The Angiotensin II Receptor Neprilysin Inhibitor LCZ696 Inhibits the NLRP3 Inflammasome By Reducing Mitochondrial Dysfunction in Macrophages and Alleviates Dextran Sulfate Sodium-induced Colitis in a Mouse Model.

The intracellular sensor protein complex known as the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in regulating inflammatory diseases by overseeing the production of interleukin (IL)-1ß and IL-18. Targeting its abnormal activation with drugs holds significant promise for inflammation treatment. This study highlights LCZ696, an angiotensin receptor-neprilysin inhibitor, as an effective suppressor of NLRP3 inflammasome activation in macrophages stimulated by ATP, nigericin, and monosodium urate. LCZ696 also reduces caspase-11 and GSDMD activation, lactate dehydrogenase release, propidium iodide uptake, and the extracellular release of NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in ATP-activated macrophages, suggesting a potential mitigation of pyroptosis. Mechanistically, LCZ696 lowers mitochondrial reactive oxygen species and preserves mitochondrial integrity. Importantly, it does not significantly impact NLRP3, proIL-1ß, inducible nitric oxide synthase, cyclooxygenase-2 expression, or NF-κB activation in lipopolysaccharide-activated macrophages. LCZ696 partially inhibits the NLRP3 inflammasome through the induction of autophagy. In an in vivo context, LCZ696 alleviates NLRP3-associated colitis in a mouse model by reducing colonic expression of IL-1ß and tumor necrosis factor-α. Collectively, these findings suggest that LCZ696 holds significant promise as a therapeutic agent for ameliorating NLRP3 inflammasome activation in various inflammatory diseases, extending beyond its established use in hypertension and heart failure treatment.

The Best Strategy for the Black Hole Phenomenon between Intravascular Ultrasound and Optical Coherence Tomography.

The black hole (BH) phenomenon is an intraluminal restenotic lesion. It was identified by intravascular ultrasound (IVUS) and optical coherence tomography (OCT) after intracoronary brachytherapy and drug-eluting stent implantation. Despite the similarity in the mode of action of brachytherapy and drug-eluting stent implantation, the BH phenomenon appears to be uncommon after drug-eluting stent implantation. Specifically, the BH phenomenon is better identified by OCT than by IVUS. Herein, we present a case of in-stent restenosis with suspected BH phenomenon on IVUS and confirmed by OCT.

Surfactin Containing Bacillus licheniformis-Fermented Products Alleviate Dextran Sulfate Sodium-Induced Colitis by Inhibiting Colonic Inflammation and the NLRP3 Inflammasome in Mice.

Inflammatory bowel disease (IBD) is a non-infectious disease characterized by chronic inflammation of the gastrointestinal tract. Currently, management of IBD is still a clinical challenge. The purpose of this study was to investigate the therapeutic potential of surfactin containing Bacillus licheniformis-fermented products (SBLF) and commercial surfactin (CS) on the treatment of dextran sulfate sodium (DSS)-induced colitis in a mouse model. We found that mice that received drinking water containing 3% DSS developed significant colitis symptoms, including increased disease activity index, body weight loss, shortening of the colon length, splenomegaly, colonic inflammation and colonic NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. Notably, orally received SBLF, CS or clinical anti-inflammatory drug 5-aminosalicylic acid improved DSS-induced colitis symptoms in mice. These findings show that SBLF can improve IBD in mice by reducing colonic inflammation and inhibiting the NLRP3 inflammasome activation, suggesting that SBLF has the potential to be used as a nutraceutical in humans or a feed additive in economic and companion animals for preventing IBD.

Profiles of Hospitalized Patients with Angiographic Coronary Heart Disease in Taiwan during 2014-2016: Report of a Tertiary Hospital.

BACKGROUND: The Taiwan Society of Cardiology (TSOC) has established multicenter registries for coronary artery disease (CAD) to investigate clinical characteristics, management and risks for mortality. However, the impacts of newly-emerged evidence-based therapies, including the use of drug-eluting stents (DESs), on patients with CAD in Taiwan remain unclear. METHODS: The Tri-Service General Hospital-Coronary Heart Disease (TSGH-CHD) registry is a single-center, prospective, longitudinal registry in Taiwan containing data from 2014-2016. Individuals who were admitted for coronary angiography were enrolled. Patient profiles, management and in-hospital outcome data were collected. RESULTS: We included 3352 patients: 2349 with stable angina and 1003 with acute coronary syndrome (ACS). In the stable angina group, both patients receiving stenting and those receiving medical treatment had a 0.7% mortality rate; DESs were used in 70.4% of the patients receiving stenting. In the ACS group, the patients receiving stenting and those receiving medical treatment had a 4.9% and 10.7% mortality rate, respectively; DESs were used in 63.1% of the patients receiving stenting. In the 2008-2010 Taiwan ACS registry, DESs were used in only 28% of all stenting procedures, and the estimated hospital mortality rate was 1.8%. Multivariate analysis indicated that older age, prior stroke, and cardiogenic shock on admission were associated with an increased risk of in-hospital mortality in the ACS group. CONCLUSIONS: Compared with the Taiwan ACS cohort, the TSGH-CHD registry revealed increased DES use and increased disease complexity and severity after 2010. Although unlikely to significantly improve survival, interventionists seemed to perform high-risk procedures for complex CAD more often in the new DES era.

miR-548aq-3p is a novel target of Far infrared radiation which predicts coronary artery disease endothelial colony forming cell responsiveness.

Non-invasive far infrared radiation (FIR) has been observed to improve the health of patients with coronary artery disease (CAD). Endothelial colony forming cells (ECFCs) contribute to vascular repair and CAD. The goal of this study was to uncover the role of FIR in ECFCs function and to reveal potential biomarkers for indication of FIR therapy in CAD patients. FIR significantly enhanced in vitro migration (transwell assay) and tube formation (tube length) capacities in a subpopulation of CAD ECFCs. Clinical parameters associated with the responsiveness of ECFCs to FIR include smoking and gender. ECFCs from CAD patients that smoke did not respond to FIR in most cases. In contrast, ECFCs from females showed a higher responsiveness to FIR than ECFCs from males. To decipher the molecular mechanisms by which FIR modulates ECFCs functions, regardless of sex, RNA sequencing analysis was performed in both genders of FIR-responsive and FIR-non/unresponsive ECFCs. Gene Ontology (GO) analysis of FIR up-regulated genes indicated that the pathways enriched in FIR-responsive ECFCs were involved in cell viability, angiogenesis and transcription. Small RNA sequencing illustrated 18 and 14 miRNAs that are up- and down-regulated, respectively, in FIR-responsive CAD ECFCs in both genders. Among the top 5 up- and down-regulated miRNAs, down-regulation of miR-548aq-3p in CAD ECFCs after FIR treatment was observed in FIR-responsive CAD ECFCs by RT-qPCR. Down-regulation of miR-548aq-3p was correlated with the tube formation activity of CAD ECFCs enhanced by FIR. After establishment of the down-regulation of miR-548aq-3p by FIR in CAD ECFCs, we demonstrated through overexpression and knockdown experiments that miR-548aq-3p contributes to the inhibition of the tube formation of ECFCs. This study suggests the down-regulation of miR-548aq-3p by FIR may contribute to the improvement of ECFCs function, and represents a novel biomarker for therapeutic usage of FIR in CAD patients.

Review of the accuracy of multi-parametric MRI prostate in detecting prostate cancer within a local reporting service.

INTRODUCTION: Multi-parametric magnetic resonance imaging of the prostate is crucial in detecting prostate cancer (CaP) and staging local disease. The Prostate Imaging Reporting and Data System (PIRADS) scoring system is used to assess and classify lesions and enables communication between clinicians and radiologists. This study aimed to assess the accuracy of PIRADSv2 in detecting CaP using histopathology specimens within our local service. METHODS: This retrospective study included 192 patients between September 2016 and May 2019. All had mpMRI prostate examinations prior to biopsy or prostatectomy. Lesions on MRI were assigned a PIRADS score and comparison made with histopathology results. Gleason score ≥7 was considered as clinically significant prostate cancer (csCaP). We calculated accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detecting all CaP and csCaP. RESULTS: In the PIRADS 3 group, 32% were Gleason 6 and 32% were Gleason 7 lesions. In the PIRADS 4 group, 37% were Gleason 6 and 41% were Gleason ≥7. For PIRADS 5 lesions, 32% were Gleason 6 and 68% were Gleason ≥7. For all CaP, sensitivity was 84.7%, specificity 54.6%, PPV 82.3% and NPV 58.8%. For csCaP Gleason ≥7, PIRADS cut-off ≥3 had sensitivity, specificity, PPV and NPV of 95.7%, 39.3%, 47.5% and 94.1%, respectively, and cut-off ≥4 had sensitivity, specificity, PPV and NPV of 84.3%, 53.3%, 50.9% and 85.5%. CONCLUSIONS: This study confirms PIRADS has high accuracy, sensitivity and NPV for detecting all CaP and csCaP. A high NPV may obviate need for biopsy in low-risk patients.

Ginkgo biloba Induces Thrombomodulin Expression and Tissue-Type Plasminogen Activator Secretion via the Activation of Krüppel-Like Factor 2 within Endothelial Cells.

The effects of thrombo-prevention, such as antiplatelet and anticoagulant activity, have been reported with the usage of Ginkgo biloba extract (GbE); however, the detailed mechanism has not yet been fully investigated, especially the role of Krüppel-like factor 2 (KLF2). This study aimed to investigate whether GbE can activate KLF2 and then induce thrombomodulin (TM) and tissue-type plasminogen activator (t-PA) secretion to enhance the effects of thrombo-prevention. Different concentrations of GbE were incubated with human umbilical vein endothelial cells (HUVECs) to evaluate its effect on endothelial cells. We found that KLF2 expression is correlated to the risk of atherosclerosis and venous thromboembolism in clinical practice. In the HUVEC cell model, GbE stimulated the expression of KLF2 in a dose-dependent manner. Moreover, TM and t-PA secretion increased when the cells were cultured with GbE. Both the expressions and activities of TM and t-PA in the GbE-treated cells declined after KLF2 was blocked by shKLF2. In sum, with GbE treatment, KLF2 expression in human endothelial cells was significantly activated, which in turn induced an increase in the protein expression and activity of TM and t-PA. After shRNA inhibited the KLF2 expression, GbE stopped inducing the expression and activity of TM and t-PA. These findings suggest that GbE exerts an antithrombotic effect on endothelial cells by increasing the TM expression and t-PA secretion; further, KLF2 is a key factor in this mechanism.

Large Non-enhancing Breast Cancer on Breast Magnetic Resonance Imaging: A Case Report.

A 55-year-old female presented with vague symptoms in the lateral left breast. Digital breast tomosynthesis and breast ultrasound showed no focal lesion, and magnetic resonance imaging (MRI) was subsequently performed. No suspicious enhancement was seen on MRI; in particular, no suspicious lesion was seen in the area of clinical concern. In view of persisting focal mastalgia and vague parenchymal changes in the symptomatic area on repeat targeted ultrasound, a core biopsy was performed. Final pathology after left mastectomy with axillary clearance showed a 42 mm grade 2 invasive ductal carcinoma. Ten out of 15 lymph nodes contained metastatic carcinoma. This case report presents a large ductal breast cancer with no enhancement on breast MRI. Factors that may contribute to the non-detection of breast cancers on MRI studies will be discussed.

Effects of Asymmetric Local Joule Heating on Silicon Nanowire-Based Devices Formed by Dielectrophoresis Alignment Across Pt Electrodes.

We demonstrate the fabrication and characterization of silicon nanowire-based devices in metal-nanowire-metal configuration using direct current dielectrophoresis. The current-voltage characteristics of the devices were found rectifying, and their direction of rectification could be determined by voltage sweep direction due to the asymmetric Joule heating effect that occurred in the electrical measurement process. The photosensing properties of the rectifying devices were investigated. It reveals that when the rectifying device was in reverse-biased mode, the excellent photoresponse was achieved due to the strong built-in electric field at the junction interface. It is expected that rectifying silicon nanowire-based devices through this novel and facile method can be potentially applied to other applications such as logic gates and sensors.

Clinical Characteristics of Patients Less than Forty Years Old with Coronary Artery Disease in Taiwan: A Cross-Sectional Study.

BACKGROUND: Coronary artery disease (CAD) rarely occurs in young adults. Our objective was to investigate the baseline characteristics and outcomes of young patients with CAD. METHODS: We retrospectively enrolled patients aged < 40 years of age who underwent coronary angiography in a tertiary hospital in Taiwan between 2002 and 2015. The baseline characteristics and in-hospital outcomes of patients with acute coronary syndrome (ACS) and occlusive CAD (stenotic lesions > 50%) were compared with those of patients without ACS and non-occlusive CAD, respectively. RESULTS: We enrolled 245 young patients including 131 (53.5%) with ACS and 178 with occlusive CAD. The median age of the patients was 36.08 years and the mean follow-up period was 4.84 years. Of all study subjects, 220 (89.8%) were men and 140 (57.1%) were current smokers; there was an overall in-hospital mortality rate of 3.3%. Furthermore, age, body mass index, smoking, total leukocyte count, neutrophil-to-lymphocyte ratio, total cholesterol, and low-density lipoprotein were higher in patients with ACS and significant CAD than in those without ACS and nonstenotic CAD. Interestingly, triglyceride (TG) levels and the TG to high-density lipoprotein ratio were significantly higher in patients with ACS and occlusive CAD than in those without ACS and non-occlusive CAD. Logistic regression analysis revealed that smoking is an independent predictor of ACS and occlusive CAD. CONCLUSIONS: Our findings suggest that classical risk factors, obesity, and inflammation remain potent contributors to occlusive CAD and ACS in young adults in Taiwan. Efforts to prevent or minimize these risk factors, such as smoking cessation and aggressive lipid control, are necessary in young adults.

Recurrence and metastasis of pheochromocytoma mimic acute ST-segment elevation myocardial infarction: a case report.

Pheochromocytomas are cathecholamine-secreting tumor and may present with numerous of general symptoms, such as hypertension,pallor, headache tachycardia, chest pain, and cold sweating. Cardiac manifestations include typical angina, electrocardiographic change, and elevated cardiac biomarker. Transient systolic dysfunction of the left ventricle sometimes may happen with, the worst, heart failure and cardiogenic shock, in a similar manner of apical ballooning syndrome (Tokotsubo or stress cardiomyopathy) and mimics ST-segment elevation myocardial infarction. Here,we presented a case with past medical record of pheochromocytoma status postsuccessful surgical adrenalectomy many years ago, and she came to the emergency department with angina symptom. As first presentation of acute coronary syndrome via symptoms, electrocardiographic change, and elevated cardiac biomarkers,she underwent coronary angiography. No significant coronary occlusion but regional wall motion abnormality was found. However, a big adrenal mass in the left abdomen and multiple hepatic radiolucent lesions were detected accidentally by the meanwhile computed tomography that supposed to rule out the acute aortic syndrome.Recurrent pheochromocytoma with cathecholamine-related stress cardiomyopathy was confirmed thereafter.

Activation of Krüppel-Like Factor 2 with Ginkgo Biloba Extract Induces eNOS Expression and Increases NO Production in Cultured Human Umbilical Endothelial Cells.

BACKGROUND: The mechanisms responsible for the effects of Ginkgo biloba extract (GbE) are not fully understood. Krüppel-like factor 2 (KLF2), a zinc transcription factor, has vasculoprotective effects if activated. The present study attempted to explore whether GbE may activate KLF2 and its consequences. METHODS: To determine the effects of GbE on endothelial cells, human umbilical vein endothelial cells (HUVECs) were incubated with various concentrations of GbE. KLF2 expression levels were determined by quantitative reverse transcription polymerase chain reaction. Cytoskeleton staining and cell migration assays were performed to determine the effects of KLF2 activation. Moreover, endothelial NO synthase (eNOS) expression levels were detected by PCR and Western blot testing. Nitric oxide (NO) production was also measured with 4,5-diaminofluorescein. A knockdown of KLF2 was performed to identify the role of KLF2 in GbE-induced eNOS expression and NO production. RESULTS: HUVECs that were incubated with GbE increased KLF2 expression. These cells demonstrated an altered cell morphology, cytoskeleton rearrangement, and inhibited migration activity. Moreover, eNOS expression and NO production increased in a dose-dependent manner when cells were treated with GbE. Correspondingly, silencing of KLF2 in HUVECs decreased eNOS expression and NO production in GbE-treated cells. CONCLUSIONS: GbE significantly activated KLF2 expression and KLF2-related endothelial function, including cytoskeleton rearrangement, inhibition of migration, eNOS activation, and NO production. These findings suggest that GbE may induce a vasculoprotective effect in endothelial cells. KEY WORDS: Endothelial cells; eNOS; Ginkgo biloba extract; KLF2; NO.