Brownolesen8470

Individual variations in xenobiotic metabolism affect the sensitivity to diseases. In this study, the impacts of sex, age, and race/ethnicity on drug-processing genes and nuclear factor erythroid 2-related factor 2 (NRF2) genes in human livers were examined via QuantiGene multiplex suspension array (226 samples) and quantitative polymerase chain reaction (qPCR) (247 samples) to profile the expression of nuclear receptors, cytochrome P450s, conjugation enzymes, transporters, bile acid metabolism, and NRF2-regulated genes. Sex differences were found in expression of about half of the genes, but in general the differences were not large. For example, females had higher transcript levels of catalase, glutamate-cysteine ligase catalytic subunit (GCLC), heme oxygenase 1 (HO-1), Kelch-like ECH-associated protein 1 (KEAP1), superoxide dismutase 1, and thioredoxin reductase-1 compared with males via qPCR. There were no apparent differences due to age, except children had higher glutamate-cysteine ligase modifier subun2 genes in normal and diseased human livers. SIGNIFICANCE STATEMENT In human liver drug-processing and nuclear factor erythroid 2-related factor 2 genes, sex differences were the main finding. There were no apparent differences due to age, except children had higher glutamate-cysteine ligase modifier subunit, and elderly had higher multidrug resistance protein 3. African Americans had lower expression of farnesoid X receptor (FXR) but higher expression of heme oxygenase 1, Caucasians had higher expression of organic anion transporter 2, and Hispanics had higher expression of FXR, small heterodimer partner, SULT2A1, and bile salt export pump.

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a well-characterised role in the metabolism and activation of endogenous glucocorticoids (GCs). However, despite its potent upregulation at sites of inflammation, its role in peripheral metabolism and action of therapeutic GCs remains poorly understood. We investigated the contribution of 11β-HSD1 to the anti-inflammatory properties of the active GC corticosterone, administered at therapeutic doses in murine models of polyarthritis.

Using the tumour necrosis factor-tg and K/BxN serum-induced models of polyarthritis, we examined the anti-inflammatory properties of oral administration of corticosterone in animals with global, myeloid and mesenchymal targeted transgenic deletion of 11β-HSD1. Disease activity and joint inflammation were scored daily. Joint destruction and measures of local and systemic inflammation were determined by histology, micro-CT, quantitative RT-PCR, fluorescence activated cell sorting and ELISA.

Global deletion of anti-inflammatory therapeutic effects. This study provides a novel mechanistic understanding of the anti-inflammatory properties of therapeutic GCs and their targeting to sites of inflammation in polyarthritis.O-acetyl serine sulfhydrylase (OASS), referred to as Cysteine Synthase (CS), synthesizes cysteine from O-acetyl serine (OAS) and sulfur in bacteria and plants. The inherent challenge for CS is to overcome 4-6 log-folds stronger affinity for its natural inhibitor, serine acetyltransferase (SAT), as compared to its affinity for substrate, OAS. Our recent study showed that CS employs a novel competitive-allosteric mechanism to selectively recruit its substrate in the presence of natural inhibitor [1]. compound library chemical In this study, we trace the molecular features that control selective substrate recruitment. To generalize our findings, we used CS from three different bacteria (Haemophilus, Salmonella, and Mycobacterium) as our model systems and analysed structural and substrate-binding features of wild type CS and its ~13 mutants. Results show that CS uses a non-catalytic residue, M120, located 20 Å away from the reaction centre, to discriminate in favour of substrate. M120A and background mutants display significantly reduced substrate binding, catalytic efficiency, and inhibitor binding. Results shows that M120 favours the substrate binding by selectively enhancing the affinity for the substrate and dis-engaging the inhibitor by 20-286 and 5-3 folds respectively. Together, M120 confers a net discriminative force in favour of substrate by 100-858 folds.The Hippo pathway controls organ size and tissue homeostasis through the regulation of cell proliferation and apoptosis. However, the exact molecular mechanisms underpinning Hippo pathway regulation is not fully understood. Here, we identify a new component of the Hippo pathway CORO7, a coronin protein family member that is involved in organization of the actin cytoskeleton. pod1, the Drosophila orthologue of CORO7, genetically interacts with key Hippo pathway genes in Drosophila. In mammalian cells, CORO7 is required for the activation of the Hippo pathway in response to cell-cell contact, serum deprivation, and cytoskeleton damage. CORO7 forms a complex with the core components of the pathway and functions as a scaffold for the Hippo core kinase complex. Collectively, these results demonstrate that CORO7 is a key scaffold controlling the Hippo pathway via modulating protein-protein interactions.

Delayed prescribing is a promising strategy to manage patient requests for unnecessary tests and treatments. The purpose of this study was to explore general practitioner (GP) and patient views of three communication tools (Overdiagnosis Leaflet, Dialogue Sheet and 'Wait-and-see' Note) to support delayed prescribing of diagnostic imaging.

Qualitative study.

Primary and emergency care in Sydney, Australia.

16 GPs and 14 patients with recent episode of low back pain.

Views on the tools to delay diagnostic imaging for low back pain. Data were collected using a combination of focus groups and individual interviews.

Two researchers independently performed a thematic analysis, and the author team reviewed and refined the analysis.

GP participants responded positively to the Overdiagnosis Leaflet. The Dialogue Sheet and 'Wait-and-see' Note raised several concerns about patient pushback, adding to time pressure and being overwhelmed with hard-to-find paper resources. GPs preferred to communicate verbally the reasons to delay an imaging test.