A Review on the Role and Function of Cinnabarinic Acid, a "Forgotten" Metabolite of the Kynurenine Pathway.

In the human body, the majority of tryptophan is metabolized through the kynurenine pathway. This consists of several metabolites collectively called the kynurenines and includes, among others, kynurenic acid, L-kynurenine, or quinolinic acid. The wealth of metabolites, as well as the associated molecular targets and biological pathways, bring about a situation wherein even a slight imbalance in the kynurenine levels, both in the periphery and central nervous system, have broad consequences regarding general health. Cinnabarinic acid (CA) is the least known trace kynurenine, and its physiological and pathological roles are not widely understood. Some studies, however, indicate that it might be neuroprotective. Information on its hepatoprotective properties have also emerged, although these are pioneering studies and need to be replicated. Therefore, in this review, I aim to present and critically discuss the current knowledge on CA and its role in physiological and pathological settings to guide future studies.

Alteration in kynurenine pathway metabolites in young women with autoimmune thyroiditis.

The kynurenine pathway (KP) of tryptophan degradation includes several compounds that reveal immunomodulatory properties. The present study aimed to investigate the alteration in KP metabolites in young women with autoimmune thyroiditis (AIT) and their associations with thyroid function. The thyroid function tests, antithyroid antibodies measurement and ultrasonography of the thyroid gland have been performed in 57 young women with AIT and 38 age-matched healthy controls. The serum levels of tryptophan, kynurenine (KYN) and its metabolites were determined, and the activity of KP enzymes was calculated indirectly as product-to-substrate ratios. KP was activated and dysregulated in AIT, along with significantly elevated levels of KYN and anthranilic acid (AA), at the expense of the reduction of kynurenic acid (KYNA), which was reflected by the increase in the AA/KYNA ratio (p < 0.001). In univariate and multiple regression analyses, peripheral deiodinase (SPINA-GD) activity in AIT was positively associated with KYNA, AA, and quinolinic acid (QA). The merger of AA, AA/KYNA ratio, QA and SPINA-GD exhibited the highest sensitivity and specificity to predict AIT (p < 0.001) in receiver operating characteristic (ROC) analysis. In conclusion, the serum KYN metabolite profile is dysregulated in young women with AIT and could serve as a new predictor of AIT risk.

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.

Metabolomic changes in adults with status epilepticus: A human case-control study.

OBJECTIVE: Status epilepticus (SE) is a life-threatening prolonged epileptic seizure that affects ~40 per 100 000 people yearly worldwide. The persistence of seizures may lead to excitotoxic processes, neuronal loss, and neuroinflammation, resulting in long-term neurocognitive and functional disabilities. A better understanding of the pathophysiological mechanisms underlying SE consequences is crucial for improving SE management and preventing secondary neuronal injury. METHODS: We conducted a comprehensive untargeted metabolomic analysis, using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS), on plasma and cerebrospinal fluid (CSF) samples from 78 adult patients with SE and 107 control patients without SE, including 29 with CSF for both groups. The metabolomic fingerprints were compared between patients with SE and controls. Metabolites with differences in relative abundances that could not be attributed to treatment or nutrition provided in the intensive care unit were isolated. Enrichment analysis was performed on these metabolites to identify the most affected pathways. RESULTS: We identified 76 metabolites in the plasma and 37 in the CSF that exhibited differential expression in patients with SE compared to controls. The enrichment analysis revealed that metabolic dysregulations in patients with SE affected primarily amino acid metabolism (including glutamate, alanine, tryptophan, glycine, and serine metabolism), pyrimidine metabolism, and lipid homeostasis. Specifically, patients with SE had elevated levels of pyruvate, quinolinic acid, and keto butyric acid levels, along with lower levels of arginine, N-acetylaspartylglutamate (NAAG), tryptophan, uracil, and uridine. The tryptophan kynurenine pathway was identified as the most significantly altered in SE, resulting in the overproduction of quinolinic acid, an N-methyl-d-aspartate (NMDA) receptor agonist with pro-inflammatory properties. SIGNIFICANCE: This study has identified several pathways that may play pivotal roles in SE consequences, such as the tryptophan kynurenine pathway. These findings offer novel perspectives for the development of neuroprotective therapeutics.

Kynurenines, Neuronal Excitotoxicity, and Mitochondrial Oxidative Stress: Role of the Intestinal Flora.

The intestinal flora has been the focus of numerous investigations recently, with inquiries not just into the gastrointestinal aspects but also the pathomechanism of other diseases such as nervous system disorders and mitochondrial diseases. Mitochondrial disorders are the most common type of inheritable metabolic illness caused by mutations of mitochondrial and nuclear DNA. Despite the intensive research, its diagnosis is usually difficult, and unfortunately, treating it challenges physicians. Metabolites of the kynurenine pathway are linked to many disorders, such as depression, schizophrenia, migraine, and also diseases associated with impaired mitochondrial function. The kynurenine pathway includes many substances, for instance kynurenic acid and quinolinic acid. In this review, we would like to show a possible link between the metabolites of the kynurenine pathway and mitochondrial stress in the context of intestinal flora. Furthermore, we summarize the possible markers of and future therapeutic options for the kynurenine pathway in excitotoxicity and mitochondrial oxidative stress.

Tryptophan metabolites and gut microbiota play an important role in pediatric migraine diagnosis.

BACKGROUND: The pathogenesis of pediatric migraine remains unclear and presents challenges in diagnosis. Recently, growing evidence has indicated that the gut microbiota can exert modulatory functions at the gut-brain axis by directly or indirectly regulating tryptophan metabolism. Consequently, we aimed to elucidate the potential association among gut microbiota, tryptophan metabolism, and pediatric migraine while also identifying diagnostic biomarkers for pediatric migraine. METHODS: The gut microbiota composition of 33 migraine children and 42 healthy children, aged less than ten years, from the GMrepo database, was analyzed using the Shannon index, Simpson index, principal coordinates analysis, and Wilcoxon rank-sum test. Microbial diagnostic biomarkers were identified using linear discriminant analysis effect size, ridge regression, and random forest. Plasma concentrations of tryptophan metabolites investigated by enzyme-linked immunosorbent assay were compared between 51 migraine children and 120 healthy children, aged less than eighteen years, using t tests and analysis of variance. The receiver operating characteristic curve was performed to evaluate the diagnostic value of microbial and metabolite biomarkers in pediatric migraine. RESULTS: Differences in the composition of gut microbiota, notably the genera that regulate tryptophan metabolism, were observed in pediatric migraine children. Further investigations revealed a significant decrease in plasma kynurenic acid levels (p < 0.001) among migraine children, along with a significant increase in serotonin (p < 0.05) and quinolinic acid (p < 0.001). Subsequently, we established the normal reference intervals for plasma concentrations of tryptophan metabolites in children. More importantly, the ratio of kynurenic acid to quinolinic acid (AUC: 0.871, sensitivity: 86.3%, specificity: 83.3%) exhibited excellent diagnostic efficacy for pediatric migraine. CONCLUSION: Our study suggests that the gut microbiota may play an important role in the development of pediatric migraine by regulating tryptophan metabolism. We believe that microbial and metabolite biomarkers are sensitive diagnostic tests for pediatric migraine. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT05969990).

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.

Relation of the kynurenine pathway with normal age: A systematic review.

BACKGROUND: The kynurenine pathway (KP) is gaining more attention as a common pathway involved in age-related conditions. However, which changes in the KP occur due to normal ageing is still largely unclear. The aim of this systematic review was to summarize the available evidence for associations of KP metabolites with age. METHODS: We used an broad search strategy and included studies up to October 2023. RESULTS: Out of 8795 hits, 55 studies were eligible for the systematic review. These studies suggest that blood levels of tryptophan decrease with age, while blood and cerebrospinal fluid levels of kynurenine and its ratio with tryptophan increase. Studies investigating associations between cerebrospinal fluid and blood levels of kynurenic acid and quinolinic acid with age reported either positive or non-significant findings. However, there is a large heterogeneity across studies. Additionally, most studies were cross-sectional, and only few studies investigated associations with other downstream kynurenines. CONCLUSIONS: This systematic review suggests that levels of kynurenines are positively associated with age. Larger and prospective studies are needed that also investigate a more comprehensive panel of KP metabolites and changes during the life-course.

Sex- and suicide-specific alterations in the kynurenine pathway in the anterior cingulate cortex in major depression.

Major depressive disorder (MDD) is a serious psychiatric disorder that in extreme cases can lead to suicide. Evidence suggests that alterations in the kynurenine pathway (KP) contribute to the pathology of MDD. Activation of the KP leads to the formation of neuroactive metabolites, including kynurenic acid (KYNA) and quinolinic acid (QUIN). To test for changes in the KP, postmortem anterior cingulate cortex (ACC) was obtained from the National Institute of Health NeuroBioBank. Gene expression of KP enzymes and relevant neuroinflammatory markers were investigated via RT-qPCR (Fluidigm) and KP metabolites were measured using liquid chromatography-mass spectrometry in tissue from individuals with MDD (n = 44) and matched nonpsychiatric controls (n = 36). We report increased IL6 and IL1B mRNA in MDD. Subgroup analysis found that female MDD subjects had significantly decreased KYNA and a trend decrease in the KYNA/QUIN ratio compared to female controls. In addition, MDD subjects that died by suicide had significantly decreased KYNA in comparison to controls and MDD subjects that did not die by suicide, while subjects that did not die by suicide had increased KYAT2 mRNA, which we hypothesise may protect against a decrease in KYNA. Overall, we found sex- and suicide-specific alterations in the KP in the ACC in MDD. This is the first molecular evidence in the brain of subgroup specific changes in the KP in MDD, which not only suggests that treatments aimed at upregulation of the KYNA arm in the brain may be favourable for female MDD sufferers but also might assist managing suicidal behaviour.

The protective effects of hesperidin as an antioxidant against quinolinic acid-induced toxicity on oligodendroglia cells: An in vitro study.

INTRODUCTION: Multiple sclerosis (MS) is a complex central nervous system disorder, marked by neurodegenerative and inflammatory processes, where overproduction of reactive oxygen species (ROS) is a key factor in demyelination and neurodegeneration. The current study aims to investigate the effect of hesperidin and Quinolinic acid (QA) on ROS and antioxidant levels, and cell viability of OLN-93 cells. METHODS: OLN-93 cell lines were treated with hesperidin and QA. OLN-93 cells were cultured in Dulbecco's modified Eagle's medium under controlled conditions. Cell viability assays were performed using resazurin to assess the toxicity of hesperidin and QA. Additionally, ROS levels were measured using DCFDA, and malondialdehyde (MDA) levels were determined to evaluate oxidative stress. Superoxide dismutase (SOD) activity and cell viability were assessed by trypan blue staining after exposure to hesperidin and QA. RESULTS: The results of the current study showed that co-administration of 8 mM QA with 50, 100, and 200 µM hesperidin significantly reduced both ROS and MDA levels, demonstrating a substantial attenuation in comparison to the elevated ROS and MDA levels induced by 8 mM QA (p-value < 0.01). Furthermore, 8 mM QA + 50, 100, and 200 µM hesperidin significantly increased SOD levels compared with QA alone (p-value < 0.01). In addition, treatment of OLN cells with 8 mM QA + 50, 100, and 200 µM hesperidin led to higher cell viability compared to QA alone (p value <0.0001). CONCLUSION: The current study demonstrated the antioxidant effect of hesperidin on OLN-93 cells suggesting new insights into the clinical application of hesperidin as an effective treatment for patients with MS. Future in vivo studies, focusing on cellular mechanisms are recommended.

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.

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.

APOE Polymorphism Is Associated with Changes in the Kynurenine Pathway.

BACKGROUND: APOE polymorphism and the Kynurenine pathway (KP) are associated with many disorders, but little is known about associations between APOE polymorphism and the KP. This study explored the associations between the KP and APOE polymorphism in disorders associated with APOE polymorphism and changes in the KP. METHODS: Subjects with morbid obesity before and after bariatric surgery (numbers 139 and 95, respectively), depression (number 49), and unspecified neurological symptoms (number 39) were included. The following grouping of the APOE genotypes was used: E2 = ɛ2ɛ2 + ɛ2ɛ3, E3 = ɛ3ɛ3 + ɛ2ɛ4, and E4 = ɛ3ɛ4 + ɛ4ɛ4. The KP metabolites Tryptophan, Kynurenine, Kynurenic acid, Quinolinic acid, and Xanthurenic acid were quantified in serum. RESULTS: The main findings were a significant positive association between E3 and Quinolinic acid (difference between E3 and E2E4: 12.0 (3.5; 18.6) ng/mL); p = 0.005), and a negative association between E4 and Kynurenine (difference between E4 and E2E3: -31.3 (-54.2; -3.2) ng/mL; p = 0.008). Quinolinic acid has been ascribed neurotoxic and inflammatory effects, and Kynurenine is a marker of inflammation. CONCLUSIONS: The findings indicate that APOE polymorphism might cause changes in the KP that contribute to the disease. Inflammation could be the link between APOE and the KP.

Hepatocyte nuclear factor 4α mediated quinolinate phosphoribosylltransferase (QPRT) expression in the kidney facilitates resilience against acute kidney injury.

Nicotinamide adenine dinucleotide (NAD+) levels decline in experimental models of acute kidney injury (AKI). Attenuated enzymatic conversion of tryptophan to NAD+ in tubular epithelium may contribute to adverse cellular and physiological outcomes. Mechanisms underlying defense of tryptophan-dependent NAD+ production are incompletely understood. Here we show that regulation of a bottleneck enzyme in this pathway, quinolinate phosphoribosyltransferase (QPRT) may contribute to kidney resilience. Expression of QPRT declined in two unrelated models of AKI. Haploinsufficient mice developed worse outcomes compared to littermate controls whereas novel, conditional gain-of-function mice were protected from injury. Applying these findings, we then identified hepatocyte nuclear factor 4 alpha (HNF4α) as a candidate transcription factor regulating QPRT expression downstream of the mitochondrial biogenesis regulator and NAD+ biosynthesis inducer PPARgamma coactivator-1-alpha (PGC1α). This was verified by chromatin immunoprecipitation. A PGC1α - HNF4α -QPRT axis controlled NAD+ levels across cellular compartments and modulated cellular ATP. These results propose that tryptophan-dependent NAD+ biosynthesis via QPRT and induced by HNF4α may be a critical determinant of kidney resilience to noxious stressors.

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.

The kynurenine pathway in major depressive disorder under different disease states: A systematic review and meta-analysis.

BACKGROUND: A disruption of the kynurenine (KYN) pathway may exist in major depressive disorder (MDD). However, the changing pattern of the KYN pathway across the different disease states in MDD is unclear. Herein, we performed a meta-analysis to examine the differences in KYN metabolites between patients in the current episode of MDD (cMDD) and patients in remission (rMDD), as well as the changes after treatments. METHODS: Literature was systematically searched from electronic databases, from inception up to September 2022. Random-effect models were used to quantify the differences in KYN metabolites between patients with MDD across acute depressive episode and remission phases, as well as the changes after treatments. RESULTS: Fifty-one studies involving 7056 participants were included. Tryptophan (TRP), KYN, kynurenic acid (KYNA), KYNA/quinolinic acid (QA), KYNA/3-hydroxykynurenine (3-HK), and KYNA/KYN were significantly lower, while KYN/TRP was significantly higher in patients with cMDD. Moreover, these effect sizes were generally larger in medication-free patients. No significant differences were found between patients with rMDD and HCs. Additionally, KYNA was found negatively correlated with depression severity and significantly increased after treatments, while the alteration was not found in QA. LIMITATIONS: The number of included studies of patients with rMDD and longitudinal studies investigating the change of the KYN metabolites after treatment with antidepressants was limited. In addition, the heterogeneity across included studies was relatively high. CONCLUSIONS: These findings showed a comprehensive image of the unique dysfunction pattern of the KYN pathway across different MDD states and highlighted KYNA as a potentially sensitive biomarker of MDD.

Effect of Quinolinic Acid on Behavior, Morphology, and Expression of Inflammatory/oxidative Status in Rats' Striatum: Is Coenzyme Q10 a Good Protector?

Quinolinic acid (QUIN) is a toxic compound with pro-oxidant, pro-inflammatory, and pro-apoptotic actions found at high levels in the central nervous system (CNS) in several pathological conditions. Due to the toxicity of QUIN, it is important to evaluate strategies to protect against the damage caused by this metabolite in the brain. In this context, coenzyme Q10 (CoQ10) is a provitamin present in the mitochondria with a protective role in cells through several mechanisms of action. Based on these, the present study was aimed at evaluating the possible neuroprotective role of CoQ10 against damage caused by QUIN in the striatum of young Wistar rats. Twenty-one-day-old rats underwent a 10-day pretreatment with CoQ10 or saline (control) intraperitoneal injections and on the 30th day of life received QUIN intrastriatal or saline (control) administration. The animals were submitted to behavior tests or euthanized, and the striatum was dissected to neurochemical studies. Results showed that CoQ10 was able to prevent behavioral changes (the open field, object recognition, and pole test tasks) and neurochemical parameters (alteration in the gene expression of IL-1ß, IL-6, SOD, and GPx, as well as in the immunocontent of cytoplasmic Nrf2 and nuclear p-Nf-κß) caused by QUIN. These findings demonstrate the promising therapeutic effects of CoQ10 against QUIN toxicity.

Relationship of tryptophan metabolites with the type and severity of multiple sclerosis.

BACKGROUND: Tryptophan is an essential amino acid primarily metabolized by the kynurenine pathway in mammals. Intermediate metabolites emerging in this pathway have been associated with many neurogenerative diseases. This study aimed to compare tryptophan pathway metabolite levels in patients with multiple sclerosis (MS) and healthy controls and reveal the relationship of tryptophan metabolites with disease subtype and the Expanded Disability Status Scale (EDSS) score. METHODS: The study included a total of 80 MS cases [53 with relapsing remitting MS (RRMS) and 27 with secondary progressive MS (SPMS)] and 41 healthy volunteers. The patients with RRMS were further divided into relapse (RRMS-attack) and non-attack (RRMS-stable) groups. Using liquid chromatography mass spectrometry, tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid levels were measured. The serum metabolite levels of the patient and control groups were compared. In addition, the link and relationship between the EDSS score and disease duration of the patients and their plasma tryptophan metabolite levels were examined. RESULTS: The tryptophan level of the patient group was significantly lower than that of the healthy controls (p<0.05). The kynurenine (105.38±65.43), quinolinic acid (10.42±3.56), kynurenine/tryptophan ratio (0.0218±0.019), and quinolinic acid/kynurenic acid ratio (1.7054±0.96141) of the patients with MS were significantly higher compared to the controls (p<0.05). In the receiver operating characteristic analysis of the power of kynurenine/tryptophan and quinolinic acid/kynurenic acid ratios in predicting the disease, both ratios predicted the diagnosis of MS (area under the curve: 0.793 and 0.645, respectively; p<0.05), albeit at low sensitivity and specificity. The parameters were similar between the RRMS-attack and RRMS-stable patient groups (p>0.05). There was also no significant difference between the RRMS and SPMS patient groups in terms of tryptophan metabolites (p>0.05). Lastly, no significant relationship was observed between tryptophan metabolites and MS subtype and the EDSS score. CONCLUSION: Our findings revealed that the kynurenine pathway involved in the tryptophan metabolism differed between the patients with MS and healthy controls, and this difference may be a limited guide in the diagnosis of MS, due to major overlaps in values for MS versus Controls, and is insufficient to determine the disease subtype.