Endothelial Dysfunction in Primary Aldosteronism Chen, Zheng-Wei; Tsai, Cheng-Hsuan; Pan, Chien-Ting ...
International journal of molecular sciences,
10/2019, Letnik:
20, Številka:
20
Journal Article
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Primary aldosteronism (PA) is characterized by excess production of aldosterone from the adrenal glands and is the most common and treatable cause of secondary hypertension. Aldosterone is a ...mineralocorticoid hormone that participates in the regulation of electrolyte balance, blood pressure, and tissue remodeling. The excess of aldosterone caused by PA results in an increase in cardiovascular and cerebrovascular complications, including coronary artery disease, myocardial infarction, stroke, transient ischemic attack, and even arrhythmia and heart failure. Endothelial dysfunction is a well-established fundamental cause of cardiovascular diseases and also a predictor of worse clinical outcomes. Accumulating evidence indicates that aldosterone plays an important role in the initiation and progression of endothelial dysfunction. Several mechanisms have been shown to contribute to aldosterone-induced endothelial dysfunction, including aldosterone-mediated vascular tone dysfunction, aldosterone- and endothelium-mediated vascular inflammation, aldosterone-related atherosclerosis, and vascular remodeling. These mechanisms are activated by aldosterone through genomic and nongenomic pathways in mineralocorticoid receptor-dependent and independent manners. In addition, other cells have also been shown to participate in these mechanisms. The complex interactions among endothelium, inflammatory cells, vascular smooth muscle cells and fibroblasts are crucial for aldosterone-mediated endothelial dysregulation. In this review, we discuss the association between aldosterone and endothelial function and the complex mechanisms from a molecular aspect. Furthermore, we also review current clinical research of endothelial dysfunction in patients with PA.
We employ Nafion‐mixed carbon dots (CDs) and low‐cost screen‐printed carbon electrodes (SPCEs) as foundation matrices for the fabrication of electrochemical biosensors. The NH2 and COOH functional ...groups present on the SPCE surface after Nafion/CDs deposition allow for pyrophosphate ions (PPis) collection. Using Fe(CN)63− as the electrochemical mediator, the SPCE‐Nafion/CDs are applied to the detection of aqueous PPi by square wave voltammetry. Between 50 and 1 μM, a linear connection is established between the square wave voltammetry current and the PPi concentration. The limit of detection is determined to be 1.01 μM, and recoveries of 113% (±1.9%) and 108% (±3.9%) are achieved for human urine samples spiked with 6 and 3 μM of PPi, respectively. Furthermore, this PPi assay is suitable for the usage of complicated urine matrices without the inclusion of heavy metals. We anticipate that this unique approach will be beneficial for PPi level monitoring in urine during therapeutic treatments of illnesses and malignancies.
An electrochemical biosensor integrating Nafion‐mixed carbon dots and screen‐printed carbon electrodes for pyrophosphate ion detection is presented. A linear connection is established between the square wave voltammetry current and the pyrophosphate ion concentration between 50 and 1 μM, and the limit of detection is determined to be 1.01 μM. This assay is suitable for the usage of complicated urine matrices without the inclusion of heavy metals, making it practical for clinical monitoring.
Abstract
The escape of bladder cancer from immunosurveillance causes monotherapy to exhibit poor efficacy; therefore, designing a multifunctional nanoparticle that boosts programmed cell death and ...immunoactivation has potential as a treatment strategy. Herein, we developed a facile one-pot coprecipitation reaction to fabricate cluster-structured nanoparticles (CNPs) assembled from Fe
3
O
4
and iron chlorophyll (Chl/Fe) photosensitizers. This nanoassembled CNP, as a multifunctional theranostic agent, could perform red-NIR fluorescence and change the redox balance by the photoinduction of reactive oxygen species (ROS) and attenuate iron-mediated lipid peroxidation by the induction of a Fenton-like reaction. The intravesical instillation of Fe
3
O
4
@Chl/Fe CNPs modified with 4-carboxyphenylboronic acid (CPBA) may target the BC wall through glycoproteins in the BC cavity, allowing local killing of cancer cells by photodynamic therapy (PDT)-induced singlet oxygen and causing chemodynamic therapy (CDT)-mediated ferroptosis. An interesting possibility is reprogramming of the tumor microenvironment from immunosuppressive to immunostimulatory after PDT-CDT treatment, which was demonstrated by the reduction of PD-L1 (lower “off” signal to the effector immune cells), IDO-1, TGF-β, and M2-like macrophages and the induction of CD8
+
T cells on BC sections. Moreover, the intravesical instillation of Fe
3
O
4
@Chl/Fe CNPs may enhance the large-area distribution on the BC wall, improving antitumor efficacy and increasing survival rates from 0 to 91.7%. Our theranostic CNPs not only demonstrated combined PDT-CDT-induced cytotoxicity, ROS production, and ferroptosis to facilitate treatment efficacy but also opened up new horizons for eliminating the immunosuppressive effect by simultaneous PDT-CDT.
MicroRNAs (miRNAs), which are inhibitors of gene expression, participate in diverse biological functions and in carcinogenesis. In this study, we show that liver‐specific microRNA‐122 (miR‐122) is ...significantly down‐regulated in liver cancers with intrahepatic metastastasis and negatively regulates tumorigenesis. Restoration of miR‐122 in metastatic Mahlavu and SK‐HEP‐1 cells significantly reduced in vitro migration, invasion, and anchorage‐independent growth as well as in vivo tumorigenesis, angiogenesis, and intrahepatic metastasis in an orthotopic liver cancer model. Because an inverse expression pattern is often present between an miRNA and its target genes, we used a computational approach and identified multiple miR‐122 candidate target genes from two independent expression microarray datasets. Thirty‐two target genes were empirically verified, and this group of genes was enriched with genes regulating cell movement, cell morphology, cell‐cell signaling, and transcription. We further showed that one of the miR‐122 targets, ADAM17 (a disintegrin and metalloprotease 17) is involved in metastasis. Silencing of ADAM17 resulted in a dramatic reduction of in vitro migration, invasion, in vivo tumorigenesis, angiogenesis, and local invasion in the livers of nude mice, which is similar to that which occurs with the restoration of miR‐122. Conclusion: Our study suggests that miR‐122, a tumor suppressor microRNA affecting hepatocellular carcinoma intrahepatic metastasis by angiogenesis suppression, exerts some of its action via regulation of ADAM17. Restoration of miR‐122 has a far‐reaching effect on the cell. Using the concomitant down‐regulation of its targets, including ADAM17, a rational therapeutic strategy based on miR‐122 may prove to be beneficial for patients with hepatocellular carcinoma. (HEPATOLOGY 2009.)
Objective
Appropriate triage in patients presenting to the emergency department (ED) is often challenging. Little is known about the role of physician gestalt in ED triage. We aimed to compare the ...accuracy of emergency physician gestalt against the currently used computerized triage process.
Methods
We conducted a prospective observational study in the ED at an academic medical center. Adult patients aged ≥20 years were included and underwent a standard triage protocol. The patients underwent system‐based triage using the computerized software the Taiwan Triage and Acuity Scale. The entire triage process was recorded, and triage data were collected. Five physician raters provided triage levels (physician‐based) according to their perceived urgency after reviewing videos. The primary outcome was hospital admission. The secondary outcomes were ED length of stay (EDLOS) and charges.
Results
In total, 656 patients were recruited (mean age 52 years, 50% male). The median system‐based triage level was 3. By contrast, the median physician‐based triage level was 4. The physician raters tended to provide lower triage levels than the system, with an average difference of 1. There was modest concordance between the two triage methods (correlation coefficient 0.30), with a weighted kappa coefficient of 0.18. The area under the receiver operating curve for the system‐ and physician‐based triage in predicting hospital admission were similar (0.635 vs. 0.631, p = 0.896). Attending physicians appeared to have better performance than residents in predicting admission. The variation explained (R2) in EDLOS and charges were similar between the two triage methods (R2 = 3% for EDLOS, 7%–9% for charges).
Conclusions
Emergency physician gestalt for triage showed similar performance to a computerized system; however, physicians redistributed patients to lower triage levels. Physician gestalt has advantages for identifying low‐risk patients. This approach may avoid undue time pressure for health care providers and promote rapid discharge.
Speech separation, sometimes known as the “cocktail party problem”, is the process of separating individual speech signals from an audio mixture that includes ambient noises and several speakers. The ...goal is to extract the target speech in this complicated sound scenario and either make it easier to understand or increase its quality so that it may be used in subsequent processing. Speech separation on overlapping audio data is important for many speech-processing tasks, including natural language processing, automatic speech recognition, and intelligent personal assistants. New speech separation algorithms are often built on a deep neural network (DNN) structure, which seeks to learn the complex relationship between the speech mixture and any specific speech source of interest. DNN-based speech separation algorithms outperform conventional statistics-based methods, although they typically need a lot of processing and/or a larger model size. This study presents a new end-to-end speech separation network called ESC-MASD-Net (effective speaker separation through convolutional multi-view attention and SuDoRM-RF network), which has relatively fewer model parameters compared with the state-of-the-art speech separation architectures. The network is partly inspired by the SuDoRM-RF++ network, which uses multiple time-resolution features with downsampling and resampling for effective speech separation. ESC-MASD-Net incorporates the multi-view attention and residual conformer modules into SuDoRM-RF++. Additionally, the U-Convolutional block in ESC-MASD-Net is refined with a conformer layer. Experiments conducted on the WHAM! dataset show that ESC-MASD-Net outperforms SuDoRM-RF++ significantly in the SI-SDRi metric. Furthermore, the use of the conformer layer has also improved the performance of ESC-MASD-Net.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Context
Primary aldosteronism (PA) patients have a higher degree of arterial stiffness, which can be reversed after adrenalectomy.
Objective
We aimed to compare the reversal of arterial ...stiffness between surgically and medically treated PA patients and to identify the predictors of effective medical treatment.
Methods
We prospectively enrolled 445 PA patients and collected data on baseline clinical characteristics, biochemistry, blood pressure, and pulse wave velocity (PWV) before treatment and 12 months after treatment. In the mineralocorticoid receptor antagonist (MRA)-treated patients, the relationship between the change in PWV after 1 year (ΔPWV) and posttreatment renin activity was explored using the restricted cubic spline (RCS) method.
Results
Of the 445 enrolled PA patients, 255 received adrenalectomy (group 1) and 190 received MRAs. In the RCS model, posttreatment plasma renin activity (PRA) 1.5 ng/mL/h was the best cutoff value. Therefore, we divided the MRA-treated patients into 2 groups: those with suppressed PRA (< 1.5 ng/mL/h, group 2), and those with unsuppressed PRA (≥ 1.5 ng/mL/h, group 3). Only group 1 and group 3 patients had a statistically significant improvement in PWV after treatment (both P < .001), whereas no significant improvement was noted in group 2 after treatment (P = .151). In analysis of variance and post hoc analysis, group 2 had a significantly lower ΔPWV than group 1 (P = .007) and group 3 (P = .031). Multivariable regression analysis of the MRA-treated PA patients identified log-transformed posttreatment PRA, age, and baseline PWV as independent factors correlated with ΔPWV.
Conclusion
The reversal of arterial stiffness was found in PA patients receiving adrenalectomy and in medically treated PA patients with unsuppressed PRA.
Aflatoxins are carcinogenic secondary metabolites of fungi that contaminate many staple crops and foods. Aflatoxin contamination is a worldwide problem, especially in developing countries, posing ...health hazards, e.g., causing aflatoxicosis and hepatocellular carcinoma, and even death. Biological solutions for aflatoxin detoxification are environmentally friendly and a cheaper alternative than chemical methods. The aims of the current study were to investigate: (1) the ability of MSMEG_5998, an aflatoxin-degrading F420H2-dependent reductase from Mycobacterium smegmatis, to degrade aflatoxin B1 (AFB1) and reduce AFB1-caused damage in HepG2 cell culture model; and (2) whether a thioredoxin (Trx) linkage of MSMEG_5998 enhanced the enzyme activity. We show that Trx-linked MSMEG_5998 degraded 63% AFB1 and native MSMEG_5998 degraded 31% after 4 h at 22 °C, indicating that the Trx-linked enzyme had a better AFB1-degrading ability. In a HepG2 cell culture model, Trx-linked MSMEG_5998 reduced DNA damage and p53-mediated apoptosis caused by AFB1 to a greater extent than the native enzyme. These findings suggest that Trx-linked MSMEG_5998 could potentially be developed to protect the liver from AFB1 damage, or as a candidate protein to reduce AFB1-related toxicity in animals.
Excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR) is believed to be a primary mechanism of neuronal injury following stroke. Thus, many drugs and therapeutic peptides were ...developed to inhibit either the NMDAR at the cell surface or its downstream intracellular death-signaling cascades. Nevertheless, the majority of focal ischemia studies concerning NMDAR antagonism were performed using the intraluminal suture-induced middle cerebral arterial occlusion (MCAO) model, which produces a large cortical and subcortical infarct leading to hypothalamic damage and fever in experimental animals. Here, we investigated whether NMDAR antagonism by drugs and therapeutic peptides was neuroprotective in a mouse model of distal MCAO (dMCAO), which produces a small cortical infarct sparing the hypothalamus and other subcortical structures. For establishment of this model, mice were subjected to dMCAO under normothermic conditions or body-temperature manipulations, and in the former case, their brains were collected at 3-72 h post-ischemia to follow the infarct development. These mice developed cortical infarction 6 h post-ischemia, which matured by 24-48 h post-ischemia. Consistent with the hypothesis that the delayed infarction in this model can be alleviated by neuroprotective interventions, hypothermia strongly protected the mouse brain against cerebral infarction in this model. To evaluate the therapeutic efficacy of NMDAR antagonism in this model, we treated the mice with MK801, Tat-NR2B9c, and L-JNKI-1 at doses that were neuroprotective in the MCAO model, and 30 min later, they were subjected to 120 min of dMCAO either in the awake state or under anesthesia with normothermic controls. Nevertheless, NMDAR antagonism, despite exerting pharmacological effects on mouse behavior, repeatedly failed to show neuroprotection against cerebral infarction in this model. The lack of efficacy of these treatments is reminiscent of the recurrent failure of NMDAR antagonism in clinical trials. While our data do not exclude the possibility that these treatments could be effective at a different dose or treatment regimen, they emphasize the need to test drug efficacy in different stroke models before optimal doses and treatment regimens can be selected for clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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