Proposed Pathway Linking Respiratory Infections with Depression.

Depression is one of the most important causes of disability and loss of useful life of people around the world. Acute respiratory infection caused a large number of severe illnesses and deaths of the world and most of these due to viral infections, which is estimated more than 80% of respiratory infections. Detection of viruses by immune pathogen recognition receptors activates the intracellular signaling cascade and eventually cause produces interferons. Inflammatory process begins with secretion of interferons and the expression of interferon-stimulated genes. One of the most important of these genes is indoleamine-pyrrole 2,3-dioxygenase (IDO), which plays a major role in tryptophan catabolism. IDO is an intracellular monomeric enzyme that is also responsible for breaking down and consuming tryptophan in the Kynurenine pathway. Increased inflammation has been linked to decrease tryptophan concentrations and increase kynurenine levels. We tried to explain the role of inflammation by viral respiratory infections in causing depression.

Transfer of uremic solutes across the human term placenta: An ex vivo study in the dual-side perfused cotyledon.

INTRODUCTION: An increasing number of women becomes pregnant while suffering from chronic kidney disease (CKD). As a result of decreased renal function, uremic solutes circulate at high levels in the maternal circulation. This study aimed to acquire more knowledge about the placental transfer of uremic solutes across the human placenta. METHODS: Placental transfer was studied in healthy term placentas, via the ex vivo dual-side human cotyledon perfusion technique (closed-closed set-up for both maternal and fetal circulations). Uremic solute concentrations in maternal and fetal perfusates were measured via LC-MS/MS over 180 min of perfusion. RESULTS: We found that the studied compounds demonstrated different degrees of placental transfer. Fetal-to-maternal perfusate ratios at t = 180 min were for anthranilic acid 1.00 ± 0.02, indole-3-acetic acid 0.47 ± 0.08, hippuric acid 0.36 ± 0.18, l-arabinitol 0.33 ± 0.04, indoxyl sulfate 0.33 ± 0.11, neopterin 0.28 ± 0.14 and kynurenic acid 0.13 ± 0.03. All uremic solutes studied also emerged in the perfusates when cotyledons were perfused in the absence of uremic solute concentrations added to the maternal reservoir. For kynurenin these concentrations were so high, it complicated the calculation of a transfer ratio for the exogenously administered compound. DISCUSSION: After 180 min of exposure the extent of placental transfer differs substantially for the solutes studied, reflecting different transfer rates. Future studies should investigate to what extent specific uremic solutes reach the fetal circulation in vivo and how they may interfere with organ function and development of the unborn child.

Immuno-Metabolic Modulation of Liver Oncogenesis by the Tryptophan Metabolism.

Metabolic rewiring in tumor cells is a major hallmark of oncogenesis. Some of the oncometabolites drive suppressive and tolerogenic signals from the immune system, which becomes complicit to the advent and the survival of neoplasia. Tryptophan (TRP) catabolism through the kynurenine (KYN) pathway was reported to play immunosuppressive actions across many types of cancer. Extensive debate of whether the culprit of immunosuppression was the depletion of TRP or rather KYN accumulation in the tumor microenvironment has been ongoing for years. Results from clinical trials assessing the benefit of inhibiting key limiting enzymes of this pathway such as indoleamine 2,3-dioxygenase (IDO1) or tryptophan 2,3-dioxygenase (TDO2) failed to meet the expectations. Bearing in mind the complexity of the tumoral terrain and the existence of different cancers with IDO1/TDO2 expressing and non-expressing tumoral cells, here we present a comprehensive analysis of the TRP global metabolic hub and the driving potential of the process of oncogenesis with the main focus on liver cancers.

Development of a liquid chromatography-mass spectrometry method for the determination of the neurotoxic quinolinic acid in human serum.

BACKGROUND: 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. METHODS: 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. RESULTS: The presented method provides high sample throughput with 25 µL 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±167 nmol/L (mean±SD) was determined. CONCLUSION: 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.