Search Results (63)

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

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

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

Psoriasis is a systemic disease affecting 2–3% of the general population. Tryptophan (TRP) is an amino acid metabolized in the kynurenine pathway (KP). The aim of this study was to assess the kynurenine pathway’s metabolites in serum and urine of psoriatic patients and explore the possible interplay with the disease’s pathogenesis and its comorbidities. The study involved 60 patients with plaque psoriasis and 30 healthy volunteers matched for gender, age, and BMI. Serum and urine samples were taken from the participants and tested for TRP, indoleamine 2,3-dioxygenase (IDO), 2,3-tryptophan dioxygenase (TDO), kynurenine (KYN), kynurenic acid (KYNA), quinolinic acid (QUIN), and numerous laboratory parameters. Correlations between the metabolites’ levels and clinical, laboratory parameters and depression occurrence were statistically evaluated. Concentrations of tryptophan, kynurenic acid, and quinolinic acid in serum and urine were significantly higher among patients with psoriasis (p < 0.05 and p < 0.001, p < 0.05 and p < 0.05 and p < 0.001 and p < 0.001, respectively). A significant stimulation of the kynurenine pathway in serum and urine of patients with psoriasis suggests its role in its pathogenesis and interplay between chronic inflammation or comorbidities. Further research is needed to discover whether the increase in KP metabolites is an indicator of inflammation or a compensatory mechanism in psoriasis. Full article

Objectives: The aim was to simultaneously investigate inflammatory biomarkers, neopterin, the kynurenine/tryptophan (Kyn/Trp) pathway, vitamin D (VitD), vitamin D binding protein (VDBP), and erythrocyte folate, in cerebral palsy (CP). Methods: A case–control study was conducted at Mersin University Hospital. Three- to ten-year-old patients with spastic CP (n = 50) and age- and gender-matched healthy controls (n = 55) were included. Serum levels of neopterin, Trp, Kyn and 25OHD, plasma VDBP, and erythrocyte folate concentrations were measured. Indoleamine-2,3-dioxygenase 1 (IDO-1) enzyme activity was evaluated according to the Kyn/Trp ratio. Comparison and correlation analyses were performed. Results: The levels of neopterin, Trp, and Kyn were lower in children with CP than in healthy controls (p = 0.037, p < 0.001, and p = 0.003, respectively). IDO1 was not significantly different between the CP and control groups (p = 0.214). The levels of VitD and VDBP were higher in children with CP (p < 0.001 and p = 0.001, respectively). The level of erythrocyte folate was also higher in children with CP (p < 0.001). No significant correlation was found between age and inflammatory biomarkers in the CP group. Neopterin was correlated with the level of Gross Motor Function Classification System (GMFCS) level (r = 0.292, p = 0.044), while there was no significant correlation between the other biomarkers and the level of GMFCS in the CP group. Conclusions: Inflammatory biomarkers of neopterin and Kyn are lower, inflammatory biomarkers of VDBP and erythrocyte folate are higher, and anti-inflammatory VitD is higher in children with spastic CP compared to healthy children. More knowledge is needed to demonstrate inflammatory and anti-inflammatory status in children with CP. Full article

Autism spectrum disorder (ASD) has been associated with disruptions in tryptophan (TRP) metabolism, affecting the production of key neuroactive metabolites. Investigating these metabolic pathways could yield valuable biomarkers for ASD severity and progression. We included 44 children with ASD and 44 healthy children, members of the same family. The average age in the ASD group was 10.7 years, while the average age in the control group was 9.4 years. Urinary tryptophan metabolites were quantified via liquid chromatography—mass spectrometry operating multiple reaction monitoring (MRM). Urinary creatinine was analyzed on an Advia 2400 analyzer using the Jaffe reaction. Statistical comparisons were made between ASD subgroups based on CARS scores. Our findings indicate that children with ASD have higher TRP concentrations (19.94 vs. 16.91; p = 0.04) than their siblings. Kynurenine (KYN) was found at higher levels in children with ASD compared to children in the control group (82.34 vs. 71.20; p = 0.86), although this difference was not statistically significant. The ASD group showed trends of higher KYN/TRP ratios and altered TRP/ indole-3-acetic acid (IAA) and TRP/5-hydroxyindoleacetic acid (5-HIAA) ratios, correlating with symptom severity. Although the numbers of the two groups were different, our findings suggest that mild and severe illnesses involve separate mechanisms. However, further comprehensive studies are needed to validate these ratios as diagnostic tools for ASD. Full article

Tryptophan (Trp)-based radiotracers have excellent potential for imaging many different types of brain pathology because of their involvement with both the serotonergic and kynurenine (KYN) pathways. However, radiotracers specific to the kynurenine metabolism pathway are limited. In addition, historically Trp-based radiopharmaceuticals were synthesized with the short-lived isotope carbon-11. A newer generation of Trp-based imaging agents using the longer half-lived and commercially available isotopes, such as fluorine-18 and iodine-124, are being developed. The newly developed amino acid-based tracers have been demonstrated to have favorable radiochemical and imaging characteristics in pre-clinical studies. However, many barriers still exist in the clinical translation of KYN pathway-specific radiotracers. Full article

Objectives: Cancer-related fatigue (CRF) is highly prevalent in patients with breast cancer, resulting in undesirable outcomes and even reduced survival rates. This cross-sectional study investigated the relationship between dietary quality and CRF in patients with breast cancer, and the potential role of gut microbiota (GM) in this association. Methods: Dietary intake and CRF were evaluated in 342 patients, with 64 fecal samples collected for 16sRNA sequencing and 106 plasma samples for tryptophan (TRP) metabolite determination. Results: A total of 149 (43.6%) patients experienced CRF, which was significantly associated with low intakes of protein, vitamin A, vitamin E, dietary fiber, phosphorus, magnesium, potassium, iron, and copper (p < 0.05), and a remarkably low Chinese Healthy Eating Index (CHEI) score (p < 0.05). CRF patients had decreased GM diversity, an unhealthier GM composition, lower TRP concentrations, and a higher kynurenine (KYN)/TRP ratio (p < 0.05). Mediation analyses revealed that both the Sobs index (ACME = −0.0005; 95% CI −0.0051, −0.0001; p = 0.034) and the Chao index (ACME = −0.0005; 95% CI −0.0050, −0.0001; p = 0.033) were significant mediators of the correlation between total CHEI score and CRF. Conclusions: The presence of CRF in patients with breast cancer might be correlated with inadequate nutrient intake and low dietary quality via GM-dependent pathways. Full article

Though the mechanisms are not fully understood, tryptophan (Trp) and physical exercise seem to regulate mechanical hypersensitivity in fibromyalgia. Here, we tested the impact of Trp supplementation and continuous low-intensity aerobic exercise on the modulation of mechanical hypersensitivity in a fibromyalgia-like model induced by acid saline in female rats. Twelve-month-old female Wistar rats were randomly divided into groups: [control (n = 6); acid saline (n = 6); acid saline + exercise (n = 6); acid saline + Trp (n = 6); and acid saline + exercise + Trp (n = 6)]. Hypersensitivity was caused using two intramuscular jabs of acid saline (20 μL; pH 4.0; right gastrocnemius), 3 days apart. The tryptophan-supplemented diet contained 7.6 g/hg of Trp. The three-week exercise consisted of progressive (30–45 min) treadmill running at 50 to 60% intensity, five times (Monday to Friday) per week. We found that acid saline induced contralateral mechanical hypersensitivity without changing the levels of Trp, serotonin (5-HT), and kynurenine (KYN) in the brain. Hypersensitivity was reduced by exercise (~150%), Trp (~67%), and its combination (~160%). The Trp supplementation increased the levels of Trp and KYN in the brain, and the activity of indoleamine 2,3-dioxygenase (IDO), and decreased the ratio 5-HT:KYN. Exercise did not impact the assessed metabolites. Combining the treatments reduced neither hypersensitivity nor the levels of serotonin and Trp in the brain. In conclusion, mechanical hypersensitivity induced by acid saline in a fibromyalgia-like model in female rats is modulated by Trp supplementation, which increases IDO activity and leads to improved Trp metabolism via the KYN pathway. In contrast, physical exercise does not affect mechanical hypersensitivity through brain Trp metabolism via either the KYN or serotonin pathways. Because this is a short study, generalizing its findings warrants caution. Full article

Kidney transplantation significantly improves the survival of patients with end-stage kidney disease (ESKD) compared to other forms of kidney replacement therapy. However, kidney transplant recipients’ outcomes are not fully satisfactory due to increased risk of cardiovascular diseases, infections, and malignancies. Immune-related complications remain the biggest challenge in the management of kidney graft recipients. Despite the broad spectrum of immunosuppressive agents available and more detailed methods used to monitor their effectiveness, chronic allograft nephropathy remains the most common cause of kidney graft rejection. The kynurenine (KYN) pathway is the main route of tryptophan (Trp) degradation, resulting in the production of a plethora of substances with ambiguous properties. Conversion of Trp to KYN by the enzyme indoleamine 2,3-dioxygenase (IDO) is the rate-limiting step determining the formation of the next agents from the KYN pathway. IDO activity, as well as the production of subsequent metabolites of the pathway, is highly dependent on the balance between pro- and anti-inflammatory conditions. Moreover, KYN pathway products themselves possess immunomodulating properties, e.g., modify the activity of IDO and control other immune-related processes. KYN metabolites were widely studied in neurological disorders but recently gained the attention of researchers in the context of immune-mediated diseases. Evidence that this route of Trp degradation may represent a peripheral tolerogenic pathway with significant implications for transplantation further fueled this interest. Our review aimed to present recent knowledge about the role of the KYN pathway in the pathogenesis, diagnosis, monitoring, and treatment of kidney transplant recipients’ complications. Full article

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

The application of intracerebroventricular injection of streptozotocin (ICV-STZ) is considered a useful animal model to mimic the onset and progression of sporadic Alzheimer’s disease (sAD). In rodents, on day 7 of the experiment, the animals exhibit depression-like behaviors. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn), is closely related to depression and AD. The present study aimed to investigate the pathophysiological mechanisms of preliminary depression-like behaviors in ICV-STZ rats in two distinct cerebral regions of the medial prefrontal cortex, the prelimbic cortex (PrL) and infralimbic cortex (IL), both presumably involved in AD progression in this model, with a focus on IDO-related Kyn pathways. The results showed an increased Kyn/Trp ratio in both the PrL and IL of ICV-STZ rats, but, intriguingly, abnormalities in downstream metabolic pathways were different, being associated with distinct biological effects. In the PrL, the neuroprotective branch of the Kyn pathway was attenuated, as evidenced by a decrease in the kynurenic acid (KA) level and Kyn aminotransferase II (KAT II) expression, accompanied by astrocyte alterations, such as the decrease in glial fibrillary acidic protein (GFAP)-positive cells and increase in morphological damage. In the IL, the neurotoxicogenic branch of the Kyn pathway was enhanced, as evidenced by an increase in the 3-hydroxy-kynurenine (3-HK) level and kynurenine 3-monooxygenase (KMO) expression paralleled by the overactivation of microglia, reflected by an increase in ionized calcium-binding adaptor molecule 1 (Iba1)-positive cells and cytokines with morphological alterations. Synaptic plasticity was attenuated in both subregions. Additionally, microinjection of the selective IDO inhibitor 1-Methyl-DL-tryptophan (1-MT) in the PrL or IL alleviated depression-like behaviors by reversing these different abnormalities in the PrL and IL. These results suggest that the antidepressant-like effects linked to Trp metabolism changes induced by 1-MT in the PrL and IL occur through different pathways, specifically by enhancing the neuroprotective branch in the PrL and attenuating the neurotoxicogenic branch in the IL, involving distinct glial cells. Full article

Indoleamine 2,3-deoxygenase (IDO) plays an important role in the catabolism of the amino acid tryptophan. Tryptophan and its metabolites are key immune modulators. Increased IDO activity has been observed in various diseases and is associated with worse clinical outcomes. However, comprehensive research regarding its role in cardiac surgery remains limited. Therefore, we aimed to investigate perioperative changes in IDO activity and pathway metabolites, along with their impact on clinical outcomes in adult patients undergoing cardiac surgery. As an observational cohort study conducted at the Inselspital in Bern from January to December 2019, we retrospectively analyzed the data of prospectively collected biobank samples of patients undergoing cardiac surgery with the use of cardiopulmonary bypass. IDO pathway metabolite analysis was conducted by mass spectrometry. Perioperative dynamics were descriptively assessed and associated with pre-defined clinical outcome measures (30-day mortality, 1-year mortality, incidence of stroke and myocardial infarction, and length of hospital stay) through a multi-step exploratory regression analysis. A cohort of 192 adult patients undergoing cardiac surgery with the use of cardiopulmonary bypass were included (median age 67.0, IQR 60.0–73.0, 75.5% male). A significant perioperative decrease in the kynurenine/tryptophan (Kyn/Trp) ratio (−2.298, 95% CI −4.028 to −596, p = 0.009) and significant perioperative dynamics in the associated metabolites was observed. No association of perioperative changes in IDO activity and pathway metabolites with clinical outcomes was found. A significant decrease in the Kyn/Trp ratio among adult patients undergoing cardiac surgery indicates a perioperative downregulation of IDO, which stands in contrast to other pro-inflammatory conditions. Further studies are needed to investigate IDO in the setting of perioperative immunomodulation, which is a key driver of postoperative complications in cardiac surgery patients. Full article

Background: Indoleamine 2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO) are the two principals enzymes involved in the catabolization of tryptophan (Trp) into kynurenine (Kyn). Despite their well-established role in the immune escape, their involvement in angiogenesis remains uncertain. We aimed to characterize TDO and IDO1 in human umbilical venular endothelial cells (HUVECs) and human endothelial colony-forming cells (ECFCs). Methods: qRT-PCR and immunofluorescence were used for TDO and IDO1 expression while their activity was measured using ELISA assays. Cell proliferation was examined via MTT tests and in in vitro angiogenesis by capillary morphogenesis. Results: HUVECs and ECFCs expressed TDO and IDO1. Treatment with the selective TDO inhibitor 680C91 significantly impaired HUVEC proliferation and 3D-tube formation in response to VEGF-A, while IDO1 inhibition showed no effect. VEGF-induced mTor phosphorylation and Kyn production were hindered by 680C91. ECFC morphogenesis was also inhibited by 680C91. Co-culturing HUVECs with A375 induced TDO up-regulation in both cell types, whose inhibition reduced MMP9 activity and prevented c-Myc and E2f1 upregulation. Conclusions: HUVECs and ECFCs express the key enzymes of the kynurenine pathway. Significantly, TDO emerges as a pivotal player in in vitro proliferation and capillary morphogenesis, suggesting a potential pathophysiological role in angiogenesis beyond its well-known immunomodulatory effects. Full article

Systemic sclerosis (SSc), a predominantly female-affected systemic autoimmune disease, requires tailored treatment strategies contingent on organ involvement and symptom severity. Given SSc’s inflammatory nature, the involvement of the kynurenine pathway (KP) in its pathophysiology is underexplored. Our study aimed to investigate sex-related differences in KP activation among SSc patients and assess the impact of angiotensin-converting enzyme (ACE) inhibitors and estimated glomerular filtration rate (eGFR) on KP metabolite concentrations. We enrolled 48 SSc patients and 53 healthy controls, quantifying KP metabolites (tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA)) in serum via high-performance liquid chromatography. Separate multivariate analyses of covariance (MANCOVAs) for women and men were performed to ascertain mean differences between patients and healthy controls while correcting for age. For our secondary objective, we conducted a MANCOVA to explore disparities in ACE inhibitor users and non-users among patients, with BMI correction. Our findings revealed decreased TRP concentrations but increased KYNA/TRP ratio and KYN/TRP ratio in both male and female SSc patients compared to their respective controls. Unlike women, SSc males exhibited higher KYN concentrations and decreased KYNA/KYN ratio relative to their controls. Additionally, SSc patients using ACE inhibitors had higher serum KYNA levels than non-users. Notably, we established a significant correlation between eGFR and KYNA in SSc patients. These results indicate differential KP activation in male and female SSc patients, with males demonstrating heightened KP activation. While ACE inhibitors may influence the KP in SSc patients, further research is necessary to comprehensively understand their impact on symptoms and prognosis in the context of these KP alterations. Full article