RESUMEN
AIM: To analyse the association between serum bile acid (BA) profile and heart failure (HF) with preserved ejection fraction (HFpEF) in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: We enrolled 163 individuals with biopsy-proven MAFLD undergoing transthoracic echocardiography for any indication. HFpEF was defined as left ventricular ejection fraction >50% with at least one echocardiographic feature of HF (left ventricular diastolic dysfunction, abnormal left atrial size) and at least one HF sign or symptom. Serum levels of 38 BAs were analysed using ultra-performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: Among the 163 patients enrolled (mean age 47.0 ± 12.8 years, 39.3% female), 52 (31.9%) and 43 (26.4%) met the HFpEF and pre-HFpEF criteria, and 38 serum BAs were detected. Serum ursodeoxycholic acid (UDCA) and hyocholic acid (HCA) species were lower in patients with HFpEF and achieved statistical significance after correction for multiple comparisons. Furthermore, decreases in glycoursodeoxycholic acid and tauroursodeoxycholic acid were associated with HF status. CONCLUSIONS: In this exploratory study, specific UDCA and HCA species were associated with HFpEF status in adults with biopsy-confirmed MAFLD.
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Ácidos y Sales Biliares , Insuficiencia Cardíaca , Volumen Sistólico , Humanos , Femenino , Masculino , Persona de Mediana Edad , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/complicaciones , Ácidos y Sales Biliares/sangre , Volumen Sistólico/fisiología , Adulto , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Ecocardiografía , Biomarcadores/sangreRESUMEN
RATIONALE & OBJECTIVE: Patients receiving maintenance hemodialysis (MHD) are highly vulnerable to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The current study was designed to evaluate the prevalence of SARS-CoV-2 infection based on both nucleic acid testing (NAT) and antibody testing in Chinese patients receiving MHD. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: From December 1, 2019, to March 31, 2020, a total of 1,027 MHD patients in 5 large hemodialysis centers in Wuhan, China, were enrolled. Patients were screened for SARS-CoV-2 infection by symptoms and initial computed tomography (CT) of the chest. If patients developed symptoms after the initial screening was negative, repeat CT was performed. Patients suspected of being infected with SARS-CoV-2 were tested with 2 consecutive throat swabs for viral RNA. In mid-March 2020, antibody testing for SARS-CoV-2 was obtained for all MHD patients. EXPOSURE: NAT and antibody testing results for SARS-CoV-2. OUTCOMES: Morbidity, clinical features, and laboratory and radiologic findings. ANALYTICAL APPROACH: Differences between groups were examined using t test or Mann-Whitney U test, comparing those not infected with those infected and comparing those with infection detected using NAT with those with infection detected by positive serology test results. RESULTS: Among 1,027 patients receiving MHD, 99 were identified as having SARS-CoV-2 infection, for a prevalence of 9.6%. Among the 99 cases, 52 (53%) were initially diagnosed with SARS-CoV-2 infection by positive NAT; 47 (47%) were identified later by positive immunoglobulin G (IgG) or IgM antibodies against SARS-CoV-2. There was a spectrum of antibody profiles in these 47 patients: IgM antibodies in 5 (11%), IgG antibodies in 35 (74%), and both IgM and IgG antibodies in 7 (15%). Of the 99 cases, 51% were asymptomatic during the epidemic; 61% had ground-glass or patchy opacities on CT of the chest compared with 11.6% among uninfected patients (P<0.001). Patients with hypertensive kidney disease were more often found to have SARS-CoV-2 infection and were more likely to be symptomatic than patients with another primary cause of kidney failure. LIMITATIONS: Possible false-positive and false-negative results for both NAT and antibody testing; possible lack of generalizability to other dialysis populations. CONCLUSIONS: Half the SARS-CoV-2 infections in patients receiving MHD were subclinical and were not identified by universal CT of the chest and selective NAT. Serologic testing may help evaluate the overall prevalence and understand the diversity of clinical courses among patients receiving MHD who are infected with SARS-CoV-2.
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Anticuerpos Antivirales/análisis , Betacoronavirus/inmunología , Infecciones por Coronavirus/diagnóstico , Fallo Renal Crónico/terapia , Neumonía Viral/diagnóstico , Diálisis Renal , COVID-19 , China/epidemiología , Comorbilidad , Infecciones por Coronavirus/epidemiología , Estudios Transversales , Femenino , Humanos , Fallo Renal Crónico/epidemiología , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/epidemiología , Prevalencia , Estudios Retrospectivos , SARS-CoV-2 , Pruebas Serológicas/métodos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Systemic chronic inflammation plays a role in the pathophysiology of both heart failure with preserved ejection fraction (HFpEF) and metabolic dysfunction-associated fatty liver disease. This study aimed to investigate whether serum hs-CRP (high-sensitivity C-reactive protein) levels were associated with the future risk of heart failure (HF) hospitalization in patients with metabolic dysfunction-associated fatty liver disease and a normal left ventricular ejection fraction. METHODS AND RESULTS: The study enrolled consecutive individuals with metabolic dysfunction-associated fatty liver disease and normal left ventricular ejection fraction who underwent coronary angiography for suspected coronary heart disease. The study population was subdivided into non-HF, pre-HFpEF, and HFpEF groups at baseline. The study outcome was time to the first hospitalization for HF. In 10 019 middle-aged individuals (mean age, 63.3±10.6 years; 38.5% women), the prevalence rates of HFpEF and pre-HFpEF were 34.2% and 34.5%, with a median serum hs-CRP level of 4.5 mg/L (interquartile range, 1.9-10 mg/L) and 5.0 mg/L (interquartile range, 2.1-10.1 mg/L), respectively. Serum hs-CRP levels were significantly higher in the pre-HFpEF and HFpEF groups than in the non-HF group. HF hospitalizations occurred in 1942 (19.4%) patients over a median of 3.2 years, with rates of 3.7% in non-HF, 20.8% in pre-HFpEF, and 32.1% in HFpEF, respectively. Cox regression analyses showed that patients in the highest hs-CRP quartile had a ≈4.5-fold increased risk of being hospitalized for HF compared with those in the lowest hs-CRP quartile (adjusted-hazard ratio, 4.42 [95% CI, 3.72-5.25]). CONCLUSIONS: There was a high prevalence of baseline pre-HFpEF and HFpEF in patients with metabolic dysfunction-associated fatty liver disease and suspected coronary heart disease. There was an increased risk of HF hospitalization in those with elevated hs-CRP levels.
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Enfermedad Coronaria , Insuficiencia Cardíaca , Enfermedad del Hígado Graso no Alcohólico , Persona de Mediana Edad , Humanos , Femenino , Anciano , Masculino , Volumen Sistólico/fisiología , Función Ventricular Izquierda/fisiología , Proteína C-Reactiva , Angiografía Coronaria , Pronóstico , HospitalizaciónRESUMEN
The intact ovine uterine vascular bed (UVB) is sensitive to α-agonists and refractory to angiotensin II (ANG II) during pregnancy; the converse occurs in the systemic circulation. The mechanism(s) responsible for these differences in uterine sensitivity are unclear and may reflect predominance of nonconstricting AT(2) receptors (AT(2)R) in uterine vascular smooth muscle (UVSM). The contribution of the placental vasculature also is unclear. Third generation and precaruncular/placental arteries from nonpregnant (n = 16) and term pregnant (n = 23) sheep were used to study contraction responses to KCl, norepinephrine (NE), and ANG II (with/without ATR specific inhibitors) and determine UVSM ATR subtype expression and contractile protein content. KCl and NE increased third generation and precaruncular/placental UVSM contractions in a dose- and pregnancy-dependent manner (P ≤ 0.001). ANG II only elicited modest contractions in third generation pregnant UVSM (P = 0.04) and none in precaruncular/placental UVSM. Moreover, compared with KCl and NE, ANG II contractions were diminished ≥ 5-fold. Whereas KCl and ANG II contracted third generation>>precaruncular/placental UVSM, NE-induced contractions were similar throughout the UVB. However, each agonist increased third generation contractions ≥ 2-fold at term, paralleling increased actin/myosin and cellular protein content (P ≤ 0.01). UVSM AT(1)R and AT(2)R expression was similar throughout the UVB and unchanged during pregnancy (P > 0.1). AT(1)R inhibition blocked ANG II-mediated contractions; AT(2)R blockade, however, did not enhance contractions. AT(2)R predominate throughout the UVB of nonpregnant and pregnant sheep, contributing to an inherent refractoriness to ANG II. In contrast, NE elicits enhanced contractility throughout the ovine UVB that exceeds ANG II and increases further at term pregnancy.
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Angiotensina II/farmacología , Arterias/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Norepinefrina/farmacología , Útero/irrigación sanguínea , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Animales , Arterias/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Modelos Animales , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Cloruro de Potasio/farmacología , Embarazo , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , Ovinos , Vasoconstricción/fisiologíaRESUMEN
BACKGROUND: Ulcerative colitis (UC) is a complicated disease caused by the interaction between genetic and environmental factors that affects mucosal homeostasis and triggers an inappropriate immune response. Single-cell RNA sequencing (scRNA-seq) can be used to rapidly obtain the precise gene expression patterns of thousands of cells in the intestine, analyze the characteristics of cells with the same phenotype, and provide new insights into the growth and development of intestinal organs, the clonal evolution of cells, and immune cell changes. These findings can provide new ideas for the diagnosis and treatment of intestinal diseases. AIM: To identify clinical phenotypes and biomarkers that can predict the response of UC patients to specific therapeutic drugs and thus aid the diagnosis and treatment of UC. METHODS: Using the Gene Expression Omnibus (GEO) database, we analyzed peripheral blood cell subtypes of patients with UC by scRNA-seq combined with bulk RNA sequencing (RNA-seq) to reveal the core genes of UC. We then combined weighted gene correlation network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) analysis to reveal diagnostic markers of UC. RESULTS: After processing the scRNA-seq data, we obtained data from approximately 24340 cells and identified 17 cell types. Through intercellular communication analysis, we selected monocyte marker genes as the candidate gene set for the prediction model. Construction of a WGCNA coexpression network identified RhoB, cathepsin D (CTSD) and zyxin (ZYX) as core genes. Immune infiltration analysis showed that these three core genes were strongly correlated with immune cells. Functional enrichment analysis showed that the differentially expressed genes were closely related to immune and inflammatory responses, which are associated with many challenges in the diagnosis and treatment of UC. CONCLUSION: Through scRNA-seq analysis, LASSO diagnostic model building and WGCNA, we identified RhoB, CTSD and ZYX as core genes of UC that are closely related to monocyte infiltration that may serve as diagnostic markers and molecular targets for UC therapeutic intervention.
RESUMEN
PURPOSE: Experimental and epidemiological studies suggest that omega-3 fatty acids have an antiarrhythmic effect. However, evidence from randomized controlled trials (RCTs) for prevention of sudden cardiac death (SCD) remains controversial. This study sought to evaluate the efficacy of omega-3 fatty acids for secondary prevention of SCD in patients with cardiovascular disease (CVD) in the era of guidelines-based therapy. METHODS: We conducted a PubMed/EMBASE/CENTRAL search for RCTs evaluating omega-3 fatty acids for CVD secondary prevention with at least 6 months follow-up and with data on SCD. Primary outcome was SCD. Secondary outcomes were cardiovascular mortality and all-cause mortality. RESULTS: Ten randomized controlled trials were identified evaluating a total of 33,429 patients with CVD. In patients with guidelines-adjusted therapy, omega-3 fatty acids did not reduce the risk ratio (RR) of SCD (RR:0.96; 95% CI: 0.84-1.10). In patients with non- guidelines-adjusted therapy, omega-3 fatty acids reduced the RR of SCD (RR: 0.64; 95% CI: 0.51-0.80). Overall, RR for cardiac death and all-cause mortality were 0.81 (95% CI: 0.69-0.95) and 0.89 (95% CI: 0.79-1.01), respectively. CONCLUSIONS: In the era of guidelines-adjusted treatment for CVD secondary prevention, omega-3 fatty acids do not appear to reduce SCD.
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Enfermedades Cardiovasculares/tratamiento farmacológico , Muerte Súbita Cardíaca/prevención & control , Ácidos Grasos Omega-3/uso terapéutico , Enfermedades Cardiovasculares/complicaciones , Muerte Súbita Cardíaca/etiología , Ácidos Grasos Omega-3/administración & dosificación , Estudios de Seguimiento , Humanos , Oportunidad Relativa , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Prevención Secundaria/métodosRESUMEN
The follicular phase of the ovine ovarian cycle demonstrates parallel increases in ovarian estrogens and uterine blood flow (UBF). Although estrogen and nitric oxide contribute to the rise in UBF, the signaling pathway remains unclear. We examined the relationship between the rise in UBF during the ovarian cycle of nonpregnant sheep and changes in the uterine vascular cGMP-dependent pathway and large-conductance Ca(2+)-activated K(+) channels (BK(Ca)). Nonpregnant ewes (n = 19) were synchronized to either follicular or luteal phase using a vaginal progesterone-releasing device (CIDR), followed by intramuscular PGF(2alpha), CIDR removal, and treatment with pregnant mare serum gonadotropin. UBF was measured with flow probes before tissue collection, and second-generation uterine artery segments were collected from nine follicular and seven luteal phase ewes. The pore-forming alpha- and regulatory beta-subunits that constitute the BK(Ca), soluble guanylyl cyclase (sGC), and cGMP-dependent protein kinase G (cPKG) isoforms (cPKG(1alpha) and cPKG(1beta)) were measured by Western analysis and cGMP levels by RIA. BK(Ca) subunits were localized by immunohistochemistry. UBF rose >3-fold (P < 0.04) in follicular phase ewes, paralleling a 2.3-fold rise in smooth muscle cGMP and 32% increase in cPKG(1alpha) (P < 0.05). sGC, cPKG(1beta), and the BK(Ca) alpha-subunit were unchanged. Notably, expression of beta(1)- and beta(2)-regulatory subunits rose 51 and 79% (P Asunto(s)
Ciclo Estral/metabolismo
, Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo
, Arteria Uterina/metabolismo
, Útero/irrigación sanguínea
, Animales
, GMP Cíclico/metabolismo
, Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo
, Femenino
, Óxido Nítrico/metabolismo
, Folículo Ovárico/crecimiento & desarrollo
, Ovulación/metabolismo
, Sistemas de Mensajero Secundario/fisiología
, Ovinos
, Transducción de Señal/fisiología
, Estadísticas no Paramétricas
RESUMEN
Entropy production along a trajectory in the stochastic irreversible Brusselator model of chemical oscillating reactions is discussed. Particular attention is paid to a parameter region near the deterministic supercritical Hopf bifurcation. In the stationary state, detailed fluctuation theorem holds due to the reversibility in the state space, which is verified by direct simulations via Gillespie's algorithm [J. Comput. Phys. 22, 403 (1976); J. Phys. Chem. 81, 2340 (1977)]. In addition, we have considered how the entropy production along a noisy limit cycle depends on the system size. Interestingly, in the large system size limit, the entropy production approaches a constant value when the control parameter stays at the deterministic steady state region, while it increases linearly in the deterministic oscillatory region. Such simulation results can be well understood by a stochastic normal form analysis.
RESUMEN
Allele frequencies for 15 short tandem repeat (STR) loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, and FGA) were obtained from 7,636 unrelated individuals of Chinese Han population living in Qinghai and Chongqing, China. Totally 206 alleles were observed, with the corresponding allele frequencies ranging from 0.0001-0.4982. Chi-square test showed that all of the STR loci agreed with the Hardy-Weinberg equilibrium. We also compared our data with previously published population data of other ethnics or areas. The results are valuable for human identification and paternity testing in Chinese Han population.
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Repeticiones de Microsatélite/genética , Alelos , China/etnología , HumanosRESUMEN
AIM: To investigate the mechanism by which Qinggan Huoxue Recipe (QGHXR) inhibits epithelial-to-mesenchymal transition (EMT) in rats with alcoholic liver fibrosis (ALF). METHODS: A total of 75 male SD rats were used to induce ALF. Serum biochemical indicators, including alanine aminotransferase, aspartate aminotransferase, laminin and hyaluronidase, were measured. Liver histopathological changes were evaluated using hematoxylin-eosin and Sirius red staining. EMT was examined by analyzing the expression of the epithelial marker E-cadherin and the mesenchymal markers vimentin and fibronectin using RT-PCR and Western blot. The inhibitory effect of QGHXR on EMT markers, as well as its effect on molecules associated with the transforming growth factor (TGF)-ß1/Smad signaling pathway, including TGF-ß1, Smad3, snail, occludin, ZO-1 and claudin, was also examined. RESULTS: Compared with normal control rats, ALF rats exhibited a decrease in E-cadherin levels (mRNA: ALF 0.16 ± 0.05 vs control 1.00 ± 0.08; protein: ALF 0.09 ± 0.05 vs control 0.70 ± 0.17, P < 0.01) and an increase in vimentin and fibronectin levels (mRNA: 11.43 ± 0.39 vs 1.00 ± 0.19 and 9.91 ± 0.34 vs 1.00 ± 0.44, respectively, P < 0.01; protein: 1.13 ± 0.42 vs 0.09 ± 0.03 and 1.16 ± 0.43 vs 0.09 ± 0.00, respectively, P < 0.01). This indicates that EMT occurred in ALF rats. In addition, the TGF-ß1/Smad signaling pathway was activated in ALF rats, as evidenced by the increase in TGF-ß1 and snail levels (mRNA: 1.76 ± 0.12 vs 1.00 ± 0.05 and 6.98 ± 0.41 vs 1.00 ± 0.10, respectively, P < 0.01; protein: 1.43 ± 0.05 vs 0.12 ± 0.03 and 1.07 ± 0.29 vs 0.07 ± 0.02, respectively, P < 0.01) and the decrease in Smad3 levels (mRNA: 0.05 ± 0.01 vs 1.00 ± 0.12, P < 0.01; protein: 0.06 ± 0.05 vs 0.89 ± 0.12, P < 0.01). Furthermore, levels of the tight junction markers occludin, ZO-1 and claudin decreased in ALF rats compared with healthy control rats (mRNA: 0.60 ± 0.09 vs 1.00 ± 0.12, 0.11 ± 0.00 vs 1.00 ± 0.12 and 0.60 ± 0.01 vs 1.00 ± 0.08, respectively, P < 0.01; protein: 0.05 ± 0.01 vs 0.87 ± 0.40, 0.09 ± 0.05 vs 0.89 ± 0.18 and 0.04 ± 0.03 vs 0.95 ± 0.21, respectively, P < 0.01). In ALF rats treated with QGHXR, E-cadherin levels increased (mRNA: QGHXR 0.67 ± 0.04 vs ALF model 0.16 ± 0.05, P < 0.01; protein: QGHXR 0.66 ± 0.21 vs ALF model 0.09 ± 0.05, P < 0.01), and vimentin and fibronectin levels decreased (mRNA: 6.57 ± 1.05 vs 11.43 ± 0.39 and 1.45 ± 1.51 vs 9.91 ± 0.34, respectively, P < 0.01; protein: 0.09 ± 0.03 vs 1.13 ± 0.42 and 0.10 ± 0.01 vs 1.16 ± 0.43, respectively, P < 0.01). In addition, QGHXR inhibited the expression of TGF-ß1 and increased the expression of Smad3 (mRNA: 1.03 ± 0.11 vs 1.76 ± 0.12, 0.70 ± 0.10 vs 0.05 ± 0.01, respectively, P < 0.05 and P < 0.01; protein: 0.12 ± 0.03 vs 1.43 ± 0.05 and 0.88 ± 0.20 vs 0.06 ± 0.05, respectively, P < 0.01). QGHXR treatment also reduced the levels of the EMT-inducing transcription factor snail (mRNA: 2.28 ± 0.33 vs 6.98 ± 0.41, P < 0.01; protein: 0.08 ± 0.02 vs 1.07 ± 0.29, P < 0.01) and increased the occludin, ZO-1 and claudin levels (mRNA: 0.73 ± 0.05 vs 0.60 ± 0.09, 0.57 ± 0.04 vs 0.11 ± 0.00 and 0.68 ± 0.03 vs 0.60 ± 0.01, respectively, P < 0.01, P < 0.01 and P < 0.05; protein: 0.92 ± 0.50 vs 0.05 ± 0.01, 0.94 ± 0.22 vs 0.09 ± 0.05 and 0.94 ± 0.29 vs 0.04 ± 0.03, respectively, P < 0.01). The effects of QGR and HXR on the TGF-ß1/Smad signaling pathway were similar to that of QGHXR; however, the QGR- and HXR-induced changes in vimentin mRNA levels, the QGR-induced changes in fibronectin mRNA levels and the HXR-induced changes in snail and TGF-ß1 mRNA levels were not significant. CONCLUSION: Qinggan Huoxue Recipe inhibits EMT in ALF rats by modulating the TGF-ß1/Smad signaling pathway, suggesting that the mechanism underlying the amelioration of ALF induced by QGHXR is associated with this pathway.
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Medicamentos Herbarios Chinos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Cirrosis Hepática Alcohólica/tratamiento farmacológico , Hígado/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Biomarcadores/sangre , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática Alcohólica/genética , Cirrosis Hepática Alcohólica/metabolismo , Cirrosis Hepática Alcohólica/patología , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Proteína smad3/genética , Proteínas de Uniones Estrechas/genética , Proteínas de Uniones Estrechas/metabolismo , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
A model of phosphorus purification in a watershed was established based on the export coefficient and purification index of phosphorus in different types of land cover. The model was employed to simulate the economic value of the ecosystem service with the expected water quality standard and marginal cost of pollutant purification of the upper reaches of Xin' an River of Anhui, China. The results revealed that from 2000 to 2010, some farmland outside the Tunxi, Jixi, Shexian, Yixian and Xiuning was converted to built-up land. The total amount of phosphorus exported to the upper Xin' an River decreased a little, and the main source of phosphorus pollution was farmland and built-up land. More than half of the exported phosphorus was efficiently purified by different types of land cover via flow accumulation. The pattern of purification and export of highly concentrated phosphorus showed the same trend which occurred in the northern part of the watershed including the Yangzhi River, Fengle River and Hengjiang River. Forestland and grassland did not efficiently purify phosphorus in the watershed owing to the irrational distribution of existing land cover. The total service value was 3.80 and 3.31 million Yuan in 2000 and 2010, respectively.
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Ecosistema , Contaminación Ambiental/prevención & control , Restauración y Remediación Ambiental/economía , Fósforo/análisis , China , Monitoreo del Ambiente , Contaminación Ambiental/economía , Modelos Teóricos , Ríos , Calidad del AguaRESUMEN
OBJECTIVE: To determine the mechanism(s) whereby daily and acute estradiol-17beta (E(2)beta) exposure modifies endothelium-derived nitric oxide synthase (eNOS) and vascular smooth muscle (VSM) neuronal nitric oxide synthase (nNOS) in reproductive and nonreproductive arteries and to localize NOS isoform expression within the vessel wall. METHODS: Oophorectomized nonpregnant ewes received E(2)beta (1 microg/kg per day) or no E(2)beta for 5-6 days or acute E(2)beta (1 microg/kg) on day 6-7 with or without daily E(2)beta. Uterine, mammary, mesenteric, and femoral arteries were collected at completion of each study, adventitia were removed, and samples were frozen and stored at -80C. After separating endothelium and VSM, NOS isoform mRNA was measured using reverse transcription-polymerase chain reaction. VSM nNOS protein was determined by Western analysis. RESULTS: Basal eNOS and nNOS mRNA was greatest (P <.02) in reproductive artery endothelium and VSM, respectively. Daily E(2)beta was required for maximum uterine vascular responses to acute E(2)beta and was associated with increased reproductive artery endothelial eNOS mRNA (>1.5-fold, P <.02) and uterine VSM nNOS mRNA (>2.5-fold, P <.003) and protein (21%, P <.05). Acute E(2)beta in the presence and absence of daily E(2)beta also increased uterine eNOS 68% and 28% (P =.01), respectively, within 90 minutes but did not affect VSM nNOS. Mammary eNOS increased 71% only after E(2)beta withdrawal; VSM nNOS was unchanged. Neither NOS isoform was altered in nonreproductive arteries by daily or acute E(2)beta. CONCLUSIONS: Basal eNOS and nNOS isoform expression is greatest in arteries from reproductive tissues, and isoform responses to E(2)beta are cell specific and transcriptionally regulated. Furthermore, optimal uterine vascular responses to acute E(2)beta exposure require daily E(2)beta exposure that enhances basal NOS expression and abundance.
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Estradiol/farmacología , Músculo Liso Vascular/enzimología , Óxido Nítrico Sintasa/biosíntesis , Ovinos/fisiología , Útero/irrigación sanguínea , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Western Blotting , Endotelio Vascular/enzimología , Endotelio Vascular/fisiología , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Inmunohistoquímica , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo I , Óxido Nítrico Sintasa de Tipo III , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Distribución Aleatoria , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba/efectos de los fármacos , Útero/enzimología , Útero/fisiologíaRESUMEN
The uteroplacental vasculature is refractory to α-adrenergic stimulation, and large conductance Ca(2+)-activated K(+) channels (BK(Ca)) may contribute. We examined the effects of uterine artery (UA) BK(Ca) inhibition with tetraethylammonium (TEA) on hemodynamic responses to phenylephrine (PE) at 101 to 117 days and 135 to 147 days of ovine gestation, obtaining dose responses for mean arterial pressure (MAP), heart rate (HR), and uteroplacental blood flow (UPBF) and vascular resistance (UPVR) before and during UA TEA infusions. The UA α(1)-adrenergic receptors (α1-ARs) were assessed. The PE increased MAP and UPVR and decreased HR and UPBF dose dependently at both gestations (P < .001, analysis of variance). The %âµMAP was less at 135 to 147 days before and during TEA infusions (P ≤ .008); however, responses during TEA were greater (P ≤ .002). The PE increased %âµUPVR>>%âµMAP, thus %âµUPBF fell. The TEA enhanced PE-mediated increases in %âµUPVR at 135 to 147 days (P ≤ .03). The UA α(1)-AR expression was unchanged in pregnancy. Uterine vascular responses to PE exceed systemic vascular responses throughout pregnancy and are attenuated by BK(Ca) activation, suggesting BK(Ca) protect UPBF.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1/farmacología , Hemodinámica/efectos de los fármacos , Canales de Potasio de Gran Conductancia Activados por el Calcio/efectos de los fármacos , Fenilefrina/farmacología , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Útero/irrigación sanguínea , Útero/efectos de los fármacos , Agonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Animales , Presión Arterial/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Edad Gestacional , Frecuencia Cardíaca/efectos de los fármacos , Infusiones Intraarteriales , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Fenilefrina/administración & dosificación , Circulación Placentaria/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Embarazo , Receptores Adrenérgicos alfa 1/metabolismo , Ovinos , Factores de Tiempo , Útero/metabolismo , Resistencia Vascular/efectos de los fármacosRESUMEN
OBJECTIVE: To analyze the expression of angiotensin II (ANG II) receptor and apoptosis in myocardium in rats of endotoxemia. METHODS: Model of endotoxemia was induced by intraperitoneal injection with lipopolysaccharide (LPS) 10 mg/kg in male Wistar rats and saline was injected into control group. The rats were killed at 2 h or 6 h after saline (control) or LPS . Expression of the correlation factors related to apoptosis of Bcl-2, Bax, AT1 and AT2 receptor in myocardial tissue were detected with immunohistochemistry (IHC), and changes of myocardial cells apoptosis was detected by the method of TUNEL. The gene expression of AT1 and AT2 receptor was examined by RT-PCR. The pathological changes of myocardial tissue were observed by electron microscope. RESULTS: Compared with control group , the expression of AT1 and AT2 receptor were significantly decreased, especially in 6 h group; and the expression of Bcl-2 and Bax were decreased, the ratio of Bcl-2/Bax had the downtrend as well as the apoptosis of myocardial cells. CONCLUSION: Interfered by LPS, the down regulation of AT1 and AT2 receptor expression has the negative relation with apoptosis of myocardial cells, this result indicated that down regulation of AT1 and AT2 receptor expression maybe related to cardiac functional impairment, which maybe help us to find a new protective path to prevent myocardial damage induced by systemic inflammatory.
Asunto(s)
Apoptosis , Endotoxemia/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , Animales , Masculino , ARN Mensajero/genética , Ratas , Ratas WistarRESUMEN
BACKGROUND: During pregnancy, uteroplacental responses to norepinephrine (NE) exceed systemic responses. In contrast, uteroplacental responses to angiotensin II (ANG II) are less than systemic. The explanation for these differences in uteroplacental sensitivity remain unclear but may reflect type 2 ANG II receptor (AT(2)R) predominance in uterine artery (UA) vascular smooth muscle (VSM). OBJECTIVE: The objective of the study was to examine VSM sensitivity to KCl, NE, and ANG II in UA from nonpregnant (NP) and pregnant (P) women and determine VSM ANG II receptor subtype expression. METHODS: Responses to KCl, NE, and ANG II were examined in endothelium-denuded UA rings from NP (n = 28) and P (n = 13; 34-40 wk gestation) women, and ANG II receptor subtype, α(1)-receptor and contractile proteins were measured. RESULTS: KCl and NE dose dependently contracted UA (P < 0.001), P exceeding NP 2-fold or greater; but α(1)-receptor expression was unchanged. ANG II did not elicit dose effects in NP or P UA; however, P responses exceeded NP approximately 2-fold (P < 0.001) and were approximately 2.5-fold less than NE (P < 0.001). AT(2)R and AT(1)R expression were similar (P > 0.1) in VSM from NP and term P women. AT(1)R blockade abolished ANG II contractions (P < 0.001); AT(2)R blockade did not enhance ANG II sensitivity in UA with or without endothelium. Actin contents increased approximately 2-fold in term UA. CONCLUSIONS: Sensitivity to α-stimulation exceeds ANG II in NP and P UA, explaining the differential uteroplacental sensitivity in pregnancy. Because AT(2)R predominate in UA VSM throughout reproduction, this contributes to the inherent refractoriness to ANG II in the uterine vasculature. The increase in UA contractile proteins at term P suggests remodeling, explaining the enhanced contractility seen.
Asunto(s)
Angiotensina II/farmacología , Resistencia a Medicamentos/efectos de los fármacos , Norepinefrina/farmacología , Arteria Uterina/efectos de los fármacos , Adulto , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Liso Vascular/irrigación sanguínea , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Embarazo , Receptores de Angiotensina/metabolismo , Útero/irrigación sanguínea , Útero/efectos de los fármacos , Útero/metabolismo , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
OBJECTIVE: To evaluate the prognostic value of chronic kidney disease (CKD) in elderly Chinese patients with chronic heart failure (CHF). METHODS: The study consisted of 327 elderly patients with CHF. All-cause mortality was chosen as an endpoint over the median follow-up period of 345 days. Cox regression analysis was used to identify the risk factors of mortality. RESULTS: The median age of the entire cohort was 85 years (60-100 years). The mortality for 168 elderly patients with CHF and CKD (51.4% of entire cohort) was 39.9% (67 deaths), which was higher than the mortality for CHF patients without CKD [25.2% (40/159 deaths)] and the mortality for entire cohort with CHF [32.7% (107/327 deaths)]. The Cox regression analysis showed that old age [hazard ratio (HR): 1.033; 95% confidence interval (95% CI): 1.004-1.064], CKD (HR: 1.705; 95% CI: 1.132-2.567), CHF New York Heart Association (NYHA) class IV (HR: 1.913; 95% CI: 1.284-2.851), acute myocardial infarction (AMI) (HR: 1.696; 95% CI: 1.036-2.777), elevated resting heart rate (HR: 1.021; 95% CI: 1.009-1.033), and decreased plasma albumin (HR: 0.883; 95% CI: 0.843-0.925) were independent risk factors of mortality for elderly patients with CHF. CONCLUSIONS: CKD was an independent risk factor of mortality for elderly Chinese patients with CHF.
RESUMEN
A new series of monoammonium-based organic electrolytes with the tetrafluoroborate (BF(4)(-)) counteranion have been synthesized. Replacing the pendant ethyl groups in the fluorenyl unit with 4-ethoxyphenyl groups dramatically improves both solubility and morphological stability. The characterization of the alcohol-processable amorphous ionic compounds as an electron-injection layer in organic light-emitting diodes (OLEDs) reveals that the organic electrolyte that comprises a rigid linear-conjugated unit provides better device performance, with respect to its counterpart containing a branched bulky moiety. The capability of these compounds to facilitate electron injection from air-stable aluminum metal is preliminarily discussed on the basis of the investigations of the electron-only devices and photovoltaic experiments.
RESUMEN
In present study, in vivo electrophysiological techniques were applied to examine the effects of anterior cingulate cortex (ACC) activation on mechanical and electrical stimuli-evoked responses in rat spinal cord wide-dynamic-range (WDR) neurons. We found that bilateral ACC electrical stimulation (100Hz, 20V, 20s) had different effects on neuronal responses to brush, pressure and pinch stimuli (10s). The brush-evoked neuronal responses at baseline, post 1min and post 5min were 60.8±15.0, 59.2±15.4 and 60.0±19.3 spikes/10s, respectively (n=10, P>0.05 vs. baseline). The pressure-evoked neuronal responses at baseline, post 1min and post 5min were 77.8±11.9, 38.0±7.8 and 45.8±7.6 spikes/10s, respectively (n=10, P<0.05 vs. baseline). The pinch-evoked neuronal responses at baseline, post 1min and post 5min were 137.6±16.7, 62.6±17.5 and 68.8±15.0 spikes/10s, respectively (n=10, P<0.05 vs. baseline). Furthermore, ACC stimulation generated distinct effects on the different components of wind-up response. The total numbers of late response (LR) and after-discharge (AD), but not early response (ER), significantly decreased. Collectively, the present study demonstrated that short-term ACC activation could generate long-term inhibitory effects on the responses of WDR neurons to noxious mechanical (pressure and pinch) and electrical stimuli. The results indicated that ACC activation could negatively regulate noxious information ascending from spinal cord with long-term effect, providing potential neuronal substrate for the modulation of ACC activation on nociception.
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Giro del Cíngulo/fisiología , Neuronas/fisiología , Médula Espinal/fisiología , Animales , Masculino , Nociceptores/fisiología , Estimulación Física , Ratas , Ratas Sprague-DawleyRESUMEN
The biological properties of cultured mesenchymal stem cells (MSC) have been intensively investigated, while there is still a paucity of information about the definite in vivo sites that harbor these stem cells due to the lack of specific surface markers. Previous data have demonstrated that human and murine MSC can be isolated from the compact bones. To investigate if it is the case for other species, the femurs from Wistar rats, Beagles, C57 mice and New Zealand rabbits were collected, minced and digested with collagenase type I. The digested bone fragments were seeded into the medium for human bone marrow culture after removal of the suspended cells in the digestion. The results showed that the fibroblast-like cells were observed to migrate from the bone fragments after several days of culture, and they gradually formed an adherent confluent layer. The adherent cells could be passaged and expressed homogenously the mesenchymal cell marker vimentin. Differentiation assays showed that these cells had the capacity to differentiate into osteoblasts and adipocytes. In conclusion, the results here provide new information for the further investigations on the in vivo biological features of MSC in the context of the simplicity of the compact bone structure.
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Huesos/citología , Células Madre Mesenquimatosas/citología , Animales , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Perros , Ratones , Ratones Endogámicos C57BL , Conejos , Ratas , Ratas WistarRESUMEN
Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, Ca(2+)-activated K(+) channels (BK(Ca)), consisting of alpha- and regulatory beta-subunits, are expressed in uterine vascular smooth muscle (UVSM) and contribute to the maintenance of UPBF in the last third of ovine pregnancy, but their expression pattern and activation pathways are unclear. We examined BK(Ca) subunit expression, the cGMP-dependent signaling pathway, and the functional role of BK(Ca) in uterine arteries (UA) from nonpregnant (n = 7), pregnant (n = 38; 56-145 days gestation; term, approximately 150 days), and postpartum (n = 15; 2-56 days) sheep. The alpha-subunit protein switched from 83-87 and 105 kDa forms in nonpregnant UVSM to 100 kDa throughout pregnancy, reversal occurring >30 days postpartum. The 39-kDa beta(1)-subunit was the primary regulatory subunit. Levels of 100-kDa alpha-subunit rose approximately 70% during placentation (P < 0.05) and were unchanged in the last two-thirds of pregnancy; in contrast, beta(1)-protein rose throughout pregnancy (R(2) = 0.996; P < 0.001; n = 13), increasing 50% during placentation and approximately twofold in the remainder of gestation. Although UVSM soluble guanylyl cyclase was unchanged, cGMP and protein kinase G(1alpha) increased (P < 0.02), paralleling the rise and fall in beta(1)-protein during pregnancy and the puerperium. BK(Ca) inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced alpha-agonist-induced vasoconstriction. UVSM BK(Ca) modify relaxation-contraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in alpha-subunit composition, alpha:beta(1)-subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BK(Ca) activation via NO-cGMP and beta(1) augmentation may contribute to the regulation of UPBF.