Inhibition of Endothelin-1-Mediated Contraction of Hepatic Stellate Cells by FXR Ligand

Activation of hepatic stellate cells (HSCs) plays an important role in the development of cirrhosis through the increased production of collagen and the enhanced contractile response to vasoactive mediators such as endothelin-1 (ET-1). The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidneys, adrenals, and intestine. FXR is also expressed in HSCs and activation of FXR in HSCs is associated with significant decreases in collagen production. However, little is known about the roles of FXR in the regulation of contraction of HSCs. We report in this study that treatment of quiescent HSCs with GW4064, a synthetic FXR agonist, significantly inhibited the HSC transdifferentiation, which was associated with an inhibition of the upregulation of ET-1 expression. These GW4064-treated cells also showed reduced contractile response to ET-1 in comparison to HSCs without GW4064 treatment. We have further shown that GW4064 treatment inhibited the ET-1-mediated contraction in fully activated HSCs. To elucidate the potential mechanism we showed that GW4064 inhibited ET-1-mediated activation of Rho/ROCK pathway in activated HSCs. Our studies unveiled a new mechanism that might contribute to the anti-cirrhotic effects of FXR ligands

Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor

Tamoxifen has been used for many years to target estrogen receptor signalling in breast cancer cells. Tamoxifen is also an agonist of the G protein-coupled estrogen receptor (GPER), a GPCR ubiquitously expressed in tissues that mediates the acute response to estrogens. Here we report that tamoxifen promotes mechanical quiescence in hepatic stellate cells (HSCs), stromal fibroblast-like cells whose activation triggers and perpetuates liver fibrosis in hepatocellular carcinomas. This mechanical deactivation is mediated by the GPER/RhoA/myosin axis and induces YAP deactivation. We report that tamoxifen decreases the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and the synthesis of extracellular matrix proteins through a mechanical mechanism that involves actomyosin-dependent contractility and mechanosensing of tissue stiffness. Our results implicate GPER-mediated estrogen signalling in the mechanosensory-driven activation of HSCs and put forward estrogenic signalling as an option for mechanical reprogramming of myofibroblast-like cells in the tumour microenvironment. Tamoxifen, with half a century of safe clinical use, might lead this strategy of drug repositioning.Peer reviewe

A healthy mistrust: how worldview relates to attitudes about breast cancer screening in a cross-sectional survey of low-income women

<p>Abstract</p> <p>Background</p> <p>Perceived racial discrimination is one factor which may discourage ethnic minorities from using healthcare. However, existing research only partially explains why some persons do accept health promotion messages and use preventive care, while others do not. This analysis explores 1) the psychosocial characteristics of those, within disadvantaged groups, who identify their previous experiences as racially discriminatory, 2) the extent to which perceived racism is associated with broader perspectives on societal racism and powerlessness, and 3) how these views relate to disadvantaged groups' expectation of mistreatment in healthcare, feelings of mistrust, and motivation to use care.</p> <p>Methods</p> <p>Using survey data from 576 African-American women, we explored the prevalence and predictors of beliefs and experiences related to social disengagement, racial discrimination, desired and actual racial concordance with medical providers, and fear of medical research. We then used both sociodemographic characteristics, and experiences and attitudes about disadvantage, to model respondents' scores on an index of personal motivation to receive breast cancer screening, measuring screening knowledge, rejection of fatalistic explanatory models of cancer, and belief in early detection, and in collaborative models of patient-provider responsibility.</p> <p>Results</p> <p>Age was associated with lower motivation to screen, as were depressive symptoms, anomie, and fear of medical research. Motivation was low among those more comfortable with African-American providers, regardless of current provider race. However, greater awareness of societal racism positively predicted motivation, as did talking to others when experiencing discrimination. Talking was most useful for women with depressive symptoms.</p> <p>Conclusion</p> <p>Supporting the Durkheimian concepts of both anomic and altruistic suicide, both disengagement (depression, anomie, vulnerability to victimization, and discomfort with non-Black physicians) as well as over-acceptance (low awareness of discrimination in society) predict poor health maintenance attitudes in disadvantaged women. Women who recognize their connection to other African-American women, and who talk about negative experiences, appear most motivated to protect their health.</p

Nutrients and chlorophyll-a dynamics in a temperate reservoir influenced by Asian monsoon along with in situ nutrient enrichment bioassays

Long-term nutrients and chlorophyll-a dynamics during 1993-2000 were analyzed in a temperate reservoir influenced by the Asian monsoon. Nonparametric Mann-Kendall tests and seasonal trend analyses indicated that there were no long-term annual increasing or decreasing trends in major trophic parameters over 8 years, but the monsoon seasonality was evident. Seasonality in chlorophyll (CHL) and total phosphorus (TP) showed a mono-modal pattern, which was closely associated with the monsoon season of July-August, and the magnitude of the mono-modal peak was greater in the headwater zone than in the downlake zone. Such temporal patterns fluctuated interannually over the study period, and the magnitude of the variation was directly controlled by the intensity of the monsoon rain. Empirical models of annual mean CHL-TP were developed supporting the view that phytoplankton in lentic ecosystems responds to P enrichment and that annual mean TP may provide a reliable basis for predicting the average algal abundance. Ambient nutrient analyses, N:P ratios and in situ nutrient enrichment bioassay experiments (NEBs) in premonsoon and postmonsoon supported the P limitation for phytoplankton growth. Ambient nutrients and non-volatile suspended solid (NVSS) data on CHL in the intense monsoon year, however, showed the possibility of light limitation, even though the NEBs did not show the direct evidence. These findings were confirmed by two-dimensional graphic approaches of trophic state index deviations (TSIDs).

Behind the Scenes of Coproduction of Smart Mobility: Evidence from a Public Values’ Perspective

The advances in information and communication technology (ICT) have extended the applicability of citizen coproduction in government service delivery and have entailed transformative changes, especially at the city level. City governments around the globe increasingly rely on the private sector to set ICT-based urban innovations, like initiatives to involve citizens in the coproduction of smart mobility. Although there are many benefits of ICT-based coproduction, there is nevertheless the potential for tension between private companies and the government with whom they are cooperating. Those tensions are built on the differences in interests and values of private and public actors, and the way of realizing them, and they can compromise the vision and duty of the government. We, therefore, aim to understand the potential impact of private companies’ involvement on the expectations and perceptions of coproducing actors towards social-oriented and service-oriented public values. We conducted an exploratory in-depth case study of the smart bike-sharing system in one of the major cities in Flanders, Belgium. Data were collected through official documents and 27 semi-structured interviews with key coproducing actors. These data were then qualitatively analyzed using Nvivo software. Our exploratory case study indicated that the private actor upholds the realization of values such as efficiency, reliability, and ease of access by bringing in resources and expertise to coproduce smart mobility. However, certain social-oriented values like citizen empowerment and engagement, and (digital) inclusiveness are not part of the private partner’s vision. The study highlights the potential assets and risks for the realization of public values when dealing with conflicting interests between coproducing actors, and in this way considers a different angle on private companies’ involvement in the coproduction of public services.status: publishe