High magnesium mitigates the vasoconstriction mediated by different types of calcium influx from monocrotaline-induced pulmonary hypertensive rats.

NEW FINDINGS: What is the central question of this study? What is the involvement of Mg2+ in mitigating the vasoconstriction in pulmonary arteries and smaller pulmonary arteries in the monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) rat model? What are the main finding and its importance? Both store-operated Ca2+ entry- and receptor-operated Ca2+ entry-mediated vasoconstriction were enhanced in the MCT-PAH model. High magnesium inhibited vasoconstriction by directly antagonizing Ca2+ and increasing NO release, and this was more notable in smaller pulmonary arteries. ABSTRACT: Increased extracellular magnesium concentration has been shown to attenuate the endothelin-1-induced contractile response via the release of nitric oxide (NO) from the endothelium in proximal pulmonary arteries (PAs) of chronic hypoxic mice. Here, we further examined the involvement of Mg2+ in the inhibition of vasoconstriction in PAs and distal smaller pulmonary arteries (sPAs) in a monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) rat model. The data showed that in control rats vasoconstriction in sPAs is more intense than that in PAs. In MCT-PAH rats, store-operated Ca2+ entry (SOCE)- and receptor-operated Ca2+ entry (ROCE)-mediated contraction were significantly strengthened. However, there was no upregulation of the vasoconstriction mediated by voltage-dependent calcium entry (VDCE). Furthermore, high magnesium greatly inhibited VDCE-mediated contraction in PAs rather than sPAs, which was the opposite of the ROCE-mediated contraction. Moreover, monocrotaline pretreatment partly eliminated the endothelium-dependent vasodilatation in PAs, which in sPAs, however, was still promoted by magnesium due to the increased NO release in pulmonary microvascular endothelial cells (PMVECs). In conclusion, the findings suggest that both SOCE- and ROCE-mediated vasoconstriction in the MCT-PAH model are enhanced, especially in sPAs. The inhibitory effect of high magnesium on vasoconstriction can be achieved partly by its direct role as a Ca2+ antagonist and partly by increasing NO release in PMVECs.

Access to P-stereogenic compounds via desymmetrizing enantioselective bromination.

A novel and efficient desymmetrizing asymmetric ortho-selective mono-bromination of bisphenol phosphine oxides under chiral squaramide catalysis was reported. Using this asymmetric ortho-bromination strategy, a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates were obtained with good to excellent yields (up to 92%) and enantioselectivities (up to 98.5 : 1.5 e.r.). The reaction could be scaled up, and the synthetic utility of the desired P-stereogenic compounds was proved by transformations and application in an asymmetric reaction.

Arg-Gly-Asp Peptide-Functionalized Superparamagnetic γ-Fe2O3 Nanoparticles Enhance Osteoblast Migration In Vitro.

Making osteoblast migration manageably target to injury sites has been the key challenging in cell therapy for bone and cartilage regeneration. Superparamagnetic materials, the magnetic guide for cell migration, have been applied to increase cell retention. However, additional targeting modifications are still needed to accelerate the low uptake efficiency and moving speed. Arg-Gly-Asp peptide (RGD)-functionalized magnetic nanoparticles showed cutting-edge competence in cell differentiation control and targeted drug delivery. However, more evidence was required to corroborate its role in osteoblast migration in bone repair. In the present study, RGD-modified γ-Fe2O3 nanoparticles (RGD-Fe2O3 NPs) were prefabricated with the grafting ratio of 33.3-37.4%. The RGD-Fe2O3 NPs unveiled excellent water dispersibility with uniform size distribution at 5-6 nm and negligibly low cytotoxicity. As a result, MC3T3-E1 osteoblasts treated with RGD-Fe2O3 NPs boosted its migration speed in a magnetic field compared with those incubated with unmodified Fe2O3 NPs. Furthermore, osteoblasts treated with RGD-Fe2O3 NPs exhibited more Fe uptake. The results exposed the fact that RGD-mediated specific cellular uptake presented higher efficiency than the non-RGD-mediated one, resulting from a stronger superparamagnetic force between the labeled cells and the magnetic field. These findings indicate that the RGD-functionalized Fe2O3 NPs can promote osteoblast migration in the magnetic field, providing a promising strategy in magnet-guided cell therapy for bone and cartilage regeneration.

Pharmacy and nursing students' attitudes toward nurse-pharmacist collaboration at a Chinese university.

BACKGROUND: The collaborative working relationship of nurses with pharmacists has increasingly captured considerable attention. This study measured pharmacy and nursing students' attitudes toward nurse-pharmacist collaboration at a university in China. METHODS: This cross-sectional study was conducted to assess the attitudes toward nurse-pharmacist collaboration using a self-developed scale delivered to a sample involving 202 nursing students and 258 pharmacy students enrolled in Wuhan University of Science and Technology. RESULTS: Completed instruments were returned by 192 nursing students (95.0% effective response rate) and 249 pharmacy students (96.5% effective response rate). The average students' score of attitudes toward nurse-pharmacist collaboration was 78.85 out of a total of 100. No significance was found for the attitudes toward nurse-pharmacist collaboration between two professions or between gender. The college freshmen (first-year) students had the maximum scores suggesting the most positive attitude toward nurse-pharmacist collaboration, followed by second- and third-year students, while final-year (fourth-year) students had the least. CONCLUSION: The students had somewhat positive attitudes toward nurse-pharmacist collaboration, but there is still room for improvement.

Magnesium attenuates endothelin-1-induced vasoreactivity and enhances vasodilatation in mouse pulmonary arteries: Modulation by chronic hypoxic pulmonary hypertension.

NEW FINDINGS: What is the central question of this study? The central goal of this study was to elucidate the role of magnesium in the regulation of pulmonary vascular reactivity in relationship to hypoxic pulmonary hypertension. What is the main finding and its importance? We found that magnesium is essential for normal vasoreactivity of the pulmonary artery. Increasing the magnesium concentration attenuates vasoconstriction and improves vasodilatation via release of nitric oxide. Pulmonary hypertension is associated with endothelial dysfunction resulting in the suppression of magnesium modulation of vasodilatation. These results provide evidence that magnesium is important for the modulation of pulmonary vascular function. ABSTRACT: Pulmonary hypertension (PH) is characterized by enhanced vasoreactivity and sustained pulmonary vasoconstriction, arising from aberrant Ca2+ homeostasis in pulmonary arterial (PA) smooth muscle cells. In addition to Ca2+ , magnesium, the most abundant intracellular divalent cation, also plays crucial roles in many cellular processes that regulate cardiovascular function. Recent findings suggest that magnesium regulates vascular functions by altering the vascular responses to vasodilator and vasoactive agonists and affects endothelial function by modulating endothelium-dependent vasodilatation in hypertension. Administration of magnesium also decreased pulmonary arterial pressure and improved cardiac output in animal models of PH. However, the role of magnesium in the regulation of pulmonary vascular function related to PH has not been studied. In this study, we examined the effects of magnesium on endothelin-1 (ET-1)-induced vasoconstriction, ACh-induced vasodilatation and the generation of NO in PAs of normoxic mice and chronic hypoxia (CH)-treated mice. Our data showed that removal of extracellular magnesium suppressed vasoreactivity of PAs to both ET-1 and ACh. A high concentration of magnesium (4.8 mm) inhibited ET-1-induced vasoconstriction in endothelium-intact or endothelium-disrupted PAs of normoxic and CH-treated mice, and enhanced the ACh-induced production of NO in PAs of normoxic mice. Moreover, magnesium enhanced ACh-induced vasodilatation in PAs of normoxic mice, and the enhancement was completely abolished after exposure to CH. Hence, in this study we demonstrated that increasing the magnesium concentration can attenuate the ET-1-induced contractile response and improve vasodilatation via release of NO from the endothelium. We also demonstrated that chronic exposure to hypoxia can cause endothelial dysfunction resulting in suppression of the magnesium-dependent modulation of vasodilatation.

[Comparison of agonists-induced contraction between main and the third-order branches of pulmonary arteries in rats].

This study was designed to observe the differences between main pulmonary arteries and the third-order branches of pulmonary arteries in the contractile response to phenylephrine (Phen), endothelin-1 (ET-1) and potassium chloride (KCl). The vascular tension changes of main and the third-order branches of pulmonary arteries induced by KCl, ET-1 and Phen were recorded by traditional vascular tone detection methods and microvascular ring technique, respectively. The results showed that Phen could cause a significant contraction in main pulmonary arteries, but did not induce apparent contraction in the third-order branches of pulmonary arteries. Compared with main pulmonary arteries, ET-1 contracted the third-order branches of pulmonary arteries with reduced maximal response value and PD2 value. In comparison with the main pulmonary arteries, contraction caused by KCl was enhanced in the third-order branches of pulmonary arteries. The results suggest that the vascular reactivity of main and the third-order branches of pulmonary arteries is different and it is important to study the vascular function of small branches of pulmonary arteries. This study could provide an important experimental basis for the further study on vascular function of small branches of pulmonary arteries and the functional changes in pulmonary hypertension.

TLR4 drives the pathogenesis of acquired cholesteatoma by promoting local inflammation and bone destruction.

Acquired cholesteatoma is a chronic inflammatory disease characterized by both hyperkeratinized squamous epithelial overgrowth and bone destruction. Toll-like receptor (TLR) activation and subsequent inflammatory cytokine production are closely associated with inflammatory bone disease. However, the expression and function of TLRs in cholesteatoma remain unclear.We observed inflammatory cell infiltration of the matrix and prematrix of human acquired cholesteatoma, as well as dramatically increased expression of TLR4 and the pro-inflammatory cytokines TNF-α and IL-1ß. TLR2 exhibited an up-regulation that was not statistically significant. TLR4 expression in human acquired cholesteatoma correlated with disease severity; the number of TLR4-positive cells increased with an increased degree of cholesteatoma, invasion, bone destruction, and hearing loss. Moreover, TLR4 deficiency was protective against experimental acquired cholesteatoma-driven bone destruction and hearing loss, as it reduced local TNF-α and IL-1ß expression and impaired osteoclast formation by decreasing expression of the osteoclast effectors receptor activator of nuclear factor (NF)-κB ligand (RANKL) and tartrate-resistant acid phosphatase (TRAP). TLR2 deficiency did not relieve disease severity, inflammatory responses, or osteoclast formation. Moreover, neither TLR2 nor TLR4 deficiency had an effect on antimicrobial peptides, inducible iNOS,BD-2 expression or bacterial clearance. Therefore, TLR4 may promote cholesteatoma-induced bone destruction and deafness by enhancing inflammatory responses and osteoclastogenesis.

Dihydrotestosterone induces SREBP-1 expression and lipogenesis through the phosphoinositide 3-kinase/Akt pathway in HaCaT cells.

BACKGROUND: The purpose of this study was to investigate the effects and mechanisms of dihydrotestosterone (DHT)-induced expression of sterol regulatory element binding protein-1 (SREBP-1), and the synthesis and secretion of lipids, in HaCaT cells. HaCaT cells were treated with DHT and either the phosphoinositide 3-kinase inhibitor LY294002 or the extracellular-signal-regulated kinase (ERK) inhibitor PD98059. Real time-PCR, Western blot, Oil Red staining and flow cytometry were employed to examine the mRNA and protein expressions of SREBP-1, the gene transcription of lipid synthesis, and lipid secretion in HaCaT cells. FINDINGS: We found that DHT upregulated mRNA and protein expressions of SREBP-1. DHT also significantly upregulated the transcription of lipid synthesis-related genes and increased lipid secretion, which can be inhibited by the addition of LY294002. CONCLUSIONS: Collectively, these results indicate that DHT induces SREBP-1 expression and lipogenesis in HaCaT cells via activation of the phosphoinositide 3-kinase/Akt Pathway.

Tanshinone IIA inhibits the dihydrotestosterone-induced secretion of lipids and activation of sterol regulatory element binding protein-1 in HaCaT cells.

To study the effects and mechanisms of Tanshinone IIA (Tan IIA) on the dihydrotestosterone (DHT)-induced expression of sterol regulatory element binding protein-1 (SREBP-1), the synthesis and secretion of lipids in HaCaT cells were examined. HaCaT cells were treated with DHT and Tan IIA at different concentrations. Real-time PCR was used to detect the expression of SREBP-1c, fatty acid synthase (FAS), acyl-CoA synthetase (ACS), stearoyl-CoA desaturase (SCD) and HMG-CoA reductase (HMGCR) mRNA in HaCaT cells. Western blotting was used to analyze the protein expression of SREBP-1 and phosphorylation of Akt. Flow cytometry and Nile red staining were used to detect the synthesis and secretion of lipids in HaCaT cells. We observed that Tan IIA inhibited the DHT-induced expression of SREBP-1 and p-AKT in HaCaT cells, which produced an effect similar to that of LY294002. Tan IIA significantly inhibited the transcription of lipid synthesis-related genes and decreased lipid secretion in HaCaT cells. In conclusion, Tan IIA downregulates the expression of lipid synthesis-related genes and decreases lipid secretion in HaCaT cells, which is correlated with the inhibitory effect on the DHT-induced mRNA and protein expression of SREBP-1 in HaCaT cells.

Characterization of the miRNA profile in UVB-irradiated normal human keratinocytes.

The aim of this study was to assess the effects of ultraviolet B (UVB) irradiation on microRNA (miRNA) expression in normal human keratinocytes. Global miRNA expression profiles of primary cultures of normal human keratinocytes 4 and 24 h postirradiation were studied using miRNA microarray with further confirmation by real-time PCR. We found that upon 30 or 60 mJ/cm(2) of UVB radiation, the expression of 44 miRNAs was up- or downregulated more than twofold compared with non-irradiated keratinocytes. MiRNAs were either up- or downregulated after 4 h and then either returned to normal levels or remained affected after 24 h, resulting in four distinct patterns of miRNA expression change. It appears that acute exposure of keratinocytes to UVB radiation results in several specific patterns of miRNA response.

Three autologous substitutes for myringoplasty: a comparative study.

OBJECTIVE: Evaluation of 3 different kinds of autologous substitutes for simple myringoplasty. STUDY DESIGN: Retrospective review of myringoplasty cases. PATIENTS: A total of 117 patients (52 women with 52 ears and 65 men with 65 ears) with an average age of 25.6 years (range, 12-51 yr) were examined. Forty-two cases exhibited large perforations, and 75 exhibited small perforations. INTERVENTION: Myringoplasty with temporal fascia, tragus perichondrium, or tragus cartilage-perichondrium composite grafts were randomly used in this comparative study. All the 117 operations were performed by a single surgeon. MAIN OUTCOME MEASURES: Otoscopic findings as assessed by a hearing examination using a quad-frequency pure-tone average air-bone gap. RESULTS: Recurrent defects were not observed in the small perforation group repaired with autologous substitutes. The graft acceptance rate in this group was 100%. For the large perforation group, the graft acceptance rate was highest with the cartilage-perichondrium composite grafts group (p < 0.05) 1 year after the operation. Tympanic membranes repaired with temporalis fascia or perichondrium eventually perforated again or seemed invaginated and adherent. Early hearing improvements in the temporalis fascia and perichondrium groups were better than that of cartilage-perichondrium composite grafts, but there was no significant difference 1 year after surgery. CONCLUSION: Temporal fascia, tragus perichondrium, and tragus cartilage-perichondrium composite grafts are all suitable for myringoplasty after a minor tympanic membrane perforation. However, cartilage-perichondrium composite graft material for myringoplasty has superior long-term benefits in regard to both hearing improvements and tympanic membrane morphology, which are especially evident in cases with large perforations.