Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis.

OBJECTIVES: Alterations in tryptophan (Trp) metabolism have been reported in inflammatory diseases, including rheumatoid arthritis (RA). However, understanding whether these alterations participate in RA development and can be considered putative therapeutic targets remains undetermined.In this study, we combined quantitative Trp metabolomics in the serum from patients with RA and corrective administration of a recombinant enzyme in experimental arthritis to address this question. METHODS: Targeted quantitative Trp metabolomics was performed on the serum from 574 previously untreated patients with RA from the ESPOIR (Etude et Suivi des POlyarthrites Indifférenciées Récentes) cohort and 98 healthy subjects. A validation cohort involved 69 established patients with RA. Dosages were also done on the serum of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) mice and controls. A proof-of-concept study evaluating the therapeutic potency of targeting the kynurenine pathway was performed in the CAIA model. RESULTS: Differential analysis revealed dramatic changes in Trp metabolite levels in patients with RA compared with healthy controls. Decreased levels of kynurenic (KYNA) and xanthurenic (XANA) acids and indole derivatives, as well as an increased level of quinolinic acid (QUIN), were found in the serum of patients with RA. They correlated positively with disease severity (assessed by both circulating biomarkers and disease activity scores) and negatively with quality-of-life scores. Similar profiles of kynurenine pathway metabolites were observed in the CAIA and CIA models. From a mechanistic perspective, we demonstrated that QUIN favours human fibroblast-like synoviocyte proliferation and affected their cellular metabolism, through inducing both mitochondrial respiration and glycolysis. Finally, systemic administration of the recombinant enzyme aminoadipate aminotransferase, responsible for the generation of XANA and KYNA, was protective in the CAIA model. CONCLUSIONS: Altogether, our preclinical and clinical data indicate that alterations in the Trp metabolism play an active role in the pathogenesis of RA and could be considered as a new therapeutic avenue.

Protocatechuic acid prevents isoproterenol-induced heart failure in mice by downregulating kynurenine-3-monooxygenase.

Protocatechuic acid (3,4-dihydroxybenzoic acid) prevents oxidative stress, inflammation and cardiac hypertrophy. This study aimed to investigate the therapeutic effects of protocatechuic acid in an isoproterenol-induced heart failure mouse model and to identify the underlying mechanisms. To establish the heart failure model, C57BL/6NTac mice were given high-dose isoproterenol (80 mg/kg body weight) for 14 days. Echocardiography revealed that protocatechuic acid reversed the isoproterenol-induced downregulation of fractional shortening and ejection fraction. Protocatechuic acid attenuated cardiac hypertrophy as evidenced by the decreased heart-weight-to-body-weight ratio and the expression of Nppb. RNA sequencing analysis identified kynurenine-3-monooxygenase (Kmo) as a potential target of protocatechuic acid. Protocatechuic acid treatment or transfection with short-interfering RNA against Kmo ameliorated transforming growth factor ß1-induced upregulation of Kmo, Col1a1, Col1a2 and Fn1 in vivo or in neonatal rat cardiac fibroblasts. Kmo knockdown attenuated the isoproterenol-induced increase in cardiomyocyte size, as well as Nppb and Col1a1 expression in H9c2 cells or primary neonatal rat cardiomyocytes. Moreover, protocatechuic acid attenuated Kmo overexpression-induced increases in Nppb mRNA levels. Protocatechuic acid or Kmo knockdown decreased isoproterenol-induced ROS generation in vivo and in vitro. Thus, protocatechuic acid prevents heart failure by downregulating Kmo. Therefore, protocatechuic acid and Kmo constitute a potential novel therapeutic agent and target, respectively, against heart failure.

Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients as a function of therapeutic transfusion and hydroxyurea treatment.

Metabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with SCD enrolled in the WALK-PHaSST study (clinicaltrials gov. Identifier: NCT00492531). Clinical covariates informed the biological interpretation of metabolomics data, including genotypes (hemoglobin [Hb] SS, hemoglobin SC), history of recent transfusion (HbA%), response to hydroxyurea treatment (fetal Hb%). We investigated metabolic correlates to the degree of intravascular hemolysis, cardiorenal function, as determined by tricuspid regurgitation velocity (TRV), estimated glomerular filtration rate (eGFR), and overall hazard ratio (unadjusted or adjusted by age). Recent transfusion events or hydroxyurea treatment were associated with elevation in plasma-free fatty acids and decreases in acyl-carnitines, urate, kynurenine, indoles, carboxylic acids, and glycine- or taurine-conjugated bile acids. High levels of these metabolites, along with low levels of plasma S1P and L-arginine were identified as top markers of hemolysis, cardiorenal function (TRV, eGFR), and overall hazard ratio. We thus uploaded all omics and clinical data on a novel online portal that we used to identify a potential mechanism of dysregulated red cell S1P synthesis and export as a contributor to the more severe clinical manifestations in patients with the SS genotype compared to SC. In conclusion, plasma metabolic signatures - including low S1P, arginine and elevated kynurenine, acyl-carnitines and bile acids - are associated with clinical manifestation and therapeutic efficacy in SCD patients, suggesting new avenues for metabolic interventions in this patient population.

NLG-919 combined with cisplatin to enhance inhibitory effect on cell migration and invasion via IDO1-Kyn-AhR pathway in human nasopharyngeal carcinoma cell.

As a common aggressive head and neck cancer, nasopharyngeal carcinoma (NPC) received cisplatin treatment as a first-line chemotherapy. Platinum-induced resistance is a major limitation of current treatment strategy in the advanced NPC. Increased indoleamine 2,3-dioxygenase (IDO1) activities are found in cisplatin-resistant NPC cells versus cisplatin-sensitive NPC cells. As an IDO1 immunosuppressant, NLG-919 has entered clinical phase I to treat advanced solid tumors. To reverse cisplatin resistance, we investigated the combinatory application of cisplatin and NLG-919 in NPC treatment. In vitro biological studies on cisplatin-resistant and cisplatin-sensitive NPC cells were taken to imply that the combination of NLG-919 and cisplatin got a stronger impact on the induction of cell apoptosis and the inhibition of cell migration, exploring superior effect of antitumor over single drug. We proved that the mechanism of the combined therapy could inhibit the activity of IDO1, blocking amino acid tryptophan conversion to kynurenine through the kynurenine pathway, which further inhibited the aryl hydrocarbon receptor expression. Our study underscored the combination of cisplatin and NLG-919 as a potent therapeutic way for the reversal of cisplatin resistance.

Evidence for an association of serum microanalytes and myofascial pain syndrome.

BACKGROUND: Myofascial Pain Syndrome (MPS) is a common pain disorder. Diagnostic criteria include physical findings which are often unreliable or not universally accepted. A precise biosignature may improve diagnosis and treatment effectiveness. The purpose of this study was to assess whether microanalytic assays significantly correlate with characteristic clinical findings in people with MPS. METHODS: This descriptive, prospective study included 38 participants (25 women) with greater than 3 months of myofascial pain in the upper trapezius. Assessments were performed at a university laboratory. The main outcome measures were the Beighton Index, shoulder range of motion, strength asymmetries and microanalytes: DHEA, Kynurenine, VEGF, interleukins (IL-1b, IL-2, IL-4, IL-5, IL-7, IL-8, IL-13), growth factors (IGF-1, IGF2, G-CSF, GM-CSF), MCP-1, MIP-1b, BDNF, Dopamine, Noradrenaline, NPY, and Acetylcholine. Mann-Whitney test and Spearman's multivariate correlation were applied for all variables. The Spearman's analysis results were used to generate a standard correlation matrix and heat map matrix. RESULTS: Mean age of participants was 32 years (20-61). Eight (21%) had widespread pain (Widespread Pain Index ≥ 7). Thirteen (34%) had MPS for 1-3 years, 14 (37%) 3-10 years, and 11 (29%) for > 10 years. The following showed strong correlations: IL1b,2,4,5,7,8; GM-CSF and IL 2,4,5,7; between DHEA and BDNF and between BDNF and Kynurenine, NPY and acetylcholine. The heat map analysis demonstrated strong correlations between the Beighton Index and IL 5,7, GM-CSF, DHEA. Asymmetries of shoulder and cervical spine motion and strength associated with select microanalytes. CONCLUSION: Cytokine levels significantly correlate with selected clinical assessments. This indirectly suggests possible biological relevance for understanding MPS. Correlations among some cytokine clusters; and DHEA, BDNF kynurenine, NPY, and acetylcholine may act together in MPS. These findings should be further investigated for confirmation that link these microanalytes with select clinical findings in people with MPS.

Endothelial Cell Indoleamine 2, 3-Dioxygenase 1 Alters Cardiac Function After Myocardial Infarction Through Kynurenine.

BACKGROUND: Ischemic cardiovascular diseases, particularly acute myocardial infarction (MI), is one of the leading causes of mortality worldwide. Indoleamine 2, 3-dioxygenase 1 (IDO) catalyzes 1 rate-limiting step of L-tryptophan metabolism, and emerges as an important regulator of many pathological conditions. We hypothesized that IDO could play a key role to locally regulate cardiac homeostasis after MI. METHODS: Cardiac repair was analyzed in mice harboring specific endothelial or smooth muscle cells or cardiomyocyte or myeloid cell deficiency of IDO and challenged with acute myocardial infarction. RESULTS: We show that kynurenine generation through IDO is markedly induced after MI in mice. Total genetic deletion or pharmacological inhibition of IDO limits cardiac injury and cardiac dysfunction after MI. Distinct loss of function of IDO in smooth muscle cells, inflammatory cells, or cardiomyocytes does not affect cardiac function and remodeling in infarcted mice. In sharp contrast, mice harboring endothelial cell-specific deletion of IDO show an improvement of cardiac function as well as cardiomyocyte contractility and reduction in adverse ventricular remodeling. In vivo kynurenine supplementation in IDO-deficient mice abrogates the protective effects of IDO deletion. Kynurenine precipitates cardiomyocyte apoptosis through reactive oxygen species production in an aryl hydrocarbon receptor-dependent mechanism. CONCLUSIONS: These data suggest that IDO could constitute a new therapeutic target during acute MI.

Epacadostat Plus Pembrolizumab and Chemotherapy for Advanced Solid Tumors: Results from the Phase I/II ECHO-207/KEYNOTE-723 Study.

BACKGROUND: Epacadostat, an oral, selective inhibitor of IDO1, has shown activity when administered with pembrolizumab. We evaluated the addition of chemotherapy to epacadostat and pembrolizumab in patients with advanced or metastatic solid tumors. One proposed mechanism of resistance to PD-1 checkpoint inhibition is through immunosuppression mediated by L-kynurenine. IDO1, indoleamine-2,3-dioxygenase 1 is the rate-limiting enzyme catalyzing the conversion of L-tryptophan to L-kynurenine. If IDO1 is a mechanism of tumor escape from checkpoint inhibition, then addition of an IDO1 inhibitor with a PD-1 checkpoint inhibitor could enable tumor response to immunotherapy. METHODS: Patients received one of 7 tumor-appropriate chemotherapy regimens. Pembrolizumab 200 mg was infused intravenously every 3 weeks. Epacadostat 100 mg was administered orally twice daily. The primary objectives of phase I were determining safety/tolerability and defining the maximum tolerated or pharmacologically active dose of epacadostat. Phase II of the study was designed to enroll efficacy-expansion cohorts and to assess changes in the tumor and tumor microenvironment via mandatory-biopsy cohorts. RESULTS: A total of 70 patients were enrolled. Twelve patients were enrolled in the phase II mandatory-biopsy cohorts. Due to early study closure, efficacy expansion did not enroll. Grades 3 and 4 treatment-emergent adverse events (TEAEs) occurred in 78.6% of patients. Neutropenia and disease progression were the only grades 3 and 4 TEAEs reported in ≥10.0% of patients. One treatment-related death was reported. The ORR was 31.4% across all treatment groups. CONCLUSION: The combination of epacadostat 100 mg bid with pembrolizumab and chemotherapy had an acceptable safety profile. This regimen showed antitumor activity across multiple types of advanced or metastatic solid tumors (ClinicalTrials.gov Identifier: NCT03085914).

Sodium Selenite Modulates IDO1/Kynurenine, TLR4, NF-κB and Bcl2/Bax Pathway and Mitigates Acetic Acid-Induced Colitis in Rat.

BACKGROUND/AIMS: Colitis is a main presentation of inflammatory bowel disease (IBD) and yet, has no definitive cure. Currently, corticosteroids, anti-tumor necrosis factor (anti-TNF) agents and 5-aminosalicylic acid derivatives are prescribed for management of colitis. Except their failure rate, they are not always tolerated because of their severe adverse effects. Additive formulas with fewer adverse effects may improve the treatment of colitis. METHODS: In this study, colitis was induced with intra-rectal injection of three concentrations of acetic acid (4, 6 and 8 v/v). Each group received sodium selenite (0.5 mg/kg) or saline, gavaged on days 0 and 1 for treatment. Two days after induction of colitis, rats were sacrificed and the end part of their colons were resected for macroscopic and microscopic evaluation and molecular measurement. RESULTS: Sodium selenite improved macroscopic and microscopic view of the colon, decreased cryptitis, crypt abscess and inflammatory cells infiltration and partly maintained mucosal structure. Sodium selenite markedly reduced tissue levels of malondialdehyde (MDA), TNF-α and interferon γ (INF-γ) and decreased myeloperoxidase (MPO) activity. Treatment with sodium selenite also significantly downregulated IL17, IL22, indoleamine 2,3-dioxygenase (IDO1), and kynurenine levels. Western blotting revealed that sodium selenite prevented apoptosis by increasing bcl2/Bax ratio. Furthermore, our findings showed that sodium selenite significantly downregulated the upstream inflammatory molecules such as nuclear factor kappa B (NF-κB) and toll-like receptor 4 (TLR4) in colitis. CONCLUSION: These findings show that sodium selenite alleviates inflammatory response and oxidative stress and protects against colitis.

A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression.

BACKGROUND: Ketamine has rapid-acting antidepressant effects but is associated with psychotomimetic and other adverse effects. A 7-chlorokynurenic acid is a potent and specific glycine site N-methyl-d-aspartate receptor antagonist but crosses the blood-brain barrier inefficiently. Its prodrug, L-4-chlorokynurenine (4-Cl-KYN), exerts acute and sustained antidepressant-like effects in rodents and has no reported psychotomimetic effects in either rodents or healthy volunteers. This study examined whether 4-Cl-KYN has rapid antidepressant effects in individuals with treatment-resistant depression. METHODS: After a 2-week drug-free period, 19 participants with treatment-resistant depression were randomized to receive daily oral doses of 4-Cl-KYN monotherapy (1080 mg/d for 7 days, then 1440 mg/d for 7 days) or placebo for 14 days in a randomized, placebo-controlled, double-blind, crossover manner. The primary outcome measure was the Hamilton Depression Rating Scale score, assessed at several time points over a 2-week period; secondary outcome measures included additional rating scale scores. Pharmacokinetic measures of 7-chlorokynurenic acid and 4-Cl-KYN and pharmacodynamic assessments were obtained longitudinally and included 1H-magnetic resonance spectroscopy brain glutamate levels, resting-state functional magnetic resonance imaging, and plasma and cerebrospinal fluid measures of kynurenine metabolites and neurotrophic factors. RESULTS: Linear mixed models detected no treatment effects, as assessed by primary and secondary outcome measures. No difference was observed for any of the peripheral or central biological indices or for adverse effects at any time between groups. A 4-Cl-KYN was safe and well-tolerated, with generally minimal associated adverse events. CONCLUSIONS: In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied.ClinicalTrials.gov identifier: NCT02484456.

Dimethyl- and monomethylfumarate regulate indoleamine 2,3-dioxygenase (IDO) activity in human immune cells.

Fumaric acid esters (FAEs) are used as an oral treatment for psoriasis. Dimethylfumarate (DMF) and its metabolite monomethylfumarate (MMF) are regarded as the pharmacologically active moieties. Indoleamine 2,3-dioxygenase (IDO) is the key enzyme for the metabolism of tryptophan. The kynurenine pathway is established as a major regulator of innate and adaptive immunity. Here, we investigated the effect of DMF and MMF on IDO activity and expression in human peripheral blood mononuclear cells (PBMCs). IDO activity was determined by measuring the concentration of kynurenine in the culture medium using a HPLC technique. IDO and kynureninase protein expressions were analysed by Western blot. Our results demonstrated that DMF and MMF dose-dependently reduced the levels of L-kynurenine in PBMCs activated by interferon-γ (IFN-γ). Furthermore, MMF had an inhibitory effect on IDO activity in vitro with an ED50 of 10 µmol/L, a value within the therapeutic concentration range for this molecule. We also observed that IDO and kynureninase expressions were reduced in PBMCs in a dose-dependent manner by DMF and MMF. The results of our study show that DMF and MMF (in therapeutic concentrations) inhibited IDO and kynureninase activity and expression in a NF-κB-dependent manner in PBMCs while also decreasing the level of L-kynurenine in these cells. As we found that FAEs inhibit both IDO expression and enzymatic activity leading to a modulation of tryptophan degradation, we believe this effect may contribute to the clinical efficacy of this drug in psoriasis by downregulating pro-inflammatory mediators generated by the kynurenine pathway.

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition.

Currently approved antidepressant drug treatment typically takes several weeks to be effective. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has shown efficacy as a rapid-acting treatment of depression, but its use is associated with significant side effects. We assessed effects following blockade of the glycineB co-agonist site of the NMDA receptor, located on the GluN1 subunit, by the selective full antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), delivered by systemic administration of its brain-penetrant prodrug 4-chlorokynurenine (4-Cl-KYN) in mice. Following administration of 4-Cl-KYN, 7-Cl-KYNA was promptly recovered extracellularly in hippocampal microdialysate of freely moving animals. The behavioral responses of the animals were assessed using measures of ketamine-sensitive antidepressant efficacy (including the 24-hour forced swim test, learned helplessness test, and novelty-suppressed feeding test). In these tests, distinct from fluoxetine, and similar to ketamine, 4-Cl-KYN administration resulted in rapid, dose-dependent and persistent antidepressant-like effects following a single treatment. The antidepressant effects of 4-Cl-KYN were prevented by pretreatment with glycine or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). 4-Cl-KYN administration was not associated with the rewarding and psychotomimetic effects of ketamine, and did not induce locomotor sensitization or stereotypic behaviors. Our results provide further support for antagonism of the glycineB site for the rapid treatment of treatment-resistant depression without the negative side effects seen with ketamine or other channel-blocking NMDA receptor antagonists.

IL-22 and IDO1 affect immunity and tolerance to murine and human vaginal candidiasis.

The ability to tolerate Candida albicans, a human commensal of the gastrointestinal tract and vagina, implicates that host defense mechanisms of resistance and tolerance cooperate to limit fungal burden and inflammation at the different body sites. We evaluated resistance and tolerance to the fungus in experimental and human vulvovaginal candidiasis (VVC) as well as in recurrent VVC (RVVC). Resistance and tolerance mechanisms were both activated in murine VVC, involving IL-22 and IL-10-producing regulatory T cells, respectively, with a major contribution by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 was responsible for the production of tolerogenic kynurenines, such that replacement therapy with kynurenines restored immunoprotection to VVC. In humans, two functional genetic variants in IL22 and IDO1 genes were found to be associated with heightened resistance to RVVC, and they correlated with increased local expression of IL-22, IDO1 and kynurenines. Thus, IL-22 and IDO1 are crucial in balancing resistance with tolerance to Candida, their deficiencies are risk factors for RVVC, and targeting tolerance via therapeutic kynurenines may benefit patients with RVVC.

Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease.

Half a century ago, chronic granulomatous disease (CGD) was first described as a disease fatally affecting the ability of children to survive infections. Various milestone discoveries have since been made, from an insufficient ability of patients' leucocytes to kill microbes to the underlying genetic abnormalities. In this inherited disorder, phagocytes lack NADPH oxidase activity and do not generate reactive oxygen species, most notably superoxide anion, causing recurrent bacterial and fungal infections. Patients with CGD also suffer from chronic inflammatory conditions, most prominently granuloma formation in hollow viscera. The precise mechanisms of the increased microbial pathogenicity have been unclear, and more so the reasons for the exaggerated inflammatory response. Here we show that a superoxide-dependent step in tryptophan metabolism along the kynurenine pathway is blocked in CGD mice with lethal pulmonary aspergillosis, leading to unrestrained Vgamma1(+) gammadelta T-cell reactivity, dominant production of interleukin (IL)-17, defective regulatory T-cell activity and acute inflammatory lung injury. Although beneficial effects are induced by IL-17 neutralization or gammadelta T-cell contraction, complete cure and reversal of the hyperinflammatory phenotype are achieved by replacement therapy with a natural kynurenine distal to the blockade in the pathway. Effective therapy, which includes co-administration of recombinant interferon-gamma (IFN-gamma), restores production of downstream immunoactive metabolites and enables the emergence of regulatory Vgamma4(+) gammadelta and Foxp3(+) alphabeta T cells. Therefore, paradoxically, the lack of reactive oxygen species contributes to the hyperinflammatory phenotype associated with NADPH oxidase deficiencies, through a dysfunctional kynurenine pathway of tryptophan catabolism. Yet, this condition can be reverted by reactivating the pathway downstream of the superoxide-dependent step.

Nociceptive improvements and kynurenine pathway alterations with diclofenac treatment in a rat model of neuropathic pain created by partial sciatic nerve ligation.

OBJECTIVE: Neuropathic pain is regulated by several metabolites of the kynurenine pathway (KYNA-kynurenic acid, and QA-quinolinic acid). Diclofenac exerts analgesic and anti-hyperalgesic effects and also alters KYNA levels, indicating a potential for therapy. We aimed to assess the nociceptive effects of different doses of diclofenac treatment in a rat model of neuropathic pain and to determine potential relationships with KYNA and QA levels (Graphical Abstract). MATERIALS AND METHODS: Twenty-eight Sprague-Dawley rats were divided into four groups: 40 mg/kg/day diclofenac (high-dose), 20 mg/kg/day diclofenac (normal-dose), non-treatment, and sham. Except for the sham group, the others underwent partial sciatic nerve ligation (left). Baseline (day 0) and post-treatment (day 3) KYNA and QA levels were measured. Allodynia and pain detection were assessed with the von Frey and hot plate tests. RESULTS: Baseline findings were similar in all groups. Compared to baseline, the non-treatment group had significantly worse allodynia on day 3. Baseline and post-treatment von Frey results (left) remained similar in the normal-dose diclofenac group (p=0.336); however, this benefit was not observed in the high-dose group. Relative to baseline, normal-dose diclofenac recipients had significantly higher KYNA concentration (p=0.046) and KYNA-to-QA ratio (p=0.028) on day 3. CONCLUSIONS: Our results show that 3-day therapy with 20 mg/kg/day diclofenac can improve nociceptive findings in neuropathic pain, and that this effect may be associated with increased KYNA or KYNA-to-QA ratio. The lack of dose-dependent effects may be associated with potential adverse influences of exceedingly high diclofenac dosage.

Kynurenines in Parkinson's disease: therapeutic perspectives.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder the pathomechanism of which is not yet fully known. With regard to the molecular mechanism of development of the disease, oxidative stress/mitochondrial impairment, glutamate excitotoxicity and neuroinflammation are certainly involved. Alterations in the kynurenine pathway, the main pathway of the tryptophan metabolism, can contribute to the complex pathomechanism. There are several possibilities for therapeutic intervention involving targeting of this altered metabolic route. The development of synthetic molecules that would shift the altered balance towards the achievement of neuroprotective effects would be of great promise for future clinical studies on PD.

The role of the kynurenine metabolism in major depression.

There are circumferential evidences that major depression is associated with mild pro-inflammatory state. Both physiological and psychological stress can induce increased production of pro-inflammatory mediators, reactive oxygen species (ROS) and hypothalamo-hypophyseal-adrenal axis disturbances. While both pro-inflammatory mediators and ROS could activate the tryptophan breakdown and kynurenine pathway with a shift toward the neurotoxic arm, chronic hypercortisolism could also enhance tryptophan breakdown and induce neurodegenerative changes. The imbalanced kynurenine metabolism in terms of neuroprotective and neurotoxic effects was demonstrated in major depression, and in drug-induced neuropsychiatric side effects, such as interferon-treated depression. The changes in periphery are shown to be associated with central changes. Those changes might be partly contributed by genetic factors. While some of the currently available antidepressants could reverse the pro-inflammatory state of the depressed patients, these medications could not efficiently improve those metabolic and neurochemical changes within the period that could induce clinical improvement. In this review, the role of kynurenine metabolism which interacts with other neurochemicals is discussed as a major contributing pathophysiological mechanism in major depression. Moreover, the future therapeutic opportunities are also discussed in this review.

Kynurenines and headache.

In parallel to serotonin synthesis, the major route of tryptophan catabolism is the kynurenine pathway, which produces neuroactive metabolites. Among these substances, kynurenic acid has potential neuroprotective action blocking glutamate release and glutamatergic neurotransmission. Glutamate is a key player in migraine pathogenesis; it is crucial in the communication of first and second-order neurons, and it has an important role in the genesis of cortical spreading depression, which is the electrophysiological correlate for migraine aura and may be involved in the activation of the trigeminal system. Thus, kynurenines may affect the pathogenesis directly, by acting on glutamate receptors and exerting other neuromodulatory effects, and indirectly via an altered serotonin metabolism. This work summarizes our current results regarding the role of the kynurenine system in trigeminal activation and other events occurring during migraine headache.

The kynurenine system and immunoregulation.

There is developing interest in the role of the kynurenines in the immune function. A considerable amount of evidence has accumulated as concerns interactions between the kynurenine pathway, cytokines and the nervous system. Indoleamine 2,3-dioxygenase (IDO) occupies a key position connecting the immune system and the kynurenine pathway. There are evidences of the immunosuppressive effect of IDO. Following the interferon (IFN)-mediated activation of antigen presenting cells, the induction of IDO and the kynurenine system exerts a counter-regulating effect, maintaining the homeostasis. Inhibition of T cell functions, activation of the regulatory T cells, and the inhibition of Natural Killer cells are among the important factors in the immunosuppressive effects of IDO and kynurenines. There is a close connection between cytokines (IFN-α, IFN-γ, TNF-α, TGF-ß, IL-4 and IL-23) and the kynurenine system, and an imbalance in the TH1/TH2 cytokine profile may possibly lead to neurologic or psychiatric disorders. As the tryptophan metabolic pathway is activated by pro-inflammatory stimuli, the anti-inflammatory effect of kynurenic acid provides a further feedback mechanism in modulating the immune responses.

Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis.

Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography-tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan-kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan-kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.

Genotypic-Phenotypic Analysis, Metabolic Profiling and Clinical Correlations in Parkinson's Disease Patients from Tamil Nadu Population, India.

Parkinson's disease (PD) is an ageing disorder caused by dopaminergic neuron depletion with age. Growing research in the field of metabolomics is expected to play a major role in PD diagnosis, prognosis and therapeutic development. In this study, we looked at how SNCA and GBA1 gene mutations, as well as metabolomic abnormalities of kynurenine and cholesterol metabolites, were linked to alpha-synuclein (α-syn) and clinical characteristics in three different PD age groups. In all three age groups, a metabolomics analysis revealed an increased amount of 27-hydroxycholesterol (27-OHC) and a lower level of kynurenic acid (KYNA). The effect of 27-OHC on SNCA and GBA1 modifications was shown to be significant (P < 0.05) only in the A53T variant of the SNCA gene in late-onset and early-onset PD groups, whereas GBA1 variants were not. Based on the findings, we observed that the increase in 27-OHC would have elevated α-syn expression, which triggered the changes in the SNCA gene but not in the GBA1 gene. Missense variations in the SNCA and GBA1 genes were investigated using the sequencing technique. SNCA mutation A53T has been linked to increased PD symptoms, but there is no phenotypic link between GBA1 and PD. As a result of the data, we hypothesise that cholesterol and kynurenine metabolites play an important role in PD, with the metabolite 27-OHC potentially serving as a PD biomarker. These findings will aid in the investigation of pathogenic causes as well as the development of therapeutic and preventative measures for PD.