Molecular Insights into the Interaction of Tryptophan Metabolites with the Human Aryl Hydrocarbon Receptor in Silico: Tryptophan as Antagonist and no Direct Involvement of Kynurenine

Frontiers in Bioscience-Landmark, Год журнала: 2024, Номер 29(9)

Опубликована: Сен. 24, 2024

Background: A direct link between the tryptophan (Trp) metabolite kynurenine (Kyn) and aryl hydrocarbon receptor (AhR) is not supported by metabolic considerations studies demonstrating failure of Kyn concentrations up to 100 μM activate in cell culture systems using proxy system cytochrome P-450-dependent metabolism. The kynurenic acid (KA) activates AhR may mediate link. Recent demonstrated down regulation antagonism activation Trp. We have addressed looking at their molecular interaction silico. Methods: Molecular docking Kyn, KA, Trp a range metabolites crystal structure human was performed under appropriate conditions. Results: 30 its docked various degrees, whereas 3-hydroxykynurenine did not. strongest observed with photooxidation product 6-Formylindolo[3,2-b]carbazole (FICZ), cinnabarinic acid, 5-hydroxytryptophan, N-acetyl serotonin indol-3-yllactic acid. Strong also other 5-hydroxyindoles. Conclusions: propose that Kyn-AhR mediated KA. strong recently reported suggest an antagonist thus play important roles body homeostasis beyond known properties or simply being precursor biologically active metabolites. Differences literature are discussed.

Язык: Английский

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Tryptophan metabolism as a ‘reflex’ feature of neuroimmune communication: Sensor and effector functions for the indoleamine‐2, 3‐dioxygenase kynurenine pathway

Journal of Neurochemistry, Год журнала: 2023, Номер unknown

Опубликована: Дек. 16, 2023

Abstract Although the central nervous system (CNS) and immune were regarded as independent entities, it is now clear that cells can influence CNS, neuroglial activity influences system. Despite many clinical implications for this ‘neuroimmune interface’, its detailed operation at molecular level remains unclear. This narrative review focuses on metabolism of tryptophan along kynurenine pathway, since products have critical actions in both systems, placing a unique position to neuroimmune communication. In particular, pathway activated by pro‐inflammatory mediators, proposed physical psychological stressors are stimuli an organismal protective reflex, with metabolites effector arm co‐ordinating neural responses. After brief interface, general perception expanded emphasize environmentally driven perspective. The initial enzymes include indoleamine‐2,3‐dioxygenase (IDO1), which induced tissue damage, inflammatory mediators or microbial products, tryptophan‐2,3‐dioxygenase (TDO), stress‐induced glucocorticoids. system, kynurenic acid modulates leucocyte differentiation, balance tolerance activating aryl hydrocarbon receptors pain via GPR35 protein. quinolinic activates N‐methyl‐D‐aspartate (NMDA)‐sensitive glutamate receptors, whereas antagonist: between glutamate, significant regulator CNS function plasticity. concept reflex coordinated protection against stress helps understand variety breadth their activity. It should also help pathological origin some psychiatric neurodegenerative diseases involving facilitating development new pharmacological strategies treatment.

Язык: Английский

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Inflammatory processes in the prefrontal cortex induced by systemic immune challenge: Focusing on neurons

Brain Behavior & Immunity - Health, Год журнала: 2023, Номер 34, С. 100703 - 100703

Опубликована: Ноя. 9, 2023

Peripheral immune challenge induces neurobiological alterations in the brain and related neuropsychiatric symptoms both humans other mammals. One of best known physiological effects systemic inflammation is sickness behavior. However, addition to this depression-like state, there are cognitive outcomes peripherally induced neuroinflammation that can be linked dysfunction higher-order cortical areas, such as prefrontal cortex (PFC). As activity PFC largely based on balanced interplay excitatory pyramidal cells inhibitory interneurons, it may hypothesized neuroinflammatory processes result a shift excitatory/inhibitory balance, which common hallmark several conditions. Indeed, many data suggest strongly associated with molecular functional changes neurons leading disturbances their synaptic networks. Different experimental approaches cause some incongruence reviewed data. commonly agreed acute leads balance by proinflammatory signaling at borders parenchyma. These cellular altered local brain-wide network inducing top-down control goal-directed behavior cognition regulated PFC. Lipopolysaccharide (LPS)-treated rodents most widely used models neuroinflammation, so majority come from studies utilizing LPS model. This limit general interpretation regarding neuronal peripheral activation. In addition, biological variables (e.g., sex, age) influence challenge, not only nature severity Therefore, would desirable investigate inflammation-related using well, focus targeted fine-tuning affected cell types via mechanisms nervous systems.

Язык: Английский

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Elevated serum kynurenic acid in individuals with first-episode psychosis and insufficient response to antipsychotics

Schizophrenia, Год журнала: 2024, Номер 10(1)

Опубликована: Июль 10, 2024

Abstract The tryptophan-metabolizing kynurenine pathway (KP) can be activated by enhanced inflammatory responses and has been implicated in the pathophysiology of schizophrenia. However, there is little evidence for KP dysregulation early course psychotic illness. We aimed to investigate potential immune-mediated hyperactivity individuals with first-episode psychosis (FEP) relationship symptom severity treatment response outcomes. Serum immunoassays were performed measure peripheral levels cytokines (IL-1β, IL-10, TNF-a), rate-limiting enzymes (IDO/TDO), kynurenic acid (KYNA) metabolite 104 antipsychotic-naïve patients FEP 80 healthy controls (HC). Positive Negative Syndrome Scale (PANSS) Global Assessment Functioning (GAF) administered assess psychopathology functioning status at admission following 4-week antipsychotics. Cytokine components substantially increased compared HC, before after antipsychotic treatment. A significant positive correlation between pro-inflammatory IL-1β KYNA was observed among patients, but not HC. Importantly, within-patient analysis revealed that those higher baseline experienced more severe negative symptoms poorer clinical improvement follow-up. These findings suggest upregulated psychosis, likely through induction IL-1β-dependent pathways, raised might represent a promising indicator non-response medication FEP.

Язык: Английский

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The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(16), С. 9040 - 9040

Опубликована: Авг. 20, 2024

It has been unequivocally established that kynurenic acid a number of actions in variety cells and tissues, raising, principle, the possibility targeting its generation, metabolism or sites action to manipulate those effects beneficial therapeutic end. However, many basic aspects biology remain unclear, potentially leading some confusion misinterpretations data. They include questions source, targets, enzyme expression, endogenous concentrations action. This essay is intended raise discuss these as source reference for more balanced discussion. Those issues are followed by examples situations which modulating correcting production activity could bring significant benefit, including neurological psychiatric conditions, inflammatory diseases cell protection. More information required obtain clear overall view pharmacological environment relevant acid, especially with respect active kynurenine metabolites vivo changed levels disease. The data ideas presented here should permit greater confidence appreciating interaction under different local conditions pathologies, enhancing our understanding itself clinical manipulating pharmacology be value.

Язык: Английский

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Kynurenine Pathway in Epilepsy: Unraveling Its Role in Glutamate Excitotoxicity, GABAergic Dysregulation, Neuroinflammation, and Mitochondrial Dysfunction

Neurotoxicity Research, Год журнала: 2025, Номер 43(2)

Опубликована: Март 28, 2025

Язык: Английский

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Sex differences in neuroimmunoendocrine communication. Involvement on longevity

Mechanisms of Ageing and Development, Год журнала: 2023, Номер 211, С. 111798 - 111798

Опубликована: Март 11, 2023

Endocrine, nervous, and immune systems work coordinately to maintain the global homeostasis of organism. They show sex differences in their functions that, turn, contribute beyond reproductive function. Females display a better control energetic metabolism improved neuroprotection have more antioxidant defenses inflammatory status than males, which is associated with robust response that males. These are present from early stages life, being relevant adulthood influencing aging trajectory each may different life lifespan between sexes.

Язык: Английский

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The immunomodulatory mechanism of acupuncture treatment for ischemic stroke: research progress, prospects, and future direction

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Май 2, 2024

Ischemic stroke (IS) is one of the leading causes death and disability. Complicated mechanisms are involved in pathogenesis IS. Immunomodulatory crucial to Acupuncture a traditional non-drug treatment that has been extensively used treat The exploration neuroimmune modulation will broaden understanding underlying acupuncture treatment. This review summarizes immune response cells, cytokines, organs after an immunomodulatory on central nervous system peripheral immunity, as well factors influence effects treatment, were summarized. We suggest prospects future directions for research IS based current progress, we hope these provide inspiration researchers. Additionally, shown favorable outcomes immune-based diseases, generating new possible targets treatments diseases.

Язык: Английский

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Understanding the Kynurenine Pathway: A Narrative Review on its Impact across Chronic Pain Conditions

Molecular Pain, Год журнала: 2024, Номер 20

Опубликована: Янв. 1, 2024

Chronic pain is a debilitating symptom with significant negative impact on the quality of life and socioeconomic status, particularly among adults elderly. Major Depressive Disorder (MDD) stands out as one most important comorbid disorders accompanying chronic pain. The kynurenine pathway serves primary route for tryptophan degradation holds critical significance in various biological processes, including regulation neurotransmitters, immune responses, cancer development, metabolism, inflammation. This review encompasses key research studies related to context headache, neuropathic pain, gastrointestinal disorders, fibromyalgia, fatigue syndrome, MDD. Various metabolites produced pathway, such kynurenic acid quinolinic acid, exhibit neuroprotective neurotoxic effects, respectively. Recent have highlighted involvement its pathophysiology Moreover, pharmacological interventions targeting shown therapeutic promise management. Understanding underlying mechanisms this presents an opportunity developing personalized, innovative, non-opioid approaches treatment. Therefore, narrative explores role association depression

Язык: Английский

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Vertebral Subluxation and Systems Biology: An Integrative Review Exploring the Salutogenic Influence of Chiropractic Care on the Neuroendocrine-Immune System

Cureus, Год журнала: 2024, Номер unknown

Опубликована: Март 15, 2024

In this paper we synthesize an expansive body of literature examining the multifaceted influence chiropractic care on processes within and modulators neuroendocrine-immune (NEI) system, for purpose generating inductive hypothesis regarding potential impacts integrated physiology. Taking a broad, interdisciplinary, integrative view two decades research-documented outcomes care, inclusive reports ranging from systematic meta-analysis randomized observational trials to case cohort studies, review encapsulates rigorous analysis research suggests appropriateness more perspective impact systemic A novel salutogenic, health-promoting effects adjustment is presented, focused improvement physical indicators well-being adaptability such as blood pressure, heart rate variability, sleep, benefits that may be facilitated through multiple neurologically mediated pathways. Our findings support biological plausibility complex intervention not limited simple neuromusculoskeletal open new avenues future research, specifically exploration mapping precise neural pathways networks influenced by adjustment.

Язык: Английский

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