Estrogen receptor-beta prevents cardiac fibrosis.

Development of cardiac fibrosis portends the transition and deterioration from hypertrophy to dilation and heart failure. Here we examined how estrogen blocks this important development. Angiotensin II (AngII) and endothelin-1 induce cardiac hypertrophy and fibrosis in humans. and we find that these agents directly stimulate the transition of the cardiac fibroblast to a myofibroblast. AngII and endothelin-1 stimulated TGFβ1 synthesis in the fibroblast, an inducer of fibrosis that signaled via c-jun kinase to Sma- and Mad-related protein 3 phosphorylation and nuclear translocation in myofibroblasts. As a result, mesenchymal proteins fibronectin and vimentin were produced, as were collagens I and III, the major forms found in fibrotic hearts. 17β-Estradiol (E2) or dipropylnitrile, an estrogen receptor (ER)β agonist, comparably blocked all these events, reversed by estrogen receptor (ER)β small interfering RNA. E2 and dipropylnitrile signaling through cAMP and protein kinase A prevented myofibroblast formation and blocked activation of c-jun kinase and important events of fibrosis. In the hearts of ovariectomized female mice, cardiac hypertrophy and fibrosis were induced by AngII infusion and prevented by E2 administration to wild type but not ERβ knockout rodents. Our results establish the cardiac fibroblast as an important target for hypertrophic/fibrosis-inducing peptides the actions of which were mitigated by E2/ERβ acting in these stromal cells

Genomic priming of the antisecretory response to estrogen in rat distal colon throughout the estrous cycle.

The secretion of Cl(-) across distal colonic crypt cells provides the driving force for the movement of fluid into the luminal space. 17beta-Estradiol (E2) produces a rapid and sustained reduction in secretion in females, which is dependent on the novel protein kinase C delta (PKC delta) isozyme and PKA isoform I targeting of KCNQ1 channels. This sexual dimorphism in the E2 response is associated with a higher expression level of PKC delta in female compared with the male tissue. The present study revealed the antisecretory response is regulated throughout the female reproductive (estrous) cycle and is primed by genomic regulation of the kinases. E2 (1-10 nm) decreased cAMP-dependent secretion in colonic epithelia during the estrus, metestrus, and diestrus stages. A weak inhibition of secretion was demonstrated in the proestrus stage. The expression levels of PKC delta and PKA fluctuated throughout the estrous cycle and correlated with the potency of the antisecretory effect of E2. The expression of PKC delta and PKA were up-regulated by estrogen at a transcriptional level via a PKC delta-MAPK-cAMP response element-binding protein-regulated pathway indicating a genomic priming of the antisecretory response. PK Cdelta was activated by the membrane-impermeant E2-BSA, and this response was inhibited by the estrogen receptor antagonist ICI 182,780. The 66-kDa estrogen receptor-alpha isoform was present at the plasma membrane of female colonic crypt cells with a lower abundance found in male colonic crypts. The study demonstrates estrogen regulation of intestinal secretion both at a rapid and transcriptional level, demonstrating an interdependent relationship between both nongenomic and genomic hormone responses

Sexual Dimorphism and Estrogen Regulation of KCNE3 Expression Modulates the Functional Properties of KCNQ1 K+ Channels

The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation, some time-dependent activation at very positive potentials, a linear current voltage relationship and a 10-fold higher sensitivity to chromanol 293B. KCNQ1:KCNE3 channels are expressed in colonic crypts and mediate basolateral K+ recycling required for Cl- secretion. We have previously reported the female-specific anti-secretory effects of estrogen via KCNQ1:KCNE3 channel inhibition in colonic crypts. This study was designed to determine whether gender and estrogen regulate the expression and function of KCNQ1 and KCNE3 in rat distal colon. Colonic crypts were isolated from Sprague-Dawley rats and used for whole-cell patch-clamp and to extract total RNA and protein. Sheets of epithelium were used for short-circuit current recordings. KCNE1 and KCNE3 mRNA and protein abundance was significantly higher in male than female crypts. No expression of KCNE2 was found and no difference was observed in KCNQ1 expression between male and female (at estrous) colonic crypts. Male crypts showed a 2.2-fold higher level of association of KCNQ1 and KCNE3 compared to female cells. In female colonic crypts, KCNQ1 and KCNE3 protein expression fluctuated throughout the estrous cycle and 17-estradiol (E2 10 nM) produced a rapid (\u3c15\u3emin) dissociation of KCNQ1 and KCNE3 in female crypts only. Whole-cell K+ currents showed a linear current-voltage relationship in male crypts, while K+ currents in colonic crypts isolated from females displayed voltage-dependent outward rectification. Currents in isolated male crypts and epithelial sheets were 10-fold more sensitive to specific KCNQ1 inhibitors, such as chromanol 293B and HMR-1556, than in female. The effect of E2 on K+ currents mediated by KCNQ1 with or without different -subunits was assayed from current-voltage relations elicited in CHO cells transfected with KCNQ1 and KCNE3 or KCNE1 cDNA. E2 (100 nM) reduced the currents mediated by the KCNQ1:KCNE3 potassium channel and had no effect on currents via KCNQ1:KCNE1 or KCNQ1 alone. Currents mediated by the complex formed by KCNQ1 and the mutant KCNE3-S82A β-subunit showed rapid run-down and insensitivity to E2. Together, these data suggest that estrogen regulates the expression of the KCNE1 and KCNE3 and with it the gating and pharmacological properties of the K+ conductance required for Cl- secretion. The decreased association of the KCNQ1:KCNE3 channel complex promoted by estrogen exposure underlies the molecular mechanism for the sexual dimorphism and estrous cycle dependence of the anti-secretory actions of estrogen in the intestine

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe