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The pivotal role of metabolic reprogramming in cancer-related drug resistance, through the tryptophan-catabolized kynurenine pathway (KP), has been particularly underscored in recent research. This pathway, driven by indoleamine 2,3-dioxygenase 1 (IDO1), facilitates immune evasion and promotes tumor progression by fostering an immunosuppressive environment. In Phase III investigation of the combination of IDO1 inhibition with immune checkpoint inhibitors (ICIs), the combination therapy was not efficacious. In this review, we revisit current advances, explore future directions, and emphasize the importance of dual inhibition of the KP rate-limiting enzymes IDO1 and tryptophan 2,3-dioxygenase-2 (TDO2) in appropriate patient populations. We propose that dual inhibition may maximize the therapeutic potential of KP inhibition. Additionally, we delve into the complex cellular interactions in cancer and metabolic dependencies within the tumor microenvironment (TME). Insights from preclinical studies, recent clinical trials, and promising therapeutic combinations will be discussed to elucidate and promote a clear path forward for the direction of KP research into cancer-related outcomes. [ABSTRACT FROM AUTHOR]

The cuprizone (CPZ) model of multiple sclerosis (MS) is excellent for studying the molecular differences behind the damage caused by poisoning. Metabolic differences in the kynurenine pathway (KP) of tryptophan (TRP) degradation are observed in both MS and a CPZ mouse model. Our goal was to analyze the kynurenine, serotonin, and indole pathways of TRP degradation on the periphery, in the neurodegenerative processes of inflammation. In our study, mice were fed with 0.2% CPZ toxin for 5 weeks. We examined the metabolites in the three pathways of TRP breakdown in urine, plasma, and relevant visceral organs with bioanalytical measurements. In our analyses, we found a significant increase in plasma TRP, 5-hydroxytryptophan (5-HTP), and indole-3-acetic acid (IAA) levels, while a decrease in the concentrations of 3-hydroxy-L-kynurenine (3-HK), xanthurenic acid (XA), kynurenic acid (KYNA), and quinaldic acid in the plasma of toxin-treated group was found. A marked decrease in the levels of 3-HK, XA, KYNA, quinaldic acid, and indole-3-lactic acid was also observed in the visceral organs by the end of the poisoning. Furthermore, we noticed a decrease in the urinary levels of the TRP, KYNA, and XA metabolites, while an increase in serotonin and 5-hydroxyindoleacetic acid in the CPZ group was noticed. The toxin treatment resulted in elevated tryptamine and indoxyl sulfate levels and reduced IAA concentration. Moreover, the urinary para-cresyl sulfate concentration also increased in the treated group. In the present study, we showed the differences in the three main metabolic pathways of TRP degradation in the CPZ model. We confirmed the relationship and correlation between the content of the kynurenine metabolites in the plasma and the tissues of the visceral organs. We emphasized the suppression of the KP and the activity of the serotonin and indole pathways with a particular regard to the involvement of the microbiome by the indole pathway. Consequently, this is the first study to analyze in detail the distribution of the kynurenine, serotonin, and indole pathways of TRP degradation in the periphery. [ABSTRACT FROM AUTHOR]

Liver health is integral to overall human well-being and the pathogenesis of various diseases. In recent years, kynurenine and its derivatives have gradually been recognized for their involvement in various pathophysiological processes, especially in the regulation of liver diseases, such as acute liver injury, non-alcoholic fatty liver disease, cirrhosis, and liver cancer. Kynurenine and its derivatives are derived from tryptophan, which is broken down by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), converting the essential amino acid tryptophan into kynurenine (KYN) and other downstream metabolites, such as kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and quinolinic acid (QA). In liver diseases, kynurenine and its derivatives can promote the activity of the transcription factor aryl hydrocarbon receptor (AhR), suppress T cell activity for immune modulation, inhibit the activation of inflammatory signaling pathways, such as NF-κB for anti-inflammatory effects, and inhibit the activation of hepatic stellate cells to slow down fibrosis progression. Additionally, kynurenine and other downstream metabolites can influence the progression of liver diseases by modulating the gut microbiota. Therefore, in this review, we summarize and explore the mechanisms by which kynurenine and its derivatives regulate liver diseases to help develop new diagnostic or prognostic biomarkers and effective therapies targeting the kynurenine pathway for liver disease treatment. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a prevalent psychiatric disorder that has damage to people's quality of life. Tryptophan is the precursor to serotonin, a critical neurotransmitter in mood modulation. In mammals, most free tryptophan is degraded by the kynurenine pathway (KP), resulting in a range of metabolites involved in inflammation, immune response, and neurotransmission. The imbalance between quinolinic acid (QA), a toxic metabolite, and kynurenic acid (KynA), a protective metabolite, is a relevant phenomenon involved in the pathophysiology of MDD. Proinflammatory cytokines increase the activity of the enzyme indoleamine 2,3-dioxygenase (IDO), leading to the degradation of tryptophan in the KP and an increase in the release of QA. IDO activates proinflammatory genes, potentiating neuroinflammation and deregulating other physiological mechanisms related to chronic stress and MDD. This review highlights the physiological mechanisms involved with stress and MDD, which are underlying an imbalance of the KP and discuss potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction: Indoleamine 2,3-dioxygenase (IDO) converts L-tryptophan (T) to L-kynurenine (K) resulting in an immunosuppressive microenvironment. The aim of the current study was to evaluate in patients with neuroendocrine tumor (NET) (1) T and K concentrations; (2) correlation with clinical outcome; (3) relationship between IDO activity and inflammatory cytokines. Methods: A cross-sectional study was performed to investigate the IDO pathway in patients in follow-up for NET. Clinicopathological features, serum levels of K and T through liquid chromatography, and serum assay of cytokines (IL-6, IL-10, IL-17A, IL-22, IL-23, TNF-α) through MAGPIX were evaluated. Results: Seventy-eight NET patients were enrolled (66 lung, 12 pancreatic): 69.2% were in postoperative remission, 14.1% in stable disease, and 16.7% in disease progression. T was significantly lower in patients older than 65 years (p = 0.003). K and T were significantly lower in patients with progression (p = 0.03, p = 0.004, respectively). T was an independent predictor factor of progression in multivariable analysis (p = 0.041). A cutoff of 7.74 μg/mL significantly differentiates patients with progression and those with stable disease. IL-6 and IL-10 were significantly associated with tumor progression in univariate analysis (p = 0.005, p = 0.001, respectively) but not in the multivariable analysis. A statistically significant negative correlation was found between T and IL-10 (r = −0.366, p value = 0.04). Conclusion: The K/T pathway may play a role as a potential predictor of tumor progression in NET. These findings need to be validated in large prospective studies investigating its metabolites as both prognostic and predictive factors for treatment response. [ABSTRACT FROM AUTHOR]

This study aims to investigate the effect of smoking on the metabolism of kynurenine and thus contribute to the elucidation of the potential mechanism of cigarette smoking.The study included 82 smokers and 63 nonsmokers who applied to the Family Medicine Polyclinic for routine check-ups. Sociodemographic data, routine laboratory results, Framingham risk scores (FRS), and Fagerström Nicotine Dependence Test (FTND) were recorded. Serum tryptophan, kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, 3-hydroxykynurenine, and quinolinic acid concentrations were measured with tandem mass spectrometry.Serum tryptophan levels (p=0.040) were statistically significantly lower in smokers, and the kynurenine/tryptophan ratio and serum kynurenine, kynurenic acid, quinolinic acid, 3-hydroxyanthranilic acid levels were higher (p<0.001). The correlation analysis in the smoker group showed a positive correlation between serum kynurenic acid levels and FTDN. The serum kynurenine levels were positively correlated with the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and FRS. There was a positive correlation between serum quinolinic acid levels and participants’ systolic and diastolic blood pressures.Our findings showed that tryptophan metabolism via the kynurenine pathway was induced in smokers. [ABSTRACT FROM AUTHOR]

Tryptophan (TRP) is an essential amino acid crucial for the production of many bioactive compounds. Disturbances in TRP metabolism have been revealed in various diseases, many of which are closely related to the immune system. In recent years, we have focused on finding blood-based biomarkers of successful immunotherapy in cancer. Thus, we aimed to develop a robust liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for TRP and its metabolites that could be used in biomarker studies. Although analyzing TRP derivatives in biological matrices is not a new topic, we encountered multiple challenges during method development. One of them was the phenomenon of cross-interferences between the analyzed molecules, which has not been explored in most published papers. We noticed that injecting a pure single-compound solution often generated a signal in the other compounds' MS/MS channels. Specifically, TRP generated unexpected peaks in the channel for kynurenine, kynurenic acid, and xanthurenic acid, while kynurenine generated peaks in the channel for kynurenic acid. We also recorded a mutual cross-talk between kynurenine and isotope-labeled TRP. Different origins of the observed cross-signal contribution were proposed. This paper draws attention to investigating cross-interferences in LC-MS/MS, especially when structurally related compounds will be analyzed. Despite all the challenges, the method was successfully validated according to international guidelines (EMA/ICH), and its applicability was confirmed in a pilot study including 20 patients with lung cancer undergoing chemoimmunotherapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Mitochondria contain multiple pathways including energy metabolism and several signaling and synthetic pathways. Mitochondrial proteomics is highly valuable for studying diseases including inherited metabolic disorders, complex and common disorders like neurodegeneration, diabetes, and cancer, since they all to some degree have mitochondrial underpinnings. Areas Covered: The main mitochondrial functions and pathways are outlined, and systematic protein lists are presented. The main energy metabolic pathways are as follows: iron-sulfur cluster synthesis, one carbon metabolism, catabolism of hydrogen sulfide, kynurenines and reactive oxygen species (ROS), and others, described with the aim of laying a foundation for systematic mitochondrial pathway analysis based on proteomics data. The links of the proteins and pathways to functional effects and diseases are discussed. The disease examples are focussed on inherited metabolic disorders, cancer, neurological, and cardiovascular disorders. Expert opinion: To elucidate the role of mitochondria in health and disease, there is a need for comprehensive proteomics analyses with stringent, systematic data treatment for proper interpretation of mitochondrial pathway data. In that way, comprehensive hypothesis-based research can be performed based on proteomics data. [ABSTRACT FROM AUTHOR]

The rising burden of type 2 diabetes mellitus (T2DM) is a growing global public health problem, particularly prominent in developing countries. The early detection of T2DM and prediabetes is vital for reversing the outcome of disease, allowing early intervention. In the past decade, various microbiome–metabolome studies have attempted to address the question of whether there are any common microbial patterns that indicate either prediabetic or diabetic gut microbial signatures. Because current studies have a high methodological heterogeneity and risk of bias, we have selected studies that adhered to similar design and methodology. We performed a systematic review to assess if there were any common changes in microbiome belonging to diabetic, prediabetic and healthy individuals. The cross-sectional studies presented here collectively covered a population of 65,754 people, with 1800 in the 2TD group, 2770 in the prediabetic group and 61,184 in the control group. The overall microbial diversity scores were lower in the T2D and prediabetes cohorts in 86% of the analyzed studies. Re-programming of the microbiome is potentially one of the safest and long-lasting ways to eliminate diabetes in its early stages. The differences in the abundance of certain microbial species could serve as an early warning for a dysbiotic gut environment and could be easily modified before the onset of disease by changes in lifestyle, taking probiotics, introducing diet modifications or stimulating the vagal nerve. This review shows how metagenomic studies have and will continue to identify novel therapeutic targets (probiotics, prebiotics or targets for elimination from flora). This work clearly shows that gut microbiome intervention studies, if performed according to standard operating protocols using a predefined analytic framework (e.g., STORMS), could be combined with other similar studies, allowing broader conclusions from collating all global cohort studies efforts and eliminating the effect-size statistical insufficiency of a single study. [ABSTRACT FROM AUTHOR]

Psoriasis is a widespread immunological disease characterised by inflammation and primarily associated with skin and joint symptoms. The kynurenine pathway significantly influences inflammation and immune system activity. The aim of this study is to determine serum concentrations of kynurenine metabolites in patients with psoriasis and investigate their correlation with disease severity.This study included 30 participants with psoriasis and 30 individuals without the disease as healthy controls. Serum levels of tryptophan, kynurenine, 3-OH anthranilic acid, quinolinic acid, 3-OH kynurenine, and kynurenic acid were determined by liquid chromatography-mass spectrometry (LC-MS/MS).Serum levels of kynurenic acid (p<0.001), tryptophan (p<0.001) and the tryptophan/kynurenine ratio (TKR) (p<0.001) were statistically significantly lower in psoriasis patients than in healthy controls, while levels of quinolinic acid (p=0.007) and kynurenine (p=0.001) were significantly higher. The Psoriasis Area Severity Index (PASI) correlated positively with 3-hydroxykynurenine and kynurenic acid.Kynurenine metabolites are associated with the pathophysiology of psoriasis and could serve as valuable candidate markers for monitoring inflammation. [ABSTRACT FROM AUTHOR]

Chlamydiosis is the major infectious disease responsible for significant morbidity and mortality in free-living koalas. Recently, it was reported that 28.5% of koalas infected with chlamydiosis were presented with no overt clinical signs. Identification and quantification of changes in plasma biomarkers' fluctuations have the potential to enhance C. pecorum detection and facilitate the monitoring of therapeutic efficacy of antibiotics to treat this disease in koalas. Therefore, concentrations of the essential amino acid tryptophan, tryptophan's metabolite kynurenine, and the kynurenine:tryptophan ratio were quantified by high-performance liquid chromatography in the plasma of clinically normal koalas (n = 35), koalas identified with chlamydial disease (n = 35) and koalas that had other non-chlamydial co-morbidities (n = 10). Results showed that there was a significant difference between the clinically normal versus diseased, and clinically normal versus 'other' (both p < 0.001) in kynurenine plasma concentrations and kynurenine:tryptophan ratio; and also between the clinically normal and diseased in tryptophan plasma concentrations (p = 0.001). Proposed reference ranges of tryptophan, kynurenine, and kynurenine:tryptophan ratio in koalas are: 4.27–10.4 μg/mL, 0.34–1.23 μg/mL, and 0.05–0.22, respectively. Proposed optimal cut-off points to differentiate between clinically normal and diseased are: ≤ 4.75 μg/mL (tryptophan), ≥ 0.88 μg/mL (kynurenine), and ≥ 0.12 (kynurenine:tryptophan); and ≤ 7.67 μg/mL (tryptophan), ≥ 1.18 μg/mL (kynurenine), and ≥ 0.16 (kynurenine:tryptophan) to differentiate between released/recovered and euthanised of the diseased/'other' koalas. Significant differences in haematological and biochemical analytes were in the plasma globulins between the clinically normal and diseased koalas (p = 0.01), and in alkaline phosphatase between the clinically normal and 'other' koalas (p = 0.03). Although these potential biomarkers, especially tryptophan, may not be specific for detecting C. pecorum from the rest of the population, kynurenine and the kynurenine:tryptophan ratio may have a role in identifying unhealthy koalas from the clinically normal ones, irrespective of the underlying cause. [ABSTRACT FROM AUTHOR]

Recent studies confirm the involvement of activated immune-inflammatory responses and increased oxidative and nitrosative stress in Long COVID (LC) disease. However, the influence of these pathways on the metabolism of tryptophan (TRP) through the TRP catabolite (TRYCAT) pathway and their mediating effects on LC pathophysiology, has not been fully explored. This meta -analysis investigates peripheral TRP and TRYCAT levels and the TRYCAT pathway in patients with LC disease. This review utilized systematic searches of PubMed, Google Scholar, SCOPUS and SciFinder, including 14 full-text articles and 1,167 participants, consisting of 480 patients with LC and 687 normal controls. The results indicated a significant increase in the kynurenine (KYN)/TRP ratio, with a large effect size (standardized mean difference, SMD = 0.755; confidence intervals, CI: 0.119;1.392), in LC patients compared to normal controls. Additionally, LC patients exhibited a significant decrease in TRP levels (SMD = −0.520, CI: −0.793; −0.246) and an increase in KYN levels after imputing missing studies (SMD = 1.176, CI: 0.474; 1.877), suggesting activation of the indoleamine 2,3-dioxygenase (IDO) enzyme and upregulation of the TRYCAT pathway. No significant elevation in TRYCAT-related neurotoxicity, kynurenic acid (KA)/KYN and 3-hydroxykynurenine (3-HK)/KYN ratios were observed in LC patients compared to normal controls. The current findings suggest that an activated TRYCAT pathway, characterized by decreased TRP levels and maybe elevated KYN levels, plays a significant role in the pathophysiology of LC. [ABSTRACT FROM AUTHOR]

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Background and Purpose Experimental Approach Key Results Conclusions and Implications Alterations in tryptophan‐kynurenine (TRP‐KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic–pituitary–adrenal (HPA) axis. We have shown that deficiency of kynurenine 3‐monooxygenase (KMO) induces depression‐like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP‐KYN pathway in stress‐induced behavioural changes and the regulation of the HPA axis.Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP‐KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS‐induced behavioural changes and an increase in serum corticosterone (CORT) concentration.CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo+/− mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short‐term CUMS. Nicotine attenuated CUMS‐induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin‐releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine.CUMS‐induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor which in certain cancer types drives pro-survival processes that facilitate tumorigenesis, malignant cell migration, invasion, and metastasis. Much of AHR's pro-tumorigenic action is due to its activation by the oncometabolite, kynurenine. Because of this AHR antagonists are being actively investigated as new anti-tumor therapy. In this study we compared the effects of treatment with the AHR antagonists, BAY2416964 and GNF351, to that of AHR knockout in PyMT murine mammary cancer cells. BAY2416964 and GNF351 effectively inhibited kynurenine-dependent increases in Cyp1a1 and Cyp1b1 mRNA levels. CRISPR/Cas9-generated PyMT AhrKO cells exhibited reduced cell proliferation compared with controls, but treatment with 1 μM BAY2416964 for 96 h had no effect on the proliferation of wildtype cells. To further examine the differences between AHR knockout and short term BAY2416964, we generated long-term BAY2416964 (LT-BAY) cells by exposing wildtype cells to 1 μM BAY2416964 for at least 6 weeks. Similar to AhrKO cells, LT-BAY cells exhibited reduced cell proliferation and migration compared with wildtype cells. No differentially expressed genes (DEGs) were identified in wildtype cells exposed to 1 μM BAY2416964 for 24 h; however, 46.4% of DEGs overlapped between AhrKO and LT-BAY cells including gene regulated cell proliferation. Our data reveal long-term pharmacological inhibition of AHR by BAY2416964 closely resembles AHR loss in a mouse model of breast cancer. [ABSTRACT FROM AUTHOR]

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 framework has shaped much of the research on conditions like neurodegenerative and neuropsychiatric disorders, as well as cancer, where metabolic imbalances are a key feature. The effects are significantly influenced by various factors, including the concentration of metabolites and the particular cellular milieu in which they are generated. A molecule that acts as neuroprotective at low concentrations may exhibit neurotoxic effects at elevated levels. The oxidative equilibrium of the surrounding environment can alter the function of KYN from an antioxidant to a pro-oxidant. This narrative review offers a comprehensive examination and analysis of the contemporary understanding of KYN metabolites, emphasizing their multifaceted biological functions and their relevance in numerous physiological and pathological processes. This underscores the pressing necessity for a paradigm shift in the comprehension of KYN metabolism. Understanding the context-dependent roles of KYN metabolites is vital for novel therapies in conditions like Alzheimer's disease, multiple sclerosis, and cancer. Comprehensive pathway modulation, including balancing inflammatory signals and enzyme regulation, offers promising avenues for targeted, effective treatments. [ABSTRACT FROM AUTHOR]

Millions of individuals around the world are afflicted with Parkinson's disease (PD), a prevalent and incapacitating neurodegenerative disorder. Dr. Reichmann, a distinguished professor and neurologist, has made substantial advancements in the domain of PD research, encompassing both fundamental scientific investigations and practical applications. His research has illuminated the etiology and treatment of PD, as well as the function of energy metabolism and premotor symptoms. As a precursor to a number of neurotransmitters and neuromodulators that are implicated in the pathophysiology of PD, he has also investigated the application of tryptophan (Trp) derivatives in the disease. His principal findings and insights are summarized and synthesized in this narrative review article, which also emphasizes the challenges and implications for future PD research. This narrative review aims to identify and analyze the key contributions of Reichmann to the field of PD research, with the ultimate goal of informing future research directions in the domain. By examining Reichmann's work, the study seeks to provide a comprehensive understanding of his major contributions and how they can be applied to advance the diagnosis and treatment of PD. This paper also explores the potential intersection of Reichmann's findings with emerging avenues, such as the investigation of Trp and its metabolites, particularly kynurenines, which could lead to new insights and potential therapeutic strategies for managing neurodegenerative disorders like PD. [ABSTRACT FROM AUTHOR]

Hypertensive disorders of pregnancy (HDP) are a significant cause of maternal and perinatal mortality and morbidity. Knowledge on the placenta-related pathophysiology of HDP is increasing. Since maternal tryptophan metabolites are involved in placentation, we investigated associations between first-trimester tryptophan metabolites and utero-placental (vascular) development, and the occurrence of HDP. 911 women were included from a prospective tertiary hospital cohort. Serum tryptophan metabolites were determined at 8.1 ± 1.4 weeks gestation. Placental volume (PV) and utero-placental vascular volume (uPVV) were determined at 7, 9 and 11 weeks gestation. HDP, including hypertension in early pregnancy, gestational hypertension, and preeclampsia, were retrieved from medical records. Associations with PV- and uPVV-trajectories were assessed using mixed models, and HDP risks were estimated by logistic regression models, adjusted for confounders. A mediation analysis was performed to evaluate whether blood pressure was a mediator in the associations with utero-placental (vascular) development. A negative association between kynurenine and PV-trajectories was found (β = −0.129, 95%CI = −0.220 to –0.039), which was not mediated by blood pressure. No significant associations between other tryptophan metabolites and PV- and uPVV-trajectories were observed. Higher 5-hydroxytryptophan was associated with hypertension in early pregnancy (OR = 1.405, 95%CI = 1.210–1.681), and with an increased risk of preeclampsia in these women. No associations between tryptophan metabolites and other HDP were found. Higher first-trimester kynurenine concentrations were associated with impaired utero-placental (vascular) development. Higher first-trimester 5-hydroxytryptophan concentrations were associated with early pregnancy hypertension, and an increased risk of preeclampsia, indicating its clinical potential as biomarker for future prediction, prevention and treatment of HDP. • Higher first-trimester kynurenine levels may reduce placental volume. • Higher first-trimester 5-hydroxytryptophan levels may increase the risk of HDP. • Placental development can be assessed using 3D ultrasound and virtual reality. [ABSTRACT FROM AUTHOR]

BackgroundInterleukin-17-producing CD4 T cells contribute to the control of Mycobacterium tuberculosis (Mtb) infection in humans; whether infection with human immunodeficiency virus (HIV) disproportionately affects distinct Th17-cell subsets that respond to Mtb is incompletely defined.MethodsWe performed high-definition characterization of circulating Mtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by liquid chromatography-mass spectrometry (LC/MS) on plasma and tested the hypothesis that tryptophan catabolism influences Th17-cell frequencies in this context.ResultsWe identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2-CD161+CD26+and subset 2 defined as CD4+Vα7.2-CCR6+CXCR3-cells of which subset 1 was significantly reduced in latent tuberculosis infection (LTBI) with HIV-ART, yet Mtb-responsive IL-17-producing CD4 T cells were preserved; we found that IL-17-producing CD4 T cells dominate the response to Mtb antigen but not cytomegalovirus (CMV) antigen or staphylococcal enterotoxin B (SEB), and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17-cell frequencies.ConclusionsWe found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL-17-producing CD4 T cells dominate responses to Mtb but not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.

Peptide p176-190, derived from the SARS-CoV-2 spike protein, is one of the major T cell epitopes that elicits the HLA-DR-restricted IL-8 response of human CD4+ T cells. Using PBMCs from a healthy individual primed with an S-protein-based SARS-CoV-2 vaccine, we established a CD4+ T cell line (TM45) and cloned T cells (TM45.2) specific for the peptide. We showed that (i) co-incubation with kynurenine leads to increased IL-8; (ii) T cells incubated in the absence of kynurenine recovered the original levels of cytokine production; and (iii) peptide p176-190 substituted at 176 Leucine for neutral hydrophilic serine completely abolished the cytokine responses of TM45.2 cells, thereby suggesting that 176 L is the first anchor residue for binding to HLA-DR. These observations collectively indicate that (i) enhanced IL-8 responses can be induced by kynurenine, which is produced under infectious conditions in COVID-19; (ii) the response is not a permanent change in the T cell phenotype; and (iii) IL-8 responses associated with harmful neutrophil extracellular traps can be abrogated by a single amino acid substitution of the viral antigens. These findings may shed light on a novel strategy for designing vaccines for viral infections that are accompanied by increased kynurenine production.

Abstract 3-Hydroxyanthranillic acid (3HAA) is one of the key metabolites from the tryptophan (TRP) metabolism pathway and is associated with aging, age-associated diseases, and healthy lifespan extension. This study aims to detect 3HAA in the sweat of healthy older adults using simple, high-performance liquid chromatography (HPLC) method. Chromatographic separation using 20 mmol/L sodium acetate, 3 mmol/L zinc acetate, and 7% (v/v) acetonitrile as mobile phase is possible to simultaneous detect 3HAA, KYN, and TRP with UV and fluorescence detection, respectively, under 6 min. This method demonstrated excellent linearity with coefficient of determination (r2) greater than 0.998 for all analytes. The linear range were 0.05–6 µg/mL for TRP, 0.1–6 µg/mL for KYN and 0.2–6 µg/mL for 3HAA. Percentage recoveries from spiked in human sweat ranged from 90 ± 7–101 ± 3 for TRP, 86 ± 1–92 ± 3 for KYN, and 96 ± 1–103 ± 4 for 3HAA. The precision (%RSD) of repeatability and reproducibility is less than 3% and 6%, respectively. This method was used in a cross-sectional study with 81 participants aged 50–79 years, selected randomly from a local primary healthcare hospital’s sampling frame. A detectable amount of 3HAA was observed in all sweat samples, marking the first report of 3HAA presence in human sweat. Additionally, the results revealed that the 3HAA sweat levels increased with age analyzed in three different age groups ranging from 50–59, 60–69, and 70–79. These findings enhance our understanding of sweat profiles and their correlation with aging, potentially further improving early diagnosis, disease monitoring, and development of customized treatment programs for older adults.

Abstract Background This study aimed to identify the roles of L-tryptophan (Trp) and its rate-limiting enzymes on the receptivity of bovine endometrial epithelial cells. Real-time PCR was conducted to analyze the differential expression of genes between different groups of bovine endometrial epithelial cells. Western blot was performed to detect Cyclooxygenase-2 (COX2) expression after treatment with Trp or kynurenine (the main metabolites of Trp). The kynurenine assay was used to examine if Trp or prostaglandin E2 (PGE2) can increase the production of kynurenine in the bovine endometrial epithelial cells. Results Trp significantly stimulates insulin growth factor binding protein 1 (IGFBP1) expression, a common endometrial marker of conceptus elongation and uterus receptivity for ruminants. When bovine endometrial epithelial cells are treated with Trp, tryptophan hydroxylase-1 remains unchanged, but tryptophan 2,3-dioxygenase 2 (TDO2) is significantly increased, suggesting tryptophan is mainly metabolized through the kynurenine pathway. Kynurenine significantly stimulates IGFBP1 expression. Furthermore, Trp and kynurenine significantly increase the expression of aryl hydrocarbon receptor (AHR). CH223191, an AHR inhibitor, abrogates the induction of Trp and kynurenine on IGFBP1. PGE2 significantly induces the expression of TDO2, AHR, and IGFBP1. Conclusions The regulation between Trp / kynurenine and PGE2 may be crucial for the receptivity of the bovine uterus.

Indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 originated from gene duplication before vertebrate divergence. While IDO1 has a well-defined role in immune regulation, the biological role of IDO2 remains unclear. Discovered in 2007, IDO2 is located near the IDO1 gene. Because of their high sequence similarity, IDO2 was initially thought to be a tryptophan (Trp)-degrading enzyme like IDO1. Differently from what expected, IDO2 displays extremely low catalytic activity toward Trp. Nevertheless, many studies, often contradictory, have tried to demonstrate that IDO2 modulates immune responses by catabolizing Trp into kynurenine, an unconvincing hypothesis linked to an incomplete understanding of IDO2's activity. In this study, we review IDO2's functional role beyond Trp metabolism. IDO2's evolutionary persistence across species, despite being almost inactive as an enzyme, suggests it has some relevant biological importance. IDO2 expression in human normal cells is poor, but significant in various cancers, with two prevalent SNPs. Overall, the comparison of IDO2 to IDO1 as a Trp-degrading enzyme may have led to misunderstandings about IDO2's true physiological and pathological roles. New insights suggest that IDO2 might function more as a signaling molecule, particularly in cancer contexts, and further studies could reveal its potential as a target for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Tryptophan is an essential amino acid involved in critical cellular processes in vertebrates, serving as a precursor for serotonin and kynurenine, which are key neuromodulators to influence neural and immune functions. Systematic and quantitative measurement of tryptophan is vital to understanding these processes. Results: Here, we utilized a robust and highly responsive green ratiometric indicator for tryptophan (GRIT) to quantitatively measure tryptophan dynamics in bacteria, mitochondria of mammalian cell cultures, human serum, and intact zebrafish. At the cellular scale, these quantitative analyses uncovered differences in tryptophan dynamics across cell types and organelles. At the whole-organism scale, we revealed that inflammation-induced tryptophan concentration increases in zebrafish brain led to elevated serotonin and kynurenine levels, prolonged sleep duration, suggesting a novel metabolic connection between immune response and behavior. Moreover, GRIT's application in detecting reduced serum tryptophan levels in patients with inflammation symptoms suggests its potential as a high-throughput diagnostic tool. Conclusions: In summary, this study introduces GRIT as a powerful method for studying tryptophan metabolism and its broader physiological implications, paving the way for new insights into the metabolic regulation of health and disease across multiple biological scales. [ABSTRACT FROM AUTHOR]

Hyperplasia of mesenteric tissues in Crohn's disease, called creeping fat (CrF), is associated with surgical recurrence. Although microbiota translocation and colonization have been found in CrF, convincing mouse phenotypes and the underlying mechanisms of CrF formation remain unclear. Utilizing single-nucleus RNA (snRNA) sequencing of CrF and different mouse models, we demonstrate that the commensal Achromobacter pulmonis induces mesenteric adipogenesis through macrophage alteration. Targeted metabolome analysis reveals that L-kynurenine is the most enriched metabolite in CrF. Upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) enhances kynurenine metabolism and drives mesenteric adipogenesis. Leveraging single-cell RNA (scRNA) sequencing of mouse mesenteric tissues and macrophage-specific IDO1 knockout mice, we verify the role of macrophage-sourced L-kynurenine in mesenteric adipogenesis. Mechanistically, L-kynurenine-induced adipogenesis is mediated by the aryl hydrocarbon receptors in adipocytes. Administration of an IDO1 inhibitor or bacteria engineered to degrade L-kynurenine alleviates mesenteric adipogenesis in mice. Collectively, our study demonstrates that microbiota-induced modulation of macrophage metabolism potentiates CrF formation. [Display omitted] • The commensal Achromobacter pulmonis induces mesenteric adipogenesis • Macrophage-derived L-kynurenine via IDO1 is responsible for mesenteric adipogenesis • L-kynurenine-induced adipogenesis is mediated by AHR activation in adipocytes • Targeting kynurenine metabolism alleviates the formation of mesenteric adipogenesis Wu et al. reveal that the commensal Achromobacter pulmonis induces mesenteric adipogenesis through macrophages alteration. Mechanistically, macrophage-derived L-kynurenine via indoleamine 2,3-dioxygenase 1 (IDO1) promotes adipogenesis by aryl hydrocarbon receptor (AHR) activation in adipocytes. Targeting kynurenine metabolism with an IDO1 inhibitor or bacteria engineered to degrade L-kynurenine alleviates mesenteric adipogenesis. [ABSTRACT FROM AUTHOR]

Background: Shared biological factors may play a role in both the cognitive deficits and the increased prevalence of metabolic syndrome observed in individuals with Schizophrenia (SCZ). These factors could entail disturbances in tryptophan (Trp) to both melatonin (MLT) and kynurenine (Kyn) metabolic pathways, as well as inflammation and alterations in the gut microbiome composition. Methods: The present research project aims to investigate this hypothesis by recruiting 170 SCZ patients from two different recruitment sites, assessing their cognitive functions and screening for the presence of metabolic syndrome. Additionally, we plan to assess the impact of a 3-month cognitive remediation therapy on 30 of these patients. We will analyze clinical data alongside serum biomarkers and gene expression related to the Trp- to MLT and Kyn metabolic pathways, markers of inflammatory and composition of the gut microbiome. The association between Trp-MLT-Kyn levels, expression levels of selected genes, inflammatory markers and clinical phenotypes will be analyses in the context of general linear models. Discussion: This project has the potential to identify some typical SCZ symptomatic clusters that will be more stringently associated with variations in the Trp-MLT-Kyn/inflammatory system and with a better response to cognitive remediation therapy. Moreover, in a future perspective, it may highlight a group of patients who may benefit from a pharmacological treatment aiming at reinstating the physiological Trp to MLT and Kyn system. Therefore, it has the potential to move research toward a personalized approach for SCZ management. [ABSTRACT FROM AUTHOR]

In the first days of life, the newborns' intestinal microbiota develops simultaneously with the intestinal gut barrier and follows intestinal immunity. The mode of delivery shows significant impact on microbial development and, thus, the initiation of the tryptophan catabolism pathway. Further antibiotics (ATB) treatment of mothers before or during delivery affects the microbial and tryptophan metabolite composition of stool of the caesarean- and vaginal-delivered newborns. The determination of microbiome and levels of tryptophan microbial metabolites in meconium and stool can characterize intestinal colonization of a newborn. From 134 samples from the Central European Longitudinal Studies of Parents and Children: The Next Generation (CELSPAC: TNG) cohort study, 16S rRNA gene sequencing was performed, and microbial tryptophan metabolites were quantified using ultra-high-performance liquid chromatography with triple-quadrupole mass spectrometry. Microbial diversity and concentrations of tryptophan metabolites were significantly higher in stool compared to meconium. Treatment of mothers with ATB before or during delivery affects metabolite composition and microbial diversity in stool of vaginal- and caesarean-delivered newborns. Correlation of microbial and metabolite composition shows significant positive correlations of indol-3-lactic acid, N-acetyl-tryptophan and indol-3-acetic acid with Bifidobacterium, Bacteroides and Peptoclostridium. The positive effect of vaginal delivery on newborns' microbiome development is degraded when mother is treated with ATB before or during delivery. Key points: • Antibiotic treatment diminishes the positive effects of vaginal delivery. • Antibiotic treatment affects metabolite and microbial composition in newborns. • Bifidobacterium and Peptoclostridium could be the producer of indole-lactic acid. [ABSTRACT FROM AUTHOR]

Altered immune system activity is one of the common pathomechanisms of depressive disorders and cancer. The aim of this study is to evaluate level of selected elements of the kynurenine pathway in groups of depressed and oncological patients. The study included 156 individuals, aged 19–65 years (M = 43.46, SD = 13.99), divided into three groups, namely depressive disorders (DD), oncology patients (OG), and a comparison group of healthy subjects (CG). A sociodemographic questionnaire and the Hamilton Depression Rating Scale (HDRS) were used in the study to assess the intensity of depressive symptoms. Level of TDO2, L-KYN, HK, AA and QA was significantly higher in patients from OG and DD groups than in the comparison group. TDO2 level in the OG group was positively correlated with the severity of depressive symptoms. When the OG and DD groups were analyzed together, level of TDO2, 3-HKYN, AA, QA correlated positively with the severity of depressive symptoms. Thus, kynurenine pathway might play an integral role in the pathogenesis of depression. [ABSTRACT FROM AUTHOR]

Background and Aims: The rise in obesity highlights the need for improved therapeutic strategies, particularly in addressing metabolic dysfunction‐associated steatotic liver disease (MASLD). We aim to assess the role of tryptophan metabolic pathways in the pathogenesis of obesity and in the different histological stages of MASLD. Materials and Methods: We used ultra‐high performance liquid chromatography to quantify circulating levels of 15 tryptophan‐related metabolites from the kynurenine, indole and serotonin pathways. A cohort of 76 subjects was analysed, comprising 18 subjects with normal weight and 58 with morbid obesity, these last being subclassified into normal liver (NL), simple steatosis (SS) and metabolic dysfunction‐associated steatohepatitis (MASH). Then, we conducted gene expression analysis of hepatic IDO‐1 and kynyrenine‐3‐monooxygenase (KMO). Results: Key findings in obesity revealed a distinct metabolic signature characterized by a higher concentration of different kynurenine‐related metabolites, a decrease in indole‐3‐acetic acid and indole‐3‐propionic acid, and an alteration in the serotonin pathway. Elevated tryptophan levels were associated with MASLD presence (37.659 (32.577–39.823) μM of tryptophan in NL subjects; 41.522 (38.803–45.276) μM in patients with MASLD). Overall, pathway fluxes demonstrated an induction of tryptophan catabolism via the serotonin pathway in SS subjects and into the kynurenine pathway in MASH. We found decreased IDO‐1 and KMO hepatic expression in NL compared to SS. Conclusions: We identified a distinctive metabolic signature in obesity marked by changes in tryptophan catabolic pathways, discernible through altered metabolite profiles. We observed stage‐specific alterations in tryptophan catabolism fluxes in MASLD, highlighting the potential utility of targeting these pathways in therapeutic interventions. [ABSTRACT FROM AUTHOR]

The model organism Caenorhabditis elegans and its relationship with the gut microbiome are gaining traction, especially for the study of neurodegenerative diseases such as Parkinson's Disease (PD). Gut microbes are known to be able to alter kynurenine metabolites in the host, directly influencing innate immunity in C. elegans. While the mitochondrial unfolded protein response (UPRmt) was first characterized in C. elegans in 2007, its relevance in host–microbiome interactions has only become apparent in recent years. In this review, we provide novel insights into the current understanding of the microbiome–gut–brain axis with a focus on tripartite interactions between the UPRmt, kynurenine pathway, and microbiome in C. elegans, and explore their relationships for PD remediations. [ABSTRACT FROM AUTHOR]

Background: Substance use disorder in the United States represents a complex and growing public health crisis, marked by increasing rates of overdose deaths and the misuse of prescription medications. There is a critical need for furthering the understanding of the molecular and genetic mechanisms that can lead to substance use disorder. Identifying significant variants in the kynurenine pathway could help identify therapeutic targets for intervention. Methods: The All of Us cohort builder evaluated the frequency of variants of four genes, TDO2, IDO1, IDO2, and KMO, encoding enzymes in the kynurenine pathway. The samples were broken into six cohorts: alcohol, cannabis, cocaine, opioid, other use disorder, and control. Using Chi-square analysis, the frequency of at least one copy of a variant allele was calculated. Results: Chi-square analysis showed a significant variation in genetic frequency (p-value < 0.005) in 14 of 18 polymorphisms analyzed. The cocaine cohort had the most significant variants (13), cannabis had 11, opioids had 3, other use disorders had 2, and alcohol had 1 significant variant. Conclusions: This study found associations of polymorphisms in the TDO2, IDO1, IDO2, and KMO genes of individuals with a substance use disorder. These results provide evidence of potential predictors of increased susceptibility to substance use disorder. [ABSTRACT FROM AUTHOR]

Background/Objectives: Substance use disorder is a crisis impacting many people in the United States. This review aimed to identify the effect addictive substances have on the kynurenine pathway. Tryptophan is an essential amino acid metabolized by the serotonin and kynurenine pathways. The metabolites of these pathways play a role in the biological reward system. Addictive substances have been shown to cause imbalances in the ratios of these metabolites. With current treatment and therapeutic options being suboptimal, identifying biochemical mechanisms that are impacted during the use of addictive substances can provide alternative options for treatment or drug discovery. Methods: A systematic literature search was conducted to identify studies evaluating the relationship between substance use disorder and tryptophan metabolism through the kynurenine pathway. A total of 32 articles meeting eligibility criteria were used to review the relationship between the kynurenine pathway, tryptophan breakdown, and addictive substances. Results: The use of addictive substances dysregulates tryptophan metabolism and kynurenine metabolite concentrations. This imbalance directly affects the dopamine reward system and is thought to promote continued substance use. Conclusions: Further studies are needed to fully evaluate the metabolites of the kynurenine pathway, along with other options for treatment to repair the metabolite imbalance. Several possible therapeutics have been identified; drugs that restore homeostasis, such as Ro 61-8048 and natural products like Tinospora cordifolia or Decaisnea insignis, are promising options for the treatment of substance use disorder. [ABSTRACT FROM AUTHOR]

3-Hydroxyanthranillic acid (3HAA) is one of the key metabolites from the tryptophan (TRP) metabolism pathway and is associated with aging, age-associated diseases, and healthy lifespan extension. This study aims to detect 3HAA in the sweat of healthy older adults using simple, high-performance liquid chromatography (HPLC) method. Chromatographic separation using 20 mmol/L sodium acetate, 3 mmol/L zinc acetate, and 7% (v/v) acetonitrile as mobile phase is possible to simultaneous detect 3HAA, KYN, and TRP with UV and fluorescence detection, respectively, under 6 min. This method demonstrated excellent linearity with coefficient of determination (r2) greater than 0.998 for all analytes. The linear range were 0.05–6 µg/mL for TRP, 0.1–6 µg/mL for KYN and 0.2–6 µg/mL for 3HAA. Percentage recoveries from spiked in human sweat ranged from 90 ± 7–101 ± 3 for TRP, 86 ± 1–92 ± 3 for KYN, and 96 ± 1–103 ± 4 for 3HAA. The precision (%RSD) of repeatability and reproducibility is less than 3% and 6%, respectively. This method was used in a cross-sectional study with 81 participants aged 50–79 years, selected randomly from a local primary healthcare hospital's sampling frame. A detectable amount of 3HAA was observed in all sweat samples, marking the first report of 3HAA presence in human sweat. Additionally, the results revealed that the 3HAA sweat levels increased with age analyzed in three different age groups ranging from 50–59, 60–69, and 70–79. These findings enhance our understanding of sweat profiles and their correlation with aging, potentially further improving early diagnosis, disease monitoring, and development of customized treatment programs for older adults. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Peptide p176-190, derived from the SARS-CoV-2 spike protein, is one of the major T cell epitopes that elicits the HLA-DR-restricted IL-8 response of human CD4+ T cells. Using PBMCs from a healthy individual primed with an S-protein-based SARS-CoV-2 vaccine, we established a CD4+ T cell line (TM45) and cloned T cells (TM45.2) specific for the peptide. We showed that (i) co-incubation with kynurenine leads to increased IL-8; (ii) T cells incubated in the absence of kynurenine recovered the original levels of cytokine production; and (iii) peptide p176-190 substituted at 176 Leucine for neutral hydrophilic serine completely abolished the cytokine responses of TM45.2 cells, thereby suggesting that 176 L is the first anchor residue for binding to HLA-DR. These observations collectively indicate that (i) enhanced IL-8 responses can be induced by kynurenine, which is produced under infectious conditions in COVID-19; (ii) the response is not a permanent change in the T cell phenotype; and (iii) IL-8 responses associated with harmful neutrophil extracellular traps can be abrogated by a single amino acid substitution of the viral antigens. These findings may shed light on a novel strategy for designing vaccines for viral infections that are accompanied by increased kynurenine production. [ABSTRACT FROM AUTHOR]

Background Understanding the precise mechanisms of ketamine is crucial for replicating its rapid antidepressant effects without inducing psychomimetic changes. Here, we explore whether the antidepressant-like effects of ketamine enantiomers are underscored by protection against cytokine-induced reductions in hippocampal neurogenesis and activation of the neurotoxic kynurenine pathway in our well-established in vitro model of depression in a dish. Methods We used the fetal hippocampal progenitor cell line (HPC0A07/03C) to investigate ketamine's impact on cytokine-induced reductions in neurogenesis in vitro. Cells were treated with interleukin- 1beta (IL-1b) (10 ng/mL) or IL-6 (50 pg/mL), alone or in combination with ketamine enantiomers arketamine (R-ketamine, 400 nM) or esketamine (S-ketamine, 400 nM) or antidepressants sertraline (1 mM) or venlafaxine (1 mM). Results Resembling the effect of antidepressants, both ketamine enantiomers prevented IL-1b– and IL-6–induced reduction in neurogenesis and increase in apoptosis. This was mediated by inhibition of IL-1b–induced production of IL-2 and IL-13 by R-ketamine and of IL-1b–induced tumor necrosis factor-alpha by S-ketamine. Likewise, R-ketamine inhibited IL-6–induced production of IL-13, whereas S-ketamine inhibited IL-6–induced IL-1b and IL-8. Moreover, both R- and S-ketamine prevented IL-1b–induced increases in indoleamine 2,3-dioxygenase expression as well as kynurenine production, which in turn was shown to mediate the detrimental effects of IL-1b on neurogenesis and apoptosis. In contrast, neither R- nor S-ketamine prevented IL-6–induced kynurenine pathway activation. Conclusions Results suggest that R- and S-ketamine have pro-neurogenic and anti-inflammatory properties; however, this is mediated by inhibition of the kynurenine pathway only in the context of IL-1b. Overall, this study enhances our understanding of the mechanisms underlying ketamine's antidepressant effects in the context of different inflammatory phenotypes, ultimately leading to the development of more effective, personalized therapeutic approaches for patients suffering from depression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]