Metabolomic-derived endotypes of age-related macular degeneration (AMD): a step towards identification of disease subgroups

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Май 27, 2024

Abstract Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with complex pathophysiology and phenotypic diversity. Here, we apply Similarity Network Fusion (SNF) to cluster AMD patients into putative metabolomics-derived endotypes. Using discovery cohort 163 from Boston, US, validation 214 Coimbra, Portugal, identified four distinct endotypes varying retinal structural functional characteristics, confirmed across both cohorts. Patients clustered Endotype 1 exhibited milder form were characterized by low levels amino acids in specific metabolic pathways. Meanwhile, 3 4 associated more severe fatty acid metabolites elevated sphingomyelins metabolites, respectively. These preliminary findings indicate that endotyping may offer refined strategy for categorizing based on their pathophysiological underpinnings, rather than relying solely traditional observational clinical indicators.

Язык: Английский

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People living with HIV display increased anti-apolipoprotein A1 auto-antibodies, inflammation, and kynurenine metabolites: a case–control study

Frontiers in Cardiovascular Medicine, Год журнала: 2024, Номер 11

Опубликована: Фев. 13, 2024

Objective This study aimed to the relationship between auto-antibodies against apolipoprotein A1 (anti-apoA1 IgG), human immunodeficiency virus (HIV) infection, anti-retroviral therapy (ART), and tryptophan pathways in HIV-related cardiovascular disease. Design case–control conducted South Africa consisted of control volunteers ( n = 50), people living with HIV (PLWH) on ART untreated PLWH 44). Cardiovascular risk scores were determined, vascular measures performed, an extensive biochemical characterisation (routine, metabolomic, inflammatory systemic profiles) was performed. Methods Anti-apoA1 IgG levels assessed by in-house ELISA. Inflammatory biomarkers measured Meso Scale Discovery® platform, kynurenine pathway metabolites using targeted metabolomic profiling liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS). Results exhibited similarities across three groups, while important differences observed pathways. seropositivity rates 15%, 40%, 70% volunteers, ART-treated, ART-naïve, respectively. Circulating anti-apoA1 significantly negatively associated CD4+ cell counts positively viremia pro-inflammatory (IFNγ, TNFα, MIPα, ICAM-1, VCAM-1). While circulating increased both PLWH, kynurenine/tryptophan ratio ART-treated. Conclusion infection increases humoral response apoA1, which is established severity criteria activation.

Язык: Английский

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Integrative Pharmacology in the Treatment of Substance Use Disorders

Journal of Dual Diagnosis, Год журнала: 2023, Номер 20(2), С. 132 - 177

Опубликована: Дек. 20, 2023

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years develop novel pharmacotherapies treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy shown be superior no treatment at all most classes. many randomized controlled trials (RCTs) revealed that monotherapy leads poorer outcomes when compared with combination specialties medicine. results RCTs suggest frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, receptors are involved pathophysiology As such, research is urgently needed determine how various neurobiological mechanisms can targeted by treatments create specific yet exceedingly comprehensive approaches SUD treatment. This article aims review neurobiology integrates pathophysiologic discuss integrative pharmacology developments may ultimately improve clinical patients Many known SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), kynurenic acid (KYNA) mechanisms. Emerging evidence indicates KYNA, a tryptophan metabolite, modulates these major Therefore, achieving KYNA homeostasis harmonizing could prove better therapeutic approach We propose KYNA-NMDA-α7nAChRcentric pathophysiology, "conductor orchestra," as concurrently. KYNA-NMDA-α7nAChR "command center" neuropsychiatry. To date, extant equivocal findings across comparison conditions, possibly because investigators single mechanisms, hit wrong targets underlying tested inadequate provide examples potential simultaneously target addition KYNA. Kynurenine pathway metabolism demonstrates greatest neuropsychiatric diseases. investigational medications include memantine, galantamine, N-acetylcysteine. Future warranted Multicenter offer promising, potentially fruitful avenue therapeutics

Язык: Английский

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Liver and Brain Disorders

Current Hepatology Reports, Год журнала: 2024, Номер 23(3), С. 404 - 413

Опубликована: Апрель 2, 2024

Язык: Английский

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Memantine and the Kynurenine Pathway in the Brain: Selective Targeting of Kynurenic Acid in the Rat Cerebral Cortex

Cells, Год журнала: 2024, Номер 13(17), С. 1424 - 1424

Опубликована: Авг. 26, 2024

Cytoprotective and neurotoxic kynurenines formed along the kynurenine pathway (KP) were identified as possible therapeutic targets in various neuropsychiatric conditions. Memantine, an adamantane derivative modulating dopamine-, noradrenaline-, serotonin-, glutamate-mediated neurotransmission is currently considered for therapy dementia, psychiatric disorders, migraines, or ischemia. Previous studies have revealed that memantine potently stimulates synthesis of neuroprotective kynurenic acid (KYNA) vitro via a protein kinase A-dependent mechanism. Here, effects acute prolonged administration on brain functional changes cerebral KP assessed rats using chromatographic enzymatic methods. Five-day but not single treatment with selectively activated cortical towards KYNA. KYNA increases accompanied by moderate decrease tryptophan (TRP) L-kynurenine (L-KYN) concentrations without 3-hydroxykynurenine (3-HK) levels. Enzymatic activity biosynthetic enzymes ex vivo was stimulated after memantine. As does directly stimulate KATs' proteins, higher KATs most probably results from increased expression respective genes. Noteworthy, KYNA, 3-HK, TRP, L-KYN striatum, hippocampus, cerebellum affected. Selective increase seems to represent one mechanisms underlying clinical efficacy It tempting hypothesize combination drugs could strongly boost provide more effective option treating pathologies at early stages. Further should evaluate this issue experimental animal models under scenarios.

Язык: Английский

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