Abstract
Quinolinic acid (QA) is a pyridine derivative that can be found in many organisms and is widely used in the chemical industry. However, QA possesses excitotoxic properties. To date, the ...catabolism of QA mediated by microorganisms has rarely been reported. In this study, a QA-degrading strain (JQ191) was isolated from sewage sludge. Based on phenotypic and 16S rRNA gene phylogenetic analysis, the strain was identified as Alcaligenes faecalis. Strain JQ191 was able to utilize QA as the sole source of carbon and nitrogen for growth. QA-cultured cells of JQ191 completely degrade 200 mg/L QA within 2 days in a mineral salt medium, whereas the LB-cultured cells experienced a 2-day lag period before degrading QA, indicating that the catabolic enzymes involved in QA degradation were induced by QA. 6-Hydroxypicolinic acid (6HPA) was identified as an intermediate of QA degradation by strain JQ191. A 6HPA monooxygenase gene picB was cloned, genetically disrupted, and heterologously expressed, and the results show that picB was responsible for catalyzing 6HPA to 3,6DHPA in JQ191. A new QA mineralization pathway was proposed. This study identifies a new bacterium candidate that has a potential application prospect in the bioremediation of QA-polluted environment, as well as provides new insights into the bacterial catabolism of QA.
A new bacterium that can degrade neurotoxic quinolinic acid(QA).
Kynurenine pathway (KP) metabolites are believed to be a link between inflammation and depression through effects on brain glutamate receptors. However, neither the relationship between plasma and ...cerebrospinal fluid (CSF) KP metabolites nor their association with inflammatory mediators is well-established in depression. Moreover, the clinical profile associated with combined activation of plasma inflammatory and kynurenine pathways is unknown. Accordingly, plasma and CSF-KP metabolites and inflammatory markers along with depressive symptoms and antidepressant treatment response were measured in 72 unmedicated depressed patients. Following bivariate analyses, component factors representing immune and kynurenine variables in the plasma and CSF were extracted and were used to examine directionality of associations in a path model. In addition, patients were clustered using individual markers that most accounted for the association between plasma immune and KP systems. Path analysis revealed a directional association extending from plasma inflammatory markers to plasma kynurenines, to CSF kynurenines. Among immune markers, plasma tumor necrosis factor (TNF) was robustly associated with plasma kynurenine (KYN) and KYN/tryptophan (TRP), which was in turn significantly associated with CSF KYN, kynurenic acid, and quinolinic acid. Clustering of patients based on plasma TNF and KYN/TRP yielded subgroups of high (N = 17) and low (N = 55) TNF-KYN/TRP groups. High TNF-KYN/TRP subjects exhibited greater depression severity, anhedonia, and treatment nonresponse. In conclusion, plasma-KP metabolites may mediate an inflammation-associated depressive symptom profile via CNS KP metabolites that can serve as a target for intervention at the level of inflammation, peripheral KYN metabolism, KYN transport to the brain, or effects of KP metabolites on glutamate receptors.
Excessive stimulation of the quinolinic acid induces neuronal cell death and is implicated in developing several neurodegenerative diseases. This study investigated whether a Wnt5a antagonist plays a ...neuroprotective role by regulating the Wnt pathway, activating cellular signaling mechanisms, including MAP kinase and ERK, and acting on the antiapoptotic and the proapoptotic genes in N18D3 neural cells. The cells were pretreated with a Wnt5a antagonist Box5, for one hour and then exposed to quinolinic acid (QUIN), an NMDA receptor agonist for 24 hours. An MTT assay and DAPI staining were used to evaluate cell viability and apoptosis, respectively, demonstrating that Box5 protected the cells from apoptotic death. In addition, a gene expression analysis revealed that Box5 prevented the QUIN-induced expression of the pro-apoptotic genes, BAD and BAX, and increased that of the anti-apoptotic genes, Bcl-xL, BCL2, and BCLW. Further examination of potential cell signaling candidates involved in this neuroprotective effect showed that the immunoreactivity of ERK was significantly increased in the cells treated with Box5. These results suggest that the neuroprotective mechanism of Box5 against QUIN-induced excitotoxic cell death involves the regulation of ERK and modulation of cell survival and death genes through decreasing the Wnt pathway, specifically Wnt5a.
Quinolinic acid (QA) is thought to be one of the most important metabolites of the kynurenine pathway with the highest biological activity in apoptotic responses and neurodegenerative diseases. The ...determination of QA might be of clinical relevance in different patient groups, but currently, only a few laborious methods with high levels of sample volume consumption are available.
We developed and validated a simple liquid chromatography–tandem mass spectrometric (LC–tandem MS) method for the determination of QA in human serum with low sample volume requirements.
The presented method provides high sample throughput with 25μL aliquots and works in the positive electrospray ionization (ESI) mode. A commercially available QA-d3 was used as internal standard. Specific transitions for QA and QA-d3 were m/z 280→m/z 78 and m/z 283→m/z 81, respectively. The intra- and inter-assay coefficients of variation (CVs) were all below 10%. Applying this method, in 50 healthy humans a mean serum concentration of QA of 350±167nmol/L (mean±SD) was determined.
The described method is suitable for large clinical trials, which is of potential clinical importance to elucidate the function of QA and its relationship to different disease patterns and may be applicable for clinical laboratory routine.
•We described a simple mass spectrometry method for quinolinic acid in serum.•The method requires only 25μL sample volume.•The method is suitable for large clinical trials.•The method may be applicable for clinical laboratory routine.•Quinolinic acid might be important in patients with neurodegenerative diseases.
The effect of a ketogenic diet (KD) on middle aged female mice is poorly understood as most of this work have been conducted in young female mice or diseased models. We have previously shown that an ...isocaloric KD started at middle age in male mice results in enhanced mitochondrial mass and function after 2 months on diet and improved cognitive behavior after being on diet for 14 months when compared with their control diet (CD) fed counterparts. Here, we aimed to investigate the effect of an isocaloric 2‐month KD or CD on healthy 14‐month‐old female mice. At 16 months of age cognitive behavior tests were performed and then serum, skeletal muscle, cortex, and hippocampal tissues were collected for biochemical analysis. Two months on a KD resulted in enhanced cognitive behavior associated with anxiety, memory, and willingness to explore. The improved neurocognitive function was associated with increased PGC1α protein in the gastrocnemius (GTN) muscle and nuclear fraction. The KD resulted in a tissue specific increase in mitochondrial mass and kynurenine aminotransferase (KAT) levels in the GTN and soleus muscles, with a corresponding decrease in kynurenine and increase in kynurenic acid levels in serum. With KAT proteins being responsible for converting kynurenine into kynurenic acid, which is unable to cross the blood brain barrier and be turned into quinolinic acid—a potent neurotoxin, this study provides a potential mechanism of crosstalk between muscle and brain in mice on a KD that may contribute to improved cognitive function in middle‐aged female mice.
Protein metabolism and inflammatory states—aging, diabetes, autoimmune disease—drive the conversion of the amino acid tryptophan to kynurenine in the liver. On a standard diet, kynurenine aminotransferase (KAT) levels are low, and kynurenine freely crosses the blood–brain‐barrier where it is converted to the neurotoxin quinolinic acid, decreasing neurocognitive function. By contrast, a ketogenic diet increases KAT levels in muscle resulting in conversion of kynurenine into kynurenic acid, which does not cross the blood–brain‐barrier, and improved neurocognitive performance.
Central kynurenine pathway shift with age in women Bie, Josien; Guest, Jade; Guillemin, Gilles J. ...
Journal of neurochemistry,
March 2016, 2016-Mar, 2016-03-00, 20160301, Letnik:
136, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Age is considered a dominant risk factor in the development of most neurodegenerative disorders. The kynurenine pathway, a major metabolic pathway of tryptophan is altered in the majority of ...neurodegenerative disorders. In this study, we have analysed CSF samples from 49 healthy women across a wide age range (0–90) for kynurenine pathway metabolites and the inflammatory marker neopterin. Our results show central tryptophan metabolism is increased with age in women, with an apparent shift towards the neurotoxin quinolinic acid. We also observed an increase in central levels of the inflammatory marker neopterin with age and a positive correlation between neopterin and kynurenine pathway activation. We conclude that, the changes that occur in the kynurenine pathway as a result of normal ageing are mechanistically linked to increased inflammatory signalling and have some explanatory potential with regard to age‐associated degenerative diseases in the CNS. Management of health in ageing and (preventative) treatment would do well to look to the kynurenine pathway for potentially novel solutions.
Both the inflammation marker neopterin and kynurenine pathway activity were increased with age in the CSF of female subjects. While levels of quinolinic acid (QUIN), picolinic acid (PIC), kynurenine and quinaldic acid (QA) were increased, 3‐hydroxykynurenine (3HK) was decreased and 3‐hydroxyanthranilic acid (3HAA) and kynurenic acid (KYNA) remained unchanged. Of particular interest is the increase in QUIN, a neuroexcitotoxin associated with neurodegeneration.
Both the inflammation marker neopterin and kynurenine pathway activity were increased with age in the CSF of female subjects. While levels of quinolinic acid (QUIN), picolinic acid (PIC), kynurenine and quinaldic acid (QA) were increased, 3‐hydroxykynurenine (3HK) was decreased and 3‐hydroxyanthranilic acid (3HAA) and kynurenic acid (KYNA) remained unchanged. Of particular interest is the increase in QUIN, a neuroexcitotoxin associated with neurodegeneration.
We investigated the effects of an acute intrastriatal QUIN administration on cellular redox and bioenergetics homeostasis, as well as on important signaling pathways in the striatum of wild-type (
...Gcdh
+/+
, WT) and knockout mice for glutaryl-CoA dehydrogenase (
Gcdh
−/−
) fed a high lysine (Lys, 4.7 %) chow. QUIN increased lactate release in both
Gcdh
+/+
and
Gcdh
−/−
mice and reduced the activities of complex IV and creatine kinase only in the striatum of
Gcdh
−/−
mice. QUIN also induced lipid and protein oxidative damage and increased the generation of reactive nitrogen species, as well as the activities of the antioxidant enzymes glutathione peroxidase, superoxide dismutase 2, and glutathione-S-transferase in WT and
Gcdh
−/−
animals. Furthermore, QUIN induced DCFH oxidation (reactive oxygen species production) and reduced GSH concentrations (antioxidant defenses) in
Gcdh
−/−
. An early increase of Akt and phospho-Erk 1/2 in the cytosol and Nrf2 in the nucleus was also observed, as well as a decrease of cytosolic Keap1caused by QUIN, indicating activation of the Nrf2 pathway mediated by Akt and phospho-Erk 1/2, possibly as a compensatory protective mechanism against the ongoing QUIN-induced toxicity. Finally, QUIN increased NF-κB and diminished IκBα expression, evidencing a pro-inflammatory response. Our data show a disruption of energy and redox homeostasis associated to inflammation induced by QUIN in the striatum of
Gcdh
−/−
mice submitted to a high Lys diet. Therefore, it is presumed that QUIN may possibly contribute to the pathophysiology of striatal degeneration in children with glutaric aciduria type I during inflammatory processes triggered by infections or vaccinations.
The tryptophan-kynurenine (KYN) pathway is linked to obesity-related systemic inflammation and metabolic health. The pathway generates multiple metabolites, with little available data on their ...relationships to early markers of increased metabolic disease risk in children. The aim of this study was to examine the association of multiple KYN pathway metabolites with metabolic risk markers in prepubertal Asian children.
Fasting plasma concentrations of KYN pathway metabolites were measured using liquid chromatography-tandem mass spectrometry in 8-year-old children (n = 552) from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) prospective mother-offspring cohort study. The child's weight and height were used to ascertain overweight and obesity using local body mass index (BMI)-for-age percentile charts. Body fat percentage was measured by quantitative magnetic resonance. Abdominal circumference, systolic and diastolic blood pressure, homeostatic model assessment for insulin resistance (HOMA-IR), triglyceride, and HDL-cholesterol were used for the calculation of Metabolic syndrome scores (MetS). Serum triglyceride, BMI, gamma-glutamyl transferase (GGT), and abdominal circumference were used in the calculation of the Fatty liver index (FLI). Associations were examined using multivariable regression analyses.
In overweight or obese children (n = 93; 16.9% of the cohort), all KYN pathway metabolites were significantly increased, relative to normal weight children. KYN, kynurenic acid (KA), xanthurenic acid (XA), hydroxyanthranilic acid (HAA) and quinolinic acid (QA) all showed significant positive associations with body fat percentage (B(95% CI) = 0.32 (0.22,0.42) for QA), HOMA-IR (B(95% CI) = 0.25 (0.16,0.34) for QA), and systolic blood pressure (B(95% CI) = 0.14(0.06,0.22) for QA). All KYN metabolites except 3-hydroxykynurenine (HK) significantly correlated with MetS (B (95% CI) = 0.29 (0.21,0.37) for QA), and FLI (B (95% CI) = 0.30 (0.21,0.39) for QA).
Higher plasma concentrations of KYN pathway metabolites are associated with obesity and with increased risk for metabolic syndrome and fatty liver in prepubertal Asian children.
Quinolinic acid (QUIN) is a neuroactive metabolite of the kinurenine pathway, and is considered to be involved in aging and some neurodegenerative disorders, including Huntington's disease. QUIN was ...injected intrastriatally into adolescent rats, and biochemical and histopathological analyses in the striatum, cortex, and hippocampus, as well as behavioral tests, were carried out in the rats over a period of 21 days after drug injection. Decreased 3Hglutamate uptake and increased 45Ca2+ uptake were detected shortly after injection in the striatum and cerebral cortex. In the hippocampus, increased 45Ca2+ uptake preceded the decreased 3Hglutamate uptake, without histopathological alterations. Also, corticostriatal astrogliosis was observed 7 days later, progressing to neuronal death at day 14. QUIN‐treated rats also showed cognitive deficits 24 h after injection, concurrently with striatal astrogliosis. Motor deficits appeared later, after corticostriatal neurodegeneration. We assume that glutamate excitotoxicity could represent, at least in part, a molecular mechanism associated with the cognitive and motor impairments, corticostriatal astrogliosis and neuronal death observed in the QUIN‐treated rats. We propose that our findings could be relevant for understanding the pathophysiology of human neurodegenerative diseases affecting young people, such as the juvenile form of Huntington's disease, and for the design of potential therapeutic strategies to slow down the progression of the disease.
Quinolinic acid intrastriatally injected in adolescent rats produced a short‐term decrease in 3H‐glutamate uptake and increase in 45Ca2+ uptake in the striatum, cerebral cortex and hippocampus, accompanied by striatal astrogliosis and cognitive deficits. Corticostriatal astrogliosis was a later event, progressing to neuronal death, while no histopathological changes were observed in the hippocampus. Motor deficits appeared later, after corticostriatal neurodegeneration.
•Baicalein attenuates motor-cognitive abnormalities of QA induced striatal lesion.•Brain neurotrophins levels were augmented after baicalein administration.•QA reverses GABAergic inhibition studied ...via TH immunohistochemical analysis.•Baicalein restrained the antioxidant disturbance due QA lesion in striatal region.
Huntington Disease (HD), a predominant Neurodegenerative Disorder which might be induced by endogenous neurotoxin called Quinolinic Acid (QA), an N-methyl-D aspartate receptor (NMDAR) agonist, the bilaterally intrastriatal administration (200 nm/2 μL of saline) offers rise to the toxic events like neuronal death, neuroinflammation by inflicting excitotoxicity and oxidative stress in the striatum of male Wistar rats by exhibiting the behavioural changes which was accessed by rotarod, open field analysis. In this study, the neuropharmacological effect of Baicalein (BC) against QA induced HD was evaluated. Baicalein (BC), scientifically 5,6,7 trihydroxy flavone present naturally in the edible plants like Scutellaria baicalensis and Oroxylum indicum possess a better neuroprotective effect in the dosage of 10 mg/kg and 30 mg/kg intraperitoneally in the striatum of HD induced rats. This study proved that BC is efficient to revive the level of enzymatic & non-enzymatic antioxidants and mitochondrial complexes by decreasing the number of inflammatory mediators such as MDA, protein carbonyls and Nitric Oxide at the significance of P < 0.01 and restores the amount of BDNF and GDNF thereby preventing the neurophysiological changes which were analysed by haematoxylin & eosin staining. Thus finally, the protective effect of Baicalein displays the up-gradation of psychological and behavioural changes induced by QA.
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