Macrophage KLF15 prevents foam cell formation and atherosclerosis via transcriptional suppression of OLR-1.

BACKGROUND: Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis. METHODS: We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE-/-- mice on a HFD. We subsequently injected mice with AAV-KLF15 and AAV-LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively. RESULTS: We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis. CONCLUSION: Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis.

Prevalence, contemporary trends and associated factors of potentially inappropriate prescription of edoxaban in real-world clinical practice: A subanalysis of the SUNSHINE registry.

AIM: As the direct oral anticoagulant most recently approved in China, data pertaining to clinical edoxaban use are still scarce. This study investigated the prevalence of and contemporary trends in edoxaban prescription among Chinese patients as well as factors associated with its inappropriate use in a multicentre registry of patients treated in real-world clinical practice. METHODS: This real-world, prospective, multicentre and non-interventional study included 1005 inpatients treated with edoxaban. According to National Medical Products Administration and European Heart Rhythm Association guidelines, edoxaban therapy was determined to be appropriate or inappropriate in each case. RESULTS: The median patient age was 70.0 years (interquartile range 61.0-78.0 years) and 46.3% were women. Overall, 456 (45.4%) patients received inappropriate edoxaban therapy, and common issues included an inappropriately low dosage (183, 18.2%) or wrong drug selection (109, 10.8%), high dosage (73, 7.3%), unreasonable off-label use (49, 4.9%), contraindicated medication combinations (27, 2.7%) and incorrect administration timing (16, 1.6%). Several factors, such as age ≥75 years (odds ratio [OR] = 1.921, 95% confidence interval [CI] 1.355-2.723, P < 0.001), weight >60 kg (OR = 2.657, 95%CI 1.970-3.583, P < 0.001), severe renal insufficiency (OR = 1.988, 95% CI 1.043-3.790, P = 0.037), current anaemia (OR = 1.556, 95% CI 1.151-2.102, P = 0.004) and history of bleeding (OR = 2.931, 95% CI 1.605-5.351, P < 0.001) were associated with an increased risk of inappropriate edoxaban therapy, whereas factors associated with cardiovascular specialties, such as admission to a cardiovascular department (OR = 0.637, 95% CI 0.464-0.873, P = 0.005), dronedarone use (OR = 0.065, 95% CI 0.026-0.165, P < 0.001) and amiodarone use (OR = 0.365, 95% CI 0.209-0.637, P < 0.001) decreased this risk. CONCLUSION: In this real-world study, 45.4% of patients received an inappropriate treatment with edoxaban. Multiple clinical characteristics can help identify patients who should receive edoxaban. Further development and implantation of educational activities and management strategies are needed to ensure the correct use of edoxaban.

Simultaneous Determination of 108 Pesticide Residues in Three Traditional Chinese Medicines Using a Modified QuEChERS Mixed Sample Preparation Method and HPLC-MS/MS.

A rapid, efficient, simple, and high-throughput method for the simultaneous determination of 108 pesticide residues in three traditional Chinese medicines (TCMs) was established, comprising an improved QuEChERS method in combination with HPLC-MS/MS based on mixed samples. A quantity of 10 mL of acetonitrile was used as extraction solvent, and 10 mg of amino-modified multi-walled carbon nanotubes (MWCNTs-NH2) and 150 mg of anhydrous magnesium sulfate (MgSO4) were selected as sorbents for dispersive solid phase extraction. The performance of the method was verified according to the analytical quality control standards of SANTE/11813/2017 guidelines. With good linearity (R2 > 0.9984) in the range of 2−200 µg/L for all pesticides in the selected matrices, and good accuracy, precision, and high sensitivity, the recoveries were in the range of 70−120% for more than 95% of the pesticides, with a relative standard deviation (RSD) of less than 16.82% for all. The limit of detection (LOD) and limit of quantification (LOQ) of the method were 0.01−3.87 µg/kg and 0.07−12.90 µg/kg, respectively, for Fritillaria thunbergii Miq (F. thunbergii), Chrysanthemum Morifolium Ramat (C. morifolium), and Dendrobium officinale Kimura et Migo (D. officinale). The method was successfully applied to 60 batches of actual samples from different regions.

Combination of puerarin and tanshinone IIA alleviates ischaemic stroke injury in rats via activating the Nrf2/ARE signalling pathway.

CONTEXT: Puerarin (Pue) and tanshinone IIA (Tan IIA) are often used in combination in the treatment of cerebrovascular diseases. OBJECTIVE: To investigate the neuroprotective effect and synergic mechanism of Pue-Tan IIA on the treatment of ischaemic stroke (IS). MATERIALS AND METHODS: IS was induced in rats by middle cerebral artery occlusion (MCAO). Rats were intraperitoneally injected with Pue (36 mg/kg), Tan IIA (7.2 mg/kg), or Pue-Tan IIA (36 and 7.2 mg/kg) for five times [30 min before ischaemia, immediately after reperfusion (0 h), 24, 48, and 72 h after reperfusion]. After administration, neurological function assessment and histological changes in the brain were performed. S-100ß and NSE levels were measured to determine the severity of brain injury. Oxidative stress parameters and inflammatory mediators were measured. The proteins involved in Nrf2/ARE signalling pathway were determined by qRT-PCR and western blot. RESULTS: After administration, the neurological function scores, infarct volume, S-100ß, and NSE levels were significantly reduced in MCAO rats, especially with Pue-Tan IIA treatment (p < 0.05). All treatments increased T-AOC, CAT, SOD, and GSH activities and reduced GSSG activity and MDA, TNF-α, IL-6, ICAM-1, and COX-2 levels in MCAO rats. Pue-Tan IIA significantly increased Nrf2 expression in the nucleus (1.81-fold) and decreased its expression in the cytoplasm (0.60-fold). Pue-Tan IIA significantly increased the expressions of HO-1 (1.87-fold) and NQO1 (1.76-fold) and decreased Keap1 expression (0.39-fold). DISCUSSION AND CONCLUSIONS: The combination of Pue and Tan IIA could alleviate ischaemic brain injury by activating Nrf2/ARE signalling pathway, providing an experimental basis for clinical applications.

microRNA-132 inhibits cardiomyocyte apoptosis and myocardial remodeling in myocardial infarction by targeting IL-1ß.

The patients suffering from myocardial infarction (MI) undergo cardiac remodeling with the features of expanded myocardial infarct size and dilated left ventricle. Multiple microRNAs (miRNAs) are emerged as crucial modulators to participate in the remodeling process. This study is mainly intended to clarify the regulatory mechanism of miR-132 in the MI-induced myocardial remodeling. miR-132 low expression, while interleukin-1ß (IL-1ß) high expression was determined in MI by reverse-transcription quantitative polymerase chain reaction and ELISA assays. MI rats showed decreased cardiac function and increased cardiomyocyte apoptosis. Moreover, miR-132 and IL-1ß levels were altered in cardiomyocytes to explore their role in MI, with levels of proapoptotic or antiapoptotic proteins in MI together with cardiac function indexes observed. In addition, upregulation of miR-132, decreased levels of Bax and Cleaved Caspase-3, increased left ventricular ejection fraction, left ventricular fractional shortening, the maximum rate of rise or decrease of left ventricular pressure (±dp/dtmax ), and Bcl-2 level, which could be reversed by overexpressing IL-1ß. All in all, miR-132 inhibits cardiomyocyte apoptosis so as to ameliorate myocardial remodeling in rats with MI through IL-1ß downregulation. Thus, miR-132 is a potential candidate for the MI treatment.

ZJ01, a Small Molecule Inhibitor of the Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) Protein-Protein Interaction, Reduces Hyperoxic Acute Lung Injury in a Mouse Model.

BACKGROUND Hyperoxic acute lung injury (ALI) is a complication of ventilation in patients with respiratory failure. Nuclear factor erythroid-2-related factor 2 (Nrf2) has an important role in ALI. Kelch-like ECH-associated protein 1 (Keap1) binds to Nrf2. ZJ01 is a small molecule inhibitor of Keap1-Nrf2 protein-protein interaction (PPI) that can reduce Keap1-induced inhibition of Nrf2. This study aimed to investigate the effects of ZJ01 and the heme oxygenase-1 (HO-1) inhibitor, zinc protoporphyrin IX (ZnPP IX), in a mouse model of hyperoxic ALI. MATERIAL AND METHODS C57BL/6J mice included five study groups: the room air+vehicle-treated group; the room air+ZJ01 group; the hyperoxia+vehicle-treated group; the hyperoxia+ZJ01 group; and the hyperoxia+ZJ01+ZnPP IX group. ZJ01, ZnPP IX, or vehicle were given 1 h after the hyperoxia challenge. The lungs from the mice were harvested at 72 h following the hyperoxia challenge. RESULTS Hyperoxia exposure for 72 h increased the activity of myeloperoxidase, the lung water content, the levels of tumor necrosis factor-alpha (TNF-alpha), and matrix metalloprotease-9 (MMP-9) in the vehicle-treated mice. ZJ01 treatment reduced hyperoxia-induced inflammation and increased the activation of Nrf2 and HO-1 compared with the vehicle-treated mice. Histology of the lungs showed that ZJ01 treatment reduced the changes of hyperoxia-induced ALI. Pretreatment with ZnPP IX reversed the beneficial effect of ZJ01. CONCLUSIONS ZJ01, a Keap1-Nrf2 PPI inhibitor, reduced hyperoxic ALI in a mouse model through the Nrf2/HO-1 pathway.

Searching for Near-Horizon Quantum Structures in the Binary Black-Hole Stochastic Gravitational-Wave Background.

Quantum gravity corrections have been speculated to lead to modifications to space-time geometry near black-hole horizons. Such structures may reflect gravitational waves, causing echoes that follow the main gravitational waves from binary black-hole coalescence. By studying two phenomenological models of the near-horizon structures under the Schwarzschild approximation, we show that such echoes, if they exist, will give rise to a stochastic gravitational-wave background, which is very substantial if the near-horizon structure has a near-unity reflectivity for gravitational waves, readily detectable by Advanced LIGO. In case the reflectivity is much less than unity, the background will mainly be arising from the first echo, with a level proportional to the power reflectivity of the near-horizon structure, but robust against uncertainties in the location and the shape of the structure-as long as it is localized and close to the horizon. Sensitivity of third-generation detectors allows the detection of a background that corresponds to power reflectivity ∼3×10^{-3}, if uncertainties in the binary black-hole merger rate can be removed. We note that the echoes do alter the f^{2/3} power law of the background spectra at low frequencies, which is rather robust against uncertainties.

Impact of Atorvastatin Combined with Ezetimibe for the Treatment of Carotid Atherosclerosis in Patients with Coronary Heart Disease.

BACKGROUND: This study aimed to investigate the impact of atorvastatin (Ato) combined with ezetimibe (Eze) for the treatment of carotid atherosclerosis in patients with coronary heart disease (CHD). METHODS: One hundred and forty-eight CHD patients with carotid atherosclerosis were divided into the control (Ato alone) and combination (Ato and Eze) groups. The treatment course was 12 months; patient blood lipids, carotid intima-media thickness (CIMT), and carotid plaque area were measured before and after treatment. RESULTS: Twelve months after treatment, there was a decrease in the CIMT, and the horizontal and vertical axes of the carotid plaque areas in both groups, compared to pretreatment values. The serum low-density lipoprotein cholesterol (LDL-C) levels were significantly decreased (p < 0.05). There were statistically significant differences (p < 0.05) in the LDL-C (2.12 ± 0.58 mmol/L vs. 2.63 ± 0.56 mmol/L) and CIMT (1.06 ± 0.12 mm vs. 1.13 ± 0.11 mm) levels between the combination and the control groups after treatment. Compared to the control group, the horizontal (0.18 ± 0.06 cm2 vs. 0.19 ± 0.05 cm2) and vertical carotid arterial plaque areas (0.40 ± 0.15 cm2 vs. 0.41 ± 0.17 cm2) of the combination group were reduced after treatment. However, the difference was not statistically significant (p > 0.05). CONCLUSIONS: The combination of Ato and Eze further reduces LDL-C levels and CIMT, and affect the progression of carotid atherosclerosis in CHD patients with hypercholesterolemia.

Advanced oxidation protein products in predicting acute kidney injury following cardiac surgery.

To test the hypothesis whether serum advanced oxidation protein products (AOPP) are associated with increased acute kidney injury (AKI) after cardiopulmonary bypass (CPB) and could serve as a biomarker in this aspect, we performed a prospective cohort study. Thirty-five (22.3%) patients developed AKI, and 32 age- and gender-matched patients without AKI were selected as control. Serum AOPP 1 h after CPB were significantly higher among AKI patients compared with non-AKI patients (81.8 ± 18.6 versus 67.4 ± 12.5 µmol/L, p < 0.001), with an area under the receiver-operating characteristic (ROC) curve of 0.714. An optimal serum AOPP 1 h after CPB cutoff of 69.9 µmol/L had a sensitivity of 74%, specificity of 63% and a positive predictive value of 68% for predicting AKI. These results demonstrated that serum AOPP might be an early biomarker for AKI after CPB.

Education is critical for medication adherence in patients with coronary heart disease.

BACKGROUND: Although non-adherence to medications is associated with increased cardiovascular risks, very little information is focused on the relationship between knowledge and medication adherence among patients with coronary heart disease (CHD). AIM: The purposes were to assess the relationship between medication adherence and medication- or disease-related knowledge in patients with CHD, and to investigate whether educating patients would alter their medication adherence behaviour. METHODS: This study was carried out at the outpatient clinic of a public university teaching hospital in China.The primary outcome was the ability of patients to follow medication instructions, which was assessed by the Morisky Medication Adherence Scale (MMSA-8). The Medication- or Disease-Related Knowledge Test (MDRKT) was used to assess patients'medication-related knowledge. We also explored patients'preferences for receiving education about medications and whether it is necessary for pharmacists to provide education. RESULTS: Among the 159 patients who completed the survey, approximately 38.4% were considered non-adherent (MMAS-8 score <6). Medication- or disease-related knowledge and concerns about adverse drug events were significantly associated with non-adherence. The MDRKT revealed that most participants had very little knowledge about their drug treatment. Specifically, 22 participants said that pharmacists were their primary source of information. Subsequently, 95.0% of participants expressed an interest in activities related to medication education. CONCLUSIONS: Knowledgeable patients with CHD are more likely to adhere to medication instructions. Many patients have difficulty acquiring medication information; thus, patients need increased access to education about their medication. Pharmacist services may be required to provide such information.