ABSTRACT
Living organisms encounter various perturbations, and response mechanisms to such perturbations are vital for species survival. Defective stress responses are implicated in many human diseases including cancer and neurodegenerative disorders. Phenol derivatives, naturally occurring and synthetic, display beneficial as well as detrimental effects. The phenol derivatives in this study, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and bisphenol A (BPA), are widely used as food preservatives and industrial chemicals. Conflicting results have been reported regarding their biological activity and correlation with disease development; understanding the molecular basis of phenol action is a key step for addressing issues relevant to human health. This work presents the first comparative genomic analysis of the genetic networks for phenol stress response in an evolutionary context of two divergent yeasts, Schizosaccharomyces pombe and Saccharomyces cerevisiae Genomic screening of deletion strain libraries of the two yeasts identified genes required for cellular response to phenol stress, which are enriched in human orthologs. Functional analysis of these genes uncovered the major signaling pathways involved. The results provide a global view of the biological events constituting the defense process, including cell cycle arrest, DNA repair, phenol detoxification by V-ATPases, reactive oxygen species alleviation, and endoplasmic reticulum stress relief through ergosterol and the unfolded protein response, revealing novel roles for these cellular pathways.
Subject(s)
Gene Regulatory Networks , Phenols/pharmacology , Saccharomyces cerevisiae/drug effects , Schizosaccharomyces/drug effects , Benzhydryl Compounds/pharmacology , Benzhydryl Compounds/toxicity , Butylated Hydroxyanisole/pharmacology , Butylated Hydroxyanisole/toxicity , Butylated Hydroxytoluene/pharmacology , Butylated Hydroxytoluene/toxicity , Cell Cycle Checkpoints , DNA Repair , Endoplasmic Reticulum Stress , Genomics , Phenols/toxicity , Reactive Oxygen Species/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae/physiology , Schizosaccharomyces/genetics , Schizosaccharomyces/metabolism , Schizosaccharomyces/physiology , Unfolded Protein ResponseABSTRACT
Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble ß-amyloid (Aß) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aß accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aß by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aß levels and Aß half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aß clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aß metabolism and defining a potential new therapeutic target in AD.
Subject(s)
Amyloid beta-Peptides/analysis , Brain/metabolism , Macrophage-1 Antigen/physiology , Microglia/physiology , Alzheimer Disease/etiology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/physiology , Animals , Benzoates/pharmacology , Mice , Mice, Inbred C57BL , Proteolysis , Thiohydantoins/pharmacologyABSTRACT
Despite progress in automated blood pressure measurement (BPM) technology, there is limited research linking hard outcomes to automated office BPM (OBPM) treatment targets and thresholds. Equivalences for automated BPM devices have been estimated from approximations of standardized manual measurements of 140/90 mmHg. Until outcome-driven targets and thresholds become available for automated measurement methods, deriving evidence-based equivalences between automated methods and standardized manual OBPM is the next best solution. The MeasureBP study group was initiated by the Canadian Hypertension Education Program to close this critical knowledge gap. MeasureBP aims to define evidence-based equivalent values between standardized manual OBPM and automated BPM methods by synthesizing available evidence using a systematic review and individual subject-level data meta-analyses. This manuscript provides a review of the literature and MeasureBP study protocol. These results will lay the evidenced-based foundation to resolve uncertainties within blood pressure guidelines which, in turn, will improve the management of hypertension.
