Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity.

Sirtuin 1 (SIRT1) is a class III histone deacetylase (HDAC3) that plays a crucial role in regulating the activation and differentiation of dendritic cells (DCs) as well as controlling the polarization and activation of T cells. Obesity, a chronic inflammatory condition, is characterized by the activation of immune cells in various tissues. We hypothesized that SIRT1 might influence the phenotype and functions of DCs through the Ido1 pathway, ultimately leading to the polarization towards pro-inflammatory T cells in obesity. In our study, we observed that SIRT1 activity was reduced in bone marrow-derived DCs (BMDCs) from obese animals. These BMDCs exhibited elevated oxidative phosphorylation (OXPHOS) and increased extracellular acidification rates (ECAR), along with enhanced expression of class II MHC, CD86, and CD40, and elevated secretion of IL-12p40, while the production of TGF-ß was reduced. The kynurenine pathway activity was decreased in BMDCs from obese animals, particularly under SIRT1 inhibition. SIRT1 positively regulated the expression of Ido1 in DCs in a PPARγ-dependent manner. To support these findings, ATAC-seq analysis revealed that BMDCs from obese mice had differentially regulated open chromatin regions compared to those from lean mice, with reduced chromatin accessibility at the Sirt1 genomic locus in BMDCs from obese WT mice. Gene Ontology (GO) enrichment analysis indicated that BMDCs from obese animals had disrupted metabolic pathways, including those related to GTPase activity and insulin response. Differential expression analysis showed reduced levels of Pparg and Sirt1 in BMDCs from obese mice, which was challenged and confirmed using BMDCs from mice with conditional knockout of Sirt1 in dendritic cells (SIRT1∆). This study highlights that SIRT1 controls the metabolism and functions of DCs through modulation of the kynurenine pathway, with significant implications for obesity-related inflammation.

The effect of prebiotic supplementation on serum levels of tryptophan and kynurenine in obese women with major depressive disorder: a double-blinded placebo-controlled randomized clinical trial.

OBJECTIVE: The objective of the present study was to examine the effect of calorie restricted diet (CRD) plus inulin supplementation on serum levels of tryptophan (Trp), kynurenine (Kyn) and Trp/Kyn ratio in obese women with major depressive disorder (MDD). RESULTS: In this double-blind placebo-controlled randomized clinical trial, 51 obese women (BMI = 30-40 kg/m2) with mild MDD were assessed for depression level using Hamilton depression rating scale (HDRS). The patients were randomly allocated into either "Prebiotic group" (received 10 g/day inulin) or "Placebo group" (received 10 g/day maltodextrin). All participants also received individualized CRD. Fasting serum levels of Trp, Kyn, and Trp/Kyn ratio were assessed at baseline and after 8 weeks. Results showed slightly greater increases in serum levels of Trp and Trp/Kyn ratio as well as reductions in serum level of Kyn and HDRS score in prebiotic group than placebo group. However, between group differences in these parameters as well as HDRS score were not statistically significant after adjusting for baseline variables at the end of the trial. Results indicates that CRD accompanied by inulin supplementation (10 g/day) did not influence serum levels of Trp, Kyn and Trp/Kyn ratio as well as HDRS score after 8 weeks. TRIAL REGISTRATION: The trial was registered in the Iranian registry of clinical trials at 2018-08-02 ( https://www.irct.ir/ ; registration number: IRCT20100209003320N15).

Tryptophan Metabolism Disorder-Triggered Diseases, Mechanisms, and Therapeutic Strategies: A Scientometric Review.

BACKGROUND: Tryptophan is widely present in foods such as peanuts, milk, and bananas, playing a crucial role in maintaining metabolic homeostasis in health and disease. Tryptophan metabolism is involved in the development and progression of immune, nervous, and digestive system diseases. Although some excellent reviews on tryptophan metabolism exist, there has been no systematic scientometric study as of yet. METHODS: This review provides and summarizes research hotspots and potential future directions by analyzing annual publications, topics, keywords, and highly cited papers sourced from Web of Science spanning 1964 to 2022. RESULTS: This review provides a scientometric overview of tryptophan metabolism disorder-triggered diseases, mechanisms, and therapeutic strategies. CONCLUSIONS: The gut microbiota regulates gut permeability, inflammation, and host immunity by directly converting tryptophan to indole and its derivatives. Gut microbial metabolites regulate tryptophan metabolism by activating specific receptors or enzymes. Additionally, the kynurenine (KYN) pathway, activated by indoleamine-2, 3-dioxygenase (IDO) and tryptophan 2, 3-dioxygenase, affects the migration and invasion of glioma cells and the development of COVID-19 and depression. The research and development of IDO inhibitors help to improve the effectiveness of immunotherapy. Tryptophan metabolites as potential markers are used for disease therapy, guiding clinical decision-making. Tryptophan metabolites serve as targets to provide a new promising strategy for neuroprotective/neurotoxic imbalance affecting brain structure and function. In summary, this review provides valuable guidance for the basic research and clinical application of tryptophan metabolism.

Causal effects of plasma metabolites on autoimmune hepatitis (AIH): a bidirectional two-sample mendelian randomization study.

Autoimmune hepatitis(AIH) is a chronic progressive inflammatory liver disease induced by loss of immune tolerance. The role of circulating metabolites in disease pathogenesis is unclear. This study aimed to investigate potential causal links between plasma metabolites and AIH risk by employing a two-sample Mendelian randomization approach. A comprehensive bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide significant variant-metabolite and variant-AIH associations in European ancestry individuals. Various methods assessed causal relationships among 1400 metabolites and AIH, incorporating sensitivity analyses to evaluate pleiotropy and heterogeneity. Fifty-eight metabolites displayed possible associations, including increased AIH risk with genetically predicted higher kynurenine (p = 2.79 × 10- 5, OR: 1.64, 95% CI 1.30-2.07) and a protective effect for the dopamine sulfate ratio (p = 1.06 × 10- 5,OR: 0.62, 95% CI 0.49-0.79). Reciprocal analysis revealed a causal effect of AIH on kynurenine( p = 2.79 × 10- 5, OR: 1.64, 95% CI 1.30-2.07), but not on the dopamine sulfate ratio(p = 0.691, OR: 1.05, 95% CI 0.67-1.64). Our genetics-based approach provides evidence supporting a causal role for specific metabolite levels in AIH risk. The results deliver evidence supporting a causal effect of a specific metabolite ratio(dopamine 4-sulfate/dopamine 3-O-sulfate) on AIH risk. Experimental validation and mechanistic examinations are warranted to confirm findings.

Gut-Brain Axis and Neuroinflammation: The Role of Gut Permeability and the Kynurenine Pathway in Neurological Disorders.

The increasing prevalence of neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis presents a significant global health challenge. Despite extensive research, the precise mechanisms underlying these conditions remain elusive, with current treatments primarily addressing symptoms rather than root causes. Emerging evidence suggests that gut permeability and the kynurenine pathway are involved in the pathogenesis of these neurological conditions, offering promising targets for novel therapeutic and preventive strategies. Gut permeability refers to the intestinal lining's ability to selectively allow essential nutrients into the bloodstream while blocking harmful substances. Various factors, including poor diet, stress, infections, and genetic predispositions, can compromise gut integrity, leading to increased permeability. This condition facilitates the translocation of toxins and bacteria into systemic circulation, triggering widespread inflammation that impacts neurological health via the gut-brain axis. The gut-brain axis (GBA) is a complex communication network between the gut and the central nervous system. Dysbiosis, an imbalance in the gut microbiota, can increase gut permeability and systemic inflammation, exacerbating neuroinflammation-a key factor in neurological disorders. The kynurenine pathway, the primary route for tryptophan metabolism, is significantly implicated in this process. Dysregulation of the kynurenine pathway in the context of inflammation leads to the production of neurotoxic metabolites, such as quinolinic acid, which contribute to neuronal damage and the progression of neurological disorders. This narrative review highlights the potential and progress in understanding these mechanisms. Interventions targeting the kynurenine pathway and maintaining a balanced gut microbiota through diet, probiotics, and lifestyle modifications show promise in reducing neuroinflammation and supporting brain health. In addition, pharmacological approaches aimed at modulating the kynurenine pathway directly, such as inhibitors of indoleamine 2,3-dioxygenase, offer potential avenues for new treatments. Understanding and targeting these interconnected pathways are crucial for developing effective strategies to prevent and manage neurological disorders.

Fructose-1,6-bisphosphate reverses hypotensive effect caused by L-kynurenine in Wistar male rats.

Hypotension is one of the main characteristics of the systemic inflammation, basically caused by endothelial dysfunction. Studies have shown that the amino acid L-kynurenine (KYN) causes vasodilation in mammals, leading to hypotensive shock. In hypotensive shock, when activated by the KYN, the voltage-gated potassium channel encoded by the family KCNQ (Kv7) gene can cause vasodilation. Fructose-1,6-bisphosphate (FBP) it is being considered in studies an anti-inflammatory, antioxidant, immunomodulator, and a modulator of some ion channels (Ca2+, Na+, and K+). We analyzed the effects of KYN and FBP on mean blood pressure (MBP), systolic and diastolic (DBP) blood pressure, and heart rate variability (HRV) in Wistar rats. Results demonstrated that the administration of KYN significant decreased MBP, DBP, and increased HRV. Importantly, the FBP treatment reversed the KYN effects on MBP, DBP, and HRV. Molecular Docking Simulations suggested that KYN and FBP present a very close estimated free energy of binding and the same position into structure of KCNQ4. Our results did demonstrate that FBP blunted the decrease in BP, provoked by KYN. Results raise new hypotheses for future and studies in the treatment of hypotension resulting from inflammation.

The Intersection between Tryptophan-Kynurenine Pathway Metabolites and Immune Inflammation, Hormones, and Gut Microbiota in Perinatal Depression.

Perinatal depression is a prevalent mental disorder among pregnant women, characterized by sleep disturbances, appetite changes, negative emotions, cognitive impairment, and suicidal or homicidal tendencies. These symptoms severely compromise personal well-being, disrupt family life, and burden society. Early detection and intervention are thus crucial. The tryptophan-kynurenine (TRP-KYN) pathway is central to the inflammatory hypothesis of depression and has gained significant attention in perinatal depression research. This pathway encompasses numerous metabolic enzymes and neuroactive metabolites that interact with other physiological systems, influencing neurotransmitter synthesis and neuronal development. Through these interactions, the TRP-KYN pathway exerts psychotropic effects. This article reviews the key metabolites and enzymes of the TRP-KYN pathway and examines its intersection with immune inflammation, hormones, and gut microbiota.

Effects of Tryptophan and Physical Exercise on the Modulation of Mechanical Hypersensitivity in a Fibromyalgia-like Model in Female Rats.

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.

Defining the molecular response to ischemia-reperfusion injury and remote ischemic preconditioning in human kidney transplantation.

BACKGROUND: Ischemia-reperfusion injury (IRI) inevitably occurs during kidney transplantation and extended ischemia is associated with delayed graft function and poor outcomes. Remote ischemic preconditioning (RIPC) is a simple, noninvasive procedure aimed at reducing IRI and improving graft function. Experimental studies have implicated the kynurenine pathway as a protective mechanism behind RIPC. METHODS: First, paired biopsies from 11 living kidney donors were analyzed to characterize the acute transcriptomic response to IRI. Second, 16 living kidney donors were subjected to either RIPC (n = 9) or no pretreatment (n = 7) to evaluate the impact of RIPC on the transcriptomic response to IRI. Finally, the effect of RIPC on plasma metabolites was analyzed in 49 healthy subjects. RESULTS: There was a robust immediate response to IRI in the renal transcriptomes of living-donor kidney transplantation, including activation of the mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) pathways. Preconditioning with RIPC did not significantly alter the transcriptomic response to IRI or the concentration of plasma metabolites. CONCLUSIONS: The present data validate living-donor kidney transplantation as a suitable model for mechanistic studies of IRI in human kidneys. The failure of RIPC to alter transcriptomic responses or metabolites in the kynurenine pathway raises the question of the robustness of the standard procedure used to induce RIPC, and might explain the mixed results in clinical trials evaluating RIPC as a method to attenuate IRI.

Effects of E2 on the IDO1-mediated metabolic KYN pathway in OVX female mice.

The aim of this study was to investigate the role of 17ß-estradiol (E2)-mediated oestrogen receptor (ER) in modulating the depressive-like behaviours of ovariectomy (OVX) mice and the associated mechanisms. E2 was administrated in OVX mice. The behaviour and physiological changes of OVX mice including immobility time in tail suspension test (TST) and forced swimming test (FST), levels of serum E2, inflammatory mediators, oxidative stress factors, indoleamine2,3-dioxygenase 1 (IDO1) and the neurotransmitters mediated by IDO1 activation were then recorded. Cell injury models established by lipopolysaccharide (LPS) or H2O2 stimulation in HT22 and BV2 cells were employed to further explore the mechanisms of E2's function. E2 treatment improved OVX-induced increase of immobility time in FST and TST. Meanwhile, E2 ameliorated the changes of inflammatory factors (NF-κB, TNF-α and IL-6), IDO1, IDO1-mediated TRP/KYN pathway and oxidative stress factors (iNOS, MDA, GSH and SOD) in the hippocampus of OVX mice. Interestingly, ERß inhibitor abolished E2's inhibitory effects on the inflammation and IDO1-mediated TRP/KYN pathway; ERß inhibitor also abolished E2's anti-oxidative stress effect. In cell experiments, ERß small interfering RNA (siRNA) pretreatment reversed E2's anti-inflammatory effect on LPS-treated HT22 and BV2 cells and E2's inhibitory effect on IDO1 expression in LPS-treated BV2 cells. ERß siRNA pretreatment also reversed E2's anti-oxidation effect on H2O2-treated HT22 cells. E2 exert the antidepressant function in OVX mice via ERß-modulated suppression of NF-κB-mediated inflammatory pathway, oxidative stress factors and IDO1-mediated TRP/KYN pathway in the hippocampus.

Molecular mechanisms and therapeutic significance of Tryptophan Metabolism and signaling in cancer.

Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes.

Tryptophan Metabolism in Obesity: The Indoleamine 2,3-Dioxygenase-1 Activity and Therapeutic Options.

Obesity activates both innate and adaptive immune responses in adipose tissue. Adipose tissue macrophages are functional antigen-presenting cells that promote the proliferation of interferon-gamma (IFN-γ)-producing cluster of differentiation (CD)4+ T cells in adipose tissue of obese subjects. The increased formation of neopterin and degradation of tryptophan may result in decreased T-cell responsiveness and lead to immunodeficiency. The activity of inducible indoleamine 2,3-dioxygenase-1 (IDO1) plays a major role in pro-inflammatory, IFN-γ-dominated settings. The expression of several kynurenine pathway enzyme genes is significantly increased in obesity. IDO1 in obesity shifts tryptophan metabolism from serotonin and melatonin synthesis to the formation of kynurenines and increases the ratio of kynurenine to tryptophan as well as with neopterin production. Reduction in serotonin (5-hydroxytryptamine; 5-HT) production provokes satiety dysregulation that leads to increased caloric uptake and obesity. According to the monoamine-deficiency hypothesis, a deficiency of cerebral serotonin is involved in neuropsychiatric symptomatology of depression, mania, and psychosis. Indeed, bipolar disorder (BD) and related cognitive deficits are accompanied by a higher prevalence of overweight and obesity. Furthermore, the accumulation of amyloid-ß in Alzheimer's disease brains has several toxic effects as well as IDO induction. Hence, abdominal obesity is associated with vascular endothelial dysfunction. kynurenines and their ratios are prognostic parameters in coronary artery disease. Increased kynurenine/tryptophan ratio correlates with increased intima-media thickness and represents advanced atherosclerosis. However, after bariatric surgery, weight reduction does not lead to the normalization of IDO1 activity and atherosclerosis. IDO1 is involved in the mechanisms of immune tolerance and in the concept of tumor immuno-editing process in cancer development. Serum IDO1 activity is still used as a parameter in cancer development and growth. IDO-producing tumors show a high total IDO immunostaining score, and thus, using IDO inhibitors, such as Epacadostat, Navoximod, and L isomer of 1-methyl-tryptophan, seems an important modality for cancer treatment. There is an inverse correlation between serum folate concentration and body mass index, thus folate deficiency leads to hyperhomocysteinemia-induced oxidative stress. Immune checkpoint blockade targeting cytotoxic T-lymphocyte-associated protein-4 synergizes with imatinib, which is an inhibitor of mitochondrial folate-mediated one-carbon (1C) metabolism. Antitumor effects of imatinib are enhanced by increasing T-cell effector function in the presence of IDO inhibition. Combining IDO targeting with chemotherapy, radiotherapy and/or immunotherapy, may be an effective tool against a wide range of malignancies. However, there are some controversial results regarding the efficacy of IDO1 inhibitors in cancer treatment.

Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities.

Both preclinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurologic and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies. SIGNIFICANCE STATEMENT: Studies have implicated the kynurenine pathway of tryptophan in the pathophysiology of neurologic and psychiatric diseases. Key enzymes of the kynurenine pathway regulate brain metabolism in both health and disease, making them promising targets for treating these disorders. Therefore, understanding the distribution, cellular expression, and regulation of these enzymes and metabolites in the brain is critical for developing effective therapeutic strategies. This review endeavors to describe these processes in detail.

Ketamine Prevents Inflammation-Induced Reduction of Human Hippocampal Neurogenesis via Inhibiting the Production of Neurotoxic Metabolites of the Kynurenine Pathway.

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.

Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex illness characterized by severe and often disabling physical and mental fatigue. So far, scientists have not been able to fully pinpoint the biological cause of the illness and yet it affects millions of people worldwide. To gain a better understanding of ME/CFS, we compared the metabolic networks in the plasma of 38 ME/CFS patients to those of 24 healthy control participants. This involved an untargeted metabolomics approach in addition to the measurement of targeted substances including tryptophan and its metabolites, as well as tyrosine, phenylalanine, B vitamins, and hypoxanthine using liquid chromatography coupled to mass spectrometry. We observed significant alterations in several metabolic pathways, including the vitamin B3, arginine-proline, and aspartate-asparagine pathways, in the untargeted analysis. The targeted analysis revealed changes in the levels of 3-hydroxyanthranilic acid, 3-hydroxykynurenine, hypoxanthine, and phenylalanine in ME/CFS patients compared to the control group. These findings suggest potential alterations in immune system response and oxidative stress in ME/CFS patients.

Tryptophan regulates the expression of IGFBP1 in bovine endometrial epithelial cells in vitro via the TDO2-AHR pathway.

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.

Kynurenines are altered in the brain in depression, in a subgroup dependent manner: Implications for targeted treatment approaches.

Major depressive disorder (MDD) is a complex and multi-faceted disorder with a high level of heterogeneity at both the clinical and molecular level. Emerging evidence suggests a significant role of the kynurenine pathway in MDD neurobiology that may be associated with specific subgroups. In a recent study, we examined the kynurenine pathway in postmortem anterior cingulate cortex tissue obtained from subjects with and without MDD. We identified significant changes in MDD that were associated with sex and suicide but found minimal changes in the kynurenine pathway when grouping our cohort as a general classification of MDD. Furthermore, we identified significant correlations between age and quinolinic acid that were specific to MDD. In this commentary, we discuss the importance of considering a range of subgroups in the design and analysis of molecular studies in psychiatric disorders. Future studies should examine the extent of subgroup-specific changes to advance our understanding of MDD and explore targeted therapeutic approaches designed to address the specific changes in these subgroups.

Heme-based dioxygenases: Structure, function and dynamics.

Tryptophan dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO) belong to a unique class of heme-based enzymes that insert dioxygen into the essential amino acid, L-tryptophan (Trp), to generate N-formylkynurenine (NFK), a critical metabolite in the kynurenine pathway. Recently, the two dioxygenases were recognized as pivotal cancer immunotherapeutic drug targets, which triggered a great deal of drug discovery targeting them. The advancement of the field is however hampered by the poor understanding of the structural properties of the two enzymes and the mechanisms by which the structures dictate their functions. In this review, we summarize recent findings centered on the structure, function, and dynamics of the human isoforms of the two enzymes.

Mesenchymal stem cells in tumor microenvironment: drivers of bladder cancer progression through mitochondrial dynamics and energy production.

Mesenchymal stem cells (MSCs) in tumor microenvironment (TME) are crucial for the initiation, development, and metastasis of cancer. The impact and mechanism of MSCs on bladder cancer are uncertain. Here we analyzed 205 patient samples to explore the relationships between tumor-stroma ratio and clinicopathological features. A co-culture model and nude mouse transplantation were used to explore the biological roles and molecular mechanisms of MSCs on bladder cancer cells. We found that a high tumor-stroma ratio was significantly associated with a larger tumor size and higher T stage, pathological grade, number of vascular invasions, and poor overall survival. MSCs in TME promoted the ability of bladder cancer cells to proliferate, migrate, and invade in vitro and in vivo. Next, we demonstrated that MSCs enhance mitochondrial autophagy and mitochondrial biogenesis of bladder cancer cells, and increase energy production, thereby promoting bladder cancer cell progression. Kynurenine (Kyn) produced by MSCs could enhance mitochondrial function by activating the AMPK pathway. IDO1 inhibitor could reverse the tumor­promoting effects of MSCs in vitro and in vivo. Our results demonstrated that tryptophan metabolites Kyn of MSCs in TME could enhance mitochondrial function by activating the AMPK pathway, thereby promoting bladder cancer cell progression.

Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.

Macrophage efferocytosis prevents apoptotic cell (AC) accumulation and triggers inflammation-resolution pathways. The mechanisms linking efferocytosis to resolution often involve changes in macrophage metabolism, but many gaps remain in our understanding of these processes. We now report that efferocytosis triggers an indoleamine 2,3-dioxygenase-1 (IDO1)-dependent tryptophan (Trp) metabolism pathway that promotes several key resolution processes, including the induction of pro-resolving proteins, such interleukin-10, and further enhancement of efferocytosis. The process begins with upregulation of Trp transport and metabolism, and it involves subsequent activation of the aryl hydrocarbon receptor (AhR) by the Trp metabolite kynurenine (Kyn). Through these mechanisms, macrophage IDO1 and AhR contribute to a proper resolution response in several different mouse models of efferocytosis-dependent tissue repair, notably during atherosclerosis regression induced by plasma low-density lipoprotein (LDL) lowering. These findings reveal an integrated metabolism programme in macrophages that links efferocytosis to resolution, with possible therapeutic implications for non-resolving chronic inflammatory diseases, notably atherosclerosis.