ABSTRACT
In the past, accelerated tryptophan breakdown was considered to be a feature of clinical conditions, such as infection, inflammation, and malignant disease. More recently, however, the focus has changed to include the additional modulation of tryptophan metabolism by changes in nutrition and microbiota composition. The regulation of tryptophan concentration is critical for the maintenance of systemic homeostasis because it integrates essential pathways involved in nutrient sensing, metabolic stress response, and immunity. In addition to tryptophan being important as a precursor for the synthesis of the neurotransmitter serotonin, several catabolites along the kynurenine axis are neuroactive. This emphasizes the importance of the immunometabolic fate of this amino acid for processes relevant to neuropsychiatric symptoms. In humans, besides hepatic catabolism, there is usually a strong relationship between immune activation-associated tryptophan breakdown and increased levels of biomarkers, such as neopterin, which has particular relevance for both acute and chronic diseases. A shift towards neopterin synthesis during oxidative stress may indicate a corresponding decrease in tetrahydrobiopterin, a cofactor of several mono-oxygenases, providing a further link between tryptophan metabolism and serotonergic and catecholaminergic neurotransmission. The psychoneuroimmunological consequences of tryptophan metabolism and the susceptibility of this pathway to modulation by a variety of nutritional and lifestyle-related factors have important implications for the development of both diagnostic and treatment options.
Subject(s)
Brain Diseases , Diet , Gastrointestinal Microbiome , Life Style , Psychoneuroimmunology , Signal Transduction , Tryptophan/metabolism , Brain Diseases/immunology , Brain Diseases/metabolism , Brain Diseases/microbiology , Brain Diseases/therapy , Gastrointestinal Microbiome/physiology , Humans , Signal Transduction/physiologyABSTRACT
Twelve new terpenoids (1-12) were isolated from the stems of Fissistigma polyanthoides, an anti-inflammatory medicinal plant traditionally used in Vietnam. Most of them (1-9) possess a sesquiterpenoid backbone (e.g., guaiane, germacrane, and cadinane) connected to a 2'-O-trans-cinnamoyl)-ß-d-glucopyranose moiety, which is rare in Nature. Among them, compounds 4 (5/8-fused ring) and 6 (spiran [4,5] ring) represent uncommonly rearranged sesquiterpenoids. Compounds 10-12 are a novel monoterpene and two megastigmane derivatives, respectively. The individual structures were elucidated by combining NMR and MS data, and their configuration was established in NOESY and ECD experiments. Compounds 1-9 were also examined for their potential to interact with nuclear factor-kappa B activator protein 1 (NF-κB/AP-1) signaling by using the myelomonocytic reporter cell line THP-1Blue-CD14. Compounds 1-5 showed dose-dependent inhibitory effects [IC50 13.7 µM (1) to 49.0 µM (5)] on lipopolysaccharide-stimulated cells. However, compounds 1 to 4 also negatively affected cell viability in the same concentration range, while compound 5 was less potently cytotoxic.
Subject(s)
Annonaceae/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Plant Stems/chemistry , Terpenes/chemistry , Terpenes/pharmacology , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Lipopolysaccharides/pharmacology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Receptor Activator of Nuclear Factor-kappa B/drug effects , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , VietnamABSTRACT
Chemical UV-filters are frequently applied as active ingredients in sunscreen to protect from detrimental effects of UV radiation. Regardless, many of these compounds are not well characterized concerning their capacity to counteract UV induced reactive oxygen species (ROS). Intracellular ROS release is an early event upon UV exposure and a crucial trigger of reaction cascades that may provoke adverse effects both in short- and long-term. We report a strategy to assess the capacity of UV-filters (ecamsule, oxybenzone and menthyl anthranilate) to counteract UVA/UVB stress in the human keratinocyte HaCaT and the wildtype Fibs E6/E7 fibroblast cell lines. The reduction of ROS levels was taken as primary endpoint. The effect of treatment on the cells' metabolic activity was analyzed as an indicator of viability post-treatment, to investigate potential immediate and late (photo)toxicity. Additionally, the compounds' antioxidative capacity was investigated using an azo-based radical generator. Established antioxidants, quercetin and N-acetylcysteine, were used as controls. Data showed remarkable differences in the mode of action of the chemical UV-filters, ranging from protective to pro-oxidative properties, indicating the need for more detailed mode of action-based investigations. Certainly, additional consideration and evaluation will be necessary to further extrapolate these in vitro data for the assessment of in vivo exposure situations. However, the presented approach enables parallel investigations of photoprotective and phototoxic effects of UV-filters, and thus can complement and extent existing in vitro testing strategies.
