The importance of the rapid vascular effects of aldosterone is increasingly appreciated. Through these rapid pathways, aldosterone has been shown to regulate vascular contractility, cell growth, and ...apoptosis. In our most recent studies, we demonstrated the effects of aldosterone on cell growth and contractility in vascular smooth muscle cells. We showed that these effects could occur via activation of the classic mineralocorticoid receptor, as well the recently characterized G protein-coupled estrogen receptor (GPER), initially characterized as an estrogen-specific receptor. However, the mechanisms underlying aldosterone's endothelium-dependent actions are unknown. Furthermore, the ERK regulatory and proapoptotic effects of aldosterone mediated by GPER activation in cultured vascular smooth muscle cells were only apparent when GPER was reintroduced into these cells by gene transfer. Whether GPER activation via aldosterone might be an important regulator in native vascular cells has been questioned. Therefore, to determine the role of GPER in mediating aldosterone's effects on cell growth and vascular reactivity in native cells, we examined rat aortic vascular endothelial cells, a model characterized by persistent robust expression of GPER, but without detectable mineralocorticoid receptor expression. In these endothelial cells, the GPER agonist G1 mediates a rapid increase in ERK phosphorylation that is wholly GPER-dependent, paralleling the actions of aldosterone. The effects of G1 and aldosterone to stimulate ERK phosphorylation paralleled their proapoptotic and antiproliferative effects. In previous studies, we reported that aldosterone mediates a rapid endothelium-dependent vasodilatory effect, antagonistic to its direct vasoconstrictor effect in endothelium-denuded preparations. Using a rat aortic ring/organ bath preparation to determine the GPER dependence of aldosterone's endothelium-dependent vasodilator effects, we demonstrate that aldosterone inhibits phenylephrine-mediated contraction. This vasodilator effect parallels the actions of the GPER agonist G1. Furthermore, the effects of aldosterone were completely ablated by the GPER antagonist G15. These data support an important role of GPER activation in aldosterone-mediated regulation of endothelial cell growth, as well as in aldosterone's endothelium-mediated regulation of vasoreactivity.
Y2O3 dispersion-strengthened Molybdenum (Mo) composites were prepared by the mechanical alloying of Mo and Y powders then consolidation by spark plasma sintering. The effects of Chromium (Cr) ...addition (0 wt. %, 5 wt. %, 10 wt. % and 15 wt. %, respectively) on the mechanical performance and high-temperature oxidation resistance of Mo-Y2O3 were investigated. The introduction of Cr had a significant influence on the mechanical property and oxidation resistance of the Mo-Y2O3 composite. The highest bending strength reached 932 MPa when the addition of Cr content was 5 wt. % (Mo–5Cr–1Y sample). This improvement is likely attributable to the dual mechanism of grain refinement and solid solution strengthening. Moreover, the Mo–5Cr–1Y sample showed the thinnest oxide layer thickness after high-temperature oxidation tests, and exhibited the best oxidation resistance performance compared with the other samples. First principle calculation reveals that Cr could improve the Mo–MoO3 interface bonding to prevent rapid spalling of the oxide layer. Meanwhile, Cr also facilitates the formation of the dense Cr2(MoO4)3 layer on the surface, which can inhibit further oxidation.
It has been increasingly appreciated that steroids elicit acute vascular effects through rapid, so-called nongenomic signaling pathways. Though aldosterone, for example, has been demonstrated to ...mediate rapid vascular effects via both mineralocorticoid receptor–dependent and –independent pathways, the mechanism(s) of this mineralocorticoid receptor–independent effect of aldosterone is yet to be determined. For estrogen, its rapid effects have been reported to be, at least in part, mediated via the 7-transmembrane–spanning, G protein–coupled receptor GPR30. Previous studies have demonstrated common response outcomes in response to both aldosterone and estrogen on GPR30 expression, ie, activation of phosphatidylinositol 3-kinase–dependent contraction and extracellular signal-regulated kinase activation in vascular smooth muscle cells. The present studies were undertaken to test the hypothesis that the rapid response to aldosterone in smooth muscle is dependent on the availability of a GPR30-dependent signaling pathway. These findings not only reconcile differences in the literature for aldosterone response in freshly isolated versus cultured aortic smooth muscle cells but also suggest alternative therapeutic strategies for modulating aldosterone actions on the vasculature in vivo.
In this study, the microstructure and microhardness of tungsten–yttrium (W–Y) composites were investigated as a function of Y doping content (0.25–3wt%). It was found that the crystallite sizes and ...the powder particle sizes were increased as a result of the increase of Y content. Nearly fully dense materials were obtained for W–Y alloys when the Y content was higher than 0.5wt%. The EDS analysis revealed that the Y rich phases were complex (W–Y) oxides formed during the sintering process. The Y doping content showed obvious influence on the refinement of tungsten grains during sintering. W–1.5Y composite showed the finest microstructure with an average grain size of 0.32μm, and thus achieved the highest Vickers microhardness with the value of 770HV0.2.
Background
The current utilization of neurokinin‐1 receptor antagonists (NK1RAs) and the impact of updated guidelines on prescription patterns of antiemetic drugs among Chinese patients receiving ...highly emetogenic chemotherapy (HEC) remain undetermined. This study aims to analyze the present situation of Chinese cancer patients using antiemetic drugs and assess the appropriateness of antiemetic regimens.
Methods
Prescription data were collected between January 2015 and December 2020 from cancer patients receiving cisplatin‐based chemotherapy at 76 hospitals in six major cities in China. Trends in the use of antiemetic drugs, prescribing patterns and adherence to antiemetic guidelines were assessed.
Results
Among the 108,611 patients included in this study, 6 classes and 17 antiemetic drugs were identified as monotherapy or combination therapy in 93,872 patients (86.4%), whereas 14,739 patients (13.6%) were administered no antiemetic treatment. 5‐hydroxytryptamine 3 receptor antagonists (5‐HT3RAs) and glucocorticoids were the two most frequently used classes of antiemetics, followed by metoclopramide. NK1RAs were underused across the six cities, only 9332 (8.6%) and 1655 (1.5%) cisplatin‐based treatments were prescribed aprepitant and fosaprepitant, respectively. Prescriptions of olanzapine and lorazepam were very low throughout the study period. In prescribing patterns of antiemetic drugs, dual combination regimens were the most common (40.0%), followed by triple combination therapy and monotherapy (25.8% and 15.1%, respectively). Overall, the adherence to antiemetic guidelines for patients undergoing cisplatin‐based regimens was only 8.1% due to inadequate prescription of antiemetic drugs. Finally, our study also revealed that 5‐HT3RAs and glucocorticoids were overprescribed in 8.8% and 1.6% of patients, respectively.
Conclusions
The current study reveals suboptimal utilization of recommended antiemetic drugs for managing cisplatin‐based HEC‐induced nausea and vomiting in China. Improving the management of CINV is crucial, and these findings provide valuable insights into optimizing antiemetic drug practices.
The results of our study indicate low adherence to antiemetic guidelines in real‐world clinical practice in China. Only 8.1% of cisplatin‐based chemotherapy received the guideline compliant NK1RA‐5‐HT3RA‐glucocorticoid with or without olanzapine therapy when assessing antiemetic drugs administered, which may further reduce when evaluating dose, frequency, and duration. These findings highlight the importance of improving the management of CINV in China and provide useful information for better drug management.
Departments of 1 Medicine and of
2 Physiology and Pharmacology, Schulich School of Medicine and Dentistry, and
3 Vascular Biology Research Group, Robarts Research Institute, University of Western ...Ontario, London, Canada; and
4 Department of Cardiovascular Biology, Meharry Medical College, Nashville, Tennessee
Submitted 30 April 2009
; accepted in final form 5 September 2009
Recent studies suggest that the rapid and nongenomic effects of estradiol may be mediated through the G protein-coupled receptor dubbed GPR30 receptor. The present study examines the role of GPR30 versus a classical estrogen receptor (ER ) in mediating the growth regulatory effects of estradiol. GPR30 is readily detectable in freshly isolated vascular tissue but barely detectable in cultured vascular smooth muscle cells (VSMC). In freshly isolated aortic tissue, estradiol stimulated extracellular signal-regulated kinases (ERK) phosphorylation. In contrast, in cultured VSMC, where GPR30 expression is significantly reduced, estradiol inhibits ERK phosphorylation. Transfer of the genes encoding GPR30 led to estradiol stimulation of ERK phosphorylation, which is opposite the effects of estradiol in the primary culture of VSMCs. Transduction of the mineralocorticoid receptor (MR) had no effect on estradiol effects on ERK. Estradiol-mediated stimulation of ERK subsequent to heterologous GPR30 expression was pertussis toxin sensitive and phosphoinositide 3-kinase (PI3 kinase) dependent; under these conditions, estradiol also inhibited protein kinase A (PKA). In contrast, in the absence of GPR30 expression in cultured VSMC, estradiol stimulated PKA activity and inhibited ERK phosphorylation. To determine the functional effect of GPR30 (vs. estrogen receptor expression), we assessed estradiol-mediated apoptosis. In the absence of GPR30 expression, estradiol inhibited apoptosis. This effect was enhanced with ER expression. In contrast, with GPR30 expression, estradiol stimulated apoptosis in an ERK-dependent manner. Thus the effect of estradiol on vascular smooth muscle cell apoptosis is likely dependent on the balance between ER-mediated PKA activation and GPR30-mediated PKA inhibition and PI3 kinase activation. Taken together, we postulate that modulation of GPR30 expression or activity may be an important determinant of the effects of estradiol in the vasculature.
steroid hormones; G protein-coupled receptor 30; extracellular signal-regulated kinase
Address for reprint requests and other correspondence: R. D. Feldman, Robarts Research Institute, 100 Perth Dr., PO Box 5015, Stn B, London, ON, Canada N6A 5K8 (e-mail: feldmanr{at}lhsc.on.ca ).
Aldosterone exerts some of its effects not by binding to mineralocorticoid receptors, but rather by acting via G protein‐coupled estrogen receptors (GPER). To determine if aldosterone binds directly ...to GPER, we studied the ability of aldosterone to compete for the binding of 3H 2‐methoxyestradiol (3H 2‐ME), a high potency GPER‐selective agonist. We used GPER gene transfer to engineer Sf9‐cultured insect cells to express GPER. We chose insect cells to avoid interactions with any intrinsic mammalian receptors for aldosterone. 3H 2‐ME binding was saturable and reversible to a high‐affinity population of receptors with Kd = 3.7 nM and Bmax = 2.2 pmol/mg. Consistent with agonist binding to G Protein‐coupled receptors, 3H 2‐ME high‐affinity state binding was reduced in the presence of the hydrolysis‐resistant GTP analog, GppNHp. 3H 2‐ME binding was competed for by the GPER agonist G1, the GPER antagonist G15, estradiol (E2), as well as aldosterone (Aldo). The order of potency for competing for 3H 2‐ME binding, namely 2ME > Aldo > E2 ≥ G1, paralleled the orders of potency for inhibition of cell proliferation and inhibition of ERK phosphorylation by ligands acting at GPER. These data confirm the ability of aldosterone to interact with the GPER, consistent with the interpretation that aldosterone likely mediates its GPER‐dependent effects by direct binding to the GPER.
Significance statement
Despite the growing evidence for aldosterone's actions via G protein‐coupled estrogen receptors (GPER), there remains significant skepticism that aldosterone can directly interact with GPER. The current studies are the first to demonstrate directly that aldosterone indeed is capable of binding to the GPER and thus likely mediates its GPER‐dependent effects by direct binding to the receptor.
This graph summarizes the EC50 values obtained from Figures 2 and 4 and the Ki values from Figure 6. Table 1 shows the values. The symbols show the fit value of the Ki or EC50; the lines show the 95%CIs.
The rapid spread of Clostridium difficile NAP1/BI/027 (C. difficile 027) has become one of the leading threats of healthcare-associated infections worldwide. However, C. difficile 027 infections have ...been rarely reported in Asia, particularly in China.
In this study, we identified a rare C. difficile bloodstream infection (BSI) from three isolates of a patient during repeated hospital admission. This finding triggered a retrospective epidemiological study to scan all cases and strains emerged from this ward during the past three years. Using medical personnel interviews, medical record reviews and the genomic epidemiology, two outbreaks in 2012 and 2013-2014 were identified. Through using whole genome sequencing, we succeeded to trace the origin of the BSI strain. Surprisingly, we found the genome sequences were similar to C. difficile 027 strain R20291, indicating the occurrence of a rare C. difficile 027 strain in China. Integrated epidemiological investigation and whole genome sequencing of all strains, we constructed a nosocomial transmission map of these two C. difficile 027 outbreaks and traced the origin of the infection.
By genome sequencing, spatio-temporal analysis and field epidemiology investigation, we can estimate their complex transform network and reveal the possible modes of transmission in this ward. Based on their genetic diversity, we can assume that the toilets, bathroom, and janitor's equipment room may be contaminated area, which may be suggested to improve infection control measures in the following health care.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The uncoupling of metabotropic glutamate receptors (mGluRs) from heterotrimeric G proteins represents an essential feedback mechanism that protects neurons against receptor overstimulation that may ...ultimately result in damage. The desensitization of mGluR signaling is mediated by both second messenger-dependent protein kinases and G protein-coupled receptor kinases (GRKs). Unlike mGluR1, the attenuation of mGluR5 signaling in HEK 293 cells is reported to be mediated by a phosphorylation-dependent mechanism. However, the mechanisms regulating mGluR5 signaling and endocytosis in neurons have not been investigated. Here we show that a 2-fold overexpression of GRK2 leads to the attenuation of endogenous mGluR5-mediated inositol phosphate (InsP) formation in striatal neurons and siRNA knockdown of GRK2 expression leads to enhanced mGluR5-mediated InsP formation. Expression of a catalytically inactive GRK2-K220R mutant also effectively attenuates mGluR5 signaling, but the expression of a GRK2-D110A mutant devoid in Gαq/11 binding increases mGluR5 signaling in response to agonist stimulation. Taken together, these results indicate that the attenuation of mGluR5 responses in striatal neurons is phosphorylation-independent. In addition, we find that mGluR5 does not internalize in response to agonist treatment in striatal neuron, but is efficiently internalized in cortical neurons that have higher levels of endogenous GRK2 protein expression. When overexpressed in striatal neurons, GRK2 promotes agonist-stimulated mGluR5 internalization. Moreover, GRK2-mediated promotion of mGluR5 endocytosis does not require GRK2 catalytic activity. Thus, we provide evidence that GRK2 mediates phosphorylation-independent mGluR5 desensitization and internalization in neurons.
1 Cell Biology and 2 Vascular Biology Research Groups, Robarts Research Institute, London, Ontario, Canada; and 3 Department of Medicine, University of Western Ontario, London, Ontario, Canada
...Submitted 27 July 2006
; accepted in final form 11 September 2006
It has been increasingly appreciated that aldosterone elicits acute vascular effects through nongenomic signaling pathways. Our previous studies demonstrated that aldosterone attenuated phenylephrine-mediated constriction in intact vessels via phosphatidylinositol 3-kinase-dependent nitric oxide synthase activation but enhanced vasoconstrictor responses in endothelium-denuded arteries. To determine the mechanism of this vasoconstrictor response, we assessed the effect of aldosterone on myosin light-chain phosphorylation and contraction in clonal adult human vascular smooth muscle cells. Acute aldosterone exposure mediated dose-dependent myosin light-chain phosphorylation, inhibited by spironolactone and phosphatidylinositol 3-kinase inhibition. These rapid effects of aldosterone were mimicked by estradiol and hydrocortisone and were also inhibitable by both spironolactone and eplerenone. In parallel to its effects on myosin light-chain phosphorylation, aldosterone mediated dose-dependent contraction responses that were inhibited by spironolactone. Comparable contractile responses were seen with both 17 -estradiol and hydrocortisone. In total, these data are consistent with a mechanism of acute aldosterone-mediated contraction common to both glucocorticoids and estrogen. Steroid-mediated vasoconstriction may represent an important pathobiological mechanism of vascular disease, especially in the setting of preexisting endothelial dysfunction.
steroid hormones; contraction; nongenomic
Address for reprint requests and other correspondence: R. D. Feldman, Robarts Research Institute, 100 Perth Dr, London, ON, Canada N6A 5K8 (e-mail: feldmanr{at}lhsc.on.ca )
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