Changes in the tryptophan-kynurenine axis in association to therapeutic response in clinically depressed patients undergoing psychiatric rehabilitation.

INTRODUCTION: In recent decades a number of studies have shown an association between the Tryptophan (Trp)-Kynurenine (Kyn) axis and neuropsychiatric disorders. However, the role of the Trp-Kyn pathway on the affective status in a general psychiatric cohort requires clarification. This study aimed to measure peripheral changes in Trp, Kyn and the Kyn/Trp-ratio as well as in the inflammatory markers high sensitive C-reactive protein (hsCRP) and interleukine-6 (IL-6) in individuals undergoing a six-week course of intensive treatment program comparing subgroups of treatment responders and non-responders. METHODS: In this investigation 87 currently depressed individuals with a life-time history of depressive disorders were divided into treatment responders (n = 48) and non-responders (n = 39). The individuals were selected for an extreme group comparison out of 598 patients undergoing a 6-week psychiatric rehabilitation program in Austria. Responders were defined according to great changes in Becks Depression Inventory (BDI-II) between time of admission and discharge (BDI-II > 29 to BDI-II <14), while non-responders had no or minimal changes (BDI >20, max. 4 points change over time). Differences in the levels of Trp, Kyn, and the Kyn/Trp ratio as well as levels of hsCRP and IL-6, were compared between groups. Differences were analyzed at the time of admission as well as at discharge. RESULTS: A significant group x time interaction was found for Kyn [F(1.82) = 5.79; p = 0.018] and the Kyn/Trp ratio [F(1.85) = 4.01, p = 0.048]. Importantly, Kyn increased significantly in the non-responder group, while the Kyn/Trp ratio decreased significantly in the responder group over time. Furthermore, changes in Kyn as well as hsCRP levels correlated significantly with changes in the body mass index over time (Kyn: r=0.24, p = 0.030; hsCRP: r=0.25, p = 0.021). No significant interactions were found for Trp and hsCRP, although they increased significantly over time. DISCUSSION: Given the limitations of the study, we could show that the therapeutic response to a multimodal treatment in clinically depressed patients not receiving cytokine treatment is associated with changes in Kyn levels and the Kyn/Trp ratio as well as with hsCRP. However, it is too early to draw any causal conclusion. Future research should clarify relevant clinical and neurobiological parameters associated with changes in Kyn levels and Kyn/Trp ratio, especially in regard to clinical response.

Immunomodulatory Effects of Diterpene Quinone Derivatives from the Roots of Horminum pyrenaicum in Human PBMC.

Several phytochemicals were shown to interfere with redox biology in the human system. Moreover, redox biochemistry is crucially involved in the orchestration of immunological cascades. When screening for immunomodulatory compounds, the two interferon gamma- (IFN-γ-) dependent immunometabolic pathways of tryptophan breakdown via indoleamine 2,3-dioxygenase-1 (IDO-1) and neopterin formation by GTP-cyclohydrolase 1 (GTP-CH-I) represent prominent targets, as IFN-γ-related signaling is strongly sensitive to oxidative triggers. Herein, the analysis of these pathway activities in human peripheral mononuclear cells was successfully applied in a bioactivity-guided fractionation strategy to screen for anti-inflammatory substances contained in the root of Horminum (H.) pyrenaicum L. (syn. Dragon's mouth), the only representative of the monophyletic genus Horminum. Four abietane diterpene quinone derivatives (horminone, 7-O-acetylhorminone, inuroyleanol and its 15,16-dehydro-derivative, a novel natural product), two nor-abietane diterpene quinones (agastaquinone and 3-deoxyagastaquinone) and two abeo 18 (4 → 3) abietane diterpene quinones (agastol and its 15,16-dehydro-derivative) could be identified. These compounds were able to dose-dependently suppress the above mentioned pathways with different potency. Beside the description of new active compounds, this study demonstrates the feasibility of integrating IDO-1 and GTP-CH-I activity in the search for novel anti-inflammatory compounds, which can then be directed towards a more detailed mode of action analysis.

Regular consumption of black tea increases circulating kynurenine concentrations: A randomized controlled trial.

BACKGROUND: Circulating neopterin and the ratio of kynurenine to tryptophan (KYN/TRP) concentrations are biomarkers of immune activation that have been linked to cardiovascular and total mortality. Several in vitro studies indicated that tea flavonoids and other antioxidants can modulate tryptophan breakdown rates and neopterin production in immune cells. We aimed to assess the effects of regular black tea consumption on tryptophan and neopterin metabolisms in vivo. METHODS: Participants were healthy individuals, with no major illnesses and having normal to mildly elevated systolic blood pressure. They were randomly assigned to consume 3 cups/day of either powdered black tea solids (tea; n = 45) or a flavonoid-free caffeine-matched beverage (control; n = 49). Serum concentrations of tryptophan, kynurenine and neopterin were assessed at baseline and again at 3 and 6 months after daily ingestion of the respective beverage. RESULTS: Regular consumption of tea over 6 months, compared to control, did not significantly alter neopterin (p = 0.13) or tryptophan (p = 0.85) concentrations, but did result in significantly higher kynurenine (p = 0.016) and KYN/TRP (p = 0.012). Relative to the control group, in the tea group kynurenine and KYN/TRP increased during the treatment period by 0.28 µmol/L (95% CI: - 0.04, 0.60) and 3.2 µmol/mmol (95% CI: - 1.6, 8.0), respectively at 3 months, and by 0.48 µmol/L (95% CI: 0.16, 0.80) and 7.5 µmol/mmol (95% CI: 2.5, 12.5), respectively at 6 months. CONCLUSIONS: Increased circulation of kynurenine and KYN/TRP following regular black tea consumption may indicate enhanced tryptophan breakdown, possibly due to immune activation-induced tryptophan degrading enzyme indoleamine 2,3-dioxygenase. GENERAL SIGNIFICANCE: The influence of black tea consumption on biomarkers of immune system activation could relate to its general health benefits. Data suggests that the net effect strongly depends on the individual immune state, being stimulatory in healthy individuals, while acting more immune dampening in situations with an inflammatory background.

High expression of TROP2 correlates with poor prognosis in pancreatic cancer.

Pancreatic cancer is one of the most devastating human malignancies. Despite considerable research efforts, it remains resistant to almost all available treatment regimens. The human trophoblast cell-surface antigen, TROP2, was found to be strongly expressed in a variety of human epithelial cancers, correlating with aggressiveness and poor prognosis. TROP2 antigen expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumour tissue samples from a series (n=197) of consecutive patients with pancreatic adenocarcinoma. Survival was calculated using Kaplan-Meier curves. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. TROP2 overexpression was observed in 109 (55%) of 197 pancreatic cancer patients and was significantly associated with decreased overall survival (P<0.01). By univariate analysis, TROP2 overexpression was found to correlate with the presence of lymph node metastasis (P=0.04) and tumour grade (P=0.01). Furthermore, in the subgroup of patients treated surgically with curative intent, TROP2 overexpression significantly correlated with poor progression-free survival (P<0.01). Multivariate analyses revealed TROP2 to be an independent prognosticator. These findings suggest for the first time that TROP2 could be a novel prognostic biomarker for pancreatic cancer. Targeting TROP2 might be a useful treatment approach for patients with pancreatic cancer overexpressing this cell-surface marker.