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Purpose: Tryptophan (TRP) degradation through the kynurenine pathway is responsible for converting 95% of free TRP into kynurenines, which modulate skeletal muscle bioenergetics, immune and central nervous system activity. Therefore, changes in the kynurenines during exercise have been widely studied but not in the context of the effects of remote ischemic preconditioning (RIPC). In this study, we analyzed the effect of 14-day RIPC training on kynurenines and TRP in runners after running intervals of 20 × 400 m. Methods: In this study, 27 semi-professional long-distance runners were assigned to two groups: a RIPC group performing 14 days of RIPC training (n = 12), and a placebo group, SHAM (n = 15). Blood was collected for analysis before, immediately after, and at 6 h and 24 h after the run. Results: After the 14-day RIPC/SHAM intervention, post hoc analysis showed a significantly lower concentration of XANA and kynurenic acid to kynurenine ratio (KYNA/KYN) in the RIPC group than in the SHAM group immediately after the running test. Conversely, the decrease in serum TRP levels was higher in the RIPC population. Conclusion: RIPC modulates post-exercise changes in XANA and TRP levels, which can affect brain health, yet further research is needed. [ABSTRACT FROM AUTHOR]

Xanthurenic acid (XA) raises a growing multidisciplinary interest based upon its oxidizing properties, its ability to complex certain metal ions, and its detoxifier capacity of 3‐hydroxykynurenine (3‐HK), its brain precursor. However, little is still known about the role and mechanisms of action of XA in the central nervous system (CNS). Therefore, many research groups have recently investigated XA and its central functions extensively. The present paper critically reviews and discusses all major data related to XA properties and neuronal activities to contribute to the improvement of the current knowledge on XA's central roles and mechanisms of action. In particular, our data showed the existence of a specific G‐protein‐coupled receptor (GPCR) for XA localized exclusively in brain neurons exhibiting Ca2+‐dependent dendritic release and specific electrophysiological responses. XA properties and central activities suggest a role for this compound in brain intercellular signaling. Indeed, XA stimulates cerebral dopamine (DA) release contrary to its structural analog, kynurenic acid (KYNA). Thus, KYNA/XA ratio could be fundamental in the regulation of brain glutamate and DA release. Cerebral XA may also represent an homeostatic signal between the periphery and several brain regions where XA accumulates easily after peripheral administration. Therefore, XA status in certain psychoses or neurodegenerative diseases seems to be reinforced by its brain‐specific properties in balance with its formation and peripheral inputs. [ABSTRACT FROM AUTHOR]

PurposeTryptophan (TRP) degradation through the kynurenine pathway is responsible for converting 95% of free TRP into kynurenines, which modulate skeletal muscle bioenergetics, immune and central nervous system activity. Therefore, changes in the kynurenines during exercise have been widely studied but not in the context of the effects of remote ischemic preconditioning (RIPC). In this study, we analyzed the effect of 14-day RIPC training on kynurenines and TRP in runners after running intervals of 20 × 400 m.MethodsIn this study, 27 semi-professional long-distance runners were assigned to two groups: a RIPC group performing 14 days of RIPC training (n = 12), and a placebo group, SHAM (n = 15). Blood was collected for analysis before, immediately after, and at 6 h and 24 h after the run.ResultsAfter the 14-day RIPC/SHAM intervention, post hoc analysis showed a significantly lower concentration of XANA and kynurenic acid to kynurenine ratio (KYNA/KYN) in the RIPC group than in the SHAM group immediately after the running test. Conversely, the decrease in serum TRP levels was higher in the RIPC population.ConclusionRIPC modulates post-exercise changes in XANA and TRP levels, which can affect brain health, yet further research is needed.

Introduction: Tryptophan’s (Trp) metabolites are undervalued markers of human health. Their serum concentrations are modified by physical exercise and other factors, among which fasting has a well-documented role. Although this mechanism is hardly explored, thus, the study aimed to determine the effect of the 8-day fasting period and the impact of such a procedure on a single bout of an endurance exercise on the concentration of kynurenine pathway (KP) metabolites. Methods: 10 participants fasted for 8 days, and 10 as a control group participated in the study. The exercise was performed at baseline after an overnight fast and repeated post 8 days. Results: The 8 days of fasting increased the resting 3-hydroxy-L-kynurenine (3HK), picolinic acid (PA), kynurenic acid (KYNA), and xanthurenic acid (XA) serum concentration. Also elevated phenylalanine (Phe) and tyrosine (Tyr) levels were recorded, suggesting expanded proteolysis of muscle proteins. In turn, physical activity caused a decrease in the concentration of 3-hydroxyanthranilic acid (3HAA) and PA after fasting. The obtained results were not recorded in controls. Conclusion: The results of this study show that the health-promoting effects of fasting are associated with changes in the KYN pathway. The increase in the concentration of PA and XA metabolites following fasting is capable of penetrating the blood-brain barrier, and KYNA, which initiates several beneficial changes, supports this assumption. [ABSTRACT FROM AUTHOR]

IntroductionTryptophan’s (Trp) metabolites are undervalued markers of human health. Their serum concentrations are modified by physical exercise and other factors, among which fasting has a well-documented role. Although this mechanism is hardly explored, thus, the study aimed to determine the effect of the 8-day fasting period and the impact of such a procedure on a single bout of an endurance exercise on the concentration of kynurenine pathway (KP) metabolites.Methods10 participants fasted for 8 days, and 10 as a control group participated in the study. The exercise was performed at baseline after an overnight fast and repeated post 8 days.ResultsThe 8 days of fasting increased the resting 3-hydroxy-L-kynurenine (3HK), picolinic acid (PA), kynurenic acid (KYNA), and xanthurenic acid (XA) serum concentration. Also elevated phenylalanine (Phe) and tyrosine (Tyr) levels were recorded, suggesting expanded proteolysis of muscle proteins. In turn, physical activity caused a decrease in the concentration of 3-hydroxyanthranilic acid (3HAA) and PA after fasting. The obtained results were not recorded in controls.ConclusionThe results of this study show that the health-promoting effects of fasting are associated with changes in the KYN pathway. The increase in the concentration of PA and XA metabolites following fasting is capable of penetrating the blood-brain barrier, and KYNA, which initiates several beneficial changes, supports this assumption.

Abstract Background Metabolic reprogramming is a critical event for cell fate and function, making it an attractive target for clinical therapy. The function of metabolic reprogramming in Helicobacter pylori (H. pylori)-infected gastric intestinal metaplasia remained to be identified. Methods Xanthurenic acid (XA) was measured in gastric cancer cells treated with H. pylori or H. pylori virulence factor, respectively, and qPCR and WB were performed to detect CDX2 and key metabolic enzymes expression. A subcellular fractionation approach, luciferase and ChIP combined with immunofluorescence were applied to reveal the mechanism underlying H. pylori mediated kynurenine pathway in intestinal metaplasia in vivo and in vitro. Results Herein, we, for the first time, demonstrated that H. pylori contributed to gastric intestinal metaplasia characterized by enhanced Caudal-related homeobox transcription factor-2 (CDX2) and mucin2 (MUC2) expression, which was attributed to activation of kynurenine pathway. H. pylori promoted kynurenine aminotransferase II (KAT2)-mediated kynurenine pathway of tryptophan metabolism, leading to XA production, which further induced CDX2 expression in gastric epithelial cells. Mechanically, H. pylori activated cyclic guanylate adenylate synthase (cGAS)-interferon regulatory factor 3 (IRF3) pathway in gastric epithelial cells, leading to enhance IRF3 nuclear translocation and the binding of IRF3 to KAT2 promoter. Inhibition of KAT2 could significantly reverse the effect of H. pylori on CDX2 expression. Also, the rescue phenomenon was observed in gastric epithelial cells treated with H. pylori after IRF3 inhibition in vitro and in vivo. Most importantly, phospho-IRF3 was confirmed to be a clinical positive relationship with CDX2. Conclusion These finding suggested H. pylori contributed to gastric intestinal metaplasia through KAT2-mediated kynurenine pathway of tryptophan metabolism via cGAS-IRF3 signaling, targeting the kynurenine pathway could be a promising strategy to prevent gastric intestinal metaplasia caused by H. pylori infection. Video Abstract

Background: Metabolic reprogramming is a critical event for cell fate and function, making it an attractive target for clinical therapy. The function of metabolic reprogramming in Helicobacter pylori (H. pylori)-infected gastric intestinal metaplasia remained to be identified. Methods: Xanthurenic acid (XA) was measured in gastric cancer cells treated with H. pylori or H. pylori virulence factor, respectively, and qPCR and WB were performed to detect CDX2 and key metabolic enzymes expression. A subcellular fractionation approach, luciferase and ChIP combined with immunofluorescence were applied to reveal the mechanism underlying H. pylori mediated kynurenine pathway in intestinal metaplasia in vivo and in vitro. Results: Herein, we, for the first time, demonstrated that H. pylori contributed to gastric intestinal metaplasia characterized by enhanced Caudal-related homeobox transcription factor-2 (CDX2) and mucin2 (MUC2) expression, which was attributed to activation of kynurenine pathway. H. pylori promoted kynurenine aminotransferase II (KAT2)-mediated kynurenine pathway of tryptophan metabolism, leading to XA production, which further induced CDX2 expression in gastric epithelial cells. Mechanically, H. pylori activated cyclic guanylate adenylate synthase (cGAS)-interferon regulatory factor 3 (IRF3) pathway in gastric epithelial cells, leading to enhance IRF3 nuclear translocation and the binding of IRF3 to KAT2 promoter. Inhibition of KAT2 could significantly reverse the effect of H. pylori on CDX2 expression. Also, the rescue phenomenon was observed in gastric epithelial cells treated with H. pylori after IRF3 inhibition in vitro and in vivo. Most importantly, phospho-IRF3 was confirmed to be a clinical positive relationship with CDX2. Conclusion: These finding suggested H. pylori contributed to gastric intestinal metaplasia through KAT2-mediated kynurenine pathway of tryptophan metabolism via cGAS-IRF3 signaling, targeting the kynurenine pathway could be a promising strategy to prevent gastric intestinal metaplasia caused by H. pylori infection. 2STnY-xvxhAA5nGkWu7hrz Video Abstract [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is a brain tumor that is among the deadliest of human cancers. The invasive spreading of the tumor cells allows subpopulations to escape chemo and radiation treatments and infiltrate other areas of the brain where they continue to grow and cause relapses. To achieve their high motility, glioblastoma cells appear to harness membrane signaling proteins including aquaporin water channels, glutamate receptors, and ion channels. Work here tested selected combinations of agents that selectively targeted sets of signaling proteins known to be enriched in glioblastomas and showed that blocking both glutamate receptor and aquaporin-1 channels is an attractive means for limiting tumor cell motility without causing cell toxicity that might negatively impact normal brain cell function. Using combinations of agents at threshold doses could enable focusing of the pharmacological effects on cancer cells specifically, minimizing off-target effects. Impairing the motility of glioblastoma multiforme (GBM) cells is a compelling goal for new approaches to manage this highly invasive and rapidly lethal human brain cancer. Work here characterized an array of pharmacological inhibitors of membrane ion and water channels, alone and in combination, as tools for restraining glioblastoma spread in human GBM cell lines U87-MG and U251-MG. Aquaporins, AMPA glutamate receptors, and ion channel classes (shown to be upregulated in human GBM at the transcript level and linked to mechanisms of motility in other cell types) were selected as pharmacological targets for analyses. Effective compounds reduced the transwell invasiveness of U87-MG and U251-MG glioblastoma cells by 20–80% as compared with controls, without cytotoxicity. The compounds and doses used were: AqB013 (14 μM); nifedipine (25 µM); amiloride (10 µM); apamin (10 µM); 4-aminopyridine (250 µM); and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; 30 µM). Invasiveness was quantified in vitro across transwell filter chambers layered with extracellular matrix. Co-application of each of the ion channel agents with the water channel inhibitor AqB013 augmented the inhibition of invasion (20 to 50% greater than either agent alone). The motility impairment achieved by co-application of pharmacological agents differed between the GBM proneural-like subtype U87-MG and classical-like subtype U251-MG, showing patterns consistent with relative levels of target channel expression (Human Protein Atlas database). In addition, two compounds, xanthurenic acid and caelestine C (from the Davis Open Access Natural Product-based Library, Griffith University QLD), were discovered to block invasion at micromolar doses in both GBM lines (IC50 values from 0.03 to 1 µM), without cytotoxicity, as measured by full mitochondrial activity under conditions matching those in transwell assays and by normal growth in spheroid assays. Mechanisms of action of these agents based on published work are likely to involve modulation of glutamatergic receptor signaling. Treating glioblastoma by the concurrent inhibition of multiple channel targets could be a powerful approach for slowing invasive cell spread without cytotoxic side effects, potentially enhancing the effectiveness of clinical interventions focused on eradicating primary tumors. [ABSTRACT FROM AUTHOR]

Catabolism of tryptophan (Trp) is modulated by physical activity and provides a pool of active compounds: Trp is considered a calmative agent, kynurenine (Kyn) and 3-hydroxykynurenine (3-HKyn) show neurotoxic effects, kynurenic acid (Kyna) and xanthurenic acid (XA) have neuroprotective properties like nicotinamide (NAm), while serotonin is the neurotransmitter. The study was conducted to investigate the dependence of exercise intensity, measured by plasma lactic acid (LA) concentration, on the level of Trp, its catabolites (serotonin, Kyn, 3-HKyn, Kyna and XA), and NAm in Thoroughbred horses. A total of 18 young race Thoroughbred horses were investigated during exercise tests. Blood samples for analysis were collected: at rest, 10 min after the end of the exercise, and 60 min after the end of the exercise. Plasma LA was determined by the enzymatic method, Trp, and other metabolites using liquid chromatography coupled with mass spectrometry. In horses performing intense exercise, the concentration of LA, Kyn, XA and NAm was increased, while Trp was decreased. Significant correlations were detected for exercise-induced increase in LA and 3-HKyn, XA, and NAm. Considering the scope of changes in analyzed data, there is an expected neutral effect on the health status of exercised horses. [ABSTRACT FROM AUTHOR]

Abstract Background Babesia bovis is one of the most significant tick-transmitted pathogens of cattle worldwide. Babesia bovis parasites have a complex lifecycle, including development within the mammalian host and tick vector. Each life stage has developmental forms that differ in morphology and metabolism. Differentiation between these forms is highly regulated in response to changes in the parasite’s environment. Understanding the mechanisms by which Babesia parasites respond to environmental changes and the transmission cycle through the biological vector is critically important for developing bovine babesiosis control strategies. Results In this study, we induced B. bovis sexual stages in vitro using xanthurenic acid and documented changes in morphology and gene expression. In vitro induced B. bovis sexual stages displayed distinctive protrusive structures and surface ruffles. We also demonstrated the upregulation of B. bovis calcium-dependent protein kinase 4 (cdpk4), tubulin-tyrosine ligase (ttl), and methyltransferase (mt) genes by in vitro induced sexual stages and during parasite development within tick midguts. Conclusions Similar to other apicomplexan parasites, it is likely that B. bovis upregulated genes play a vital role in sexual reproduction and parasite transmission. Herein, we document the upregulation of cdpk4, ttl, and mt genes by both B. bovis in vitro induced sexual stages and parasites developing in the tick vector. Understanding the parasite's biology and identifying target genes essential for sexual reproduction will enable the production of non-transmissible live vaccines to control bovine babesiosis. Graphical abstract

In the coming decades, eliminating malaria is the foremost goal of many tropical countries. Transmission control, along with an accurate and timely diagnosis of malaria, effective treatment and prevention are the different aspects that need to be met synchronously to accomplish the goal. The current review is focused on one of these aspects i.e., transmission control, by looking deeper into the event called gametogenesis. In the Plasmodium life cycle, gametocytes are the first life forms of the sexual phase. The transmission of the parasite and the disease is critically dependent on the number, viability and sex ratio of mature gametocytes and their further development inside mosquito vectors. Gametogenesis, the process of conversion of gametocytes into viable gametes, takes place inside the mosquito midgut, and is a tightly regulated event with fast and multiple rounds of DNA replication and diverse cellular changes going on within a short period. Interrupting the gametocyte-gamete transition is ought to restrict the successful transmission and progression of the disease and hence an area worth exploring for designing transmission-blocking strategies. This review summarizes an in-depth and up-to-date understanding of the biochemical and physiological mechanism of gametogenesis in Plasmodium , which could be targeted to control parasite and malaria transmission. This review also raises certain key questions regarding gametogenesis biology in Plasmodium and brings out gaps that still accompany in understanding the spectacular process of gametogenesis. [ABSTRACT FROM AUTHOR]

In the coming decades, eliminating malaria is the foremost goal of many tropical countries. Transmission control, along with an accurate and timely diagnosis of malaria, effective treatment and prevention are the different aspects that need to be met synchronously to accomplish the goal. The current review is focused on one of these aspects i.e., transmission control, by looking deeper into the event called gametogenesis. In the Plasmodium life cycle, gametocytes are the first life forms of the sexual phase. The transmission of the parasite and the disease is critically dependent on the number, viability and sex ratio of mature gametocytes and their further development inside mosquito vectors. Gametogenesis, the process of conversion of gametocytes into viable gametes, takes place inside the mosquito midgut, and is a tightly regulated event with fast and multiple rounds of DNA replication and diverse cellular changes going on within a short period. Interrupting the gametocyte-gamete transition is ought to restrict the successful transmission and progression of the disease and hence an area worth exploring for designing transmission-blocking strategies. This review summarizes an in-depth and up-to-date understanding of the biochemical and physiological mechanism of gametogenesis in Plasmodium, which could be targeted to control parasite and malaria transmission. This review also raises certain key questions regarding gametogenesis biology in Plasmodium and brings out gaps that still accompany in understanding the spectacular process of gametogenesis.

Catabolism of tryptophan (Trp) is modulated by physical activity and provides a pool of active compounds: Trp is considered a calmative agent, kynurenine (Kyn) and 3-hydroxykynurenine (3-HKyn) show neurotoxic effects, kynurenic acid (Kyna) and xanthurenic acid (XA) have neuroprotective properties like nicotinamide (NAm), while serotonin is the neurotransmitter. The study was conducted to investigate the dependence of exercise intensity, measured by plasma lactic acid (LA) concentration, on the level of Trp, its catabolites (serotonin, Kyn, 3-HKyn, Kyna and XA), and NAm in Thoroughbred horses. A total of 18 young race Thoroughbred horses were investigated during exercise tests. Blood samples for analysis were collected: at rest, 10 min after the end of the exercise, and 60 min after the end of the exercise. Plasma LA was determined by the enzymatic method, Trp, and other metabolites using liquid chromatography coupled with mass spectrometry. In horses performing intense exercise, the concentration of LA, Kyn, XA and NAm was increased, while Trp was decreased. Significant correlations were detected for exercise-induced increase in LA and 3-HKyn, XA, and NAm. Considering the scope of changes in analyzed data, there is an expected neutral effect on the health status of exercised horses.

Tryptophan and its bioactive metabolites are associated with health conditions such as systemic inflammation, cardiometabolic diseases, and neurodegenerative disorders. There are dynamic interactions among metabolites of tryptophan. The interactions between metabolites, particularly those that are strong and temporally reproducible could be of pathophysiological relevance. Using a targeted metabolomics approach, the concentration levels of tryptophan and 18 of its metabolites across multiple pathways was quantified in 24-hours urine samples at 2 time-points, age 17 years (baseline) and 18 years (follow-up) from 132 (52% female) apparently healthy adolescent participants of the DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study. In sex-specific analyses, we applied 2 network approaches, the Gaussian graphical model and Bayesian network to (1) explore the network structure for both time-points, (2) retrieve strongly related metabolites, and (3) determine whether the strongly related metabolites were temporally reproducible. Independent of selected covariates, the 2 network approaches revealed 5 associations that were strong and temporally reproducible. These were novel relationships, between kynurenic acid and indole-3-acetic acid in females and between kynurenic acid and xanthurenic acid in males, as well as known relationships between kynurenine and 3-hydroxykynurenine, and between 3-hydroxykynurenine and 3-hydroxyanthranilic acid in females and between tryptophan and kynurenine in males. Overall, this epidemiological study using network-based approaches shed new light into tryptophan metabolism, particularly the interaction of host and microbial metabolites. The 5 observed relationships suggested the existence of a temporally stable pattern of tryptophan and 6 metabolites in healthy adolescent, which could be further investigated in search of fingerprints of specific physiological states. The metabolites in these relationships may represent a multi-biomarker panel that could be informative for health outcomes. [ABSTRACT FROM AUTHOR]

Background: Babesia bovis is one of the most significant tick-transmitted pathogens of cattle worldwide. Babesia bovis parasites have a complex lifecycle, including development within the mammalian host and tick vector. Each life stage has developmental forms that differ in morphology and metabolism. Differentiation between these forms is highly regulated in response to changes in the parasite's environment. Understanding the mechanisms by which Babesia parasites respond to environmental changes and the transmission cycle through the biological vector is critically important for developing bovine babesiosis control strategies. Results: In this study, we induced B. bovis sexual stages in vitro using xanthurenic acid and documented changes in morphology and gene expression. In vitro induced B. bovis sexual stages displayed distinctive protrusive structures and surface ruffles. We also demonstrated the upregulation of B. bovis calcium-dependent protein kinase 4 (cdpk4), tubulin-tyrosine ligase (ttl), and methyltransferase (mt) genes by in vitro induced sexual stages and during parasite development within tick midguts. Conclusions: Similar to other apicomplexan parasites, it is likely that B. bovis upregulated genes play a vital role in sexual reproduction and parasite transmission. Herein, we document the upregulation of cdpk4, ttl, and mt genes by both B. bovis in vitro induced sexual stages and parasites developing in the tick vector. Understanding the parasite's biology and identifying target genes essential for sexual reproduction will enable the production of non-transmissible live vaccines to control bovine babesiosis. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) that are induced upon pathogen infection plays an important role in host defence. The rickettsial pathogen Anaplasma phagocytophilum, which is primarily transmitted by Ixodes scapularis ticks in the United States, has evolved many strategies to escape ROS and survive in mammalian cells. However, little is known on the role of ROS in A. phagocytophilum infection in ticks. Our results show that A. phagocytophilum and hemin induce activation of l‐tryptophan pathway in tick cells. Xanthurenic acid (XA), a tryptophan metabolite, supports A. phagocytophilum growth in tick cells through inhibition of tryptophan dioxygenase (TDO) activity leading to reduced l‐kynurenine levels that subsequently affects build‐up of ROS. However, hemin supports A. phagocytophilum growth in tick cells by inducing TDO activity leading to increased l‐kynurenine levels and ROS production. Our data reveal that XA and kynurenic acid (KA) chelate hemin. Furthermore, treatment of tick cells with 3‐hydroxyl l‐kynurenine limits A. phagocytophilum growth in tick cells. RNAi‐mediated knockdown of kynurenine aminotransferase expression results in increased ROS production and reduced A. phagocytophilum burden in tick cells. Collectively, these results suggest that l‐tryptophan pathway metabolites influence A. phagocytophilum survival by affecting build up of ROS levels in tick cells. [ABSTRACT FROM AUTHOR]

Despite the identification of molecular mechanisms associated with pain persistence, no significant therapeutic improvements have been made. Advances in the understanding of the molecular mechanisms that induce pain hypersensitivity will allow the development of novel, effective, and safe therapies for chronic pain. Various pro-inflammatory cytokines are known to be increased during chronic pain, leading to sustained inflammation in the peripheral and central nervous systems. The pro-inflammatory environment activates additional metabolic routes, including the kynurenine (KYN) and tetrahydrobiopterin (BH4) pathways, which generate bioactive soluble metabolites with the potential to modulate neuropathic and inflammatory pain sensitivity. Inflammation-induced upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) and guanosine triphosphate cyclohydrolase I (GTPCH), both rate-limiting enzymes of KYN and BH4 biosynthesis, respectively, have been identified in experimental chronic pain models as well in biological samples from patients affected by chronic pain. Inflammatory inducible KYN and BH4 pathways upregulation is characterized by increase in pronociceptive compounds, such as quinolinic acid (QUIN) and BH4, in addition to inflammatory mediators such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). As expected, the pharmacologic and genetic experimental manipulation of both pathways confers analgesia. Many metabolic intermediates of these two pathways such as BH4, are known to sustain pain, while others, like xanthurenic acid (XA; a KYN pathway metabolite) have been recently shown to be an inhibitor of BH4 synthesis, opening a new avenue to treat chronic pain. This review will focus on the KYN/BH4 crosstalk in chronic pain and the potential modulation of these metabolic pathways that could induce analgesia without dependence or abuse liability. [ABSTRACT FROM AUTHOR]

Ommochromes are one of the least studied groups of natural pigments, frequently confused with melanin and, so far, exclusively found in invertebrates such as cephalopods and butterflies. In this study focused on the purple color of the shells of a mollusk, Crassostrea gigas, the first evidence of a metabolite of ommochromes, xanthurenic acid (XA), was obtained by liquid chromatography combined with mass spectrometry (UPLC-MS). In addition to XA and various porphyrins previously identified, a second group of high molecular weight acid-soluble pigments (HMASP) has been identified with physicochemical and structural characteristics similar to those of ommochromes. In addition, fragmentation of HMASP by tandem mass spectrometry (MS/MS) has revealed a substructure common to XA and ommochromes of the ommatin type. Furthermore, the presence of melanins was excluded by the absence of characteristic by-products among the oxidation residues of HMASP. Altogether, these results show that the purple color of the shells of Crassostrea gigas is a complex association of porphyrins and ommochromes of potentially ommatin or ommin type.

Spider silk is a natural fiber with remarkable strength, toughness, and elasticity that is attracting attention as a biomaterial of the future. Golden orb-weaving spiders (Trichonephila clavata) construct large, strong webs using golden threads. To characterize the pigment of golden T. clavata dragline silk, we used liquid chromatography and mass spectrometric analysis. We found that the major pigment in the golden dragline silk of T. clavata was xanthurenic acid. To investigate the possible function of the pigment, we tested the effect of xanthurenic acid on bacterial growth using gram-negative Escherichia coli and gram-positive Bacillus subtilis. We found that xanthurenic acid had a slight antibacterial effect. Furthermore, to investigate the UV tolerance of the T. clavata threads bleached of their golden color, we conducted tensile deformation tests and scanning electron microscope observations. However, in these experiments, no significant effect was observed. We therefore speculate that golden orb-weaving spiders use the pigment for other purposes, such as to attract their prey in the sunlight.

Highlights • Systematic analysis of bioactive molecules in red wine. • First NMR-based identification of xanthurenic acid in red wine. • First NMR-based identification of oleanic acid in red wine. • Major bioactives contained in wine from Vitis vinifera L. cv Aglianico grapes. Abstract Experimental evidence suggests that moderate consumption of wine has health promoting properties that have been mainly attributed to the wine polyphenol content. However, a systematic analysis of the major healthy molecules contained in wines has not been conducted yet. Our study explored the potential arsenal of beneficial molecules contained in wine from both a qualitative and quantitative perspective. The experimental approach was based on chromatography and untargeted NMR spectroscopy. In addition to already known bioactive molecules, for the first time, xanthurenic acid and oleanic acid were identified in wine in relatively high concentrations. On account of their many biological activities, these two molecules widen the range of potential beneficial effects of wine and pave the way toward the evaluation of their still unexplored sensory properties. [ABSTRACT FROM AUTHOR]

Abstract In this study, a novel Cu-based metal−organic frameworks (Cu-MOFs) composite material was prepared, and used to develop a sensitive and efficient electrochemical ratiometric sensor for dopamine detection. Gold nanoparticles (NPs) and the conductive poly(xanthurenic acid) p(XA) were assembled on the Cu-tetrakis (4-carboxyphenyl) porphyrin (TCPP) surface by electrodeposition and cyclic voltammetry (CV) method, which greatly improved the electrocatalytic performance of the Cu-MOF modified electrode. Two substances (dopamine/DA, paracetamol/PA) with different electrochemical peaks were added to the electrolyte solutions, where DA was the analyte and PA was as a reference. The ratiometric value of differential pulse voltammetry (DPV) oxidation current (I DA /I PA) linearly increased with the increasing concentration of DA with low detection limit. This electrochemical ratiometric approach based on the metal−organic framework composites is expected to be a valuable strategy for detection of other analytes. Graphical abstract In this study, a novel Cu-based metal−organic frameworks (Cu-MOFs) composite material was prepared, and used to develop a sensitive and efficient electrochemical ratiometric sensor for dopamine detection. Unlabelled Image Highlights • A novel Cu-MOFs-based composites were prepared and used as excellent electrocatalyst for redox probes. • A sensitive and efficient ratiometric electrochemical sensor was constructed for dopamine detection. • This composite with good conductivity greatly facilitated the electrocatalytic performance of the sensor. [ABSTRACT FROM AUTHOR]

Defects in tryptophan metabolism on the l -kynurenine pathway (KP) are implicated in a number of human diseases, including chronic kidney disease, brain edema or injury, tuberculosis and malaria – as well as cancer, neurodegenerative and autoimmune disorders. However, it is unclear to what extent detrimental effects of exposure to tryptophan metabolites might impact the early development of organism. Thus, this study examined the effects of KP exposure in zebrafish embryos starting at the blastula period (4 hpf) and the segmentation stage (24 hpf). 24-hour EC 50 and LC 50 values were determined in 4 hpf embryos as: 26.74 and 331.6 μM for anthranilic acid (AA), 62.88 and 616.4 μM for quinolinic acid (QUIN), and EC 50 – 96.10 μM for picolinic acid (PA) and LC 50 – 400 μM in kynurenic acid (KYNA). In addition, treatment with nanomolar concentrations of KYNA (50 nM, 48 and 72 hpf embryos) caused a dose-dependent increase in heartbeat. The increase was also seen with l -kyn treatment (50 μM, 72 hpf), which was the opposite of other applied l -kyn metabolites. A significant drop in heartbeat was observed after a 20-min acute exposure to 626 μM PA, 594 μM XA and 499 μM QUIN, and complete recovery was seen only when PA had been removed. Concentrations of KP metabolites reached in people with different pathological conditions did not exert toxicity to zebrafish embryos and seems to be safe for developing embryos and therefore, the risk of developing impairments in pregnancy of women carrying KP-associated pathologies is initially low. [ABSTRACT FROM AUTHOR]

Anopheline mosquitoes are major vectors of malaria parasites. When the gametocytes of the malaria parasite are transferred from a vertebrate to mosquitoes, they differentiate into gametes, and are fertilized in the midguts of mosquitoes. Xanthurenic acid (XA), a waste product of the ommochrome synthesis pathway, has been shown to induce exflagellation during microgametogenesis in vitro; however, it currently remains unclear whether endogenous XA affects the infectivity of anopheline mosquitoes to malaria parasites in vivo due to the lack of appropriate experimental systems such as a XA-deficient line. In the present study, we produced a XA-deficient line in Anopheles stephensi using transcription activator-like effector nuclease (TALEN)-mediated gene targeting (knockout) of the kynurenine 3-monooxygenase (kmo) gene, which encodes an enzyme that participates in the ommochrome synthesis pathway. The knockout of kmo resulted in the absence of XA, and oocyst formation was inhibited in the midguts of these XA-deficient mosquitoes, which, in turn, reduced sporozoite numbers in their salivary glands. These results suggest that endogenous XA stimulates exflagellation, and enhances the infectivity of anopheline mosquitoes to malaria parasites in vivo. The XA-deficient line of the anopheline mosquito provides a useful system for analyzing and understanding the associated factors of malaria gametogenesis in the mosquito midgut. [ABSTRACT FROM AUTHOR]

The kynurenine pathway of tryptophan metabolism is activated by pro-inflammatory cytokines. L-kynurenine, an upstream metabolite of the pathway, acts as a putative endothelium-derived relaxing factor, and has been hypothesized to play a causative role in the pathophysiology of inflammation-induced hypotension. Here, we show that xanthurenic acid (XA), the transamination product of 3-hydroxykynurenine, is more efficacious than L-kynurenine in causing relaxation of a resistance artery, but fails to relax pre-contracted aortic rings. In the mesenteric artery, XA enhanced activating phosphorylation of endothelial nitric oxide synthase (NOS), and the relaxing action of XA was abrogated by pharmacological inhibition of NOS and endothelial-derived hyperpolarizing factor. Systemic injection of XA reduced blood pressure in mice, and serum levels of XA increased by several fold in response to a pulse with the endotoxin, lipopolysaccharide (LPS). LPS-induced hypotension in mice was prevented by pre-treatment with the kynurenine monooxygenase (KMO) inhibitor, Ro-618048, which lowered serum levels of XA but enhanced serum levels of L-kynurenine. UPF 648, another KMO inhibitor, could also abrogate LPS-induced hypotension. Our data identify XA as a novel vasoactive compound and suggest that formation of XA is a key event in the pathophysiology of inflammation-induced hypotension.

The kynurenine pathway of tryptophan metabolism is activated by pro-inflammatory cytokines. L-kynurenine, an upstream metabolite of the pathway, acts as a putative endothelium-derived relaxing factor, and has been hypothesized to play a causative role in the pathophysiology of inflammation-induced hypotension. Here, we show that xanthurenic acid (XA), the transamination product of 3-hydroxykynurenine, is more efficacious than L-kynurenine in causing relaxation of a resistance artery, but fails to relax pre-contracted aortic rings. In the mesenteric artery, XA enhanced activating phosphorylation of endothelial nitric oxide synthase (NOS), and the relaxing action of XA was abrogated by pharmacological inhibition of NOS and endothelial-derived hyperpolarizing factor. Systemic injection of XA reduced blood pressure in mice, and serum levels of XA increased by several fold in response to a pulse with the endotoxin, lipopolysaccharide (LPS). LPS-induced hypotension in mice was prevented by pre-treatment with the kynurenine monooxygenase (KMO) inhibitor, Ro-618048, which lowered serum levels of XA but enhanced serum levels of L-kynurenine. UPF 648, another KMO inhibitor, could also abrogate LPS-induced hypotension. Our data identify XA as a novel vasoactive compound and suggest that formation of XA is a key event in the pathophysiology of inflammation-induced hypotension. [ABSTRACT FROM AUTHOR]

Cinnabarinic and xanthurenic acids are kynurenine metabolites generated by oxidative dimerization of 3-hydroxyanthranilic acid and transamination of 3-hydroxykynurenine, respectively. Recent evidence suggests that both compounds can affect brain function and neurotransmission and interact with metabotropic glutamate (mGlu) receptors. Cinnabarinic acid behaves as an orthosteric agonist of mGlu4 receptors, whereas some of the in vitro and in vivo effects produced by xanthurenic acid appear to be mediated by the activation of mGlu2 and mGlu3 receptors. Cinnabarinic acid could play an important role in mechanisms of neuroinflammation acting as a linking bridge between the immune system and the CNS. Xanthurenic acid has potential implications in the pathophysiology of schizophrenia and is a promising candidate as a peripheral biomarker of the disorder. The action of cinnabarinic acid and xanthurenic acid may extend beyond the regulation of mGlu receptors and may involve several diverse molecular targets, such as the aryl hydrocarbon receptor for cinnabarinic acid and vesicular glutamate transporters for xanthurenic acid. The growing interest on these two metabolites of the kynurenine pathway may unravel new aspects in the complex interaction between tryptophan metabolism and brain function, and lead to the discovery of new potential targets for the treatment of neurological and psychiatric disorders. This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’. [ABSTRACT FROM AUTHOR]

In 2000, a novel secondary metabolite (erebusinone, Ereb) was isolated from the Antarctic sea sponge, Isodictya erinacea . The bioactivity of Ereb was investigated, and it was found to inhibit molting when fed to the arthropod species Orchomene plebs . Xanthurenic acid (XA) is a known endogenous molt regulator present in arthropods. Experimental studies have confirmed that XA inhibits molting by binding to either (or both) of two P450 enzymes (CYP315a1 or CYP314a1) that are responsible for the final two hydroxylations in the production of the molt-inducing hormone, 20-hydroxyecdysone (20 E ). The lack of crystal structures and biochemical assays for CYP315a1 or CYP314a1, has prevented further experimental exploration of XA and Ereb's molt inhibition mechanisms. Herein, a wide array of computational techniques – homology modeling, molecular dynamics simulations, binding site bioinformatics, flexible receptor–flexible ligand docking, and molecular mechanics-generalized Born surface area calculations – have been employed to elucidate the structure–function relationships between the aforementioned P450s and the two described small molecule inhibitors (Ereb and XA). Results indicate that Ereb likely targets CYP315a1 by interacting with a network of aromatic residues in the binding site, while XA may inhibit both CYP315a1 and CYP314a1 because of its aromatic, as well as charged nature. [ABSTRACT FROM AUTHOR]

• The CCp family is important for interrupting transmission of Babesia spp. and Plasmodium spp.. • In silico identification and prediction of conserved domain of CCp family in B. gibsoni. • Successful screening of conditions for the induction of sexual stages in B. gibsoni. • Anti-CCp mouse polycolonal antibodies could react with sexual stages of B. gibsoni. Babesia gibsoni is an intraerythrocytic apicomplexan parasite transmitted by Haemaphysalis longicornis and causes canine babesiosis. Within the tick, the Babesia parasite undergoes sexual conjugation and the sporogony process of its life cycle. To control B. gibsoni infection, prompt and effective treatment of acute infections and curing chronic carriers are urgently needed. Gene disruption of Plasmodium CCps resulted in blocking the transition of sporozoites from the mosquito midgut to the salivary glands, showing that these proteins are potential targets for the development of a transmission-blocking vaccine. In this study, we described the identification and characterization of three members of the CCp family in B. gibsoni , named CCp1, CCp2, and CCp3. The B. gibsoni sexual stages were induced in vitro by exposing parasites to xanthurenic acid (XA), dithiothreitol (DTT), and tris (2-carboxyethyl) phosphine (TCEP) at serial concentrations. Among them, 100 µM XA-exposed and cultured at 27 °C without CO 2 B. gibsoni presented diverse morphologies, including parasites with long projections, gradually increased free merozoites, and aggregated and round forms, indicative of sexual stage induction. Then, the expression of CCp proteins of induced parasites was confirmed by real-time reverse transcription PCR, immunofluorescence, and western blot. The results showed that Bg CCp genes were highly significantly increased at 24 h post-sexual stage induction (p < 0.01). The induced parasites were recognized by anti-CCp mouse antisera and anti-CCp 1, 2, and 3 antibodies weakly reacted with sexual stage proteins of expected molecular weights of 179.4, 169.8, and 140.0 KDa, respectively. Our observations on morphological changes and confirmation of sexual stage protein expression will advance elemental biological research and lay the foundation for the development of transmission-blocking vaccines against canine babesiosis. [Display omitted] [ABSTRACT FROM AUTHOR]