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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.

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]

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.

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]

• 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]

Toxicological research of combined antitubercular preparation. «Protub-2®» that contains a pyridoxine hydrochloride (vitamin B). It was established, that introduction of pyridoxine hydrochloride in the structure of preparation «Protub-2®» allowed to reduce the majority of toxic effects caused by isoniazid and rifampicin that are parts of studied, preparation.

Looking for early diagnostic markers and therapeutic targets is the key to ensuring prompt treatment of myocardial ischemia (MI). Here, a novel biomarker xanthurenic acid (XA) was identified based on metabolomics and exhibited high sensitivity and specificity in the diagnosis of MI patients. Additionally, the elevation of XA was proved to induce myocardial injury in vivo by promoting myocardial apoptosis and ferroptosis. Combining metabolomics and transcriptional data further revealed that kynurenine 3-monooxygenase (KMO) profoundly increased in MI mice, and was closely associated with the elevation of XA. More importantly, pharmacological or heart-specific inhibition of KMO obviously suppressed the elevation of XA and profoundly ameliorated the OGD-induced cardiomyocytes injury and the ligation-induced MI injury. Mechanistically, KMO inhibition effectively restrained myocardial apoptosis and ferroptosis by modulating mitochondrial fission and fusion. In addition, virtual screening and experimental validation were adopted to identify ginsenoside Rb3 as a novel inhibitor of KMO and exhibited great cardioprotective effects by regulating mitochondrial dynamical balance. Taken together, targeting KMO may provide a new approach for the clinical treatment of MI through maintaining mitochondrial fusion and fission balance, and ginsenoside Rb3 showed great potential to be developed as a novel therapeutic drug targeting KMO., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

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]

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]

Kynurenine pathway metabolites (KPM) are thought to be synthesized mainly by non-neuronal cells in the mammalian brain. KPM are of particular interest because several studies demonstrated their implication in various disorders of the nervous system. Among KPM is xanthurenic acid (XA) deriving from the catabolism of 3-hydroxykynurenine. Based on its chemical structure, XA appears as a close analog of kynurenic acid which has been extensively investigated and is considered as a potent neuroprotective compound. Contrary to kynurenic acid (KYNA), XA has received little attention and its role in the brain remains not elucidated. We have previously described several characteristics of XA, suggesting its possible involvement in neurotransmission. XA is also proposed as a potential modulator at glutamatergic synapses. Here, we used a selective antibody against XA and various neuronal, glial and synaptic markers to show that XA is essentially localized in the soma and dendrites of brain neurons, but is absent from axonal compartments and terminal endings. Our results also reveal that XA-like immunoreactivity is not expressed by glial cells. To double-check our findings, we have also used another XA antibody obtained from a commercial source to confirm the neuronal expression of XA. Together, our results suggest that, differently to several other KPM produced by glial cells, XA exhibits a neuronal distribution in the mouse brain. [ABSTRACT FROM AUTHOR]

The reaction of nickel(II) chloride with xanthurenic acid afforded two crystalline products, [Ni(HXan) 2 (H 2 O) 4 ]·6H 2 O ( 1 ) and [Ni 3 (Xan) 2 (H 2 O) 10 ][Ni(Xan) 2 ]·4{(CH 3 ) 2 CO}·2H 2 O ( 2 ), with HXan − and Xan 2− standing for the deprotonated forms of the acid. Both compounds were unambiguously characterized by means of X-ray structure analysis. Their solid state structures give evidence of a presence of different xanthurenate ions and their tautomeric forms in the solution. Compound 1 is a mononuclear nickel(II) complex with metal ion in a nearly octahedral environment of six ligands: four aqua ligands and two trans positioned HXan − ions, each coordinated in a monodentate manner via a carboxylate oxygen. Compound 2 consists of trinuclear complex cations [Ni 3 (Xan) 2 (H 2 O) 10 ] 2+ and mononuclear complex anions [Ni(Xan) 2 ] 2− . The Xan 2− ions of the complex ions in 2 are not the same, they differ in the position of the ionized hydroxyl moiety. With both compounds possessing several hydrogen bond donors and acceptors, intricate patterns of intramolecular connectivity may be observed in their solid state structures. [ABSTRACT FROM AUTHOR]

Previously, we demonstrated that the endogenous glutamate receptor antagonist kynurenic acid dose-dependently and significantly affected rat heart mitochondria. Now we have investigated the effects of L-tryptophan, L-kynurenine, 3-hydroxykynurenine and kynurenic, anthranilic, 3-hydroxyanthranilic, xanthurenic and quinolinic acids on respiratory parameters (ie, state 2, state 3), respiratory control index (RC) and ADP/oxygen ratio in brain, liver and heart mitochondria of adult rats. Mitochondria were incubated with glutamate/malate (5 mM) or succinate (10 mM) and in the presence of L-tryptophan metabolites (1 mM) or in the absence, as control. Kynurenic and anthranilic acids significantly reduced RC values of heart mitochondria in the presence of glutamate/malate. Xanthurenic acid significantly reduced RC values of brain mitochondria in the presence of glutamate/malate. Furthermore, 3-hydroxykynurenine and 3-hydroxyanthranilic acid decreased RC values of brain, liver and heart mitochondria using glutamate/malate. In the presence of succinate, 3-hydroxykynurenine and 3-hydroxyanthranilic acid affected RC values of brain mitochondria, whereas in liver and heart mitochondria only 3-hydroxykynurenine lowered RC values significantly. Furthermore, lowered ADP/oxygen ratios were observed in brain mitochondria in the presence of succinate with 3-hydroxykynurenine and 3-hydroxyanthranilic acid, and to a lesser extent with glutamate/malate. In addition, 3-hydroxyanthranilic acid significantly lowered the ADP/oxygen ratio in heart mitochondria exposed to glutamate/malate, while in the liver mitochondria only a mild reduction was found. Tests of the influence of L-tryptophan and its metabolites on complex I in liver mitochondria showed that only 3-hydroxykynurenine, 3-hydroxyanthranilic acid and L-kynurenine led to a significant acceleration of NADH-driven complex I activities. The data indicate that L-tryptophan metabolites had different effects on brain, liver and heart mitochondria. Alterations of L-tryptophan metabolism might have an impact on the bioenergetic activities of brain, liver and/or heart mitochondria and might be involved in the development of clinical symptoms such as cardiomyopathy, hepatopathy and dementia. [ABSTRACT FROM AUTHOR]

About 350 million people worldwide have type 2 diabetes (T2D). The major risk factor of T2D is impaired glucose tolerance (pre-diabetes) with 10 % of pre-diabetes subjects develop T2D every year. Understanding of mechanisms of development of T2D from pre-diabetes is important for prevention and treatment of T2D. Chronic stress and chronic low-grade inflammation are prominent risk factors for T2D development in pre-diabetic subjects. However, molecular mechanisms mediating effect of stress and inflammation on development of T2D from pre-diabetes remain unknown. One of such mechanisms might involve kynurenine (KYN) pathway (KP) of tryptophan (TRP) metabolism. We suggested that chronic stress- or chronic low-grade inflammation-induced upregulation of formation of upstream KTP metabolites, KYN and 3-hydroxyKYN, combined with chronic stress- or chronic low-grade inflammation-induced deficiency of pyridoxal 5′-phosphate, a co-factor of downstream enzymes of KTP, triggers overproduction of diabetogenic downstream KYN metabolites, kynurenic acid (KYNA) and 3-hydroxyKYNA (also known as xanthurenic acid (XA)). As the initial assessment of our working hypothesis, we evaluated plasma levels of up- and downstream KP metabolites in the same samples of T2D patients. KYN, XA, and KYNA levels in plasma samples of T2D patients were higher than in samples of non-diabetic subjects. Our results provide further support of 'kynurenine hypothesis of insulin resistance and its progression to T2D' that suggested that overproduction of diabetogenic KP metabolites, induced by chronic stress or chronic low-grade inflammation, is one of the mechanisms promoting development of T2D from pre-diabetes. Downstream metabolites of KP might serve as biomarkers of T2D and targets for clinical intervention. [ABSTRACT FROM AUTHOR]

Kynurenine pathway, the quantitatively main branch of tryptophan metabolism, has been long been considered a source of nicotinamide adenine dinucleotide, although several of its products, the so-called kynurenines, are endowed with the capacity to activate glutamate receptors, thus potentially influencing a large group of functions in the central nervous system (CNS). Migraine, a largely unknown pathology, is strictly related to the glutamate system in the CNS pathologic terms. Despite the large number of studies conducted on migraine etio-pathology, the kynurenine pathway has been only recently linked to this disease. Nonetheless, some evidence suggests an intriguing role for some kynurenines, and an exploratory study on the serum kynurenine level might be helpful to better understand possible alterations of the kynurenine pathway in patients suffering from migraine. [ABSTRACT FROM AUTHOR]

Incorporation of fatty acids into phospholipids has been investigated using samples of rat liver tissue homogenate, Krebs-Ringer-phosphate buffer (pH=7.4) containing 0.3% albumin, fatty acid mixture and glycerol. The addition of anthranilic acid (2.2 and 4 nmol/g wet weight), kynurenic acid (4 and 40 nmol/ g wet weight), xanthurenic acid (4 and 40 nmol/g wet weight), picolinic acid (0.2 and 2 nmol/g wet weight) induced an increase of saturated and a decrease of polyunsaturated fatty acids incorporation into phospholipids as well as an eleyation of choksterol concentration in samples used for phospholipid biosynthesis in vitro. These changes were similar to those observed after addition of kynurenine and neopterin to the same test system, An inverse relationship has been observed after addition of nicotinic acid to samples used for phospholipid biosynthesis in vitro. Nicrotinic acid induced .1 decrease of saturated and an increase of unsaturated fatty acids incorporation into phospholipids as well as decrease of cholesterol concentration in samples, These changes were similar to those observed after addition of 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic, acid, 5,6],8-tetrahydrobiopterin and its precursors to the same test system used rex phospholipid biosynthesis in vitro. In parallel anthranilic acid, kynurenic acid, xanthurenic acid and picolinic acid decrease while nicotinic acid increases membrane fluidity in the studied concentrations.

The 3-hydroxykynurenine transaminase (3-HKT) gene plays a vital role in the development of malaria parasites by participating in the synthesis of xanthurenic acid, which is involved in the exflagellation of microgametocytes in the midgut of malaria vector species. The 3-HKT enzyme is involved in the tryptophan metabolism of Anophelines. The gene had been studied in the important global malaria vector, Anopheles gambiae. In this report, we have conducted a preliminary investigation to characterize this gene in the two important vector species of malaria in India, Anopheles culicifacies and Anopheles stephensi. The analysis of the genetic structure of this gene in these species revealed high homology with the An. gambiae gene. However, four non-synonymous mutations in An. stephensi and seven in An. culicifacies sequences were noted in the exons 1 and 2 of the gene; the implication of these mutations on enzyme structure remains to be explored.

This study reports the synthesis of novel mixed ligand complexes of copper(II) with the xanthurenate anion (Xan) and nicotinamide ligand (NA): [Cu(Xan)(NA)(HO)]·HO and [Cu(Xan)(NA)(HO)]·3HO. The compounds were characterized by single crystal X-ray diffraction, IR spectroscopy, and thermal analysis. The first coordination sphere of copper(II) in [Cu(Xan)(NA)(HO)] consists of a water molecule, a nicotinamide ligand coordinated via the pyridine nitrogen and a xanthurenate dianion coordinated in a tridentate manner via carboxylate oxygen, nitrogen, and phenolate oxygen. The five donor atoms define a distorted square pyramid whose apex is occupied by the aqua ligand. The antioxidant activities of the compounds were investigated by the 2,2-diphenyl-1-picrylhydrazyl scavenging method, which showed that the IC values for both compounds are higher than for related [Cu(Xan)(HO)] complex. The title compounds also exhibit superoxide dismutase mimetic activity. Graphical abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) underlines aging and aging-associated medical (diabetes, obesity, dyslipidemia, hypertension) and psychiatric (depression, cognitive decline) disorders. Molecular mechanisms of IR in genetically or metabolically predisposed individuals remain uncertain. Current review of the literature and our data presents the evidences that dysregulation of tryptophan (TRP)-kynurenine (KYN) and KYN-nicotinamide adenine dinucleotide (NAD) metabolic pathways is one of the mechanisms of IR. The first and rate-limiting step of TRP-KYN pathway is regulated by enzymes inducible by pro-inflammatory factors and/or stress hormones. The key enzymes of KYN-NAD pathway require pyridoxal-5-phosphate (P5P), an active form of vitamin B, as a cofactor. Deficiency of P5P diverts KYN-NAD metabolism from production of NAD to the excessive formation of xanthurenic acid (XA). Human and experimental studies suggested that XA and some other KYN metabolites might impair production, release, and biological activity of insulin. We propose that one of the mechanisms of IR is inflammation- and/or stress-induced upregulation of TRP-KYN metabolism in combination with P5P deficiency-induced diversion of KYN-NAD metabolism towards formation of XA and other KYN derivatives affecting insulin activity. Monitoring of KYN/P5P status and formation of XA might help to identify subjects at risk for IR. Pharmacological regulation of the TRP-KYN and KYN-NAD pathways and maintaining of adequate vitamin B status might contribute to prevention and treatment of IR in conditions associated with inflammation/stress-induced excessive production of KYN and deficiency of vitamin B, e.g., type 2 diabetes, obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection. [ABSTRACT FROM AUTHOR]

Herein, we present the electrochemical co-deposition of Al/graphene composites directly from an aqueous mixture containing graphene oxide (GO) and Al. The obtained Al/graphene composites with good electrochemical activity were regarded as an appropriate immobilization platform for double-stranded DNA (dsDNA). The nontoxic redox probe xanthurenic acid (XA) was successfully applied to recognize single-stranded DNA and dsDNA. We illustrated that the scission of dsDNA caused by GO combining with some metal ions could be detected by monitoring the electrochemical signals of XA. [ABSTRACT FROM AUTHOR]

A bifunctional sensor for determination of reduced β-nicotinamide adenine dinucleotide (NADH) and hydrogen peroxide (H2O2) has been successfully fabricated by xanthurenic acid (Xa), flavin adenine dinucleotide (FAD), and functionalized carbon nanotubes (CNTs). The hybrid composites can be easily prepared by the electrocodeposition of polyXa/FAD and the adsorption of functionalized CNTs. These composites can be constructed of “polyXa/FAD/CNTs” and “CNTs/polyXa/FAD” according to the immobilization order of polyXa/FAD “before” and “after” the adsorption of CNTs. They are surface-confined and stable in various scan rates and different pH conditions. Particularly, the polyXa/FAD/MWCNTs show more efficient activity to target species due to the compact structure and more active surface area. It provides linear concentration range of 5×10−6–1.7×10−4 M and 1×10−4–2.9×10−3 M, with sensitivity of 155μAmM−1 cm−2 and 60μAmM−1 cm−2, and detection limit of 10−6 M and 10−4 M (S/N=3) for NADH and H2O2, respectively. No interference except of the case for NADH determination in the presence of AA. It can be a good electrocatalyst to determine NADH and H2O2 and the linear sweep voltammetry (LSV) technique can help to analyze NADH from the AA interference. [ABSTRACT FROM AUTHOR]

The authors focus on the role of rat/human organic anion transporters including rOATl, hOATl and rOAT3 in the transport of xanthurenic acid, a derivative of carboxylic acid. They inform that researchers have performed an uptake experiment using Xenopus laevis oocytes in order to examine the transport of xanthurenic acid by the transporters and found that transport activity of xanthurenic acid by hOATl is greater than rOATI.

Sexual reproduction of apicomplexan parasites in haematophagous arthropods requires that intracellular sexual stages of these protozoa escape vertebrate erythrocytes in the blood meal. Although cues that signal sexual stages of the human malaria parasite ( Plasmodium falciparum Welch, 1897) to emerge from erythrocytes are well documented, such signals are poorly known for other blood-dwelling Apicomplexa. The objective of this comparative study was to investigate conditions required to induce in vitro emergence of sexual stages of Hepatozoon clamatae (Stebbins, 1905) from frog erythrocytes. Blood was drawn from Green Frogs ( Rana clamitans Latreille in Sonnini de Manoncourt and Latreille, 1801 = Lithobates clamitans clamitans (Latreille in Sonnini de Manoncourt and Latreille, 1801)) infected with H. clamatae and treated with solutions of various concentrations of saline, pH, and xanthurenic acid at different temperatures. Hypertonic saline solutions of 200 and 222 mmol/L at pH 7.4 and 7.7 elicited emergence of nearly 100% of gamonts from frog erythrocytes, but at pH 8.0 resulted in decreased emergence. Solutions containing 1, 10, and 100 μmol/L xanthurenic acid increased gamont emergence at saline concentrations of 156, 178, and 244 mmol/L, but decreased emergence at 200 and 222 mmol/L. Gamont emergence increased as incubation temperatures increased from 18 to 26 °C. These results suggest that conditions necessary for emergence of sexual stages of bloodstream Apicomplexa from erythrocytes vary among genera. [ABSTRACT FROM AUTHOR]

Abstract: Xanthurenic acid (XA), a molecule arising from tryptophan metabolism by transamination of 3-hydroxykynurenine, has recently been identified as an endogenous Group II (mGlu2 and mGlu3) metabotropic glutamate (mGlu) receptor ligand in vitro. Impairments in Group II mGlu receptor expression and function have been implicated in the pathophysiology of schizophrenia, as have multiple steps in the kynurenine metabolism pathway. Therefore, we examined XA in vivo to further investigate its potential as a Group II mGlu receptor ligand using a preparation that has been previously demonstrated to efficiently reveal the action of other Group II mGlu receptor ligands in vivo. Extracellular single-neurone recordings were made in the rat ventrobasal thalamus (VB) in conjunction with iontophoresis of agonists, an antagonist and a positive allosteric modulator and/or intravenous (i.v.) injection of XA. We found the XA effect on sensory inhibition, when applied iontophoretically and i.v., was similar to that of other Group II mGlu receptor agonists in reducing inhibition evoked in the VB from the thalamic reticular nucleus upon physiological sensory stimulation. Furthermore, we postulate that XA may be the first potential endogenous allosteric agonist (termed ‘endocoid’) for the mGlu receptors. As the Group II receptors and kynurenine metabolism pathway have both been heavily implicated in the pathophysiology of schizophrenia, XA could play a pivotal role in antipsychotic research as this potential endocoid represents both a convergence within these two biological parameters and a novel class of Group II mGlu receptor ligand. This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’. [Copyright &y& Elsevier]

Abstract: The poly-xanthurenic acid (poly-Xa)/multi-walled carbon nanotube (MWCNT)/glassy carbon modified electrode (poly-Xa/MWCNT/GCE) was successfully applied for the simultaneous determination of ascorbic (AA) and uric (UA) acids. Cyclic voltammetric results show that the modified electrode displays an excellent eletrocatalytic activity toward the oxidation of AA at a low potential (0.05V versus Ag/AgCl) and anodic peak resolution (ΔE pa), close to 300mV versus Ag/AgCl, in solutions containing AA and UA. Values in the order of 106 Lmol−1 s−1 were obtained for the kinetic constant k cat for the catalytic oxidation of AA, upon evaluation by cyclic voltammetry, chronoamperometry and RDE. Furthermore, the sensor provided limits of detection of 0.19μmolL−1 and 0.31μmolL−1 for AA and UA, respectively. The sensor was applied for the simultaneous determination of AA and UA in urine samples and the average recoveries for these samples were 99.9 (±2.5)% and 99.9 (±2.6)%, respectively. [Copyright &y& Elsevier]

Abstract: AX10185, the phenyl amide of xanthurenic acid, was found to be a sub-100nM inhibitor of Lp-PLA2. However, in the presence of EDTA the inhibitory activity of AX10185 was extinguished while the enzymatic activity of Lp-PLA2 did not change. Subsequent metal screening experiments determined the inhibition to be Zn2+ dependent. Structure–activity relationship studies indicated the presence of the 4-hydroxy group to be critical and selected substituted phenyl, polycyclic, and cycloaliphatic amides of xanthurenic acid to be well tolerated. [Copyright &y& Elsevier]

Abstract: Sulfotransferase enzymes are known to regulate physiologically active substances such as steroids and catecholamines in mammals. Although invertebrates also express sulfotransferases, their biological function is mostly unclear. In a previous study, we reported that 4-nitrocatechol and the gallete ester are substrates for the silkworm sulfotransferase bmST1. The K m of bmST1 for these substrates is high. However, endogenous substrates of bmST1 have not yet been determined. We therefore investigated endogenous bmST1 substrates and carried out a detailed expression profile analysis of bmST1. We found that xanthurenic acid, a tryptophan metabolite, is a possible endogenous substrate of bmST1. The K m of bmST1 for xanthurenic acid is low, in the μM range, which is lower than that for previously reported substrates. Additionally, xanthurenic acid is a tryptophan metabolite that characteristically shows toxicity in vivo. High dose administration of xanthurenic acid resulted in inhibition of cuticular biosynthesis. The expression of the bmST1 gene reached a maximal level in the Malpighian tubule at the 4th molting stage, when amino acid metabolism might be activated. Our results suggest that bmST1 plays a role in detoxification of xanthurenic acid in the silkworm. [Copyright &y& Elsevier]

Abstract: This paper describes, for the first time, the development of a simple and highly sensitive chemical sensor based on a new electroactive material, electrogenerated in situ from xanthurenic acid on an electrode modified with MWCNT. The modified electrode shows efficient electrocatalytic oxidation activity towards NADH at an applied potential of 0.1V vs. Ag/AgCl. The kinetic constant, k kin, for the electrocatalytic oxidation of NADH, evaluated by chronoamperometry and voltammetry using RDE, provided values close to 105 mol−1 Ls−1. [Copyright &y& Elsevier]

A simple, rapid isocratic liquid chromatographic procedure with ultraviolet and fluorimetric detection is described for the separation and quantification of L-tryptophan (Trp) and six of its kynurenine metabolites (kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic, kynurenic, xanthurenic and anthranilic acids). Using the Perkin Elmer LC 200 system, a reverse phase Synergi 4 μ fusion-RP80 A column (250 × 4.6 mm) (Phenomenex), and a mobile phase of 10 mM sodium dihydrogen phosphate: methanol (73:27, by vol) at pH 2.8 and a flow rate of 1.0-1.2 ml/min at 37 °C, a run took 13 min. The run took <7 min at 40 °C and a 1.4 ml/min flow rate. Limits of detection of all 7 analytes were 5-72 nM and their recoveries from human plasma and rat serum and liver varied between 62% and 111%. This simple method is suitable for high throughput work and can be further developed to include quinolinic acid and other Trp metabolites. [ABSTRACT FROM AUTHOR]