Search Results (379)

This story began half a century ago with the discovery of an unusually high presence of tryptophan (Trp, W) in transthyretin (TTR), one of the three carrier proteins of thyroid hormones. With the Trp-rich retinol-binding protein (RBP), TTR forms a plasma complex implicated in the delivery of retinoid compounds to body tissues. W has the lowest concentration among all AAs involved in the sequencing of human body proteins. The present review proposes molecular maps focusing on the ratio of W/AA residues found in the sequence of proteins involved in immune events, allowing us to ascribe the guidance of inflammatory processes as fully under the influence of W. Under the control of cytokine stimulation, plasma biomarkers of protein nutritional status work in concert with major acute-phase reactants (APRs) and with carrier proteins to release, in a free and active form, their W and hormonal ligands, interacting to generate hot spots affecting the course of acute stress disorders. The prognostic inflammatory and nutritional index (PINI) scoring formula contributes to identifying the respective roles played by each of the components prevailing during the progression of the disease. Glucagon demonstrates ambivalent properties, remaining passive under steady-state conditions while displaying stronger effects after cytokine activation. In developing countries, inappropriate weaning periods lead to toddlers eating W-deficient cereals as a staple, causing a dramatic reduction in the levels of W-rich biomarkers in plasma, constituting a novel nutritional deficiency at the global scale. Appropriate counseling should be set up using W implementations to cover the weaning period and extended until school age. In adult and elderly subjects, the helpful immune protections provided by W may be hindered by the surge in harmful catabolites with the occurrence of chronic complications, which can have a significant public health impact but lack the uncontrolled surges in PINI observed in young infants and teenagers. Biomarkers of neurodegenerative and neoplastic disorders measured in elderly patients indicate the slow-moving elevation of APRs due to rampant degradation processes. Full article

Background/Objectives: Gut-derived tryptophan (Trp) metabolites play important roles in metabolic and cardiovascular regulation. Although animal studies suggest their protective effects against metabolic dysfunction, data in adolescents, particularly those with obesity, remain limited. The objective of this study was to evaluate associations between circulating gut-derived Trp metabolites and markers of cardiometabolic, vascular, and platelet health in adolescents with obesity. Methods: Data were analyzed from 28 adolescents (ages 13–18; mean BMI = 36 ± 6.4 kg/m²). Fasting blood was collected to assess lipid profiles using a clinical analyzer and insulin resistance using the homeostatic model assessment for insulin resistance (HOMA-IR). Gut-derived Trp metabolites were measured by UPLC–mass spectrometry, peak oxygen uptake (VO_{2 peak}) by gas exchange during an incremental cycle ergometer test, and body composition by dual-energy X-ray absorptiometry. Platelet spare respiratory capacity (SRC), endothelial function, and liver fat were measured using high-resolution respirometry, flow-mediated dilation (FMD) of the brachial artery, and magnetic resonance imaging respectively. Results: Indole-3-propionic acid was inversely associated with diastolic blood pressure (rho = −0.39, p = 0.047), total cholesterol (rho = −0.55, p = 0.002), and LDL-C (rho = −0.57, p = 0.0014), independent of sex and obesity severity. Indoxyl sulfate was positively correlated with fasting glucose (rho = 0.47, p = 0.012), and adolescents with impaired fasting glucose had 1.6-fold higher IS levels. Indole-3-acetaldehyde declined with age (rho = −0.50, p = 0.007), and Indole-3-acetic acid and indole were higher in Hispanics vs. non-Hispanics. No significant associations were observed between Trp metabolites and FMD, VO₂ peak, or SRC. Conclusions: Gut-derived Trp metabolites, particularly indole-3-propionic and indoxyl sulfate, are associated with markers of cardiometabolic risk in adolescents with obesity. These findings support their potential relevance in early-onset cardiovascular disease risk. Full article

Diabetic wounds are a devastating complication that cause chronic pain, recurrent infections, and limb amputations due to impaired healing. Despite advances in wound care, existing therapies often fail to address the underlying molecular dysregulation, highlighting the need for innovative and safe therapeutic approaches. Among these, D-amino acids such as D-tryptophan (D-Trp) have emerged as key regulators of cellular processes; however, their therapeutic potential in diabetic wounds remains largely unexplored. Here, we investigate the therapeutic potential of D-Trp in streptozotocin (STZ)-induced diabetic mice, comparing it with phosphate-buffered saline (PBS) controls and vascular endothelial growth factor (VEGF) as a positive control. Wound healing, inflammation, and histopathology were assessed. Protein and gene expression were analyzed via Western blot and RT-qPCR, respectively. Biolayer interferometry (BLI) measured the binding of D-Trp to hypoxia-inducible factor-1α (HIF-1α). D-Trp accelerated wound healing by modulating extracellular matrix (ECM) remodeling, signaling, and apoptosis. It upregulated matrix metalloproteinases (MMP1, MMP3, MMP-9), Janus kinase 2 (JAK2), and mitogen-activated protein kinase (MAPK) proteins while reducing pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], IL-6). D-Trp also suppressed caspase-3 and enhanced angiogenesis through HIF-1α activation. These findings suggest that D-Trp promotes healing by boosting ECM turnover, reducing inflammation, and activating MAPK/JAK pathways. Thus, D-Trp is a promising therapeutic for diabetic wounds. Full article

Serotoninomics is an expanding field that focuses on the comprehensive study of the serotoninergic system, including serotonin’s biosynthesis, metabolism, and regulation, as well as related scientific methodologies 5-hydroxytryptamine (5-HT). This field explores serotonin’s complex roles in various physiological and pathological contexts. The essential amino acid tryptophan (Trp) is a precursor for several metabolic and catabolic pathways, with the kynurenine (KYN) pathway being particularly significant, representing about 95% of Trp metabolism. In contrast, only a small portion (1–2%) of dietary Trp enters the serotonin pathway. Anthranilic acid (AA), a metabolite in the KYN pathway, has emerged as a potential biomarker and therapeutic target for schizophrenia. Elevated serum AA levels in patients with schizophrenia have been associated with neurotoxic effects and disruptions in neurotransmission, suggesting AA’s critical role in the disorder’s pathophysiology. Furthermore, the 5-HT_2A receptor’s involvement is particularly noteworthy, especially in relation to schizophrenia’s positive symptoms. Recent findings indicate that 5-HT_2A receptor hyperactivity is linked to positive symptoms of schizophrenia, such as hallucinations and delusions. This study investigates serotoninomics’ implications for neuropsychiatric disorders, focusing on AA in schizophrenia and analysing recent research on serotonin signalling pathways and AA’s neurochemical effects. Understanding the roles of the 5-HT_2A receptor and AA in neuropsychiatric disorders could lead to the development of more precise and less invasive diagnostic tools, specific therapeutic strategies, and improved clinical outcomes. Ongoing research is essential to uncover these pathways’ exact mechanisms and therapeutic potential, thereby advancing personalised medicine and innovative treatments in neuropsychiatry. Full article

Enteroendocrine cells (EECs) are specialized secretory cells in the gut epithelium that differentiate from intestinal stem cells (ISCs). Mature EECs secrete incretin hormones that stimulate pancreatic insulin secretion and regulate appetite. Decreased EEC numbers and impaired secretion of the incretin glucagon-like peptide-1 (GLP1) have been implicated in obesity-associated metabolic complications. Gut microbial metabolites of dietary tryptophan (TRP) were recently shown to modulate ISC proliferation and differentiation. However, their specific effects on EEC differentiation are not known. We hypothesized that the gut microbial metabolites of dietary tryptophan counteract impaired GLP1 production and function in obesity by stimulating EEC differentiation from ISCs. We utilized complementary models of human and rat intestines to determine the effects of obesity or TRP metabolites on EEC differentiation. EEC differentiation was assessed by the EEC marker chromogranin A (CHGA) levels in the intestinal mucosa of normal versus obese rats. The effects of TRP metabolites on EEC differentiation were determined in human intestinal organoids treated with indole, a primary TRP metabolite, or the culture supernatant of Lactobacillus acidophilus grown in TRP media (LA-CS-TRP). Our results showed that the mRNA and protein levels of CHGA, the EEC marker, were significantly decreased (~60%) in the intestinal mucosa of high-fat-diet-induced obese rat intestines. The expression of the transcription factors that direct the ISC differentiation towards the EEC lineage was also decreased in obesity. In human organoids, treatment with indole or LA-CS-TRP significantly increased (more than 2-fold) CHGA levels, which were blocked by the aryl hydrocarbon receptor (AhR) antagonist CH-223191. Thus, the stimulation of EEC differentiation by colonic microbial metabolites highlights a novel therapeutic role of TRP metabolites in obesity and associated metabolic disorders. Full article

This study investigates the effect of tryptophan treatment on aged pig oocytes, focusing on its potential to reduce oxidative stress and improve oocyte quality. An oxidative stress model was induced using hydrogen peroxide (H₂O₂) to mimic aging effects on oocytes. Fresh ovaries from young sows were collected, and oocytes were aspirated and cultured for in vitro maturation. Oocytes in the H₂O₂ and the H₂O₂+Trp groups were exposed to 100 µM H₂O₂ for 30 min, with the H₂O₂+Trp group receiving an additional 50 µM tryptophan supplementation. RNA-sequencing was performed to study the underlying mechanism through which tryptophan mitigated the H₂O₂-induced oxidative stress in oocytes. The results demonstrated that tryptophan supplementation significantly reduced oxidative stress markers such as H₂O₂ and malonaldehyde (MDA) while restoring key antioxidant enzymes such as superoxide dismutase (SOD), and catalase (CAT) confirming its antioxidant role. Furthermore, tryptophan improved cumulus cell expansion, and oocyte quality, which were compromised by oxidative stress. Transcriptomics study revealed the enrichment of several KEGG pathways, such as P13K-Akt signaling pathways as a critical regulator of cell survival and function, emphasizing the protective effects of tryptophan on oocyte integrity. Moreover, the protein–protein interaction (PPI) network identified several hub genes in the tryptophan-treated group compared with H₂O₂, including TIMP1, CCN2, and MMP12 as key players in ECM remodeling and cellular adhesion, which are critical for restoring oocyte quality. These findings suggest that tryptophan supplementation not only mitigated oxidative stress but also modulated gene expression related to cellular functions and stress response. These results propose that tryptophan could be a valuable therapeutic strategy for improving reproductive outcomes in aging sows and other mammals facing age-related oocyte dysfunction. Full article

Rice-field eel (Monopterus albus) slices, an important aquatic product in Southeast Asia, are prone to spoilage and deterioration during cold chain storage. In this study, the effects of a composite preservative (ε-polylysine, Vitamin C (Vc), epigallocatechin gallate (EGCG), and phloretin) on the muscle quality (color, texture, water holding capacity (WHC)) of rice-field eel slices during refrigeration storage at 4 °C for up to 7 days was investigated, and the underlying mechanism was elucidated by the integrated microbiome and metabolomics, in addition to Elisa and Low-Field Nuclear Magnetic Resonance (LF-NMR). After 7 days of storage, the WHC, shear force, and a* decreased by 11.39%, 34.37%, and 49.20% in treated samples, and by 19.18%, 38.38%, and 54.87% in control samples, respectively. The addition of the composite preservative significantly increased Hexokinase, Pyruvate kinase, and Creatine kinase, while it decreased the total viable count (TVC), total volatile basic nitrogen (TVB-N), thiobarbituric acid reactive substance (TBARS), and Lactic acid. Preservative treatment maintained the moisture content of the eel slices during storage and prevented bright red oxymyoglobin from transforming into brown metmyoglobin. Microbiota composition (especially Pseudomonas) and metabolic pathways (including amino acid and its metabolites, nucleotide and its metabolite, and organic acid and its derivatives, etc.) were obviously altered by the preservative treatment. Pseudomonas, tryptophan-aspartic acid (Trp-Asp), D-Glucose 6-phosphate, Succinic Acid, Biliverdin 1, 5-Diaminopentane, and Tyramine, etc., are potential biomarkers for the quality changes of eel slices during refrigeration. These findings provide an in-depth understanding of the improvement of the eel slice quality during refrigeration storage by the composite preservative. Full article

Shelter environments can be inherently stressful for dogs, a highly social species that forms strong attachment bond with humans. This study evaluated stress responses in 26 shelter dogs during routine veterinary examinations, analyzing behavioral scores alongside physiological and hormonal parameters, including heart rate, body temperature, cortisol (CRT), oxytocin (OXT), serotonin (5-HT), tryptophan (TRP), and interleukin-6 (IL-6). A significant negative correlation was observed between OXT and CRT (ρ = –0.540, p = 0.007), particularly in dogs exhibiting relaxed behavior. OXT was also negatively correlated with body temperature (ρ = –0.435, p = 0.034), supporting its potential role in modulating stress-induced hyperthermia. No significant associations were found between TRP, 5-HT, IL-6, or other physiological measures and behavioral scores. The absence of correlation between TRP and 5-HT may be due to blood–brain barrier regulation, while IL-6′s lack of association suggests further investigation is needed to clarify its role in canine stress responses. These findings highlight OXT’s possible buffering effect on the hypothalamic–pituitary–adrenal axis and suggest that behavioral assessment may offer a more sensitive measure of canine stress than hormonal or physiological parameters alone. Future studies with larger and more diverse samples are needed to confirm and expand upon these results. Full article

Background: Seasonal influenza infection poses substantial risks to pregnant women, yet the immunological mechanisms underlying their heightened disease susceptibility remain incompletely characterized. Methods: This study employed multiparametric immunophenotyping and metabolic profiling to investigate cellular immunity, cytokine dynamics, and serum biomarkers in pregnant women infected with H3N2 across gestational stages. Through integrated flow cytometric analysis of peripheral blood mononuclear cells (PBMCs), multiple cytokine quantification, and LC-MS-based serum metabolomics, we compared immunological parameters, serum cytokines, and metabolites across trimesters in pregnant women infected and not infected with H3N2. Results: The results revealed reduced CD4⁺/CD8⁺ T cell ratios, a diminished CD27⁺ memory B cell population in pregnant women infected with H3N2, and elevated NK cells and Th2-skewed cytokines (IL-4, IL-6, IL-10) in severe influenza cases. Metabolomic profiling identified the dysregulation of the tryptophan–kynurenine (Trp–Kyn) pathway, with a 15-fold increase in the Kyn/Trp ratio in severe influenza compared to a normal pregnancy as a potential biomarker. Conclusions: These results elucidate synergistic pathophysiological axes-immune dysregulation and tryptophan metabolism alteration that potentially drive adverse outcomes. The identified biomarker panel (CD4/CD8 ratio, IL-6, Kyn/Trp ratio) shows potential clinical promise for early risk stratification in high-risk pregnancies with influenza infection. Full article

SEC31A-related neurodevelopmental disorder (Halperin–Birk syndrome) was recently identified in two siblings who shared the phenotype of profound developmental delay, structural brain defects, spastic quadriplegia with multiple contractures, seizures, dysmorphism, and optic nerve atrophy. Both patients died during childhood. In this study, we identified an additional patient who suffers from global developmental delay and seizures. Genetic analysis inclusive of whole exome and genome sequencing identified a homoallelic variant in the SEC31A (p.Cys453Trp). Various in silico classifiers predicted a deleterious effect of the replacement of cystein with tryptophan at the 453rd position. Protein–protein interaction (PPI) network analysis of SEC31A revealed high-confidence interactions with SEC13, SEC23A, and SEC23B, suggesting potential regulatory roles in these processes. Structural analysis of the SEC31A–SEC13 interaction and the Cys453Trp mutant in SEC31A predicted that the stability of coat protein complex II would be compromised. Our findings support the clinical correlation of SEC31A variants with neurodevelopmental disorder. Full article

The demand for L-tryptophan (L-Trp) has been rapidly increasing across various industries, including pharmaceuticals, food, and animal feed. However, traditional production methods have been unable to efficiently meet this growing demand. Hence, this study aimed to develop strategies for enhancing L-Trp production in Escherichia coli. Firstly, an L-Trp-producing strain was selected and subjected to atmospheric and room temperature plasma (ARTP) mutagenesis to generate a mutant library. This was followed by high-throughput screening using an L-Trp-specific riboswitch and a yellow fluorescent protein (YFP)-based biosensor in a flow cytometric cell sorting (FACS) system. Among the screened mutants, GT3938 exhibited a 1.94-fold increase in L-Trp production. Subsequently, rational metabolic engineering was applied to GT3938 by knocking out the L-Trp intracellular transporter gene (tnaB), enhancing the expression of the aromatic amino acid exporter (YddG) and optimizing precursor supply pathways. The resulting strain, zh08, achieved an L-Trp titer of 3.05 g/L in shake-flask fermentation, representing a 7.71-fold improvement over the original strain. This study demonstrated an effective strategy for industrial strain development by integrating biosensor-assisted, high-throughput screening with rational metabolic engineering. Full article

Background: The kynurenine (KYN) pathway of tryptophan metabolism has been linked to inflammation and cardiovascular risk, but its long-term prognostic value remains unclear. Methods: We analyzed 492 patients from the KORONEF registry who underwent coronary and renal angiography and were followed for a median of 10.2 years. Plasma levels of tryptophan (TRP), KYN, and downstream metabolites were measured. The primary endpoint was all-cause mortality. Results: The mean age was 64.4 ± 9.9 years, and 37.2% of patients were female. Common comorbidities included hypertension (74.8%), dyslipidemia (46.0%), and diabetes (25.8%). Overall mortality reached 29.5% and increased across KYN tertiles: 17.6% (T1), 28.2% (T2), and 42.9% (T3) (p < 0.001). In a multivariable Cox analysis, KYN independently predicted mortality (HR: 1.79; 95% CI: 1.15–2.44; p < 0.001), alongside age, diabetes, prior myocardial infarction, chronic kidney disease, and left ventricular ejection fraction. Other kynurenine pathway metabolites were not independently associated with outcomes. Conclusions: Elevated kynurenine levels independently predict 10-year all-cause mortality in patients undergoing coronary angiography. KYN may represent a useful prognostic biomarker beyond traditional clinical and angiographic variables. Full article

Yeast metabolism significantly contributes to functional beverage production by generating bioactive compounds such as tryptophan derivatives (dTRPs). While Saccharomyces cerevisiae is traditionally used, non-Saccharomyces yeasts like Torulaspora delbrueckii and Zygosaccharomyces bailii are gaining interest for their ability to enhance aroma profiles and influence metabolite synthesis. This study evaluated the dTRP production of T. delbrueckii CBS1146^T and Z. bailii ATCC36947^T in synthetic medium and Cabernet Sauvignon must supplemented with 100 mg/L tryptophan. LC-MS/MS analysis revealed strain-dependent differences in metabolite profiles, with a predominance of kynurenine pathway compounds and the first identification of two tryptophan-ethylester (TEE) isomers. T. delbrueckii exhibited significant TEE production, correlating with the consumption of dTRPs; conversely, Z. bailii synthesized diverse metabolites, including 5OH-tryptophan and kynurenic acid. Notably, melatonin was not detected. The fermentation matrix strongly influenced dTRP biosynthesis, with must conditions enhancing TEE and kynurenic acid accumulation. These findings highlight the role of growth medium composition in modulating yeast metabolism and support the potential of non-Saccharomyces yeasts for functional beverage development. Full article

This study aimed to evaluate the effects of the standardized ileal digestible tryptophan-to-lysine (SID Trp–Lys) ratio through the supplementation of different levels of L-tryptophan on pig performance and immune response following an LPS challenge. A total of 120 entire male pigs, with an average body weight of 16.5 ± 0.50 kg, were allocated in a randomized block design with four treatments, ten replicates per treatment, and three animals per experimental unit. The experimental treatments consisted of SID Trp–Lys ratios of 16%, 18%, 21%, and 24%, achieved through L-tryptophan supplementation. The evaluated performance parameters included the final body weight (BW), average daily gain (ADG), average daily feed intake (ADFI), and feed conversion ratio (FCR). Blood samples were collected on day 21 to determine serum serotonin levels, and on day 26, pigs were inoculated with LPS to induce an immune challenge, followed by blood sampling to assess cytokine responses. The results showed that pigs fed the 16% SID Trp–Lys ratio exhibited a lower FBW (p < 0.05). The SID Trp–Lys ratios influenced performance parameters, with quadratic responses (p < 0.05) observed for the FBW and FCR, where the highest FBW and lowest FCR were recorded at 22.05% and 21% SID Trp–Lys, respectively. A linear increase (p < 0.05) was observed for ADG, with a trend for a linear increase (p = 0.056) in ADFI. No effects (p > 0.10) of the SID Trp–Lys ratios were detected on serum serotonin levels. An increase in cytokine levels (GM-CSF, IFN-γ, IL-1α, IL-1β, IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, and TNF-α) was observed in pigs challenged with LPS (p < 0.10) compared to non-challenged animals. An interaction effect (p < 0.10) was detected for IL-2 and IL-18. SID Trp–Lys ratios between 21% and 24% optimize growth performance in pigs from 16 to 33 kg and modulate the immune response under LPS-induced challenge conditions. Full article

Background: Quinoline-derived metabolites exhibit notable chemical complexity. What causes minor structural alterations to induce significant changes in disease outcomes? Historically, eclipsed by more straightforward scaffolds, these chemicals serve as a dynamic hub in tryptophan metabolism, linking immunomodulation, excitotoxicity, and cancer. However, many of these compounds struggle to cross the blood–brain barrier, and we still do not fully understand how certain structural changes affect their bioavailability or off-target effects. Thus, contemporary research highlights halogenation, esterification, and computational modeling to enhance structure–activity relationships. Summary: This narrative review emphasizes the integration of rational drug design, multi-target ligands, and prodrug methods in enhancing quinoline scaffolds. We explore each molecule’s therapeutic promise, refine each scaffold’s design, and develop each derivative to maximize clinical utility. Translating these laboratory findings into clinical practice, however, remains a formidable challenge. Conclusions: Through the synthesis of findings regarding NMDA receptor antagonism, improved oral bioavailability, and reduced metabolic instability, we demonstrate how single-site changes might modulate excitotoxicity and immunological signaling. Advancing quinoline-based medicines will yield significant advancements in neurology, psychiatry, and oncology. This enlarged framework fosters collaborative discovery, engages various audiences, and advances the field towards next-generation disease-modifying therapies. Robust preclinical validation, patient classification, and comprehensive toxicity evaluations are crucial stages for achieving these extensive endeavors and fostering future therapeutic discoveries globally. Full article