Regulator of G‐protein signalling 5 protects against atherosclerosis in apolipoprotein E‐deficient mice

Background and Purpose

Atherosclerosis is a chronic inflammatory disease, in which ‘vulnerable plaques’ have been recognized as the underlying risk factor for coronary disease. Regulator of G‐protein signalling (RGS) 5 controls endothelial cell function and inflammation. In this study, we explored the effect of RGS5 on atherosclerosis and the potential underlying mechanisms.

Experimental Approach

RGS5^−/− apolipoprotein E (ApoE)^−/− and ApoE ^−/− littermates were fed a high‐fat diet for 28 weeks. Total aorta surface and lipid accumulation were measured by Oil Red O staining and haematoxylin–eosin staining was used to analyse the morphology of atherosclerotic lesions. Inflammatory cell infiltration and general inflammatory mediators were examined by immunofluorescence staining. Apoptotic endothelial cells and macrophages were assayed with TUNEL. Expression of RGS5and adhesion molecules, and ERK1/2 phosphorylation were evaluated by co‐staining with CD31. Expression of mRNA and protein were determined by quantitative real‐time PCR and Western blotting respectively.

Key Results

Atherosclerotic phenotypes were significantly accelerated in RGS5^−/− ApoE ^−/− mice, as indicated by increased inflammatory mediator expression and apoptosis of endothelial cells and macrophages. RGS5 deficiency enhanced instability of vulnerable plaques by increasing infiltration of macrophages in parallel with the accumulation of lipids, and decreased smooth muscle cell and collagen content. Mechanistically, increased activation of NF‐κB and MAPK/ERK 1/2 could be responsible for the accelerated development of atherosclerosis in RGS5‐deficient mice.

Conclusions and Implications

RGS5 deletion accelerated development of atherosclerosis and decreased the stability of atherosclerotic plaques partly through activating NF‐κB and the MEK‐ERK1/2 signalling pathways.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

ApoE

apolipoprotein E

CHD

coronary heart disease

H&E

haematoxylin‐eosin

ICAM‐1

intercellular adhesion molecue‐1

LDL

low‐density lipoprotein

MEK

MAPK/ERK kinase

RGS

regulator of G‐protein signalling

SMC

smooth muscle cell

VCAM‐1

vascular cell adhesion molecule‐1

Tables of Links

Acute morphine affects the rat circadian clock via rhythms of phosphorylated ERK1/2 and GSK3β kinases and Per1 expression in the rat suprachiasmatic nucleus

Background and Purpose

Opioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling.

Experimental Approach

A time-dependent effect of morphine (1 mg·kg⁻¹, i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3β, c-Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light-induced pERK and c-Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [³⁵S]-GTPγS binding assay.

Key Results

Morphine stimulated a rise in pERK1/2 and pGSK3β levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light-induced level of pERK1/2 and c-Fos in the SCN. The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the δ receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3β levels in the rat ventrolateral and dorsomedial SCN.

Conclusions and Implications

Our data suggest that the phase-shifting effect of opioids may be mediated via post-translational modification of clock proteins by means of activated ERK1/2 and GSK3β.Tables of Links

Chemical constituents from the root of Polygonum multiflorum and their soluble epoxide hydrolase inhibitory activity

Archives of Pharmacal Research - Fourteen compounds were isolated from a methanol extract of Polygonum multiflorum roots, and their structures were elucidated by comparing spectroscopic data to...     

Detection of resveratrol by phosphorescence quantum dots without conjunction and mutual impact exploration

In this study, a convenient and sensitive method for the detection of resveratrol was established based on phosphorescence quenching of resveratrol for MPA-capped Mn:ZnS QDs. The quenching intensity was in proportion to the concentration of resveratrol within a certain range. Under optimal conditions, the present assay was valid for detecting resveratrol in the range from 0.03 μM to 14 μM with a detection limit of 0.01 μM. The mechanism of action was also explored, and its application in actual samples was also demonstrated with satisfactory results. This study aims to provide a convenient method for the detection of resveratrol.

In this study, a convenient and sensitive method for the detection of resveratrol was established based on phosphorescence quenching of resveratrol for MPA-capped Mn:ZnS QDs.     

Usefulness of optical coherence tomography to detect central serous chorioretinopathy in monkeys

Many systemic drugs can induce ocular toxicity and several ocular side‐effects have been identified in clinical studies. However, it is difficult to detect ocular toxicity in preclinical studies because of the lack of appropriate evaluation methods. Optical coherence tomography (OCT) is useful because it can provide real‐time images throughout a study period, whereas histopathology only provides images of sacrificed animals. Using OCT alongside histopathology, attempts were made to find effective approaches for screening of drug‐induced ocular toxicity in monkeys. Such approaches could be used in preclinical studies prior to human trials. Six male cynomolgus monkeys (Macaca fascicularis Raffles) were orally administered one of six candidate MAPK/ERK kinase (MEK) inhibitors. Central serous chorioretinopathy, a known side‐effect of such inhibitors, was identified in four monkeys by OCT. Artifacts generated during tissue processing meant that histopathology could not detect edematous changes. Thus, OCT is a useful tool to detect ocular toxicity which cannot be detected by histopathology in preclinical studies. Copyright © 2014 John Wiley & Sons, Ltd.     

Quantitative toxicoproteomic analysis of zebrafish embryos exposed to a retinoid X receptor antagonist UVI3003

Retinoid X receptor (RXR) antagonists, including some environmental endocrine disruptors, have a teratogenic effect on vertebrate embryos. To investigate the toxicological mechanism on the protein expression level, a quantitative proteomic study was conducted to analyze the proteome alterations of zebrafish (Danio rerio) embryos exposed to gradient concentrations of a representative RXR antagonist UVI3003. Using isobaric Tags for Relative and Absolute Quantitation (iTRAQ) labeling coupled nano high‐performance liquid chromatography‐tandem mass spectrometry (nano HPLC‐MS/MS), in total 6592 proteins were identified, among which 195 proteins were found to be differentially expressed by more than a two‐fold change in exposed groups compared with the control. Gene ontology analysis showed that these differential proteins were mostly involved in anatomical structure development, biosynthetic process, ion binding and oxidoreductase activity. Moreover, the biological pathways of translation, lipoprotein metabolism, cell survival and gluconeogenesis were intensively inhibited after exposure. Some significantly downregulated proteins such as apolipoprotein A‐I and vitellogenin and upregulated proteins such as calcium activated nucleotidase 1b, glutathione S‐transferase and glucose 6‐dehydrogenases showed a strong dose‐dependent response. The results provided new insight into the molecular details of RXR antagonist‐induced teratogenicity and added novel information of pathways and potential biomarkers for evaluation of RXR interfering activity. Copyright © 2015 John Wiley & Sons, Ltd.     

Kinetics of Serologic Responses to MERS Coronavirus Infection in Humans,South Korea

We investigated the kinetics of serologic responses to Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using virus neutralization and MERS-CoV S1 IgG ELISA tests. In most patients, robust antibody responses developed by the third week of illness. Delayed antibody responses with the neutralization test were associated with more severe disease.     

WS2/g-C3N4 composite as an efficient heterojunction photocatalyst for biocatalyzed artificial photosynthesis

A heterogeneous WS₂/g-C₃N₄ composite photocatalyst was prepared by a facile ultrasound-assisted hydrothermal method. The WS₂/g-C₃N₄ composite was used for photocatalytic regeneration of NAD⁺ to NADH, which were coupled with dehydrogenases for sustainable bioconversion of CO₂ to methanol under visible light irradiation. Compared with pristine g-C₃N₄ and the physical mixture of WS₂ and g-C₃N₄, the fabricated WS₂/g-C₃N₄ composite catalyst with 5 wt% of WS₂ showed the highest activity for methanol synthesis. The methanol productivity reached 372.1 μmol h⁻¹ g_cat⁻¹, which is approximately 7.5 times higher than that obtained using pure g-C₃N₄. For further application demonstration, the activity of the WS₂/g-C₃N₄ composite catalyst toward photodegradation of Rhodamine B (RhB) was evaluated. RhB removal ratio approaching 100% was achieved in 1 hour by using the WS₂/g-C₃N₄ composite catalyst with 5 wt% of WS₂, at an apparent degradation rate approximately 2.6 times higher than that of pure g-C₃N₄. Based on detailed investigations on physiochemical properties of the photocatalysts, the significantly enhanced reaction efficiency of the WS₂/g-C₃N₄ composite was considered to be mainly benefiting from the formation of a heterojunction interface between WS₂ and g-C₃N₄. Upon visible-light irradiation, the photo-induced electrons can transfer from the conduction band of g-C₃N₄ to WS₂, thus recombination of electrons and holes was decreased and the photo-harvesting efficiency was enhanced.

A heterogeneous WS₂/g-C₃N₄ composite photocatalyst was prepared by a facile ultrasound-assisted hydrothermal method.     

Correction: Highly sensitive and wearable gas sensors consisting of chemically functionalized graphene oxide assembled on cotton yarn

Correction for ‘Highly sensitive and wearable gas sensors consisting of chemically functionalized graphene oxide assembled on cotton yarn’ by Min-A. Kang et al., RSC Adv., 2018, 8, 11991–11996.

The authors regret that one of the funding bodies listed in the Acknowledgements section of the original article is incorrect. A revised version of the Acknowledgements section, in which ‘NRF-2016M3A7B4900119’ is replaced by ‘NRF-2017M3D9A1073502’, can be found below.This research was supported by a grant (2011-0031636) from the Center for Advanced Soft Electronics under the Global Frontier Research Program of the Ministry of Science, ICT and Future Planning, Korea. This research was also supported by Nano/Material Technology Development Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2017M3D9A1073502).The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

浅谈IS0 9001质量管理体系在疾控中心计算机网络管理中的应用

<正>ISO 9001是由全球第一个质量管理体系标准BS 5750(BSI撰写)转化而来的,ISO 9001是迄今为止世界上最成熟的质量框架,全球有161个国家/地区的超过75万个组织正在使用这一框架。ISO9001不仅为质量管理体系,也为总体管理体系设立了标准。它帮助各类组织通过客户满意度的改进、员工积极性的提升以及持续改进来获得成功。马