Site-Specific Integration of Hexagonal Boron Nitride Quantum Emitters on 2D DNA Origami Nanopores.

Optical emitters in hexagonal boron nitride (hBN) are promising probes for single-molecule sensing platforms. When engineered in nanoparticle form, they can be integrated as detectors in nanodevices, yet positional control at the nanoscale is lacking. Here we demonstrate the functionalization of DNA origami nanopores with optically active hBN nanoparticles (NPs) with nanometer precision. The NPs are active under three wavelengths of visible illumination and display both stable and blinking emission, enabling their accurate localization by using wide-field optical nanoscopy. Correlative opto-structural characterization reveals deterministic binding of bright, multicolor hBN NPs at the pore rim due to π-π stacking interactions at site-specific locations on the DNA origami. Our work provides a scalable, bottom-up approach toward deterministic assembly of solid-state emitters on arbitrary structural elements based on DNA origami. Such a nanoscale arrangement of optically active components can advance the development of single-molecule platforms, including optical nanopores and nanochannel sensors.

Chronic diseases spectrum and multimorbidity in elderly inpatients based on a 12-year epidemiological survey in China.

BACKGROUND: The number and proportion of the elderly population have been continuously increasing in China, leading to the elevated prevalence of chronic diseases and multimorbidity, which ultimately brings heavy burden to society and families. Meanwhile, the status of multimorbidity tends to be more complex in elderly inpatients than community population. In view of the above concerns, this study was designed to investigate the health status of elderly inpatients by analyzing clinical data in Chinese People's Liberation Army (PLA) General Hospital from 2008 to 2019, including the constitution of common diseases, comorbidities, the status of multimorbidity, in-hospital death and polypharmacy among elderly inpatients, so as to better understand the diseases spectrum and multimorbidity of elderly inpatients and also to provide supporting evidence for targeted management of chronic diseases in the elderly. METHODS: A clinical inpatients database was set up by collecting medical records of elderly inpatients from 2008 to 2019 in Chinese PLA General Hospital, focusing on diseases spectrum and characteristics of elderly inpatients. In this study, we collected data of inpatients aged ≥ 65 years old, and further analyzed the constitution of diseases, multimorbidity rates and mortality causes in the past decade. In addition, the prescriptions were also analyzed to investigate the status of polypharmacy in elderly inpatients. RESULTS: A total of 210,169 elderly patients were hospitalized from January 1st, 2008 to December 31st, 2019. The corresponding number of hospitalizations was 290,833. The average age of the study population was 72.67 years old. Of the total population, 73,493 elderly patients were re-admitted within one year, with the re-hospitalization rate of 25.27%. Malignant tumor, hypertension, ischemic heart disease, diabetes mellitus and cerebrovascular disease were the top 5 diseases. Among the study population, the number of patients with two or more long-term health conditions was 267,259, accounting for 91.89%, with an average of 4.68 diseases. In addition, the average number of medications taken by the study population was 5.4, among which, the proportion of patients taking more than 5 types of medications accounted for 55.42%. CONCLUSIONS: By analyzing the constitution of diseases and multimorbidity, we found that multimorbidity has turned out to be a prominent problem in elderly inpatients, greatly affecting the process of healthy aging and increasing the burden on families and society. Therefore, multidisciplinary treatment should be strengthened to make reasonable preventive and therapeutic strategies to improve the life quality of the elderly. Meanwhile, more attention should be paid to reasonable medications for elderly patients with multimorbidity to avoid preventable side effects caused by irrational medication therapy.

Scavenger receptor-AI targeted theranostic nanoparticles for regression of atherosclerotic plaques via ABCA1 modulation.

ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in atherosclerotic formation through mediated cholesterol efflux in macrophage-derived foam cells. In this study, a scavenger receptors AI (SR-AI) targeted theranostic nanoparticles was constructed for atherosclerosis regression via ABCA1 activation in foam cells. ABCA1-upregulator 5242331 and IR780 were encapsulated in PLGA-PEG micelles which were conjugated with SR-AI targeting peptide (PP1) to formulate the nanoparticles (SAU-NPs). Immunostaining revealed that SR-AI was highly expressed both in macrophage foam cells and in atherosclerotic plaque of ApoE-/- mice. The SAU-NPs have shown more active targeting to plaque lesion with higher stability compared with non-SR-AI targeted nanoparticles. The transformation from macrophage to foam cells was inhibited by SAU-NPs carried 5242331. Cholesterol deposition was effectively reduced in foam cells by SAU-NPs through activating the LXRα-ABCA1/ABCG1/SR-BI pathway. In conclusion, theranostic SAU-NPs which carried ABCA1-upregulator 5242331 exert beneficial effects on atherosclerosis regression via LXRα activation.

Fluorescent Photoelectric Detection of Peroxide Explosives Based on a Time Series Similarity Measurement Method.

Due to the characteristics of peroxide explosives, which are difficult to detect via conventional detection methods and have high explosive power, a fluorescent photoelectric detection system based on fluorescence detection technology was designed in this study to achieve the high-sensitivity detection of trace peroxide explosives in practical applications. Through actual measurement experiments and numerical simulation methods, the derivative dynamic time warping (DDTW) algorithm and the Spearman correlation coefficient were used to calculate the DDTW-Spearman distance to achieve time series correlation measurements. The detection sensitivity of triacetone triperoxide (TATP) and H2O2 was studied, and the detection of organic substances of acetone, acetylene, ethanol, ethyl acetate, and petroleum ether was carried out. The stability and specific detection ability of the fluorescent photoelectric detection system were determined. The research results showed that the fluorescence photoelectric detection system can effectively identify the detection data of TATP, H2O2, acetone, acetonitrile, ethanol, ethyl acetate, and petroleum ether. The detection limit of 0.01 mg/mL of TATP and 0.0046 mg/mL of H2O2 was less than 10 ppb. The time series similarity measurement method improves the analytical capabilities of fluorescence photoelectric detection technology.

Dendritic mesoporous nanoparticles for the detection, adsorption, and degradation of hazardous substances in the environment: State-of-the-art and future prospects.

Equipped with hierarchical pores and three-dimensional (3D) center-radial channels, dendritic mesoporous nanoparticles (DMNs) make their pore volumes extremely large, specific surface areas super-high, internal spaces especially accessible, and so on. Other entities (like organic moieties or nanoparticles) can be modified onto the interfaces or skeletons of DMNs, accomplishing their functionalization for desirable applications. This comprehensive review emphasizes on the design and construction of DMNs-based systems which serve as sensors, adsorbents and catalysts for the detection, adsorption, and degradation of hazardous substances, mainly including the construction procedures of brand-new DMNs-based materials and the involved hazardous substances (like industrial chemicals, chemical dyes, heavy metal ions, medicines, pesticides, and harmful gases). The sensitive, adsorptive, or catalytic performances of various DMNs have been compared; correspondingly, the reaction mechanisms have been revealed strictly. It is honestly anticipated that the profound discussion could offer scientists certain enlightenment to design novel DMNs-based systems towards the detection, adsorption, and degradation of hazardous substances, respectively or comprehensively.

The Tumor-Suppressive Human Circular RNA CircITCH Sponges miR-330-5p to Ameliorate Doxorubicin-Induced Cardiotoxicity Through Upregulating SIRT6, Survivin, and SERCA2a.

RATIONALE: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is restricted because it poses a risk of severe cardiotoxicity. Previous work has established that CircITCH (circular RNA ITCH [E3 ubiquitin-protein ligase]) is a broad-spectrum tumor-suppressive circular RNA and that its host gene, ITCH (E3 ubiquitin protein ligase), is involved in doxorubicin-induced cardiotoxicity (DOXIC). Whether CircITCH plays a role in DOXIC remains unknown. OBJECTIVE: We aimed to dissect the role of CircITCH in DOXIC and further decipher its potential mechanisms. METHODS AND RESULTS: Circular RNA sequencing was performed to screen the potentially involved circRNAs in DOXI pathogenesis. Quantitative polymerase chain reaction and RNA in situ hybridization revealed that CircITCH was downregulated in doxorubicin-treated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as well as in the autopsy specimens from cancer patients who suffered from doxorubicin-induced cardiomyopathy. Cell death/viability assays, detection of cardiomyocyte necrosis markers, microelectrode array, and cardiomyocyte functional assays revealed that CircITCH ameliorated doxorubicin-induced cardiomyocyte injury and dysfunction. Detection of cellular/mitochondrial oxidative stress and DNA damage markers verified that CircITCH alleviated cellular/mitochondrial oxidative stress and DNA damage induced by doxorubicin. RNA pull-down assays, Ago2 immunoprecipitation and double fluorescent in situ hybridization identified miR-330-5p as a direct target of CircITCH. Moreover, CircITCH was found to function by acting as an endogenous sponge that sequestered miR-330-5p. Bioinformatic analysis, luciferase reporter assays, and quantitative polymerase chain reaction showed that SIRT6 (sirtuin 6), BIRC5 (baculoviral IAP repeat containing 5, Survivin), and ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2, SERCA2a [SR Ca2+-ATPase 2]) were direct targets of miR-330-5p and that they were regulated by the CircITCH/miR-330-5p axis in DOXIC. Further experiments demonstrated that CircITCH-mediated alleviation of DOXIC was dependent on the interactions between miR-330-5p and the 3'-UTRs of SIRT6, BIRC5, and ATP2A2 mRNA. Finally, AAV9 (adeno-associated virus serotype 9) vector-based overexpression of the well-conserved CircITCH partly prevented DOXIC in mice. CONCLUSIONS: CircITCH represents a novel therapeutic target for DOXIC because it acts as a natural sponge of miR-330-5p, thereby upregulating SIRT6, Survivin and SERCA2a to alleviate doxorubicin-induced cardiomyocyte injury and dysfunction.

Effect of long-term intensive cholesterol control on the plaque progression in elderly based on CTA cohort study.

OBJECTIVES: To investigate the long-term effects of intensive LDL cholesterol-lowering treatments on lumen stenosis severity, plaque calcification, spotty calcifications, percent calcified plaque volume (PCPV), and Agatston coronary artery calcium score (CACS) based on coronary computed tomography angiography (CCTA) in elderly patients. METHODS: A total of 240 patients over 60 years old (comprising 754 lesions) who underwent serial CCTA were retrospectively enrolled in this 5-year cohort study. Patients were divided into three groups: an intensive lipid-lowering group, a lipid-lowering group, and a control group. The stenosis severity, plaque volume (PV), plaque composition, PCPV, and high-risk plaque (HRP) presence were quantitatively analyzed. The CACS was calculated at baseline and follow-up. RESULTS: All patients were male with an average age of 66.8 ± 5.8 years old. Over time, increases in the percentages of obstructive coronary lesions (p < 0.001) were observed. Compared with those at baseline, the percentage of obstructive lesions remained unchanged (p = 0.077), and the percentage of spotty calcifications significantly decreased (p < 0.05) at the follow-up CCTA scan in the intensive lipid-lowering group. Patients in the intensive lipid-lowering group demonstrated a higher progression in calcified PV, CACS, and PCPV (all p < 0.05), and a significantly greater attenuation in fibrous-fatty and lipid-rich PV (all p < 0.05) than patients in other groups. CONCLUSIONS: The PV and contents increased gradually with time in all groups. Intensive LDL-C lowering was associated with slower progression of stenosis severity and reduction of high-risk plaque features, with increased plaque calcification and higher progression in PCPV. Comprehensive serial plaque evaluations by CCTAs may contribute to further refinement of risk stratification and reasonable lipid-lowering treatment in elderly patients. KEY POINTS: • Intensive LDL-C lowering increased coronary calcification and percent calcified plaque volume progression. • Comprehensive serial plaque evaluations by serial CCTAs may help to refine risk stratification.

Prevalence and conservation of ebp genes in Enterococcus faecalis originated from animals.

AIMS: The study aimed to investigate the prevalence and conservation of endocarditis and biofilm-associated pili (ebp) genes in Enterococcus faecalis originated from animals and the potential of developing Ebp into serological diagnostic and vaccine targets. METHODS AND RESULTS: In this work, we investigated the prevalence and conservation of ebp genes in 116 strains of E. faecalis originated from animals by using PCR and sequencing methods. The results demonstrated the presence of ebp genes (ebpA, ebpB and ebpC) in all 116 strains of E. faecalis, and their amino acid homology ranges from 96.6% to 100.0%. Moreover, the phylogenetic analysis of ebp genes in all 164 E. faecalis strains (including 48 reference strains) revealed that ebp genes show no significant correlation with species origins and regions of E. faecalis, indicating that ebp genes are conserved features in E. faecalis, even though it evolved under environmental pressures from various regions and origins. Given that EbpA1 as a part of the adhesion protein EbpA has immunogenicity, we further determined whether amino acid mutations have effects on the function and 3D structure of EbpA1. The results showed that two of the 26 mutations, at amino acids positions 178 and 387, had deleterious effects on the biological function of EbpA1 protein, while all mutations had no effect on the 3D structure or binding pockets of EbpA1 protein. CONCLUSIONS: This study suggests that ebp genes are prevalent and conserved in E. faecalis originated from diverse animal origins and regions. EbpA1 could be a potential target for serological diagnosis and vaccine development to prevent E. faecalis infection. SIGNIFICANCE AND IMPACT OF STUDY: The current study provides data to support further research on Ebp as a serological diagnostic and vaccine target against E. faecalis infection.

Prevalence and factors associated with atrial fibrillation in older patients with obstructive sleep apnea.

PURPOSE: This study sought to identify the prevalence and factors associated with atrial fibrillation (AF) in older patients with obstructive sleep apnea (OSA) in China.  METHODS: This was an explorative cross-sectional study. Between January 2015 and October 2017, we continuously recruited 1285 older patients with OSA who underwent overnight polysomnography from sleep centers of multiple hospitals. They were assessed using 12-lead ECG or 24-h dynamic ECG, and their baseline demographics, clinical characteristics, sleep parameters, and medical history were determined. Multivariate binary logistic regression analysis was used to investigate the factors related to AF in these older patients with OSA. RESULTS: The clinician classified 122 (9.5%) patients as having AF. The prevalence of AF significantly increased with age (P < 0.05) but did not significantly differ between the mild, moderate, and severe OSA groups. Additionally, the prevalence of paroxysmal AF was 7.2% among the overall study population, and it increased with OSA severity or advanced age (P < 0.05). Persistent AF was noted in 2.3% participants, and the prevalence also increased with age. The logistic regression analysis showed that age (OR = 1.054, 95%CI: 1.027-1.018, P < 0.001), history of drinking (OR = 1.752, 95%CI: 1.070-2.867, P < 0.05), chronic heart disease (OR = 1.778, 95%CI: 1.156-2.736, P < 0.01), diabetes mellitus (OR = 1.792, 95%CI: 1.183-2.713, P < 0.01), and reduced diastolic function (OR = 2.373, 95%CI = 1.298-4.337, P < 0.01) were relevant to AF among participants with OSA. CONCLUSION: The prevalence of AF is significantly common in older patients with OSA. Age, history of drinking, chronic heart disease, diabetes mellitus, and reduced diastolic function are independently related to AF in these patients.

Persistence Infection of TGEV Promotes Enterococcus faecalis Infection on IPEC-J2 Cells.

Transmissible gastroenteritis virus (TGEV) is a coronavirus causing diarrhea with high incidence in swine herds. Its persistent infection might lead to epithelial-mesenchymal transition (EMT) of swine intestinal epithelial cells, followed by subsequent infections of other pathogens. Enterococcus faecalis (E. faecalis) is a member of the enteric microorganisms and an opportunistic pathogen. There is no report of secondary E. faecalis infection to TGEV, even though they both target to the intestinal tracts. To investigate the interactions between TGEV and E. faecalis, we set up an in vitro infection model by the swine IPEC-J2 cells. Dynamic changes of cell traits, including EMT and cell motility, were evaluated through qPCR, Western blot, electronic microscopy, scratch test, Transwell migration test and invasion test, respectively. The adhesion and invasion tests of E. faecalis were taken to verify the impact of the preceding TGEV infection. The cell morphology and molecular marker evaluation results showed that the TGEV persistent infection induced EMT on IPEC-J2 cells; increased cellular motility and invasion potential were also observed. Spontaneously, the expression levels of fibronectin (FN) and the membrane protein integrin-α5, which are dominant bacterial receptors on IPEC-J2 cells, were upgraded. It indicated that the bacteria E. faecalis adhered to IPEC-J2 cells through the FN receptor, and then invaded the cells by binding with the integrin-α5, suggesting that both molecules were critical for the adhesion and invasion of E. faecalis to IPEC-J2 cells. Additionally, it appeared that E. faecalis alone might trigger certain EMT phenomena, implying a vicious circle might occur. Generally, bacterial and viral co-infections are frustrating yet common in both human and veterinary medicines, and our observations on enteric TGEV and E. faecalis interactions, especially the diversity of bacterial invasion strategies, might provide new insights into the mechanisms of E. faecalis pathogenicity.

Impact of obstructive sleep apnea complicated with type 2 diabetes on long-term cardiovascular risks and all-cause mortality in elderly patients.

BACKGROUND: The prognostic significance of obstructive sleep apnea (OSA) in elderly patients with type 2 diabetes is unclear. The aim of this study was to determine the risk of cardiovascular disease (CVD) and mortality in elderly patients with OSA complicated with type 2 diabetes compared to patients with OSA without type 2 diabetes. METHODS: From January 2015 to October 2017, 1113 eligible elderly patients with OSA, no history of cardiovascular, ≥60 years of age, and complete follow-up records were enrolled in this consecutive multicentre prospective cohort study. All patients had completed polysomnography (PSG) examinations. An apnoea-hypopnoea index of ≥5 events per hour recorded by polysomnography was defined as the diagnostic criterion for OSA. We collected baseline demographics, clinical characteristics, sleep parameters and follow-up outcomes. The primary aim of this study was to identify the risk of incident major adverse cardiovascular events (MACE). Secondary outcomes were all-cause mortality, components of MACE and a composite of all events. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate whether type 2 diabetes was associated with incident events. RESULTS: A total of 266 (23.9%) patients had OSA complicated with type 2 diabetes. MACE occurred in 97 patients during the median 42-month follow-up. Kaplan-Meier survival curves indicated a significant relationship between type 2 diabetes and MACE (log-rank P = 0.003). Multivariable Cox regression analysis showed that type 2 diabetes increased the risk of MACE (HR = 1.64, 95% CI:1.08-2.47, P = 0.019), hospitalisation for unstable angina (HR = 2.11, 95% CI:1.23-3.64, P = 0.007) and a composite of all events in elderly patients with OSA (HR = 1.70, 95% CI:1.17-2.49, P = 0.007). However, there were no significant differences in the incidence of cardiovascular death, all-cause mortality, MI and hospitalisation for heart failure between patients with and without diabetes (P > 0.05). The subgroup analysis demonstrated that females (AHR = 2.46, 95% CI:1.17-5.19, P = 0.018), ≥ 70 years (AHR = 1.95, 95% CI:1.08-3.52, P = 0.027), overweight and obese (AHR = 2.04, 95% CI:1.29-3.33, P = 0.002) with mild OSA (AHR = 2.42, 95% CI: 1.03-5.71, P = 0.044) were at a higher risk for MACE by diabetes. CONCLUSION: OSA and type 2 diabetes are interrelated and synergistic with MACE, hospitalisation for unstable angina and a composite of all events development. Overweight and obese females, ≥ 70 years with mild OSA combined with type 2 diabetes presented a significantly high MACE risk.

Reduced Sirtuin1 signalling exacerbates diabetic mice hindlimb ischaemia injury and inhibits the protective effect of a liver X receptor agonist.

Diabetes mellitus causes endothelial dysfunction, which further exacerbates peripheral arterial disease (PAD). Improving endothelial function via reducing endothelial oxidative stress (OS) may be a promising therapy for diabetic PAD. Activation of liver X receptor (LXR) inhibits excessive OS and provides protective effects on endothelial cells in diabetic individuals. Therefore, we investigated the effects of LXR agonist treatment on diabetic PAD with a focus on modulating endothelial OS. We used a streptozotocin-induced diabetes mouse model combined with a hindlimb ischaemia (HLI) injury to mimic diabetic PAD, which was followed by LXR agonist treatment. In our study, the LXR agonist T0901317 protected against HLI injury in diabetic mice by attenuating endothelial OS and stimulating angiogenesis. However, a deficiency in endothelial Sirtuin1 (SIRT1) largely inhibited the therapeutic effects of T0901317. Furthermore, we found that the underlying therapeutic mechanisms of T0901317 were related to SIRT1 and non-SIRT1 signalling, and the isoform LXRß was involved in LXR agonist-elicited SIRT1 regulation. In conclusion, LXR agonist treatment protected against HLI injury in diabetic mice via mitigating endothelial OS and stimulating cellular viability and angiogenesis by LXRß, which elicited both SIRT1-mediated and non-SIRT1-mediated signalling pathways. Therefore, LXR agonist treatment may be a promising therapeutic strategy for diabetic PAD.

Impact of the residual SYNTAX score on clinical outcomes after percutaneous coronary intervention for patients with chronic renal insufficiency.

OBJECTIVES: This study demonstrated the prognostic value of the residual SYNTAX score (rSS) for patients with chronic renal insufficiency (CRI). BACKGROUND: The rSS has been proposed as a useful tool for quantifying and stratifying the degree and complexity of residual stenosis and predicting long-term clinical outcomes following percutaneous coronary intervention (PCI). However, it has never been validated for patients with CRI. METHODS: A total of 2,468 consecutive patients with an estimated glomerular filtration rate <90 ml/min/1.73 m2 who underwent PCI were retrospectively enrolled. Patients with rSS >0 were defined as having incomplete revascularization and were stratified into the reasonable incomplete revascularization (RICR; 0 < rSS ≤ 8) group or the incomplete revascularization (ICR; rSS >8) group. Their outcomes were compared to those of the complete revascularization (CR) group. RESULTS: During follow-up (median, 3 years; range, 1.5-5 years), the ICR group had the highest incidence of all-cause death, cardiac death, myocardial infarction (MI), unplanned revascularization, stroke, and major adverse cardiovascular and cerebrovascular events (MACCE). Despite having higher rates of unplanned revascularization and MACCE, RICR group had comparable all-cause mortality, cardiac mortality, MI, and stroke with CR group. A multivariable Cox analysis indicated that rSS was an independent predictor of cardiac death, MI, unplanned revascularization, stroke, and MACCE. Furthermore, compared with baseline SYNTAX score, rSS had stronger prognostic accuracy when predicting the risk of unplanned revascularization, stroke, and MACCE at the 3-year follow-up. CONCLUSIONS: The rSS is a powerful indicator of clinical outcomes and may help determine reasonable levels of revascularization for patients with CRI following PCI.

Evaluation of fractional flow reserve in patients with stable angina: can CT compete with angiography?

BACKGROUND: We aimed to compare the performance of FFRCT and FFRQCA in assessing the functional significance of coronary artery stenosis in patients suffering from coronary artery disease with stable angina. METHOD: A total of 101 stable coronary heart disease (CAD) patients with 181 lesions were recruited. FFRCT and FFRQCA were compared using invasive fractional flow reserve (FFR) as a reference standard. Comparisons between FFRCT and FFRQCA were conducted based on strategies of the geometric reconstruction, boundary conditions, and geometric characteristics. The performance of FFRCT and FFRQCA in detecting hemodynamic significance was also investigated. RESULTS: The performance of FFRCT and FFRQCA in discriminating hemodynamically significant lesions was compared. Good correlation and agreement with invasive FFR was found using FFRCT and FFRQCA (r = 0.809, p < 0.001 and r = 0.755, p < 0.001). A significant difference was observed in the complex coronary artery tree, in which relatively better prediction was observed using FFRCT than FFRQCA when analyzing the stenosis distributed in the middle segment of a stenotic branch (p = 0.036). Moreover, FFRCT was found to be better at predicting hemodynamically insignificant stenosis than FFRQCA (p = 0.007), while the performance of the two parameters was similar in discriminating functional significant lesions using an FFR threshold of ≤ 0.8 as a reference standard. CONCLUSION: FFRCT and FFRQCA could both accurately rule out functional insignificant lesions in stable CAD patients. FFRCT was found to be better for the noninvasive screening of CAD patients with stable angina than FFRQCA. KEY POINTS: • FFR CT and FFR QCA were both in good correlation and agreement with invasive FFR measurements. • FFR CT is superior in accuracy and consistency compared to FFR QCA in patients with stenoses distributed in left coronary artery. • The noninvasive nature of FFR CT could provide potential benefit for stable CAD patients on disease management.

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin-conferred cardioprotection against myocardial ischemia/reperfusion injury.

Accumulated pieces of evidence have proved the beneficial effects of melatonin on myocardial ischemia/reperfusion (MI/R) injury, and these effects were largely dependent on melatonin membrane receptor activation. In humans and other mammals, there are two types of melatonin receptors, including the melatonin receptor 1 (MT1, melatonin receptor 1a or MTNR1A) and melatonin receptor 1 (MT2, melatonin receptor 1b or MTNR1B) receptor subtypes. However, which receptor mediates melatonin-conferred cardioprotection remains unclear. In this study, we employed both loss-of-function and gain-of-function approaches to reveal the answer. Mice (wild-type; MT1 or MT2 silencing by in vivo minicircle vector; and those overexpressing MT1 or MT2 by in vivo AAV9 vector) were exposed to MI/R injury. Both MT1 and MT2 were present in wild-type myocardium. MT2, but not MT1, was essentially upregulated after MI/R Melatonin administration significantly reduced myocardial injury and improved cardiac function after MI/R Mechanistically, melatonin treatment suppressed MI/R-initiated myocardial oxidative stress and nitrative stress, alleviated endoplasmic reticulum stress and mitochondrial injury, and inhibited myocardial apoptosis. These beneficial actions of melatonin were absent in MT2-silenced heart, but not the MT1 subtype. Furthermore, AAV9-mediated cardiomyocyte-specific overexpression of MT2, but not MT1, mitigated MI/R injury and improved cardiac dysfunction, which was accompanied by significant amelioration of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Mechanistically, MT2 protected primary cardiomyocytes against hypoxia/reoxygenation injury via MT2/Notch1/Hes1/RORα signaling. Our study presents the first direct evidence that the MT2 subtype, but not MT1, is a novel endogenous cardiac protective receptor against MI/R injury. Medications specifically targeting MT2 may hold promise in fighting ischemic heart disease.

Development of a new doubly-labeled fluorescent ceramide probe for monitoring the metabolism of sphingolipids in living cells.

A new ceramide analog, 1, containing two fluorescent dyes, NBD in the N-acyl part and KFL5 in the alkyl part, was synthesized. The fluorescence from both NBD and KFL5 was detected in living cells in a time-dependent manner. A multi-wavelength fluorescence detector was used to detect ceramide metabolites including sphingosine, sphingosine-1-phosphate, glucosylceramide, and sphingomyelin, which are connected to the fluorescent dyes, simultaneously in a single TLC plate.

Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells.

Aldehyde dehydrogenase 2 (ALDH2) is a key mitochondrial enzyme in the metabolism of aldehydes and may have beneficial cardiovascular effects for conditions such as cardiac hypertrophy, heart failure, myocardial I/R injury, reperfusion, arrhythmia, coronary heart disease and atherosclerosis. In this study we investigated the role of ALDH2 in the progression of atherosclerosis and the underlying mechanisms, with a focus on endoplasmic reticulum (ER) stress. A clinical study was performed in 248 patients with coronary heart disease. The patients were divided into two groups according to their ALDH2 genotype. Baseline clinical characteristics and coronary angiography were recorded, and the coronary artery Gensini score was calculated. Serum levels of 4-hydroxy-2-nonenal (4-HNE) were detected. The clinical study revealed that the mutant ALDH2 genotype was an independent risk factor for coronary heart disease. ALDH2 gene polymorphism is closely associated with atherosclerosis and the severity of coronary artery stenosis. Serum levels of 4-HNE were significantly higher in patients with the mutant ALDH2 genotype than in patients with the wild-type ALDH2 genotype. As an in vitro model of atherosclerosis, rat smooth muscle cells (SMCs) were treated with oxygenized low-density lipoprotein (ox-LDL), which significantly elevated the levels of ER markers glucose-regulated protein78 (GRP78), protein kinase R-like ER kinase (PERK), phosphorylated eukaryotic translation initiation factor α subunit (p-eIF2α), activating transcription factor-4 (ATF-4), CEBP homologous protein (CHOP) and 4-HNE in the cells. All the ox-LDL-induced responses were significantly attenuated in the presence of Alda-1 (an ALDH2 activating agent), and accentuated in the presence of daidzin (an ALDH2 inhibitor). Furthermore, pretreatment with ALDH2 activator Alda-1 significantly decreased ox-LDL-induced apoptosis. Similarly, overexpression of ALDH2 protected SMCs against ox-LDL-induced ER stress as well as ER stress-induced apoptosis. These findings suggest that ALDH2 may slow the progression of atherosclerosis via the attenuation of ER stress and apoptosis in smooth muscle cells.

A human cell panel for evaluating safe application of nano-ZrO2/polymer composite in water remediation.

Nanomaterials, such as ZrO2 nanoparticles (ZrO2 NPs), are very effective in water remediation. However, the safety issues related to nanoparticle release and toxicity to humans remain to be resolved. Here we evaluated the cytotoxicity of ZrO2 NPs and their adducts with pollutants using a human cell panel containing stomach, intestine, liver and kidney cells. We found that different pollutants or ZrO2NP/pollutant adducts targeted cells from different organs, suggesting the necessity of a cell panel to model oral exposures. The cooperation of ZrO2 NPs and pollutants was quite complex, consisting of synergistic, antagonistic, or additive effects. For example, ZrO2 NPs enhanced the cytotoxicity of Pb2+ in GES-1 cells and of Pb2+, Cd2+ in FHC cells, while alleviating the toxicity of Pb2+ and As (III) in HepG2 and Hek293 cells. Our results also indicated that even concentrations of pollutants that meet the national standard, the ZrO2 NPs concentration should be kept below 17 µg/mL to avoid ZrO2 NP/pollutant adduct synergistic toxicity.

Long-term clinical outcomes of successful revascularization with drug-eluting stents for chronic total occlusions: A systematic review and meta-analysis.

OBJECTIVES: To determine whether successful percutaneous coronary intervention (PCI) using drug-eluting stents (DESs) have beneficial effects on long-term outcomes in patients with chronic total occlusions (CTOs) compared with failed PCIs for CTOs. BACKGROUND: Several observational studies have evaluated the long-term clinical outcomes of successful PCIs using DESs for CTOs. However, the results of these studies were inconsistent and inconclusive. METHODS: We searched five online electronic databases to identify all the publications assessing the long-term outcomes of successful and failed PCIs using DESs for CTOs. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by STATA software. RESULTS: A total of nine studies involving 5958 CTO patients who underwent successful PCI and 1511 CTO patients who underwent failed PCI were included in this meta-analysis. The results of the analysis indicated that successful CTO PCIs using DESs were associated with lower long-term all-cause mortality(OR = 0.55, 95% CI = 0.45-0.67, P < 0.001), lower risk of myocardial infarction (OR = 0.45, 95% CI = 0.23-0.74, P = 0.002), lower risk of major adverse cardiac events (MACEs, OR = 0.44, 95% CI = 0.27-0.72, P = 0.001), and less incidence of subsequent coronary artery bypass grafting (OR = 0.10, 95% CI = 0.05-0.21, P < 0.001) than failed CTO PCIs. However, there was no difference in the incidence of target vessel revascularization (OR = 1.06, 95% CI = 0.17-6.60, P > 0.05) between the two groups. CONCLUSION: Successful CTO PCI using DESs can reduce long-term all-cause mortality and the risks of MI, MACEs, and CABG in patients with CTOs. © 2017 Wiley Periodicals, Inc.