Kynurenic Research Articles

Enhanced Targeted Drug Delivery for Scar Prevention: Clathrin‐Coated Solid Lipid Nanoparticles for Model Drug Encapsulation

AbstractExcessive scar formation is a major complication of wound healing. Premature release of anti‐scarring drugs can negatively impact healing. This study aims to develop a targeted delivery system for the controlled release of anti‐scarring drugs during the scar formation stage. Solid lipid nanoparticles (SLNs) coated with Clathrin, a cage‐like protein, to prevent premature drug release is developed. Insulin‐like growth factor (IGF) is conjugated to the SLNs for targeted delivery via its affinity for connective tissue growth factor (CTGF), a protein overexpressed during scar formation. The IGF‐Clathrin‐SLNs exhibited a size of 300 ± 20 nm and a zeta potential of 9.23 ± 0.4 mV. In vitro studies demonstrated sustained release of the encapsulated drug‐ kynurenic acid; less than 10% of kynurenic acid is released within three days, while over 50% is released within 10 h upon Clathrin removal using a surfactant at pH 8. Cellular uptake studies confirmed targeting efficacy. Fibroblasts with low CTGF expression displayed low uptake (<10%), whereas MCF7 cells with high CTGF expression showed significantly higher uptake (80%). This work demonstrates a promising targeted delivery platform for the controlled release of anti‐scarring drugs during scar formation.

Neurobiological mechanisms in the kynurenine pathway and major depressive disorder.

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

Computed Tomography and Fluorescence Spectroscopy Blood Plasma Analysis Study for Kynurenic Acid as a Diagnostic Approach to Chronic Coenurosis in Sheep.

Coenurosis is a parasitic disease caused by the larval stage of Taenia multiceps, Coenurus cerebralis, typically found in the central nervous system of different livestock such as sheep and goats. The blood plasma from fifteen clinically healthy sheep and six sheep with neurological symptoms was studied by fluorescence spectroscopy in order to establish the contribution of kynurenic acid (KYNA), the neuroprotective metabolite of the kynurenine pathway, to the total fluorescence of the plasma. CT scans were used to confirm the presence of cysts in the central nervous system of sheep with neurological symptoms. The fluorescence spectroscopy analysis and further spectra deconvolution process revealed some significantly lower KYNA contributions to the total plasma fluorescence in sheep with coenurosis compared to healthy controls. Our results indicate that KYNA emission parameters could serve as valuable diagnostic markers, particularly for detecting preclinical cases of coenurosis, thus allowing for improved farm management practices.

Integrative microbiome and metabolome profiles reveal the impacts of periodontitis via oral-gut axis in first-trimester pregnant women

BackgroundPeriodontitis results from host-microbe dysbiosis and the resultant dysregulated immunoinflammatory response. Importantly, it closely links to numerous systemic comorbidities, and perplexingly contributes to adverse pregnancy outcomes (APOs). Currently, there are limited studies on the distal consequences of periodontitis via oral-gut axis in pregnant women. This study investigated the integrative microbiome-metabolome profiles through multi-omics approaches in first-trimester pregnant women and explored the translational potentials.MethodsWe collected samples of subgingival plaques, saliva, sera and stool from 54 Chinese pregnant women at the first trimester, including 31 maternal periodontitis (Perio) subjects and 23 Non-Perio controls. By integrating 16S rRNA sequencing, untargeted metabolomics and clinical traits, we explored the oral-gut microbial and metabolic connection resulting from periodontitis among early pregnant women.ResultsWe demonstrated a novel bacterial distinguisher Coprococcus from feces of periodontitis subjects in association with subgingival periodontopathogens, being different from other fecal genera in Lachnospiraceae family. The ratio of fecal Coprococcus to Lachnoclostridium could discriminate between Perio and Non-Perio groups as the ratio of subgingival Porphyromonas to Rothia did. Furthermore, there were differentially abundant fecal metabolic features pivotally enriched in periodontitis subjects like L-urobilin and kynurenic acid. We revealed a periodontitis-oriented integrative network cluster, which was centered with fecal Coprococcus and L-urobilin as well as serum triglyceride.ConclusionsThe current findings about the notable influence of periodontitis on fecal microbiota and metabolites in first-trimester pregnant women via oral-gut axis signify the importance and translational implications of preconceptional oral/periodontal healthcare for enhancing maternal wellbeing.

Prospective Clinical Study: Full-Body Blue Irradiation in the Treatment of Atopic Dermatitis.

Ultraviolet-free (UV-free) blue light phototherapy has emerged as a promising option due to its reported efficacy and minimal adverse effects. This study aims to evaluate the effectiveness of full-body blue light irradiation in both adult and pediatric patients with atopic dermatitis (AD), assessing its impact on skin condition and mood regulation by investigating serum concentrations of serotonin and kynurenine pathway metabolites. 20 patients (age 9-45) with moderate and severe AD were included in the study. Treatment consisted of 10 irradiations with Full Body Blue device (453nm). Serum concentrations of serotonin, quinolinic acid, kynurenic acid, tryptophan, and kynurenine were measured before and after irradiations. After 10 sessions of full blue light therapy (453nm) statistically significant improvements were observed in Eczema Area Severity Index (EASI 13.16 vs. 8.65; p = 0.00016), SCORing Atopic Dermatitis (SCORAD 44.99 vs. 23.73; p < 0.00001), Visual Analogue Scale (VAS 6.53 vs. 3.95; p = 0.00251), 10-item pruritus severity scale (13.32 vs. 7.05; p < 0.00001). Moreover, statistically significant decrease in Dermatology Life Quality Index (DLQI) was noted (14.37 vs. 7.42; p = 0.00351). Additionally, increase in the serum concentration of serotonin was observed after completing 10 irradiation sessions (median 139.77mg/ml vs. 274.92mg/ml; p < 0.00001). Blue light may be a promising and safe treatment in patients with AD. It might also positively influence mood. Further investigations are needed to confirm those findings. ClinicalTrials.gov identifier, NCT06516783.

Abstract P141: Salt tips the balance of tryptophan metabolism between host and gut microbiota in a sex specific manner

Introduction: Tryptophan (Trp) diet attenuates hypertension in male Dahl salt sensitive (S) rats with unknown mechanisms. Kynurenine (a vasodilator) and serotonin (mixed effects on blood pressure) are host-derived Trp metabolites while indole is produced exclusively by the gut microbiota. We have previously shown that the gut microbiota of male, but not female, S rats is susceptible to salt, causing a higher indole level that elevated blood pressure. In this study, we reported the sex differences in all Trp metabolites with a focus on the impact of salt and the mechanisms by which female gut microbiota is more resilient. Methodology: S rats of both sexes (10–13-week-old, n = 4-7/group) were maintained on either a low-salt (0.3 % NaCl, LS) or high-salt (2 % NaCl, HS) diet for 3 weeks. Trp metabolites were analyzed in serum and cecum by LC-MS/MS. To investigate if estrogen shape gut microbiota, gonadectomy was performed on 7-week-old Spontaneously Hypertensive Rats (SHR) of both sexes (n=5/group). β-estradiol (2.8 mg/kg) was administered subcutaneously for 12 weeks before fecal 16S rRNA gene sequencing. Results: Females had elevated levels of kynurenine (Kyn) compared to male S rats on both LS (5.5 ± 1.4 vs. 2.1 ± 0.5 µM; P &lt;0.05) and HS (7 ± 1.3 vs. 4.2 ± 1 µM; P &lt;0.05). Kyn metabolites including kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid were elevated in the serum of females compared with males, and HS amplified this difference (all P &lt;0.05). Further, HS significantly decreased the serum serotonin levels in both sexes ( P &lt;0.01 in females, P &lt;0.0001 in males). Intriguingly, HS increased cecal indole levels in male ( P &lt;0.05), but not in female rats. Microbiota analysis of gonadectomized (GDX) SHR rats revealed (1) Significant differences in β-diversity between intact vs. GDX rats ( P &lt;0.01), and between GDX male vs. female rats ( P =0.01); (2) Estrogen supplementation eliminates the gut microbiota differences between GDX females and males ( P =0.18). Conclusion: We demonstrated sex differences in Trp metabolism in response to high salt. Further, estrogen masked the microbial differences between GDX male and female SHR rats. In summary, salt led to an elevated Trp-Kyn metabolism in female host, and an enhanced Trp-indole metabolism in male gut microbiota, which could be due to the estrogen’s effect on shaping gut microbiota. Thus, the Trp metabolism in salt-sensitive hypertension is regulated in a sex-specific manner.

Kynurenic Acid Modulates the Expression of Genes and the Activity of Cellular Antioxidant Enzymes in the Hypothalamus and Hippocampus in Sheep.

Kynurenic acid (KYNA), a tryptophan metabolite, is believed to exert neuromodulatory and neuroprotective effects in the brain. This study aimed to examine KYNA's capacity to modify gene expression and the activity of cellular antioxidant enzymes in specific structures of the sheep brain. Anestrous sheep were infused intracerebroventricularly with two KYNA doses-lower (4 × 5 μg/60 μL/30 min, KYNA20) and higher (4 × 25 μg/60 μL/30 min, KYNA100)-at 30 min intervals. The abundance of superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPx1) mRNA, as well as enzyme activities, were determined in the medial-basal hypothalamus (MBH), the preoptic (POA) area of the hypothalamus, and in the hippocampal CA1 field. Both doses of KYNA caused a decrease (p < 0.01) in the expression of SOD2 and CAT mRNA in all structures examined compared to the control group (except for CAT in the POA at the KYNA100 dose). Furthermore, lower levels of SOD2 mRNA (p < 0.05) and CAT mRNA (p < 0.01) were found in the MBH and POA and in the POA and CA, respectively, in sheep administered with the KYNA20 dose. Different stimulatory effects on GPx1 mRNA expression were observed for both doses (p < 0.05-p < 0.01). KYNA exerted stimulatory but dose-dependent effects on SOD2, CAT, and GPx1 activities (p < 0.05-p < 0.001) in all brain tissues examined. The results indicate that KYNA may influence the level of oxidative stress in individual brain structures in sheep by modulating the expression of genes and the activity of at least SOD2, CAT, and GPx1. The present findings also expand the general knowledge about the potential neuroprotective properties of KYNA in the central nervous system.

Memantine and the Kynurenine Pathway in the Brain: Selective Targeting of Kynurenic Acid in the Rat Cerebral Cortex.

Cytoprotective and neurotoxic kynurenines formed along the kynurenine pathway (KP) were identified as possible therapeutic targets in various neuropsychiatric conditions. Memantine, an adamantane derivative modulating dopamine-, noradrenaline-, serotonin-, and glutamate-mediated neurotransmission is currently considered for therapy in dementia, psychiatric disorders, migraines, or ischemia. Previous studies have revealed that memantine potently stimulates the synthesis of neuroprotective kynurenic acid (KYNA) in vitro via a protein kinase A-dependent mechanism. Here, the effects of acute and prolonged administration of memantine on brain kynurenines and the functional changes in the cerebral KP were assessed in rats using chromatographic and enzymatic methods. Five-day but not single treatment with memantine selectively activated the cortical KP towards neuroprotective KYNA. KYNA increases were accompanied by a moderate decrease in cortical tryptophan (TRP) and L-kynurenine (L-KYN) concentrations without changes in 3-hydroxykynurenine (3-HK) levels. Enzymatic studies revealed that the activity of cortical KYNA biosynthetic enzymes ex vivo was stimulated after prolonged administration of memantine. As memantine does not directly stimulate the activity of KATs' proteins, the higher activity of KATs most probably results from the increased expression of the respective genes. Noteworthy, the concentrations of KYNA, 3-HK, TRP, and L-KYN in the striatum, hippocampus, and cerebellum were not affected. Selective cortical increase in KYNA seems to represent one of the mechanisms underlying the clinical efficacy of memantine. It is tempting to hypothesize that a combination of memantine and drugs could strongly boost cortical KYNA and provide a more effective option for treating cortical pathologies at early stages. Further studies should evaluate this issue in experimental animal models and under clinical scenarios.

Alterations in the Blood Kynurenine Pathway Following Long-Term PM2.5 and PM10 Exposure: A Cross-Sectional Study.

Human exposure to PM2.5 and PM10 has been linked to respiratory and cardiovascular diseases through inflammation activation. The kynurenine pathway is associated with inflammation, and it is necessary to investigate the effects of long-term PM2.5 and PM10 exposure on this pathway. This study aimed to conduct a cross-sectional analysis of long-term PM2.5 and PM10 exposure's impact on the kynurenine pathway using proton NMR spectroscopy (1H-NMR). The participants were divided into a low-PM-exposure group (LG; n = 98), and a high-PM-exposure group (HG; n = 92). The metabolites of tryptophan were determined in blood by 1H-NMR. Serotonin, cinnabarinic acid, xanthurenic acid, 5-hydroxytryptophan, indoleacetic acid, tryptamine, melatonin, L-tryptophan, 5-hydroxy-L-tryptophol, indoxyl, 2-aminobenzoic acid, 5-HTOL, hydroxykynurenine, L-3-hydroxykynurenine, N-formyl kynurenine, 3-hydroxy anthranilic acid, kynurenic acid, and picolinic acid significantly increased (p < 0.05) in the HG group. Conversely, NAD and quinolinic acid significantly decreased in the HG group compared to the LG group. The enzyme activities of indoleamine 2,3-dioxygenase and formamidase significantly decreased, while kynureninase and kynurenine monooxygenase significantly increased. The kynurenine pathway is linked to inflammation and non-communicable diseases. Disruption of the kynurenine pathway from particulate matter might promote diseases. Reducing exposure to the particulate matter is crucial for preventing adverse health effects.

Short communications: Exploring temporal fluorescent changes in the composition of human semen stains

Semen traces are considered important pieces of evidence in forensic investigations, especially those involving sexsual offenses. Recently, our research group developed a fluorescence-based technique to accurately determine the age of semen traces. However, the specific compounds resonsible for the fluoresescent behaviour of ageing semens remain unknown. As such, in this exploratory study, the aim is to identify the components associated with the fluorescent behavior of ageing semen traces. In this investigation semen stains and various biofluorophores commonly found in body fluids were left to aged for 0, 2, 4, 7, 14 and 21 days. Subsequently, thin-layer chromatography (TLC) and ultra-performance liquid chromatography (UPLC) mass spectrometry were performed to identify the biofluorophores present in semen. Several contributors to the autofluorescence could be identified in semen stain, these include tryptophan, kynurenine, kynurenic acid, and norharman. The study sheds light on the.

The Biology and Biochemistry of Kynurenic Acid, a Potential Nutraceutical with Multiple Biological Effects.

Kynurenic acid (KYNA) is an antioxidant degradation product of tryptophan that has been shown to have a variety of cytoprotective, neuroprotective and neuronal signalling properties. However, mammalian transporters and receptors display micromolar binding constants; these are consistent with its typically micromolar tissue concentrations but far above its serum/plasma concentration (normally tens of nanomolar), suggesting large gaps in our knowledge of its transport and mechanisms of action, in that the main influx transporters characterized to date are equilibrative, not concentrative. In addition, it is a substrate of a known anion efflux pump (ABCC4), whose in vivo activity is largely unknown. Exogeneous addition of L-tryptophan or L-kynurenine leads to the production of KYNA but also to that of many other co-metabolites (including some such as 3-hydroxy-L-kynurenine and quinolinic acid that may be toxic). With the exception of chestnut honey, KYNA exists at relatively low levels in natural foodstuffs. However, its bioavailability is reasonable, and as the terminal element of an irreversible reaction of most tryptophan degradation pathways, it might be added exogenously without disturbing upstream metabolism significantly. Many examples, which we review, show that it has valuable bioactivity. Given the above, we review its potential utility as a nutraceutical, finding it significantly worthy of further study and development.

The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy.

It has been unequivocally established that kynurenic acid has a number of actions in a variety of cells and tissues, raising, in principle, the possibility of targeting its generation, metabolism or sites of action to manipulate those effects to a beneficial therapeutic end. However, many basic aspects of the biology of kynurenic acid remain unclear, potentially leading to some confusion and misinterpretations of data. They include questions of the source, generation, targets, enzyme expression, endogenous concentrations and sites of action. This essay is intended to raise and discuss many of these aspects as a source of reference for more balanced discussion. Those issues are followed by examples of situations in which modulating and correcting kynurenic acid production or activity could bring significant therapeutic benefit, including neurological and psychiatric conditions, inflammatory diseases and cell protection. More information is required to obtain a clear overall view of the pharmacological environment relevant to kynurenic acid, especially with respect to the active concentrations of kynurenine metabolites in vivo and changed levels in disease. The data and ideas presented here should permit a greater confidence in appreciating the sites of action and interaction of kynurenic acid under different local conditions and pathologies, enhancing our understanding of kynurenic acid itself and the many clinical conditions in which manipulating its pharmacology could be of clinical value.

Activation of nociception-sensitive ionotropic glutamate receptor-expressing rostroventrolateral medulla neurons by stimulation of cardiac afferents in rats.

Myocardial ischemia causes the release of bradykinin, which activates afferent nerve endings in the ventricular epicardium. This elicits a sympathetically mediated increase in arterial pressure and heart rate, referred to as the cardiogenic sympathetic afferent reflex. The rostroventrolateral medulla (RVLM) is a key sympathetic brain stem site for regulating cardiovascular activity. This study aimed to determine the importance of non-barosensitive nociception sympathetic activity and the role of glutamate receptor activation of RVLM neurons in the cardiogenic sympathetic afferent reflex. We tested the hypothesis that inhibition of barosensitive sympathetic activity attenuates but does not abolish the reflex response to cardiac visceral afferents. Renal sympathetic nerve activity (RSNA), arterial pressure, and heart rate responses to epicardial bradykinin application were recorded in anesthetized rats before and after bilateral RVLM microinjection of either GABAA agonist muscimol, ionotropic glutamate receptor antagonist kynurenic acid, N-methyl-d-aspartate (NMDA) receptor antagonist 2-amino-5- phosphonopentanoic acid (AP5), or non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Baroreceptor loading-induced inhibition of barosensitive activity attenuated the bradykinin-induced RSNA response (93 ± 14% increase) and tachycardia (18 ± 3 bpm). While RVLM muscimol microinjection abolished the RSNA response (1.6 ± 4.2% from baseline, 0.49 ± 0.38 μV*s), surprisingly, it did not abolish the tachycardia (27 ± 4 bpm). Kynurenic acid microinjection blocked the arterial pressure and RSNA responses, while AP5 or CNQX only attenuated the responses. These data suggest that nociception-sensitive sympathetic activity that does not appear to be barosensitive is also involved in the cardiogenic sympathetic afferent reflex. Importantly, while muscimol and kynurenic acid abolished the arterial pressure and RSNA response, neither affected the tachycardia, suggesting an alternate cardiac pathway independent of RVLM.

Kynurenic acid protects against ischemia/reperfusion injury by modulating apoptosis in cardiomyocytes

Acute myocardial infarction, often associated with ischemia/reperfusion injury (I/R), is a leading cause of death worldwide. Although the endogenous tryptophan metabolite kynurenic acid (KYNA) has been shown to exert protection against I/R injury, its mechanism of action at the cellular and molecular level is not well understood yet. Therefore, we examined the potential involvement of antiapoptotic mechanisms, as well as N-methyl-D-aspartate (NMDA) receptor modulation in the protective effect of KYNA in cardiac cells exposed to simulated I/R (SI/R). KYNA was shown to attenuate cell death induced by SI/R dose-dependently in H9c2 cells or primary rat cardiomyocytes. Analysis of morphological and molecular markers of apoptosis (i.e., membrane blebbing, apoptotic nuclear morphology, DNA double-strand breaks, activation of caspases) revealed considerably increased apoptotic activity in cardiac cells undergoing SI/R. The investigated apoptotic markers were substantially improved by treatment with the cytoprotective dose of KYNA. Although cardiac cells were shown to express NMDA receptors, another NMDA antagonist structurally different from KYNA was unable to protect against SI/R-induced cell death. Our findings provide evidence that the protective effect of KYNA against SI/R-induced cardiac cell injury involves antiapoptotic mechanisms, that seem to evoke independently of NMDA receptor signaling.

Establishment of a UPLC-MS method for quantitative analysis of tryptophan-kynurenine metabolism in IBS-D model rats

Background and Aims Abnormalities in tryptophan (TRP) metabolism induce abdominal pain and intestinal motility disorders. The study of TRP metabolism in diarrhea-predominant-irritable bowel syndrome (IBS-D) is important for the prevention, diagnosis, and treatment of this disease. In this study, a rapid and reliable ultra performance liquid chromatography-mass spectrometry (UPLC-MS) method was established to quantify tryptophan-kynurenine (TRP-Kyn) metabolism in the colon of a rat model with IBS-D. Methods The proteins were precipitated by methanol, chromatographically separated on a Welch Ultimate® Polar RP column with a gradient elution for 12 min, and detected by high-resolution tandem mass spectrometry. Pure water were used as an alternative mechanism for standard calibration, and the stable structural analog 2-Cl-Phe was used as an internal standard. Results Within a certain range, the r of TRP, kynurenine (Kyn) and quinolinic acid (QA), kynurenic acid (KA) are greater than 0.99, were found to be accurate and precise. The metabolism of TRP was significantly up-regulated along the Kyn pathway in the IBS-D model rats and normalized after treatment with pivacurium bromide. Conclusion This study investigates the mechanisms of IBS-D gastrointestinal dysfunction from the perspective of colonic TRP metabolism, and also provides new directions for the diagnosis and therapeutic approach of this disease.

Customized flexible platform - starting point for the development of wearable sensor for the direct electrochemical detection of kynurenic acid in biological samples

Kynurenic acid (KA) is an active metabolite of tryptophan with notable biological effects, such as antioxidant, neuroprotective, and anti-inflammatory properties. It often undergoes changes of the concentration in biological fluids in chronic diseases. Thus, detecting KA is of great importance for diagnosing inflammatory and neurodegenerative conditions, monitoring disease progression, and assessing responses to pharmacological treatment.This study aimed to design a tailored, flexible platform for sensitive and direct electrochemical detection of KA in biological fluids. Carbon-based electrodes were custom-printed in the lab using specialized inks and flexible substrates. The working electrodes were further functionalized with graphene oxide and subsequently electrochemically reduced to increase the sensitivity toward the analyte. An optimized differential pulse voltammetry protocol was developed for KA detection. The elaborated platform was firstly characterized and then evaluated regarding the analytical performances. It showed a good limit of detection (3 nM and demonstrated the capability to detect KA across a broad concentration range (0.01–500 μM). Finally, the elaborated flexible platform, was succesfully applied for KA determination in serum and saliva samples, in comparison with an optimized HPLC-UV method.The developed platform is the first example of in-lab printed flexible platform reported in literature so far for KA detection. It is also the first study reported in the literature of detection of KA in raw saliva collected from 10 subjects. The sensitivity towards the target analyte, coupled with the adaptability and portability, showcases the potential of this platform for thus illustrating great potential for further development of wearable sensors and biomedical applications.

Immune-based Machine learning Prediction of Diagnosis and Illness State in Schizophrenia and Bipolar Disorder

BackgroundSchizophrenia and bipolar disorder frequently face significant delay in diagnosis, leading to being missed or misdiagnosed in early stages. Both disorders have also been associated with trait and state immune abnormalities. Recent machine learning-based studies have shown encouraging results using diagnostic biomarkers in predictive models, but few have focused on immune-based markers. Our main objective was to develop supervised machine learning models to predict diagnosis and illness state in schizophrenia and bipolar disorder using only a panel of peripheral kynurenine metabolites and cytokines. MethodsThe cross-sectional I-GIVE cohort included hospitalized acute bipolar patients (n = 205), stable bipolar outpatients (n = 116), hospitalized acute schizophrenia patients (n = 111), stable schizophrenia outpatients (n = 75) and healthy controls (n = 185). Serum kynurenine metabolites, namely tryptophan (TRP), kynurenine (KYN), kynurenic acid (KA), quinaldic acid (QUINA), xanthurenic acid (XA), quinolinic acid (QUINO) and picolinic acid (PICO) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), while V-plex Human Cytokine Assays were used to measure cytokines (interleukin-6 (IL-6), IL-8, IL-17, IL-12/IL23-P40, tumor necrosis factor-alpha (TNF-ɑ), interferon-gamma (IFN-γ)). Supervised machine learning models were performed using JMP Pro 17.0.0. We compared a primary analysis using nested cross-validation to a split set as sensitivity analysis. Post-hoc, we re-ran the models using only the significant features to obtain the key markers. ResultsThe models yielded a good Area Under the Curve (AUC) (0.804, Positive Prediction Value (PPV) = 86.95; Negative Prediction Value (NPV) = 54.61) for distinguishing all patients from controls. This implies that a positive test is highly accurate in identifying the patients, but a negative test is inconclusive. Both schizophrenia patients and bipolar patients could each be separated from controls with a good accuracy (SCZ AUC 0.824; BD AUC 0.802). Overall, increased levels of IL-6, TNF-ɑ and PICO and decreased levels of IFN-γ and QUINO were predictive for an individual being classified as a patient. Classification of acute versus stable patients reached a fair AUC of 0.713. The differentiation between schizophrenia and bipolar disorder yielded a poor AUC of 0.627. ConclusionsThis study highlights the potential of using immune-based measures to build predictive classification models in schizophrenia and bipolar disorder, with IL-6, TNF-ɑ, IFN-γ, QUINO and PICO as key candidates. While machine learning models successfully distinguished schizophrenia and bipolar disorder from controls, the challenges in differentiating schizophrenic from bipolar patients likely reflect shared immunological pathways by the both disorders and confounding by a larger state-specific effect. Larger multi-centric studies and multi-domain models are needed to enhance reliability and translation into clinic.

Blueberry extract for the treatment of ischaemic stroke through regulating the gut microbiota and kynurenine metabolism.

Although the gut microbiota and kynurenine (KYN) metabolism have significant protective effects against ischaemic stroke (IS), the exact mechanism has yet to be fully elucidated. Combined serum metabolomics and 16S rRNA gene sequencing were used to reveal the differences between the gut microbiota and metabolites in rats treated with or without blueberry extract. Faecal microbiota transplantation (FMT) was employed to validate the protective role of the gut microbiota in IS. Furthermore, the interaction between Prevotella and IS was also confirmed in patients. Rats with IS experienced neurological impairments accompanied by an impaired intestinal barrier and disturbed intestinal flora, which further contributed to heightened inflammatory responses. Furthermore, Prevotella played a critical role in IS pathophysiology, and a positive correlation between Prevotella and KYN was detected. The role of KYN metabolism in IS was further demonstrated by the finding that IDO was significantly upregulated and that the use of the IDO inhibitor, attenuated KYN metabolic pathway activity and ameliorated neurological damage in rats with IS. Prevotella intervention also significantly improved stroke symptoms and decreasing KYN levels in rats with IS. FMT showed that the beneficial effects of blueberry extract on IS involve gut bacteria, especially Prevotella, which were confirmed by microbiological analyses conducted on IS patients. Moreover, blueberry extract led to significant changes in kynurenic acid levels and tryptophan and IDO levels through interactions with Prevotella. Our study demonstrates for the first time that blueberry extract could modulate "intestinal microecology-KYN metabolism" to improve IS.

Gestational administration of Bifidobacterium dentium results in intergenerational modulation of inflammatory, metabolic, and social behavior

Prenatal stress (PNS) profoundly impacts maternal and offspring health, with enduring effects including microbiome alterations, neuroinflammation, and behavioral disturbances such as reductions in social behavior. Converging lines of evidence from preclinical and clinical studies suggest that PNS disrupts tryptophan (Trp) metabolic pathways and reduces gut Bifidobacteria, a known beneficial bacterial genus that metabolizes Trp. Specifically, previous work from our lab demonstrated that human prenatal mood disorders in mothers are associated with reduced Bifidobacterium dentium in infants at 13 months. Given that Bifidobacterium has been positively associated with neurodevelopmental and other health benefits and is depleted by PNS, we hypothesized that supplementing PNS-exposed pregnant dams with B. dentium would ameliorate PNS-induced health deficits. We measured inflammatory outputs, Trp metabolite levels and enzymatic gene expression in dams and fetal offspring, and social behavior in adult offspring. We determined that B. dentium reduced maternal systemic inflammation and fetal offspring neuroinflammation, while modulating tryptophan metabolism and increasing kynurenic acid and indole-3-propionic acid intergenerationally. Additional health benefits were demonstrated by the abrogation of PNS-induced reductions in litter weight. Finally, offspring of the B. dentium cohort demonstrated increased sociability in males primarily and increased social novelty primarily in females. Together these data illustrate that B. dentium can orchestrate interrelated host immune, metabolic and behavioral outcomes during and after gestation for both dam and offspring and may be a candidate for prevention of the negative sequelae of stress.

Biomarker Profiling with Targeted Metabolomic Analysis of Plasma and Urine Samples in Patients with Type 2 Diabetes Mellitus and Early Diabetic Kidney Disease.

Background: Over the years, it was noticed that patients with diabetes have reached an alarming number worldwide. Diabetes presents many complications, including diabetic kidney disease (DKD), which can be considered the leading cause of end-stage renal disease. Current biomarkers such as serum creatinine and albuminuria have limitations for early detection of DKD. Methods: In our study, we used UHPLC-QTOF-ESI+-MS techniques to quantify previously analyzed metabolites. Based on one-way ANOVA and Fisher's LSD, untargeted analysis allowed the discrimination of six metabolites between subgroups P1 versus P2 and P3: tryptophan, kynurenic acid, taurine, l-acetylcarnitine, glycine, and tiglylglycine. Results: Our results showed several metabolites that exhibited significant differences among the patient groups and can be considered putative biomarkers in early DKD, including glycine and kynurenic acid in serum (p < 0.001) and tryptophan and tiglylglycine (p < 0.001) in urine. Conclusions: Although we identified metabolites as potential biomarkers in the present study, additional studies are needed to validate these results.