A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease.

Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body's ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.

Assessment of amyloid ß in pathologically confirmed frontotemporal dementia syndromes.

INTRODUCTION: The diagnostic utility of in vivo amyloid ß (Aß) imaging to aid in the clinical distinction between frontotemporal dementia (FTD) and Alzheimer's disease remains unclear without data on the prevalence and severity of Aß in pathologically confirmed FTD syndromes. METHODS: Aß was assessed in 98 autopsy-confirmed FTD and 36 control cases, and the pathological accuracy of 11C-Pittsburgh compound B (PiB)-positron emission tomography imaging was assessed in a subset of FTD cases (n = 15). RESULTS: Aß was identified in a similar proportion of FTD syndromes and age-matched controls and increases with age. Alzheimer's disease pathology was identified in all cases with high PiB retention and in one case with low PiB retention. We further demonstrate a strong regional correlation between volume fraction of histological Aß with PiB standard uptake value ratio scaled to the white matter. DISCUSSION: The present study provides a pathologic reference to assist in the interpretation of in vivo assessments in FTD syndromes.

Experimental design and analysis of activators regenerated by electron transfer-atom transfer radical polymerization experimental conditions for grafting sodium styrene sulfonate from titanium substrates.

A 24 factorial design was used to optimize the activators regenerated by electron transfer-atom transfer radical polymerization (ARGET-ATRP) grafting of sodium styrene sulfonate (NaSS) films from trichlorosilane/10-undecen-1-yl 2-bromo-2-methylpropionate (ester ClSi) functionalized titanium substrates. The process variables explored were: (1) ATRP initiator surface functionalization reaction time; (2) grafting reaction time; (3) CuBr2 concentration; and (4) reducing agent (vitamin C) concentration. All samples were characterized using x-ray photoelectron spectroscopy (XPS). Two statistical methods were used to analyze the results: (1) analysis of variance with [Formula: see text], using average [Formula: see text] XPS atomic percent as the response; and (2) principal component analysis using a peak list compiled from all the XPS composition results. Through this analysis combined with follow-up studies, the following conclusions are reached: (1) ATRP-initiator surface functionalization reaction times have no discernable effect on NaSS film quality; (2) minimum (≤24 h for this system) grafting reaction times should be used on titanium substrates since NaSS film quality decreased and variability increased with increasing reaction times; (3) minimum (≤0.5 mg cm-2 for this system) CuBr2 concentrations should be used to graft thicker NaSS films; and (4) no deleterious effects were detected with increasing vitamin C concentration.

Oxytocin: recent developments.

Oxytocin is a neurohypophyseal hormone that is produced centrally by neurons in the paraventricular nucleus and supraoptic nucleus of the hypothalamus. It is released directly into higher brain centres and into the peripheral circulation where it produces a multitude of effects. Classically, oxytocin is known for inducing uterine contractions at parturition and milk ejection during suckling. Oxytocin also acts in a species and gender specific manner as an important neuromodulator. It can affect behaviours associated with stress and anxiety, as well social behaviours including sexual and relationship behaviours, and maternal care. Additionally, oxytocin has been shown to have a variety of physiological roles in peripheral tissues, many of which appear to be modulated largely by locally produced oxytocin, dispelling the notion that oxytocin is a purely neurohypophyseal hormone. Oxytocin levels are altered in several diseases and the use of oxytocin or its antagonists have been identified as a possible clinical intervention in the treatment of mood disorders and pain conditions, some cancers, benign prostatic disease and osteoporosis. Indeed, oxytocin has already been successful in clinical trials to treat autism and schizophrenia. This review will report briefly on the known functions of oxytocin, it will discuss in depth the data from recent clinical trials and highlight future targets for oxytocinergic modulation.

Oxytocin in health and disease.

Oxytocin is a nonapeptide of the neurohypophyseal protein family that binds specifically to the oxytocin receptor to produce a multitude of central and peripheral physiological responses. Within the central nervous system oxytocin is expressed by the neurons of the hypothalamus that project into higher brain centres and the posterior pituitary gland, from where it enters the circulation by release into the portal capillaries. Centrally, it modulates, maternal, sexual, social and stress related behaviour. Peripheral actions of oxytocin are commonly associated with smooth muscle contraction, particularly within the female and male reproductive tracts. Local synthesis of oxytocin along with its receptor in these regions indicates the presence of local oxytocinergic systems. More sinister implications for oxytocin in autism, depression and several cancers have recently been identified. A greater understanding of the role of oxytocinergic mechanisms will determine the potential for targeting this regulatory peptide in the pharmacological management of these disorders.