Variations in Quinolinic Acid Levels in Tuberculosis Patients with Diabetes Comorbidity: A Pilot Prospective Cohort Study.

Objective: We aimed to investigate dysregulated metabolic pathways and identify diagnostic and therapeutic targets in patients with tuberculosis-diabetes (TB-DM). Methods: In our prospective cohort study, plasma samples were collected from healthy individuals, diabetic (DM) patients, untreated TB-only (TB-0)/TB-DM patients (TB-DM-0), and cured TB (TB-6)/TB-DM patients (TB-DM-6) to measure the levels of amino acids, fatty acids, and other metabolites in plasma using high-throughput targeted quantification methods. Results: Significantly different biological processes and biomarkers were identified in DM, TB-DM-0, and TB-DM-6 patients. Moreover, quinolinic acid (QA) showed excellent predictive accuracy for distinguishing between DM patients and TB-DM-0 patients, with an AUC of 1 (95% CI 1-1). When differentiating between TB-DM-0 patients and TB-DM-6 patients, the AUC was 0.9297 (95% CI 0.8460-1). Compared to those in DM patients, the QA levels were significantly elevated in TB-DM-0 patients and decreased significantly after antituberculosis treatment. We simultaneously compared healthy controls and untreated tuberculosis patients and detected an increase in the level of QA in the plasma of tuberculosis patients, which decreased following treatment. Conclusion: These findings improve the current understanding of tuberculosis treatment in patients with diabetes. QA may serve as an ideal diagnostic biomarker for TB-DM patients and contribute to the development of more effective treatments.

Continuous theta burst stimulation for bipolar depression: A multicenter, double-blind randomized controlled study exploring treatment efficacy and predictive potential of kynurenine metabolites.

BACKGROUND: While theta burst stimulation (TBS) shows promise in Major Depressive Disorder (MDD), its effectiveness in bipolar depression (BD-D) remains uncertain. Optimizing treatment parameters is crucial in the pursuit of rapid symptom relief. Moreover, aligning with personalized treatment strategies and increased interest in immunopsychiatry, biomarker-based stratification of patients most likely to benefit from TBS might improve remission rates. We investigated treatment effectiveness of continuous TBS (cTBS) compared to sham in BD-D, and assessed the capacity of plasma kynurenine pathway metabolites to predict treatment outcome. METHODS: Thirty-seven patients with BD-D underwent accelerated active or sham cTBS treatment in a multicenter, double-blind, randomized controlled trial. Depressive symptoms were measured with the 17-item Hamilton Depression Rating Scale (HDRS-17) before treatment (T0), 3-4 days posttreatment (T1) and 10-11 days posttreatment (T2). Plasma tryptophan, kynurenine, kynurenic acid and quinolinic acid concentrations were quantified with ELISA. Linear mixed models were used for statistical analyses. RESULTS: Although the total sample showed depressive symptom improvement, active cTBS did not demonstrate greater symptom alleviation compared to sham. However, higher baseline quinolinic acid significantly predicted symptom improvement in the active treatment group, not in sham-stimulated patients. LIMITATIONS: The modest sample size limited the power to detect significant differences with regard to treatment effect. Also, the follow-up period was 10-11 days, whereas similar studies usually follow up for at least one month. CONCLUSION: More research is required to optimize cTBS for BD-D and explore the involvement of quinolinic acid in treatment outcome.

VEEV TC-83 Triggers Dysregulation of the Tryptophan-Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice.

Neurodegenerative diseases are chronic conditions affecting the central nervous system (CNS). Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid beta in the limbic and cortical brain regions. AD is presumed to result from genetic abnormalities or environmental factors, including viral infections, which may have deleterious, long-term effects. In this study, we demonstrate that the Venezuelan equine encephalitis virus (VEEV) commonly induces neurodegeneration and long-term neurological or cognitive sequelae. Notably, the effects of VEEV infection can persistently influence gene expression in the mouse brain, suggesting a potential link between the observed neurodegenerative outcomes and long-term alterations in gene expression. Additionally, we show that alphavirus encephalitis exacerbates the neuropathological profile of AD through crosstalk between inflammatory and kynurenine pathways, generating a range of metabolites with potent effects. Using a mouse model for ß-amyloidosis, Tg2576 mice, we found that cognitive deficits and brain pathology were more severe in Tg2576 mice infected with VEEV TC-83 compared to mock-infected controls. Thus, during immune activation, the kynurenine pathway plays a more active role in the VEEV TC-83-infected cells, leading to increases in the abundance of transcripts related to the kynurenine pathway of tryptophan metabolism. This pathway generates several metabolites with potent effects on neurotransmitter systems as well as on inflammation, as observed in VEEV TC-83-infected animals.

An exploratory study on the effect of kynurenine metabolites on sEnd-2 endothelioma cells.

Cancer is the second leading cause of mortality worldwide. The development of anticancer therapy plays a crucial role in mitigating tumour progression and metastasis. Epithelioid hemangioendothelioma is a very rare cancer, however, with a high systemic involvement. Kynurenine metabolites which include l-kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid have been shown to inhibit T-cell proliferation resulting in a decrease in cell growth of natural killer cells and T cells. Furthermore, metabolites such as  l-kynurenine have been shown to inhibit proliferation of melanoma cells in vitro. Considering these metabolite properties, the present study aimed to explore the in vitro effects of  l-kynurenine, quinolinic acid and kynurenic acid on endothelioma sEnd-2 cells and on endothelial (EA. hy926 cells) (control cell line). The in vitro effect at 24, 48, and 72 h exposure to a range of 1-4 mM of the respective kynurenine metabolites on the two cell lines in terms of cell morphology, cell cycle progression and induction of apoptosis was assessed. The half inhibitory concentration (IC50), as determined using nonlinear regression, for  l-kynurenine, quinolinic acid and kynurenic acid was 9.17, 15.56, and 535.40 mM, respectively. Optical transmitted light differential interference contrast and hematoxylin and eosin staining revealed cells blocked in metaphase, formation of apoptotic bodies and compromised cell density in  l-kynurenine-treated cells. A statistically significant increase in the number of cells present in the sub-G1 phase was observed in  l-kynurenine-treated sample. To our knowledge, this was the first in vitro study conducted to investigate the mechanism of action of kynurenine metabolites on endothelioma sEnd-2 cells. It can be concluded that  l-kynurenine exerts an antiproliferative effect on the endothelioma sEnd-2 cell line by decreasing cell growth and proliferation as well as a metaphase block. These hallmarks suggest cell death via apoptosis. Further research will be conducted on  l-kynurenine to assess the effect on cell adhesion in vitro and in vivo as cell-cell adhesion has been shown to increase metastasis to distant organs therefore, the inhibition of adhesion may lead to a decrease in metastasis.

Kynurenine Metabolites in CSF and Plasma in Healthy Males.

In recent years, kynurenine metabolites generated by tryptophan catabolism have gained increasing attention in the context of brain diseases. The question of importance is whether there is a relationship between peripheral and central levels of these metabolites. Some of these compounds do not cross the blood-brain barrier; in particular, kynurenic acid, and most analyses of kynurenines from psychiatric patients have been performed using plasma samples. In the present study, we recruited 30 healthy volunteers with no history of psychiatric or neurological diagnosis, to analyze tryptophan, kynurenine, kynurenic acid, and quinolinic acid levels in CSF and plasma. In addition, kynurenic acid was analyzed in urine. The most important finding of this study is that CSF kynurenic acid levels do not correlate with those in plasma or urine. However, we found a correlation between plasma kynurenine and CSF kynurenic acid. Further, plasma kynurenine and plasma quinolinic acid were correlated. Our findings clarify the distribution of tryptophan and its metabolites in various body compartments and may serve as a guide for the analysis of these metabolites in humans. The most significant finding of the present study is that a prediction of brain kynurenic acid by of the analysis of the compound in plasma cannot be made.

Neopterin, kynurenine metabolites, and indexes related to vitamin B6 are associated with post-stroke cognitive impairment: The Nor-COAST study.

BACKGROUND AND AIMS: We have previously shown that systemic inflammation was associated with post-stroke cognitive impairment (PSCI). Because neopterin, kynurenine pathway (KP) metabolites, and B6 vitamers are linked to inflammation, in our study we investigated whether those biomarkers were associated with PSCI. MATERIAL AND METHODS: The Norwegian Cognitive Impairment After Stroke study is a prospective multicenter cohort study of patients with acute stroke recruited from May 2015 through March 2017. Plasma samples of 422 participants (59 % male) with ischemic stroke from the index hospital stay and 3 months post-stroke were available for analyses of neopterin, KP metabolites, and B6 vitamers using liquid chromatography-tandem mass spectrometry. Mixed linear regression analyses adjusted for age, sex, and creatinine, were used to assess whether there were associations between those biomarkers and cognitive outcomes, measured by the Montreal Cognitive Assessment scale (MoCA) at 3-, 18-, and 36-month follow-up. RESULTS: Participants had a mean (SD) age of 72 (12) years, with a mean (SD) National Institutes of HealthStroke Scale score of 2.7 (3.6) at Day 1. Higher baseline values of quinolinic acid, PAr (i.e., an inflammatory marker based on vitamin B6 metabolites), and HKr (i.e., a marker of functional vitamin B6 status based on selected KP metabolites) were associated with lower MoCA score at 3, 18, and 36 months post-stroke (p < 0.01). Higher baseline concentrations of neopterin and 3-hydroxykynurenine were associated with lower MoCA scores at 18 and 36 months, and higher concentrations of xanthurenic acid were associated with higher MoCA score at 36 months (p < 0.01). At 3 months post-stroke, higher concentrations of neopterin and lower values of pyridoxal 5́-phosphate were associated with lower MoCA scores at 18- and 36-month follow-up, while lower concentrations of picolinic acid were associated with a lower MoCA score at 36 months (p < 0.01). CONCLUSION: Biomarkers and metabolites of systemic inflammation, including biomarkers of cellular immune activation, indexes of vitamin B6 homeostasis, and several neuroactive metabolites of the KP pathway, were associated with PSCI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02650531.

Marked IDO2 expression and activity related to autophagy and apoptosis in brain tissue of fatal tuberculous meningitis.

In about 1% of tuberculosis (TB) patients, Mycobacterium tuberculosis (M. tuberculosis) can disseminate to the meninges, causing tuberculous meningitis (TBM) with mortality rate up to 60%. Chronic granulomatous inflammation (non-necrotizing and necrotizing) in the brain is the histological hallmark of TBM. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and the generated kynurenine metabolites exert major effector functions relevant to TB granuloma functioning. Here we have assessed immunohistochemically IDO1 expression and activity and its effector function and that of its isoform, IDO2, in post-mortem brain tissue of patients that demised with neurotuberculosis. We also related these findings to brain tissue of fatal/severe COVID-19. In this study, IDO1 and IDO2 were abundantly expressed and active in tuberculoid granulomas and were associated with the presence of M. tuberculosis as well as markers of autophagy and apoptosis. Like in fatal/severe COVID-19, IDO2 was also prominent in specific brain regions, such as the inferior olivary nucleus of medulla oblongata and cerebellum, but not associated with granulomas or with M. tuberculosis. Spatially associated apoptosis was observed in TBM, whereas in fatal COVID-19 autophagy dominated. Together, our findings highlight IDO2 as a potentially relevant effector enzyme in TBM, which may relate to the symptomology of TBM.

Ginsenoside Rk3 Regulates Tryptophan Metabolism along the Brain-Gut Axis by Targeting Tryptophan Hydroxylase and Remodeling the Intestinal Microenvironment to Alleviate Depressive-Like Behavior in Mice.

Depression is a neuropsychiatric disease that significantly impacts the physical and mental health of >300 million people worldwide and places a major burden on society. Ginsenosides are the main active ingredient in ginseng and have been proven to have various pharmacological effects on the nervous system. Herein, we investigated the antidepressant effect of ginsenoside Rk3 and its underlying mechanism in a murine model of depression. Rk3 significantly improved depression-like behavior in mice, ameliorated the disturbance of the hypothalamus-pituitary-adrenal axis, and alleviated neuronal damage in the hippocampus and prefrontal cortex of mice. Additionally, Rk3 improved the abnormal metabolism of tryptophan in brain tissue by targeting tryptophan hydroxylase, thereby reducing neuronal apoptosis and synaptic structural damage in the mouse hippocampus and prefrontal cortex. Furthermore, Rk3 reshaped the composition of the gut microbiota of mice and regulated intestinal tryptophan metabolism, which alleviated intestinal barrier damage. Thus, this study provides valuable insights into the role of Rk3 in the tryptophan metabolic cycle along the brain-gut axis, suggesting that Rk3 may have the potential for treating depression.

MM165 - A Small Hybrid Molecule Modulates the Kynurenine Pathway and Attenuates Lipopolysaccharide-Induced Memory Deficits and Inflammation.

Cognitive dysfunctions are now recognized as core symptoms of various psychiatric disorders e.g., major depressive disorder. Sustained immune activation may leads to cognitive dysfunctions. Proinflammatory cytokines shunt the metabolism of tryptophan towards kynurenine and quinolinic acid may accumulate at toxic concentrations. This acid triggers an increase in neuronal nitric oxide synthase function and promotes oxidative stress. The searching for small molecules that can regulate tryptophan metabolites produced in the kynurenic pathway has become an important goal in developing treatments for various central nervous system diseases with an inflammatory component. Previously we have identified a small hybrid molecule - MM165 which significantly reduces depressive-like symptoms caused by inflammation induced by lipopolysaccharide administration. In the present study, we investigated whether this compound would mitigate cognitive deficits induced by lipopolysaccharide administration and whether treatment with it would affect the plasma or brain levels of quinolinic acid and kynurenic acid. Neuroinflammation was induced in rats by administering lipopolysaccharide at a dose of 0.5 mg/kg body weight for 10 days. We conducted two tests: novel object recognition and object location, to assess the effect on memory impairment in animals previously treated with lipopolysaccharide. In plasma collected from rats, the concentrations of C-reactive protein and tumor necrosis factor alfa were determined. The concentrations of kynurenic acid and quinolinic acid were determined in plasma and homogenates obtained from the cerebral cortex of rats. Interleukin 6 in the cerebral cortex of rats was determined. Additionally, the body and spleen mass and spontaneous activity were measured in rats. Our study shows that MM165 may mitigate cognitive deficits induced by inflammation after administration of lipopolysaccharide and alter the concentrations of tryptophan metabolites in the brain. Compounds exhibiting a mechanism of action analogous to that of MM165 may serve as foundational structures for the development of a new class of antidepressants.

The dangerous "West Coast Swing" by hyperglycaemia and chronic stress in the mouse hippocampus: Role of kynurenine catabolism.

Growing epidemiological studies highlight a bi-directional relationship between depressive symptoms and diabetes mellitus. However, the detrimental impact of their co-existence on mental health suggests the need to treat this comorbidity as a separate entity rather than the two different pathologies. Herein, we characterized the peculiar mechanisms activated in mouse hippocampus from the concurrent development of hyperglycaemia, characterizing the different diabetes subtypes, and chronic stress, recognized as a possible factor predisposing to major depression. Our work demonstrates that kynurenine overproduction, leading to apoptosis in the hippocampus, is triggered in a different way depending on hyperglycaemia or chronic stress. Indeed, in the former, kynurenine appears produced by infiltered macrophages whereas, in the latter, peripheral kynurenine preferentially promotes resident microglia activation. In this scenario, QA, derived from kynurenine catabolism, appears a key mediator causing glutamatergic synapse dysfunction and apoptosis, thus contributing to brain atrophy. We demonstrated that the coexistence of hyperglycaemia and chronic stress worsened hippocampal damage through alternative mechanisms, such as GLUT-4 and BDNF down-expression, denoting mitochondrial dysfunction and apoptosis on one hand and evoking the compromission of neurogenesis on the other. Overall, in the degeneration of neurovascular unit, hyperglycaemia and chronic stress interacted each other as the partners of a "West Coast Swing" in which the leading role can be assumed alternatively by each partner of the dance. The comprehension of these mechanisms can open novel perspectives in the management of diabetic/depressed patients, but also in the understanding the pathogenesis of other neurodegenerative disease characterized by the compromission of hippocampal function.

Identification of kynurenine and quinolinic acid as promising serum biomarkers for drug-induced interstitial lung diseases.

BACKGROUND: Drug-induced interstitial lung disease (DILD) is a lung injury caused by various types of drugs and is a serious problem in both clinical practice and drug development. Clinical management of the condition would be improved if there were DILD-specific biomarkers available; this study aimed to meet that need. METHODS: Biomarker candidates were identified by non-targeted metabolomics focusing on hydrophilic molecules, and further validated by targeted approaches using the serum of acute DILD patients, DILD recovery patients, DILD-tolerant patients, patients with other related lung diseases, and healthy controls. RESULTS: Serum levels of kynurenine and quinolinic acid (and kynurenine/tryptophan ratio) were elevated significantly and specifically in acute DILD patients. The diagnostic potentials of these biomarkers were superior to those of conventional lung injury biomarkers, Krebs von den Lungen-6 and surfactant protein-D, in discriminating between acute DILD patients and patients with other lung diseases, including idiopathic interstitial pneumonia and lung diseases associated with connective tissue diseases. In addition to identifying and evaluating the biomarkers, our data showed that kynurenine/tryptophan ratios (an indicator of kynurenine pathway activation) were positively correlated with serum C-reactive protein concentrations in patients with DILD, suggesting the potential association between the generation of these biomarkers and inflammation. Our in vitro experiments demonstrated that macrophage differentiation and inflammatory stimulations typified by interferon gamma could activate the kynurenine pathway, resulting in enhanced kynurenine levels in the extracellular space in macrophage-like cell lines or lung endothelial cells. Extracellular quinolinic acid levels were elevated only in macrophage-like cells but not endothelial cells owing to the lower expression levels of metabolic enzymes converting kynurenine to quinolinic acid. These findings provide clues about the molecular mechanisms behind their specific elevation in the serum of acute DILD patients. CONCLUSIONS: The serum concentrations of kynurenine and quinolinic acid as well as kynurenine/tryptophan ratios are promising and specific biomarkers for detecting and monitoring DILD and its recovery, which could facilitate accurate decisions for appropriate clinical management of patients with DILD.

Modeling Huntington's disease: An insight on in-vitro and in-vivo models.

Huntington's disease is a neurodegenerative illness that causes neuronal death most extensively within the basal ganglia. There is a broad class of neurologic disorders associated with the expansion of polyglutamine (polyQ) repeats in numerous proteins. Several other molecular mechanisms have also been implicated in HD pathology, including brain-derived neurotrophic factor (BDNF), mitochondrial dysfunction, and altered synaptic plasticity in central spiny neurons. HD pathogenesis and the effectiveness of therapy approaches have been better understood through the use of animal models. The pathological manifestations of the disease were reproduced by early models of glutamate analog toxicity and mitochondrial respiration inhibition. Because the treatments available for HD are quite limited, it is important to have a definite preclinical model that mimics all the aspects of the disease. It can be used to study mechanisms and validate candidate therapies. Although there hasn't been much success in translating animal research into clinical practice, each model has something special to offer in the quest for a deeper comprehension of HD's neurobehavioral foundations. This review provides insight into various in-vitro-and in-vivo models of HD which may be useful in the screening of newer therapeutics for this incapacitating disorder.

Role of the immune-kynurenine pathway in treatment-resistant schizophrenia.

BACKGROUND: The immune-inflammatory response system (IRS) and kynurenine pathway (KP) have been implicated in the pathophysiology of schizophrenia. Studies have shown inflammation-related effects on KP metabolism in patients with schizophrenia. This study investigated the relationship between KP metabolites, IRS, and the compensatory immune-regulatory reflex system (CIRS) in patients with treatment-resistant schizophrenia (TRS). METHODS: Patients with (n = 53) and without TRS (n = 47), and healthy controls (HCs, n = 49) were enrolled. We quantified plasma levels of pro-inflammatory cytokines (interleukin [IL]-1ß, IL-2, IL-6, soluble(s)IL-6 receptor, IL-8, IL-12, IL-17, IL-18, interferon-γ, and tumor necrosis factor[TNF]-α) and anti-inflammatory cytokines (IL-1 receptor antagonist, IL-4, IL-10, tumor growth factor [TGF]-ß1, TGF-ß2, soluble (s) IL-2 receptor subunit α, sIL-2 receptor subunit ß, and sTNF-α receptor 1) and calculated the IRS/CIRS ratio. We also tested serum metabolites of the KP, including kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN), along with the QUIN/KYNA ratio. RESULTS: Patients with TRS had significantly higher IRS/CIRS ratio than non-TRS patients (p = 0.002) and HCs (p = 0.007), and significantly lower KYN (p = 0.001) and KYNA (p = 0.01) levels than HCs. Binary logistic regression analysis revealed that a younger age at illness onset (odds ratio [OR] = 0.91, p = 0.02) and a higher IRS/CIRS ratio (OR = 1.22; p = 0.007) were risk factors for patients with TRS. After further adjusted for age of onset, the QUIN/KYNA ratio (ß = 0.97; p = 0.02) significantly moderated the relationship between IRS/CIRS and TRS, showing that in the higher QUIN/KYNA condition, higher IRS/CIRS ratio were significantly and more likely to be associated with patients with TRS (ß = 0.12, z = 3.19, p = 0.001), whereas in the low QUIN/KYNA condition, the association between IRS/CIRS ratio and TRS was weak and insignificant. CONCLUSIONS: The peripheral immune response was imbalanced in TRS and was preferentially directed towards the IRS compared to patients without TRS and healthy controls, which is likely to play a role in neurotoxicity. Additionally, peripheral KP activation was also imbalanced, as evidenced by significantly reduced KYN and KYNA levels in patients with TRS compared to healthy controls, but none of KP metabolisms were significantly difference in non-TRS patients compared to healthy controls. QUIN/KYNA ratio involving to the degree of activation of NMDA receptors, indicated the neurotoxic level of the KP activation. The interaction between IRS/CIRS and QUIN/KYNA ratio was significant in predicting TRS, and our findings suggest a potential role for the immune-kynurenine pathway in TRS pathogenesis.

Impedimetric detection of gut-derived metabolites using 2D Germanene-based materials.

Apart from the extensively researched graphene under the Group 14 2D materials, monolayered germanene and its derivatives have been gaining interest lately as alternative class of 2D materials owing to their facile synthesis, and attractive electronic and optical properties. Herein, three different functionalized germanene-based nanomaterials, namely Ge-H, Ge-CH3 and Ge-C3-CN were investigated on their novel incorporation in impedimetric immunosensors for the detection of gut-derived metabolites associated with neurological diseases, such as kynurenic acid (KA) and quinolinic acid (QA). The designed germanene-based immunosensor relies on an indirect competitive mechanism using disposable electrode printed chips. The competition for a fixed binding site of a primary antibody occurs between the bovine serum albumin-conjugated antigens on the electrode surface and the free antigens in the solution. Among the three materials, Ge-H displayed superior bioanalytical performance in KA and QA detection. Lower limits of detection of 5.07-11.38 ng/mL (26.79-68.11 nM) were attained for KA and QA with a faster reaction time than previously reported methods. Also, minimal cross-reactivity with interfering compounds, good reproducibility in impedimetric responses (RSD = 2.43-7.51 %) and long-term stability up to a month at 4 °C were the other attributes that the proposed Ge-H competitive impedimetric immunosensor has accomplished. The application of the developed Ge-H immunosensor to serum samples allowed an accurate KA and QA quantification at physiologically relevant levels. This work serves as a stepping-stone in the development of germanene-based nanomaterials for their implementation into cost-effective, miniaturized, portable and rapid impedimetric immunosensors, which are highly desirable for point-of-care testing in clinical settings.

The kynurenine pathway in treatment-resistant schizophrenia at the crossroads between pathophysiology and pharmacotherapy.

Two cardinal elements in the complex and multifaceted pathophysiology of schizophrenia (SCZ) are neuroinflammation and dysregulation of glutamatergic neurotransmission, with the latter being especially involved in treatment-resistant schizophrenia (TRS). Interestingly, the Kynurenine (KYN) pathway (KP) is at the crossroad between them, constituting a potential causal link and a therapeutic target. Although there is preclinical and clinical evidence indicating a dysregulation of KP associated with the clinical phenotype of SCZ, clinical studies investigating the possible relationship between changes in biomarkers of the KP and response to pharmacotherapy are still limited. Therefore, we have studied possible differences in the circulating levels of biomarkers of the metabolism of tryptophan along the KP in 43 responders to first-line treatments (FLR) and 32 TRS patients treated with clozapine, and their possible associations with psychopathology in the two subgroups. Plasma levels of KYN were significantly higher in TRS patients than in FLR patients, indicating a greater activation of KP. Furthermore, the levels of quinolinic (NMDA receptor agonist) and kynurenic acid (NMDA negative allosteric modulator) showed a negative and a positive correlation with several dimensions and the overall symptomatology in the whole sample and in FLR, but not in TRS, suggesting a putative modulating effect of clozapine elicited through the NMDA receptors. Despite the cross-sectional design of the study that prevents us from demonstrating causation, these findings show a significant relationship among circulating KP biomarkers, psychopathology, and response to pharmacotherapy in SCZ. Therefore, plasma KP biomarkers should be further investigated for developing personalized medicine approaches in SCZ.

Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process.

Senescent microglia are a distinct microglial phenotype present in aging brain that have been implicated in the progression of aging and age-related neurodegenerative diseases. However, the specific mechanisms that trigger microglial senescence are largely unknown. Quinolinic acid (QA) is a cytotoxic metabolite produced upon abnormal activation of microglia. Brain aging and age-related neurodegenerative diseases have an elevated concentration of QA. In the present study, we investigated whether QA promotes aging and aging-related phenotypes in microglia and C. elegans. Here, we demonstrate for the first time that QA, secreted by abnormal microglial stimulation, induces impaired mitophagy by inhibiting mitolysosome formation and consequently promotes the accumulation of damaged mitochondria due to reduced mitochondrial turnover in microglial cells. Defective mitophagy caused by QA drives microglial senescence and poor healthspan in C. elegans. Moreover, oxidative stress can mediate QA-induced mitophagy impairment and senescence in microglial cells. Importantly, we found that restoration of mitophagy by mitophagy inducer, urolithin A, prevents microglial senescence and improves healthspan in C. elegans by promoting mitolysosome formation and rescuing mitochondrial turnover inhibited by QA. Thus, our study indicates that mitolysosome formation impaired by QA is a significant aetiology underlying aging-associated changes. QA-induced mitophagy impairment plays a critical role in neuroinflammation and age-related diseases. Further, our study suggests that mitophagy inducers such as urolithin A may offer a promising anti-aging strategy for the prevention and treatment of neuroinflammation-associated brain aging diseases.

Tryptophan metabolism as a 'reflex' feature of neuroimmune communication: Sensor and effector functions for the indoleamine-2, 3-dioxygenase kynurenine pathway.

Although the central nervous system (CNS) and immune system were regarded as independent entities, it is now clear that immune system cells can influence the CNS, and neuroglial activity influences the immune system. Despite the many clinical implications for this 'neuroimmune interface', its detailed operation at the molecular level remains unclear. This narrative review focuses on the metabolism of tryptophan along the kynurenine pathway, since its products have critical actions in both the nervous and immune systems, placing it in a unique position to influence neuroimmune communication. In particular, since the kynurenine pathway is activated by pro-inflammatory mediators, it is proposed that physical and psychological stressors are the stimuli of an organismal protective reflex, with kynurenine metabolites as the effector arm co-ordinating protective neural and immune system responses. After a brief review of the neuroimmune interface, the general perception of tryptophan metabolism along the kynurenine pathway is expanded to emphasize this environmentally driven perspective. The initial enzymes in the kynurenine pathway include indoleamine-2,3-dioxygenase (IDO1), which is induced by tissue damage, inflammatory mediators or microbial products, and tryptophan-2,3-dioxygenase (TDO), which is induced by stress-induced glucocorticoids. In the immune system, kynurenic acid modulates leucocyte differentiation, inflammatory balance and immune tolerance by activating aryl hydrocarbon receptors and modulates pain via the GPR35 protein. In the CNS, quinolinic acid activates N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors, whereas kynurenic acid is an antagonist: the balance between glutamate, quinolinic acid and kynurenic acid is a significant regulator of CNS function and plasticity. The concept of kynurenine and its metabolites as mediators of a reflex coordinated protection against stress helps to understand the variety and breadth of their activity. It should also help to understand the pathological origin of some psychiatric and neurodegenerative diseases involving the immune system and CNS, facilitating the development of new pharmacological strategies for treatment.

A systematic review and meta-analysis of the kynurenine pathway of tryptophan metabolism in rheumatic diseases.

There is an increasing interest in the pathophysiological role of the kynurenine pathway of tryptophan metabolism in the regulation of immune function and inflammation. We sought to address the link between this pathway and the presence rheumatic diseases (RD) by conducting a systematic review and meta-analysis of studies reporting the plasma or serum concentrations of tryptophan, kynurenine, and other relevant metabolites in RD patients and healthy controls. We searched electronic databases for relevant articles published between inception and the 30th of June 2023. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and the Grades of Recommendation, Assessment, Development and Evaluation Working Group system. In 24 studies selected for analysis, compared to controls, RD patients had significantly lower tryptophan (standard mean difference, SMD= -0.71, 95% CI -1.03 to -0.39, p<0.001; I2 = 93.6%, p<0.001; low certainty of evidence), and higher kynurenine (SMD=0.69, 95% CI 0.35 to 1.02, p<0.001; I2 = 93.2%, p<0.001; low certainty), kynurenine to tryptophan ratios (SMD=0.88, 95% CI 0.55 to 1.21, p<0.001; I2 = 92.9%, p<0.001; moderate certainty), 3-hydroxykynurenine (SMD=0.74, 95% CI 0.30 to 1.18, p=0.001; I2 = 87.7%, p<0.001; extremely low certainty), and quinolinic acid concentrations (SMD=0.71, 95% CI 0.31 to 1.11, p<0.001; I2 = 88.1%, p<0.001; extremely low certainty). By contrast, there were non-significant between-group differences in kynurenic acid, 3-hydroxyanthranilic acid, kynurenic acid to kynurenine ratio, or quinolinic acid to kynurenine acid ratio. In meta-regression, the SMD of tryptophan, kynurenine, and kynurenine to tryptophan ratio were not associated with age, publication year, sample size, RD duration, C-reactive protein, or use of anti-rheumatic drugs and corticosteroids. In subgroup analysis, the SMD of tryptophan, kynurenine, and kynurenine to tryptophan ratio was significant across different types of RD, barring rheumatoid arthritis. Therefore, we have observed significant alterations in tryptophan, kynurenine, 3-hydroxykynurenine, and quinolinic acid concentrations in RD patients. Further research is warranted to determine whether these biomarkers can be useful for diagnosis and management in this patient group. (PROSPERO registration number: CRD CRD42023443718). Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD CRD42023443718.

Kynurenine, Kynurenic Acid, Quinolinic Acid and Interleukin-6 Levels in the Serum of Patients with Autism Spectrum Disorder.

Background and Objectives: It is known that inflammatory processes play a role in the pathogenesis of autism spectrum disorder (ASD). It is also reported that immune activation induces the kynurenine pathway (KP), as known as the tryptophan destruction pathway. In our study, we aimed to investigate whether the serum levels of KP products and interleukin (IL)-6 activating indolamine 2-3 dioxygenase (IDO) enzyme are different in healthy developing children and children with ASD. Materials and Methods: Forty-three ASD children aged 2-9 were included in this study. Forty-two healthy developing children, similar to the patient group in terms of age and gender, were selected as the control group. Serum levels of kynurenic acid, kynurenine, quinolinic acid and IL-6 were analyzed using the ELISA method. ASD severity was evaluated with the Autism Behavior Checklist (ABC). Results: The mean age of children with ASD was 42.4 ± 20.5 months, and that of healthy controls was 48.1 ± 15.8 months. While the serum levels of kynurenic acid, kynurenine and interleukin-6 were higher in the group with ASD (p < 0.05), there was no significant difference (p > 0.05) in terms of the quinolinic acid level. There was no significant difference between the ABC total and subscale scores of children with ASD and biochemical parameters (p > 0.05). Conclusions: We conclude that these biomarkers must be measured in all ASD cases. They may be important for the diagnosis of ASD.

The possible role of quinolinic acid as a predictive marker in patients with SARS-CoV-2.

BACKGROUND AND AIMS: Quinolinic acid (QA) is a metabolite of the kynurenine pathway, which is activated by inflammatory stimuli during viral infection. We investigated the role of QA in patients infected with SARS-CoV-2, particularly its prognostic value for survival. METHODS: Overall, 104 unvaccinated inpatients were included, divided into a survival (N = 80) and a deceased group (N = 24). Plasma levels of tryptophan, kynurenine, QA, C-reactive protein (CRP) and procalcitonin (PCT) were measured on admission and after seven days. The QA/TRP ratio and the relative differences between the measurements for QA (QA-Diff) and QA/TRP (Diff-QA/TRP) were calculated. RESULTS: Among the kynurenine pathway markers, QA-Diff showed the highest discriminatory power for the survival prognosis (Youden index 0.467, cut-off -1.3 %, AUC 0.733, p < 0.001, sensitivity 0.79, specificity 0.675). Among the inflammatory markers, CRP showed the highest discriminatory power (Youden index 0.533, cut-off 25.0 mg/L, AUC 0.794, p < 0.001, sensitivity 0.958, specificity 0.575). A significant correlation between QA and PCT was found on admission and after one week (Spearman's rho 0.455 and 0.539, all p-values < 0.001). CONCLUSIONS: QA may serve as prognostic marker for survival in patients with SARS-CoV-2. The repeated measurements during the first week of the disease may enhance the prognostic power.