Cooperative roles of the suprachiasmatic nucleus central clock and the adrenal clock in controlling circadian glucocorticoid rhythm

The mammalian circadian timing system consists of the central clock in the hypothalamic suprachiasmatic nucleus (SCN) and subsidiary peripheral clocks in other tissues. Glucocorticoids (GCs) are adrenal steroid hormones with widespread physiological effects that undergo daily oscillations. We previously demonstrated that the adrenal peripheral clock plays a pivotal role in circadian GC rhythm by driving cyclic GC biosynthesis. Here, we show that the daily rhythm in circulating GC levels is controlled by bimodal actions of central and adrenal clockwork. When mice were subjected to daytime restricted feeding to uncouple central and peripheral rhythms, adrenal GC contents and steroidogenic acute regulatory protein expression peaked around zeitgeber time 00 (ZT00), consistent with shifted adrenal clock gene expression. However, restricted feeding produced two distinct peaks in plasma GC levels: one related to adrenal GC content and the other around ZT12, which required an intact SCN. Light pulse-evoked activation of the SCN increased circulating GC levels in both wild-type and adrenal clock-disrupted mutant mice without marked induction of GC biosynthesis. In conclusion, we demonstrate that adrenal clock-dependent steroidogenesis and a SCN-driven central mechanism regulating GC release cooperate to produce daily circulatory GC rhythm. © The Author(s) 2017.1

A systemic review and meta-analysis on the antihypertensive effect of aromatherapy essential oils

Purpose: This study is a systemic review of experimental results on the effects of aromatherapy on blood pressure. Materials and Methods: Journal articles published to December, 2017, were retrieved from twelve databases. Randomized controlled trials in which were evaluated for changes in blood pressure following aromatherapy were selected. Risks of bias were assessed using the risk-of-bias (ROB) tool of the Cochrane Collaboration. Meta-analysis were dine using RevMan. Results: Of the 2545 articles retrieved from the electronic databases, 580 duplicate articles and 1891 articles that were unrelated to the PICO (patient/problem, intervention, comparison, outcome) elements or did not satisfy the inclusion criteria excluded. Of the remaining 74 articles, 15 found to satisfy the inclusion criteria after full-text review and therefore selected for analysis. The findings of meta-analysis of 11 of these 15 articles revealed that essential oil inhalation and massage effectively decreased both systolic (n = 379; mean difference [MD], -4.72; 95% confidence interval [CI], -8.38 to -1.07) and diastolic (n = 379; MD, -2.42; 95% CI, -4.46 to -0.38) pressure. Conclusions: Essential oil inhalation and massage therapy can effectively decrease systolic and diastolic pressure in health adults as well as in patients with hypertension

Metabolic Flux Profiling of Reaction Modules in Liver Drug Transformation. Pac Symp Biocomput

With appropriate models, the metabolic profile of a biological system may be interrogated to obtain both significant discriminatory markers as well as mechanistic insight into the observed phenotype. One promising application is the analysis of drug toxicity, where a single chemical triggers multiple responses across cellular metabolism. Here, we describe a modeling framework whereby metabolite measurements are used to investigate the interactions between specialized cell functions through a metabolic reaction network. As a model system, we studied the hepatic transformation of troglitazone (TGZ), an antidiabetic drug withdrawn due to idiosyncratic hepatotoxicity. Results point to a welldefined TGZ transformation module that connects to other major pathways in the hepatocyte via amino acids and their derivatives. The quantitative significance of these connections depended on the nutritional state and the availability of the sulfur containing amino acids. 1

Synthesis of DPIE [2-(1,2-Diphenyl-1H-indol-3-yl)ethanamine] Derivatives and Their Regulatory Effects on Pro-Inflammatory Cytokine Production in IL-1β-Stimulated Primary Human Oral Cells

Interleukin-1 beta (IL-1β) has diverse physiological functions and plays important roles in health and disease. In this report, we focus on its function in the production of pro-inflammatory cytokines, including IL-6 and IL-8, which are implicated in several autoimmune diseases and host defense against infection. IL-1β activity is markedly dependent on the binding affinity toward IL-1 receptors (IL-1Rs). Several studies have been conducted to identify suitable small molecules that can modulate the interactions between 1L-1β and 1L-1R1. Based on our previous report, where DPIE [2-(1,2-Diphenyl-1H-indol-3-yl)ethanamine] exhibited such modulatory activity, three types of DPIE derivatives were synthesized by introducing various substituents at the 1, 2, and 3 positions of the indole group in DPIE. To predict a possible binding pose in complex with IL-1R1, a docking simulation was performed. The effect of the chemicals was determined in human gingival fibroblasts (GFs) following IL-1β induction. The DPIE derivatives affected different aspects of cytokine production. Further, a group of the derivatives enabled synergistic pro-inflammatory cytokine production, while another group caused diminished cytokine production compared to DPIE stimulation. Some groups displayed no significant difference after stimulation. These findings indicate that the modification of the indole site could modulate IL-1β:IL1R1 binding affinity to reduce or enhance pro-inflammatory cytokine production

Systems Biology Modular Decomposition of Metabolic Reaction Networks based on Flux Analysis and Pathway Projection

Motivation: The rational decomposition of biochemical networks into sub-structures has emerged as a useful approach to study the design of these complex systems. A biochemical network is characterized by an inhomogeneous connectivity distribution, which gives rise to several organizational features, including modularity. To what extent the connectivity-based modules reflect the functional organization of the network remains to be further explored. In this work, we examine the influence of physiological perturbations on the modular organization of cellular metabolism. Results: Modules were characterized for two model systems, liver and adipocyte primary metabolism, by applying an algorithm for topdown partition of directed graphs with non-uniform edge weights. The weights were set by the engagement of the corresponding reactions as expressed by the flux distribution. For the base case of the fasted rat liver, three modules were found, carrying out the following biochemical transformations: ketone body production, glucose synthesis, and transamination. This basic organization was further modified when different flux distributions were applied that describe the liver’s metabolic response to whole body inflammation. For the fully mature adipocyte, only a single module was observed, integrating all of the major pathways needed for lipid storage. Weaker levels of integration between the pathways were found for the early stages of adipocyte differentiation. Our results underscore the inhomogeneous distribution of both connectivity and connection strengths, and suggest that global activity data such as the flux distribution can be used to study the organizational flexibility of cellular metabolism.

Encoding and verification of a computer- interpretable guideline: a case study of pressure-ulcer management

Abstract This study examined ways to improve the accuracy of translating clinical practice guidelines (CPGs) into a computer-interpretable guideline (CIG) for pressure-ulcer management using the Shareable Active Guideline Environment (SAGE) guideline model, and aimed to verify the accuracy of the obtained CIG. The study was conducted using the following procedures: selecting CPGs, extracting rules from the selected CPGs, developing a CIG using the SAGE guideline model, and verifying the obtained CIG with test cases using an execution engine. The CIG for pressure-ulcer management was developed based on 38 rules and three algorithms at the semiformal representation level using MS Excel and MS Visio. The CIG was encoded by two Activity Graphs consisting of 115 instances representing algorithms and rules as knowledge elements in the SAGE guideline model. Two errors were found and corrected. Results of the study demonstrated that a CIG representing knowledge on pressure-ulcer management can be effectively developed using commonly available programs and the SAGE guideline model, and that the obtained CIG can be verified with a locally developed execution engine. The CIG developed in the study could contribute to health information management once it is implemented successfully in a clinical decision support system