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Parkinson's disease (PD) is a complex multi-factorial neurodegenerative disorder where various altered metabolic pathways contribute to the progression of the disease. Tryptophan (TRP) is a major precursor in kynurenine pathway (KP) and it has been discussed in various in vitro studies that the metabolites quinolinic acid (QUIN) causes neurotoxicity and kynurenic acid (KYNA) acts as neuroprotectant respectively. More studies are also focused on the effects of other KP metabolites and its enzymes as it has an association with ageing and PD pathogenesis. Until now, very few studies have targeted the role of genetic mutations in abnormal KP metabolism in adverse conditions of PD. Therefore, the present review gives an updated research studies on KP in connection with PD. Moreover, the review emphasizes on the urge for the development of biomarkers and also this would be an initiative in generating an alternative therapeutic approach for PD., Graphical abstract Unlabelled Image, Highlights • KP metabolites and enzymes act on NAD+ levels. • The catabolism of TRP and NAD+ biogenesis are linked through KP. • KMO and ACMSD genetic alterations involved in PD. • Genetic link between KP and PD were discussed. • KP as a therapeutic intervention in PD.

Mental disorders (MDs) are highly prevalent and potentially debilitating complex disorders which causes remain elusive. Looking into deeper aspects of etiology or pathophysiology underlying these diseases would be highly beneficial, as the scarce knowledge in mechanistic and molecular pathways certainly represents an important limitation. Association between MDs and inflammation/neuroinflammation has been widely discussed and accepted by many, as high levels of pro-inflammatory cytokines were reported in patients with several MDs, such as schizophrenia (SCZ), bipolar disorder (BD) and major depression disorder (MDD), among others. Correlation of pro-inflammatory markers with symptoms intensity was also reported. However, the mechanisms underlying the inflammatory dysfunctions observed in MDs are not fully understood yet. In this context, microglial dysfunction has recently emerged as a possible pivotal player, as during the neuroinflammatory response, microglia can be over-activated, and excessive production of pro-inflammatory cytokines, which can modify the kynurenine and glutamate signaling, is reported. Moreover, microglial activation also results in increased astrocyte activity and consequent glutamate release, which are both toxic to the Central Nervous System (CNS). Also, as a result of increased microglial activation in MDs, products of the kynurenine pathway were shown to be changed, influencing then the dopaminergic, serotonergic, and glutamatergic signaling pathways. Therefore, in the present review, we aim to discuss how neuroinflammation impacts on glutamate and kynurenine signaling pathways, and how they can consequently influence the monoaminergic signaling. The consequent association with MDs main symptoms is also discussed. As such, this work aims to contribute to the field by providing insights into these alternative pathways and by shedding light on potential targets that could improve the strategies for pharmacological intervention and/or treatment protocols to combat the main pharmacologically unmatched symptoms of MDs, as the SCZ., Highlights • Alterations in the cytokine profile in mental disorders patients. • Unbalanced kynurenine pathway leads to excitotoxicity and NMDA hypoactivation. • Increased glutamate production leads to excitotoxicity. • Microglial and astrocytic activation influences in neurotransmission pathways.

Background Kynurenine aminotransferase 3 (KAT3) catalyzes the transamination of Kynurenine to kynurenic acid, and is identical to cysteine conjugate beta-lyase 2 (CCBL2) and glutamine transaminase L (GTL). GTL was previously purified from the rat liver and considered as a liver type glutamine transaminase. However, because of the substrate overlap and high sequence similarity of KAT3 and KAT1, it was difficult to assay the specific activity of each KAT and to study the enzyme localization in animals. Methods KAT3 transcript and protein levels as well as enzyme activity in the liver and kidney were analyzed by regular reverse transcription-polymerase chain reaction (RT-PCR), real time RT-PCR, biochemical activity assays combined with a specific inhibition assay, and western blotting using a purified and a highly specific antibody, respectively. Results This study concerns the comparative biochemical characterization and localization of KAT 3 in the mouse. The results showed that KAT3 was present in both liver and kidney of the mouse, but was much more abundant in the kidney than in the liver. The mouse KAT3 is more efficient in transamination of glutamine with indo-3-pyruvate or oxaloacetate as amino group acceptor than the mouse KAT1. Conclusions Mouse KAT3 is a major glutamine transaminase in the kidney although it was named a liver type transaminase. General significance Our data highlights KAT3 as a key enzyme for studying the nephrotoxic mechanism of some xenobiotics and the formation of chemopreventive compounds in the mouse kidney. This suggests tissue localizations of KAT3/GTL/CCBL2 in other animals may be carefully checked., Highlights • Mouse kynurenine aminotransferase 3 (KAT3) was specifically inhibited by methionine. • Mouse KAT3 is more abundant in the kidney than in the liver. • Mouse KAT3 is a major glutamine transaminase in the kidney although it was named a liver transaminase.

Hyperhomocysteinemia results from hepatic metabolism dysfunction and is characterized by a high plasma homocysteine level, which is also an independent risk factor for cardiovascular disease. Elevated levels of homocysteine in plasma lead to hepatic lesions and abnormal lipid metabolism. Therefore, lowering homocysteine levels might offer therapeutic benefits. Recently, we were able to lower plasma homocysteine levels in mice with moderate hyperhomocysteinemia using an adenoviral construct designed to restrict the expression of DYRK1A, a serine/threonine kinase involved in methionine metabolism (and therefore homocysteine production), to hepatocytes. Here, we aimed to extend our previous findings by analyzing the effect of hepatocyte-specific Dyrk1a gene transfer on intermediate hyperhomocysteinemia and its associated hepatic toxicity and liver dysfunction. Commensurate with decreased plasma homocysteine and alanine aminotransferase levels, targeted hepatic expression of DYRK1A in mice with intermediate hyperhomocysteinemia resulted in elevated plasma paraoxonase-1 and lecithin:cholesterol acyltransferase activities and apolipoprotein A–I levels. It also rescued hepatic apolipoprotein E, J, and D levels. Further, Akt/GSK3/cyclin D1 signaling pathways in the liver of treated mice were altered, which may help prevent homocysteine-induced cell cycle dysfunction. DYRK1A gene therapy could be useful in the treatment of hyperhomocysteinemia in populations, such as end-stage renal disease patients, who are unresponsive to B-complex vitamin therapy., Highlights • Dyrk1a overexpression reduces plasma ALT levels in mice with intermediate hyperhomocysteinemia. • A negative correlation is found between plasma homocysteine levels and LCAT activity. • Dyrk1a overexpression rescues hepatic IkB levels in mice with intermediate hyperhomocysteinemia.

Breast milk is the only source of the essential amino acid tryptophan (TRP) in breast-fed infants. Low levels of TRP could have implications for infant neurodevelopment. The objectives of the present study were to compare the relationship of TRP and its neuroactive pathway metabolites kynurenine (Kyn) and kynurenic acid (KynA) in preterm and term expressed breast milk (EBM) in the first 14 d following birth, and the relationship of TRP metabolism to maternal stress and immune status. A total of twenty-four mothers were recruited from Cork University Maternity Hospital: twelve term (>38 weeks) and twelve preterm (P< 0·05), free TRP levels were lower (P< 0·05). Kyn, KynA and the Kyn:TRP ratio increased significantly in term EBM from day 7 to day 14 (P< 0·05), but not in preterm EBM. TNF-α, IL-6 and IL-8 were higher in day 7 preterm and term EBM in comparison with day 14. There were no significant differences between term and preterm EBM cortisol levels. Increased availability of total TRP, lower levels of free TRP and alterations in the temporal dynamics of TRP metabolism in preterm compared with term EBM, coupled with higher EBM inflammatory markers on day 7, may have implications for the neurological development of exclusively breast-fed preterm infants.