Kynurenine inhibits melanogenesis in human melanocyte-keratinocyte co-cultures and in a reconstructed 3D skin model.

Kynurenine (KYN), the most abundant metabolite of tryptophan, is classically associated with immune tolerance and tumor immune escape. In the last years, KYN is in the spotlight in other biological processes. Here, we showed that KYN inhibited tyrosinase expression and melanin content in primary human melanocyte and keratinocyte co-cultures. Furthermore, KYN decreased melanosome content in a 3D human skin reconstruction model. In these experiments, we used tyrosine + NH4 Cl to induce pigmentation. We compared the inhibitory effect of KYN on melanogenesis with the already known inhibitory effect promoted by IFN-γ. Since increased KYN production depends on the IFN-γ-inducible enzyme indoleamine-2,3-dioxygenase (IDO), we propose that part of the effect of IFN-γ on melanogenesis involves KYN production. From that, we tested if, during melanogenesis, changes in tryptophan metabolism would occur. For this purpose, we measured tryptophan, KYN and downstream products along with pigmentation. There were no significant changes in Trp metabolism, except for the high consumption of kynurenic acid. Our data identify the skin as a potential target for the action of KYN relevant for skin physiology and pigmentation. The results are discussed concerning the high production of KYN in skin inflammatory disorders and cancer.

Recovery of Diabetic Rats After Physical Exhaustion: Kinetic Alterations in Muscle Inflammation and Muscle-Signaling Proteins to Atrophy and Hypertrophy.

The complexity of the adaptive response of diabetics to intense exercise is still poorly understood. To optimize exercise interventions in diabetics, the chronology of inflammatory mediators in muscle and the signaling involved in muscle hypertrophy/atrophy must be understood. Herein, we studied the kinetic inflammatory profile and cellular signaling pathways modulated by physical exhaustion after the induction of type 1 diabetes by streptozotocin in rats. Soleus muscle samples were obtained from diabetic and control groups at the following moments: baseline (no exercise); immediately after exhaustive exercise; and at 2 h, 24 h, 48 h, and 72 h after a treadmill exhaustive exercise. Kinetic production of cytokines and kinetic activation of proteins related to muscle synthesis (p70S6K and Akt) and degradation (GSK3, MuRF1, and MAFbx) were measured in the soleus muscle. We observed that the muscle TNF-α (0.9-fold; p = 0.0007), IL-1ß (0.8-fold; p = 0.01), IL-6 (0.8-fold; p = 0.0013), L-selectin (1.0-fold; p = 0.0019), and CINC-2α/ß (0.9-fold; p = 0.04) levels were higher in almost all stages of the study in the diabetic animals compared with the control group. Our data showed that exhaustive exercise decreased MAFbx expression in diabetic animals compared to the control group in a time-dependent manner. The decreased activation ratios of MAFbx were followed by a decrease in TNF-α, IL-1ß, and IL-6 levels. p70S6k phosphorylation was also decreased in the diabetic group compared to the control group after physical exhaustion. Regarding the activation of proteins related to muscle synthesis and degradation, we found that the alterations induced by exhaustive exercise in the diabetic rats might involve pathways related to synthesis and muscle breakdown. Moreover, after an exhaustive exercise session, the recovery of the inflammatory response in the diabetic animals was slower than that in the control rats while the return of inflammatory cytokines to baseline levels was more effective in the diabetic animals.

Topical anti-inflammatory activity of palmitoleic acid improves wound healing.

This study investigated the effects of palmitoleic acid on different phases of the healing process. Macroscopic analyses were performed on wounds in rats with or without palmitoleic acid treatment, and the results showed that palmitoleic acid directly hastened wound closure. The topical treatment of wounds with palmitoleic acid resulted in smaller wounds than those observed in the control group. The anti-inflammatory activity of palmitoleic acid may be responsible for healing, especially in the stages of granulation tissue formation and remodelling. Palmitoleic acid modified TNF-α, IL-1ß, IL-6, CINC-2α/ß, MIP-3α and VEGF-α profiles at the wound site 24, 48, 120, 216 and 288 hours post-wounding. Assays assessing neutrophil migration and exudate formation in sterile inflammatory air pouches revealed that palmitoleic acid had potent anti-inflammatory activity, inhibiting the LPS-induced release of TNF-α (73.14%, p≤0.05), IL-1ß (66.19%, p≤0.001), IL-6 (75.19%, p≤0.001), MIP-3α (70.38%, p≤0.05), and l-selectin (16%, p≤0.05). Palmitoleic acid also inhibited LPS-stimulated neutrophil migration. We concluded that palmitoleic acid accelerates wound healing via an anti-inflammatory effect.

Marathon Race Affects Neutrophil Surface Molecules: Role of Inflammatory Mediators.

The fatigue induced by marathon races was observed in terms of inflammatory and immunological outcomes. Neutrophil survival and activation are essential for inflammation resolution and contributes directly to the pathogenesis of many infectious and inflammatory conditions. The aim of this study was to investigate the effect of marathon races on surface molecules related to neutrophil adhesion and extrinsic apoptosis pathway and its association with inflammatory markers. We evaluated 23 trained male runners at the São Paulo International Marathon 2013. The following components were measured: hematological and inflammatory mediators, muscle damage markers, and neutrophil function. The marathon race induced an increased leukocyte and neutrophil counts; creatine kinase (CK), lactate dehydrogenase (LDH), CK-MB, interleukin (IL)-6, IL-10, and IL-8 levels. C-reactive protein (CRP), IL-12, and tumor necrosis factor (TNF)-α plasma concentrations were significantly higher 24 h and 72 h after the marathon race. Hemoglobin and hematocrit levels decreased 72 h after the marathon race. We also observed an increased intercellular adhesion molecule-1 (ICAM-1) expression and decreasedTNF receptor-1 (TNFR1) expression immediately after and 24 h after the marathon race. We observed an increased DNA fragmentation and L-selectin and Fas receptor expressions in the recovery period, indicating a possible slow rolling phase and delayed neutrophil activation and apoptosis. Marathon racing affects neutrophils adhesion and survival in the course of inflammation, supporting the "open-window" post-exercise hypothesis.

Marathon Race Affects Neutrophil Surface Molecules: Role of Inflammatory Mediators

The fatigue induced by marathon races was observed in terms of inflammatory and immunological outcomes. Neutrophil survival and activation are essential for inflammation resolutionand contributes directly to the pathogenesis of many infectious and inflammatory conditions.nThe aim of this study was to investigate the effect of marathon races on surface moleculesrelated to neutrophil adhesion and extrinsic apoptosis pathway and its association with inflammatory markers. We evaluated 23 trained male runners at the São Paulo International Marathon 2013. The following components were measured: hematological and inflammatory mediators, muscle damage markers, and neutrophil function. The marathon raceinduced an increased leukocyte and neutrophil counts; creatine kinase (CK), lactate dehydrogenase(LDH), CK-MB, interleukin (IL)-6, IL-10, and IL-8 levels. C-reactive protein(CRP), IL-12, and tumor necrosis factor (TNF)-α plasma concentrations were significantlyhigher 24 h and 72 h after the marathon race. Hemoglobin and hematocrit levels decreased72 h after the marathon race. We also observed an increased intercellular adhesion molecule-1(ICAM-1) expression and decreasedTNF receptor-1 (TNFR1) expression immediatelyafter and 24 h after the marathon race. We observed an increased DNA fragmentation and L-selectin and Fas receptor expressions in the recovery period, indicating a possibleslow rolling phase and delayed neutrophil activation and apoptosis. Marathon racing affectsneutrophils adhesion and survival in the course of inflammation, supporting the “openwindow”post-exercise hypothesis...