Результаты поиска

Covalent Protein Inhibitors via Tyrosine and Tryptophan Conjugation with Cyclic Imine Mannich Electrophiles.

Targeted covalent inhibitors (TCIs) are increasingly popular as drug candidates and chemical probes. Among current TCIs, the chemistry is largely limited to cysteine and lysine side chain reactivity. Here, we investigated the utility of cyclic imine Mannich electrophiles as covalent warheads to target protein tyrosine and tryptophan side chains. We characterized the intrinsic reaction rates of several cyclic imines to tyrosine and other amino acid side chains and validated reactivity using protein affinity labeling of a cyclic imine-modified trimethoprim with tyrosine and tryptophan mutants of…

Poly(sarcosine)-block-oligo(l-tryptophan) Copolymers as Noncovalent Inhibitors of Protein Aggregation.

Irreversible protein aggregation can cause loss of function of proteins during storage and transport, presenting a challenge in biotherapeutics, biocatalysis, and the food industry, as well as in basic research. New tools to inhibit protein aggregation are required to unlock ambient temperature biologic transportation to reduce the reliance on the cold chain, lower the carbon footprint of biopharmaceutic delivery, and for equitable sharing of medicines. Here we use N-carboxyanhydride polymerization to synthesize block copolymers with short oligo-tryptophan tails to target aggregation-prone reg…

Tryptophan metabolism reprogramming regulates Th1/Th2 immune balance and inhibits mast cell activation.

Asthma is characterized by chronic airway inflammation and an imbalanced Th1/Th2 response. Although tryptophan metabolism has been implicated in immune regulation, its direct influence on Th1/Th2 differentiation and mast-cell activation remains insufficiently understood. CD4⁺ T cells were cultured under graded tryptophan concentrations (25, 50, 75 and 100 µM) to examine how tryptophan availability alters Th1/Th2 polarization. Flow cytometry, western blotting and RT-qPCR were used to evaluate phenotype markers and related metabolic pathways. In parallel, IgE-activated LAD2 mast cells were expos…

Tryptophan degradation by intestinal Bacteroides induces anti-tumor immunity and limits melanoma growth.

Study of gut microbiota control of anti-tumor immunity (ATI) identifies Bacteroides rodentium and the human-related Bacteroides uniformis species to be capable of inducing ATI and limiting melanoma development in germ-free (GF), complex microbiome, or wild-type (WT) mice. Enhanced CD8+ T cell infiltration within tumors of mice harboring B. rodentium coincides with increased expression of immune-stimulating pathways. Metabolomic analyses identify lower tryptophan levels in the cecal samples of GF mice harboring B. rodentium. In silico genomic reconstruction reveals that B. rodentium and B. unif…

The role of tryptophan hydroxylase-1 in metabolic dysfunction-associated steatotic liver disease.

IMPORTANCE: Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by dysregulated lipid metabolism, inflammation, and mitochondrial dysfunction. Given the rising burden of MASLD in children and adolescents, identifying experimentally tractable mechanisms relevant to pediatric diseases is of considerable interest. Tryptophan hydroxylase-1 (TPH1), the rate-limiting enzyme for peripheral serotonin synthesis, has been implicated in metabolic disorders, but its hepatic role in MASLD remains unclear. OBJECTIVE: To investigate whether Tph1 suppression alleviates lipid accumulati…

Jingning formula alleviates ADHD by restoring gut microbiota dysbiosis and tryptophan metabolic dysfunction.

Jingning Fang (JNF), a clinically used herbal medicine for attention deficit hyperactivity disorder (ADHD), demonstrates significant efficacy in alleviating core symptoms such as hyperactivity and impulsivity in pediatric patients. To systematically investigate its therapeutic mechanisms, we implemented an integrated approach encompassing UPLC-Q-TOF/MS-based untargeted metabolomics profiling of brain, serum, and fecal specimens, targeted quantification of tryptophan pathway metabolites across these biological compartments, and gut microbiome characterization via 16S rRNA sequencing. Our analys…

Tryptophan enforced alg-iron oxide nanoconjugates: A potential evalution for synergistic cancer therapy.

The contribution of magnetic nanoparticles towards the diagnosis and therapy of cancer has seen an upward graph for the past decade owing to … dy the properties of alginate-coated iron oxide nanoparticles conjugated to the aromatic amino acid tryptophan for cancer targeting. The investigation involves fabrication of the conjugated nano-system followed by analysis of the physico-chemical properties using XRD and FT-IR, evaluation of its magnetic property using VSM which shows a good superparamagneti …

Zn64 aspartate modulates inflammation, tryptophan metabolism, and pancreatic function in diet-induced obesity.

Obesity-induced metabolic syndrome is characterized by chronic inflammation, hormonal imbalance, and altered neurotransmitter metabolism. Zinc plays a critical role in immune regulation and energy balance; however, the effects of isotopically modified chelate complexes in metabolic functions remain unexplored. This study investigated the therapeutic effects of isotopically enriched Zn64 Aspartate in a rat model of diet-induced obesity, focusing on inflammation, adipokine secretion, and tryptophan metabolism across serum, brain, duodenum, the pancreas, and adipose tissues. Male Wistar rats were…

Tryptophan-kynurenine metabolites associate with inflammation and immunologic phenotypes in common variable immunodeficiency.

BACKGROUND: A large proportion of patients with common variable immunodeficiency (CVID) have autoimmune and inflammatory manifestations characterized by chronic T-cell- and monocyte/macrophage activation of unknown etiology. The tryptophan-kynurenine pathway has previously been linked to immune activation involving T cells and monocytes/macrophages, as well as with gut microbial dysbiosis in some inflammatory diseases. OBJECTIVE: We aimed to characterize the tryptophan-kynurenine pathway in CVID and its potential association with clinical/immunologic phenotype and gut microbial dysbiosis. ME…

Baitouweng decoction alleviates ulcerative colitis by regulating tryptophan metabolism through DOPA decarboxylase promotion.

BACKGROUND: Baitouweng decoction (BTW) is a classic botanical drugs formula that has been widely used clinically for the treatment of gut-re … low cytometry. Protein levels were analyzed by proteomics and functionally annotated. The levels of tryptophan metabolites in mouse serum and colon were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Alcian Blue/Phosphate Acid Schiff (AB/PAS) staining, immunohistochemistry and western blot were used to assess the intestinal barrier fu …

Tryptophan metabolites and gut microbiota play an important role in pediatric migraine diagnosis.

BACKGROUND: The pathogenesis of pediatric migraine remains unclear and presents challenges in diagnosis. Recently, growing evidence has indicated that the gut microbiota can exert modulatory functions at the gut-brain axis by directly or indirectly regulating tryptophan metabolism. Consequently, we aimed to elucidate the potential association among gut microbiota, tryptophan metabolism, and pediatric migraine while also identifying diagnostic biomarkers for pediatric migraine. METHODS: The gut microbiota composition of 33 migraine children and 42 healthy children, aged less than ten years, fr…

Late-stage peptide modification and macrocyclization enabled by tertiary amine catalyzed tryptophan allylation.

Late-stage modification of peptides could potentially endow peptides with significant bioactivity and physicochemical properties, and thereby provide novel opportunities for peptide pharmaceutical studies. Since tryptophan (Trp) bears a unique indole ring residue and plays various critical functional roles in peptides, the modification methods for tryptophan were preliminarily developed with considerable progress via transition-metal mediated C-H activation. Herein, we report an unprecedented tertiary amine catalyzed peptide allylation via the SN2'-SN2' pathway between the N1 position of the i…

Temporal drivers of tryptophan-like fluorescent dissolved organic matter along a river continuum.

Tryptophan-like fluorescence (TLF) is used to indicate anthropogenic inputs of dissolved organic matter (DOM), typically from wastewater, in rivers. We hypothesised that other sources of DOM, such as groundwater and planktonic microbial biomass can also be important drivers of riverine TLF dynamics. We sampled 19 contrasting sites of the River Thames, UK, and its tributaries. Multivariate mixed linear models were developed for each site using 15 months of weekly water quality observations and with predictor variables selected according to the statistical significance of their linear relationsh…

IDO1 promotes CSFV replication by mediating tryptophan metabolism to inhibit NF-κB signaling.

Tryptophan metabolism plays a crucial role in facilitating various cellular processes essential for maintaining normal cellular function. Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the conversion of tryptophan (Trp) into kynurenine (Kyn), thereby initiating the degradation of Trp. The resulting Kyn metabolites have been implicated in the modulation of immune responses. Currently, the role of IDO1-mediated tryptophan metabolism in the process of viral infection remains relatively unknown. In this study, we discovered that classical swine fever virus (CSFV) infection of PK-15 cells can induc…

Characterization of βB2-crystallin tryptophan mutants reveals two different folding states in solution.

Conserved tryptophan residues are critical for the structure and the stability of β/γ-crystallin in the lenses of vertebrates. During aging, in which the lenses are continuously exposed to ultraviolet irradiation and other environmental stresses, oxidation of tryptophan residues in β/γ-crystallin is triggered and impacts the lens proteins to varying degrees. Kynurenine derivatives, formed by oxidation of tryptophan, accumulate, resulting in destabilization and insolubilization of β/γ-crystallin, which correlates with age-related cataract formation. To understand the contribution of tryptophan …

Sleep Patterns and Tryptophan Consumption among Students at Spanish Universities: The Unihcos Project.

The objective of this cross-sectional study was to explore sleep patterns and the potential relationship between sleep and tryptophan intake among Spanish university students. A total of 11,485 students self-reported their sleep and dietary patterns and habits. Tryptophan intake was calculated using a food intake matrix and results were presented as quartiles of total intake. Short sleep duration prevalence was 51.0%, with males exhibiting a significantly higher frequency. A total of 55.0% of participants presented inadequate sleep efficiency, with males again presenting a higher rate. Median …

Переосмысление ролей: парадигм-смещение в метеоболизме триптофана-Кинуренина для инновационных клинических прикладных программ.

Траектория триптофан-кинуренина (KYN) давно признана за ее важнейшую роль в генерировании метаболитов, влияющих на различные физиологические процессы. Традиционно эти метаболиты подразделяются на отдельные, зачастую противоположные группы, такие, как прооксидант против антиоксиданта, эксцитотоксичный/нейротоксичный или нейрозащитный. Эта дихотомическая система сформировала большую часть исследований таких заболеваний, как нейродегенеративные и нейропсихиатрические расстройства, а также рак, где метаболические дисбалансы являются ключевой особенностью. Воздействие в значительной степени зависит

Совпадение в аннотации оригинала
The tryptophan-kynurenine (KYN) pathway has long been recognized for its essential role in generating metabolites that influence various physiological processes. Traditionally, these metabolites have been categorized into distinct, often opposing groups, such as pro-oxidant versus antioxidant, excitotoxic/neurotoxic versus neuroprotective. This dichotomous f…

The tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase 1 regulates polycystic kidney disease progression.

Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic nephropathy, is characterized by phenotypic variability that exceeds genic effects. Dysregulated metabolism and immune cell function are key disease modifiers. The tryptophan metabolites, kynurenines, produced through indoleamine 2,3-dioxygenase 1 (IDO1), are known immunomodulators. Here, we study the role of tryptophan metabolism in PKD using an orthologous disease model (C57BL/6J Pkd1RC/RC). We found elevated kynurenine and IDO1 levels in Pkd1RC/RC kidneys versus wild type. Further, IDO1 levels were increased in …

CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation.

BACKGROUND: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clin … re statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73-89), then quinolinic acid …

Discrete interplay of gut microbiota L-tryptophan metabolites in host biology and disease.

The gut microbiota and the host maintain a conjoint relationship and together achieve optimal physiology via a multitude of interactive signalling cues. Dietary-derived L-tryptophan (L-trp) is enzymatically metabolized by the resident symbiotic gut microbiota to indole and various indole derivatives. Indole and indole metabolites secreted by the gut bacteria act locally in the intestinal cells as well as distally and modulate tissue-specific functions which are beneficial to the host. Functions attributed to these microbial indole metabolites in the host include regulation of intestinal permea…