregulation this is implicated various diseases, Alzheimer’s Parkinson’s mood disorders, neuronal autoimmune diseases multiple sclerosis (MS), cancer. In article, we describe impact 5-HT, Trp, indole, on Furthermore, review microbiome-derived that affect immune contribute maintaining homeostasis, especially an experimental encephalitis model MS.

Language: Английский

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The role of kynurenines in migraine-related neuroimmune pathways

The Journal of Headache and Pain, Journal Year: 2024, Volume and Issue: 25(1)

Published: Aug. 6, 2024

Abstract Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by immune may play role in migraine pathophysiology. Neuroinflammation is often associated with attacks, cytokines serving as crucial mediators process. Elevated levels pro-inflammatory cytokines, such interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed blood cerebrospinal fluid individuals experiencing These capacity sensitize pain pathways brain, thereby increasing sensitivity stimuli. This phenomenon, known central sensitization, believed contribute intensity persistence pain. Kynurenines, endogenous glutamatergic mechanisms, can significantly influence pathophysiology disorders. The kynurenine collectively pathway (KP), which act on multiple receptors, glutamate aryl hydrocarbon receptors (AhRs), G protein-coupled 35 (GPR35), α-7 nicotinic acetylcholine (α7 nACh) receptors. are also found various cells system, so KP pathomechanism headaches be through them. In this review, our goal show possible link between context inflammation migraine. Migraine research recent years has focused neuropeptides, calcitonin gene-related peptide (CGRP) pituitary adenylate cyclase-activating polypeptide (PACAP) potential pathogenic factors therapeutic approaches. peptides share many similarities their characteristics roles. For instance, they exhibit potent vasodilation, occur both peripheral nervous systems, transmitting nociception neurogenic inflammation. investigation connections aforementioned neuropeptides could significant uncovering identifying new drug candidates.

Language: Английский

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The Biology and Biochemistry of Kynurenic Acid, a Potential Nutraceutical with Multiple Biological Effects

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 9082 - 9082

Published: Aug. 21, 2024

Kynurenic acid (KYNA) is an antioxidant degradation product of tryptophan that has been shown to have a variety cytoprotective, neuroprotective and neuronal signalling properties. However, mammalian transporters receptors display micromolar binding constants; these are consistent with its typically tissue concentrations but far above serum/plasma concentration (normally tens nanomolar), suggesting large gaps in our knowledge transport mechanisms action, the main influx characterized date equilibrative, not concentrative. In addition, it substrate known anion efflux pump (ABCC4), whose vivo activity largely unknown. Exogeneous addition L-tryptophan or L-kynurenine leads production KYNA also many other co-metabolites (including some such as 3-hydroxy-L-kynurenine quinolinic may be toxic). With exception chestnut honey, exists at relatively low levels natural foodstuffs. bioavailability reasonable, terminal element irreversible reaction most pathways, might added exogenously without disturbing upstream metabolism significantly. Many examples, which we review, show valuable bioactivity. Given above, review potential utility nutraceutical, finding significantly worthy further study development.

Language: Английский

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Aromatic Amino Acid Metabolites: Molecular Messengers Bridging Immune-Microbiota Communication

Immune Network, Journal Year: 2025, Volume and Issue: 25(1)

Published: Jan. 1, 2025

Aromatic amino acid (AAA) metabolites, derived from tryptophan, phenylalanine, and tyrosine through coordinated host microbial metabolism, have emerged as critical modulators of immune function. We examine the complex journey AAAs dietary intake intestinal absorption metabolic transformation, highlighting crucial role host-microbe networks in generating diverse immunomodulatory compounds. This review provides a unique integrative perspective by mapping molecular mechanisms which these metabolites orchestrate responses. Through detailed analysis metabolite-receptor metabolite-transporter interactions, we reveal how specific recognition drives cell type-specific Our comprehensive examination signaling networks-from membrane receptor engagement to nuclear activation post-translational modifications- demonstrates same metabolite can elicit distinct functional outcomes different populations. The context-dependent nature interactions presents both challenges opportunities for therapeutic development, particularly inflammatory conditions where pathways are dysregulated. Understanding complexity regulatory remaining knowledge gaps is fundamental advancing metabolite-based strategies immune-mediated disorders.

Language: Английский

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Activation of GPR35 by kynurenic acid inhibits IL-1β secretion in macrophages during CR-hvKP-induced pneumonia

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 153, P. 114416 - 114416

Published: March 18, 2025

Carbapenemase-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is a common pathogen that can cause severe pneumonia. The innate immune response, especially the response of macrophages, plays crucial role in host's defense against bacterial infections. Glycolysis implicated modulation functions macrophages. Here, we provide evidence supporting GPR35 decreasing glycolysis and reducing secretion IL-1β macrophages by inhibiting transcription HK2 during K. pneumoniae-induced Mice with knock-out exhibit higher mortality increased lung burdens. Mechanistically, activation kynurenic acid inhibits caspase-1 cleavage reduces specifically suppressing NLRP3 inflammasome. These findings underscore regulating inflammation pneumonia suggest potential therapeutic target for clinical treatment.

Language: Английский

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Revolutionizing GPCR–ligand predictions: DeepGPCR with experimental validation for high-precision drug discovery

Briefings in Bioinformatics, Journal Year: 2024, Volume and Issue: 25(4)

Published: May 23, 2024

Abstract G-protein coupled receptors (GPCRs), crucial in various diseases, are targeted of over 40% approved drugs. However, the reliable acquisition experimental GPCRs structures is hindered by their lipid-embedded conformations. Traditional protein–ligand interaction models falter GPCR–drug interactions, caused limited and low-quality structures. Generalized models, trained on soluble pairs, also inadequate. To address these issues, we developed two DeepGPCR_BC for binary classification DeepGPCR_RG affinity prediction. These use non-structural GPCR–ligand data, leveraging graph convolutional networks mol2vec techniques to represent binding pockets ligands as graphs. This approach significantly speeds up predictions while preserving critical physical–chemical spatial information. In independent tests, surpassed Autodock Vina Schrödinger Dock with an area under curve 0.72, accuracy 0.68 true positive rate 0.73, whereas demonstrated a Pearson correlation 0.39 root mean squared error 1.34. We applied screen drug candidates GPR35 (Q9HC97), yielding promising results three (F545-1970, K297-0698, S948-0241) out eight candidates. Furthermore, successfully obtained six active inhibitors GLP-1R. Our GPCR-specific pave way efficient accurate large-scale virtual screening, potentially revolutionizing discovery GPCR field.

Language: Английский

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ITGAX promotes gastric cancer progression via epithelial-mesenchymal transition pathway

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

Published: Jan. 8, 2025

Gastric cancer is the fifth most common and fourth leading cause of cancer-related deaths worldwide, accounting for nearly 800,000 fatalities annually. ITGAX (Integrin alpha X) closely associated with immune cells, such as macrophages dendritic cells. Its involvement in gastric was identified through an analysis The Gene Expression Omnibus (GEO) database, which highlighted one four key genes. Our study demonstrates that expression significantly elevated tumor tissues compared to normal positively correlated clinical prognosis patients from GEO database. Moreover, enhanced cell proliferation, invasion, tumorigenic capacity mouse models. Furthermore, we explored underlying role using Kyoto Encyclopedia Genes Genomes (KEGG) protein-protein interaction networks (PPI) analysis. findings reveal promotes progression by driving epithelial-mesenchymal transition pathway (EMT), suggesting its potential a biomarker early diagnosis cancer.

Language: Английский

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GPR35 prevents drug-induced liver injury via the Gαs-cAMP-PKA axis in macrophages

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Acetaminophen (APAP) overdose induces acute liver injury and represents the most frequent cause of drug-induced worldwide. Macrophage-mediated inflammation plays detrimental roles during early stage injury. However, potential targets regulating to improve remains undefined. In this study, we reported that G protein-coupled receptor 35 (GPR35) improves by blocking macrophage-mediated via Gαs-cyclic AMP-protein kinase A (Gαs-cAMP-PKA) pathway. The ablation GPR35 exacerbates APAP-induced injury, characterized higher levels alanine aminotransferase aspartate in sera, larger damaged areas, increased pro-inflammatory cytokines. More hepatic macrophages appeared inflamed mice with deficiency. contrast, agonists alleviated depletion abolished GPR35-mediated protection. Mechanistically, facilitated activation AKT, MAPK, NF-κB signaling pathways at downstream Toll-like receptors macrophages. activated Gαs-cAMP-PKA inhibit these then suppress inflammatory response Thus, our findings demonstrate prevents pathway, indicating is a target for development novel medicines control

Language: Английский

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Molecular Structure and GPR35 Receptor Docking of 1,3-Phenylene Bis-Oxalamide Derivatives

Crystals, Journal Year: 2025, Volume and Issue: 15(4), P. 371 - 371

Published: April 17, 2025

A series of three 1,3-phenylene bis-oxamides 3a–c, structurally related to the GPR35 receptor-agonist drug lodoxamide, has been synthesized by reacting bis-oxalamates 2a and 2b with amines. The obtained compounds were characterized 1H 13C NMR, IR spectroscopy, they showed characteristic signals for aromatic, N―H, C=O groups. Molecular structure was determined using single-crystal X-ray diffraction. supramolecular architecture is driven N―H···O=C, N―H···N, C—H···π, O=C···O=C interactions depicting a helix (3a) tapes (3b–c). Intermolecular studied Hirshfeld surface analysis, where N―H∙∙∙X (X = N, O) hydrogen bonding represents 30.2% 3a 17.8–18.8% 3b–c. most energetic involve amide N—H∙∙∙O bonding, contributing in −113.9 −97.0 kJ mol−1 range crystal energy, being more dispersive than electrostatic nature. molecular docking study performed evaluate binding ability 3a–c receptor, showing favorable similar way lodoxamide.

Language: Английский

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Transcriptome analysis of macrophages during Brucella abortus infection clarifies the survival mechanisms of the bacteria

Diagnostic Microbiology and Infectious Disease, Journal Year: 2024, Volume and Issue: 110(1), P. 116401 - 116401

Published: June 12, 2024

Brucellosis is a critical zoonotic disease impacting humans and animals globally, causing symptoms like fever arthritis in reproductive issues animals. The stems from the Brucella genus, adept at evading immune system proliferating within host cells. This study explores how abortus manipulates cellular mechanisms to sustain infection, focusing on interaction with murine macrophages over 24 h. Initial defenses involve innate responses, while Brucella's survival strategies include lysosomal degradation modulating cell functions through various pathways. research identified significant transcriptional changes post-infection, highlighting pathways such as cytokine storm, pyroptosis signaling, Toll-like receptor pathways, LXRs/RXRs signaling. findings shed light complex undermine underscore need for further investigation into therapeutic targets combat brucellosis.

Language: Английский

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