Rational Design of Quinoxalinone-Based Red-Emitting Probes for High-Affinity and Long-Term Visualizing Amyloid-ß In Vivo.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with insidious onset, and the deposition of amyloid-ß (Aß) is believed to be one of the main cause. Fluorescence imaging is a promising technique for this task, but the Aß gold standard probe ThT developed based on this still has shortcomings. The development of a new fluorescent probe to detect Aß plaques is thought to be essential. Herein, a series of red to near-infrared emitting fluorescent probes QNO-ADs with newly quinoxalinone skeleton are designed to detect Aß plaques. They all demonstrate excellent optical properties and high binding affinity (∼Kd = 20 nM) to Aß aggregates. As the most outstanding candidate, QNO-AD-3 shows significant signal-to-noise (S/N) ratio at the level of in vitro binding studies, and the brilliant fluorescence staining results in favor of grasping the approximate distribution of Aß plaques in the brain slice. In vivo Aß plaques imaging suggests that QNO-AD-3 can cross the BBB and have a long retention time in the brain with low biological toxicity. In addition, the results of docking theoretical calculation also provide some references for the design of Aß probe. Overall, given the high affinity of QNO-AD-3 and the ability to monitor Aß plaques for a long time that is not common now, we believe QNO-AD-3 will be an effective tool for an Aß-related matrix and AD disease research in the future.

Prevalence of recommended anticoagulation by guidelines preadmission and its impact on the incidence of acute myocardial infarction (AMI) and in-hospital outcomes after AMI in atrial fibrillation patients.

This study was designed to explore the prevalence of recommended anticoagulation by guidelines before admission and its impact on the incidence of acute myocardial infarction (AMI) and the AMI associated in-hospital outcomes in patients with atrial fibrillation (AF). 10,725 patients with AF at their first hospitalizations in our hospitals were retrospectively reviewed, with a prevalence of recommended anticoagulation preadmission 24.41% (Number = 2618). They had lower risk of AMI incidence (Adjusted OR 0.66, 95%CI 0.54-0.81, p < 0.001) compared to those without recommended anticoagulation after multivariate logistic regression. Furthermore, recommended anticoagulation preadmission reduced in-hospital all-cause death associated with AMI in univariate logistic analysis, but had no impact on the risk of in-hospital bleeding and stroke after AMI both in univariate and multivariate logistic analysis. The prevalence of recommended anticoagulation before admission was 24.41% in China. Recommended anticoagulation reduced incidence of hospitalized AMI, but had no impact on the associated in-hospital bleeding and stroke risk after AMI.

Alkaloid Derivative (Z)-3ß-Ethylamino-Pregn-17(20)-en Inhibits Triple-Negative Breast Cancer Metastasis and Angiogenesis by Targeting HSP90α.

Metastasis is an important cause of cancer-related death. Previous studies in our laboratory found that pregnane alkaloids from Pachysandra terminalis had antimetastatic activity against breast cancer cells. In the current study, we demonstrated that treatment with one of the alkaloid derivatives, (Z)-3ß-ethylamino-pregn-17(20)-en (1), led to the downregulation of the HIF-1α/VEGF/VEGFR2 pathway, suppressed the phosphorylation of downstream molecules Akt, mTOR, FAK, and inhibited breast cancer metastasis and angiogenesis both in vitro and in vivo. Furthermore, the antimetastasis and antiangiogenesis effects of 1 treatment (40 mg/kg) were more effective than that of Sorafenib (50 mg/kg). Surface plasmon resonance (SPR) analysis was performed and the result suggested that HSP90α was a direct target of 1. Taken together, our results suggested that compound 1 might represent a candidate antitumor agent for metastatic breast cancer.

Discovery of an Ultra-rapid and Sensitive Lysosomal Fluorescence Lipophagy Process.

Non-invasive dynamic tracking of lysosomes and their interactions with other organelles is important for the study of lysosomal function and related diseases. However, many fluorescent dyes developed so far to target lysosomes cannot be used to monitor these processes due to the high concentrations required for imaging, long cell penetration times, and non-ideal photostability. In this regard, we synthesized three lysosomal targeting probes with large Stokes shifts, good stability, and high brightness. The Q-P-ARh dye, developed by us for the first time, can stain lysosomes at ultra-low concentrations (1.0 nM) without affecting the physiological functions of the lysosomes. More importantly, its excellent anti-interference ability and ultrafast lysosomal staining ability (within 1.0 min) clearly monitored the entire dynamic process of lipophagy. Ultimately, this method can greatly contribute to the study of autophagy pathways. This novel fluorescence platform shows great promise for the development of biological probes for application in pathological environments.

Patients with acute myocardial infarction and atrial fibrillation: association of anaemia with risk of in-hospital bleeding, stroke and other death causes.

PURPOSES: To explore the association of anaemia with risk of outcomes of in-hospital patients with acute myocardial infarction (AMI) and atrial fibrillation (AF). METHODS: Patients with AF and AMI at their first hospitalizations in three hospitals (Beijing Tongren Hospital, Beijing Friendship Hospital, Capital Medical University and China-Japan Friendship Hospital) were retrospectively reviewed and divided into two groups (with vs. without anaemia) according to haemoglobin within one day before or after admission. RESULTS: 864 patients with AF and AMI (mean age:74.22 years; 39.9% female) were included in the current study. Patients with anaemia had increased risk of any bleeding (adjusted OR: 2.29, 95% CI: 1.43-3.68, p = 0.001), minor bleeding (adjusted OR: 2.37, 95% CI:1.40-4.01, p = 0.001), gastrointestinal bleeding (adjusted OR: 2.53, 95% CI:1.51-4.25, p < 0.001) and other death causes (adjusted OR: 1.71, 95% CI: 1.07-2.72, p = 0.02) compared to those without anaemia according to logistic regression. However, there was no difference in the risk of stroke or/and systematic embolism (SE) between patients with and without anaemia. CONCLUSIONS: In the Chinese in-hospital AMI and AF cohort, anaemia was shown to be associated with increased risk of any bleeding, minor bleeding, gastrointestinal bleeding and other death causes, but not the risk of stroke or/and SE.

The relationship among social capital, eHealth literacy and health behaviours in Chinese elderly people: a cross-sectional study.

BACKGROUND: Social capital has been linked to health behaviours, but the underlying mechanism is unclear. Previous studies have found that health literacy played the role of a mediator in the relationships among social capital, individual physical activity and nutrition. But it is not clear whether eHealth literacy mediates the impact of social capital on health behaviours. Therefore, our research aimed to explore the relationships among social capital (structural and cognitive social capital), eHealth literacy, and the health behaviours of elderly people, and to analyse the mediating effect of eHealth literacy, while providing a theoretical basis for a health behaviour intervention for elderly people. METHODS: From January to February 2019, we conducted a cross-sectional survey of 1201 Chinese people aged over 60 years using the Chinese Shortened Social Capital Scale (contains two subscales of structural social capital and cognitive social capital), eHealth Literacy Scale, and Health-Promoting Lifestyle Profile. We used structural equation modelling to test a hypothetical mediation model. RESULTS: The mean scores of social capital was 72.07 (SD = 13.03), 17.24 (SD = 9.34) for eHealth literacy, and 112.23 (SD = 23.25) for health behaviours. Social capital and eHealth literacy were significantly correlated with health behaviours, and social capital and structural social capital were significantly correlated with eHealth literacy. Lastly, eHealth literacy mediated the relationship between structural social capital and health behaviours. CONCLUSIONS: eHealth literacy was an important mediating factor for elderly people's structural social capital and health behaviours. Therefore, social capital and eHealth literacy must be considered when designing and implementing health behaviour intervention programmes for elderly people.

Global identification of alternative splicing in Shiraia bambusicola and analysis of its regulation in hypocrellin biosynthesis.

Hypocrellins, as natural pigments from Shiraia bambusicola, have extensive applications in the agricultural, cosmetic, food, and feed industries, and play a vital role in photodynamic therapy for anticancer and antiviral treatments. However, environmental stresses are always the bottlenecks for increasing hypocrellin yield during the process of fermentation. Pre-mRNA alternative splicing (AS) is an essential mechanism in the defense of abiotic stresses in the animal and plant kingdom, but is seldom involved in fungi. In this study, AS from genome-wide sequencing and RNA-seq data for S. bambusicola was analyzed for the first time. Interestingly, the proportion of AS in S. bambusicola was 38.44% (most of them participated in metabolic processes, covering pigmentation and response to stimulus), a much higher ratio than seen in that of other fungal species (1.3-18%). Here, we identified the relationship of AS and secondary metabolic (SM) biosynthesis under a series of abiotic stresses. Suitable fungicides suppressed hypocrellin production significantly, and AS occurred in key functional genes (sbFLO, sbMFS, sbPKS) of hypocrellin biosynthesis. In contrast, H2O2 improved the yield of hypocrellins, but AS were not found in the corresponding gene cluster. A further study showed that overexpressing an isoform of sbPKS (sbPKSa) in Shiraia bambusicola could dramatically down-regulate the expression of the original gene sbPKS and nearly inhibit the production of hypocrellins. Altogether, our study strongly supported the hypothesis that AS had a vital role in the regulation of hypocrellin biosynthesis under stresses, and initially explored whether SM functional genes were relevant for fungi.

High-efficiency biosynthesis of hypocrellin A in Shiraia sp. using gamma-ray mutagenesis.

Hypocrellin A (HA), well known as one of the best natural pigments and bioactive agent to treat skin diseases, is further anticipated to play a vital role in photodynamic therapy (PDT) in anticancer and antiviral treatments. In this study, an HA-producing strain ZZZ816 (Shiraia sp.) was isolated from the moso bamboo (Phyllostachys edulis) seeds, and gamma irradiation was used to mutagenize spores of the original strain. After treatment with cobalt-60 gamma ((60)Coγ) with different doses (20, 50, 80, 100, 150, 180, 300, and 500 Gy), the 100 Gy was selected as the optimal condition, which led to 77.2 % lethality of spores and 35 % positive mutant frequency. The extracted compound of the most excellent HA-producing strain (H-4-2) was precisely analyzed by a combination of seven detection methods, and the maximum HA content was shown to reach 2018.3 mg/L. HA production in H-4-2 increased by 414.9 % compared to that of original strain ZZZ816 (392 mg/L) and was significantly higher than all the other industrial HA-producing strains in published reports.

Radiomics in Carotid Plaque: A Systematic Review and Radiomics Quality Score Assessment.

Imaging modalities provide information on plaque morphology and vulnerability; however, they are operator dependent and miss a great deal of microscopic information. Recently, many radiomics models for carotid plaque that identify unstable plaques and predict cardiovascular outcomes have been proposed. This systematic review was aimed at assessing whether radiomics is a reliable and reproducible method for the clinical prediction of carotid plaque. A systematic search was conducted to identify studies published in PubMed and Cochrane library from January 1, 2001, to September 30, 2022. Both retrospective and prospective studies that developed and/or validated machine learning models based on radiomics data to classify or predict carotid plaques were included. The general characteristics of each included study were selected, and the methodological quality of radiomics reports and risk of bias were evaluated using the radiomics quality score (RQS) tool and Quality Assessment of Diagnostic Accuracy Studies-2, respectively. Two investigators independently reviewed each study, and the consensus data were used for analysis. A total of 2429 patients from 16 studies were included. The mean area under the curve of radiomics models for diagnostic or predictive performance of the included studies was 0.88 ± 0.02, with a range of 0.741-0.989. The mean RQS was 9.25 (standard deviation: 6.04), representing 25.7% of the possible maximum value of 36, whereas the lowest point was -2, and the highest score was 22. Radiomics models have revealed additional information on patients with carotid plaque, but with respect to methodological quality, radiomics reports are still in their infancy, and many hurdles need to be overcome.

Discovery of Antimetastatic Chiral Ionone Alkaloid Derivatives Targeting HIF-1α/VEGF/VEGFR2 Pathway.

Novel chiral ionone alkaloid derivatives were synthesized and their antimetastatic effects were evaluated in human breast cancer cells using chemotaxis assay. Compared with positive control LY294002, a PI3 K inhibitor, derivatives 10 a, 11 a, 11 c, 11 g, 11 j, 11 k and 11 w exhibited significant inhibitory effects against cancer cell migration. Especially, the IC50 for compound 11 g was as low as 0.035±0.004 µM. Further investigations on compound 11 g revealed that it could exert inhibitory effects on the adhesion, migration and invasion of MDA-MB-231 cells. The mechanisms for the antitumor metastatic effects of 11 g might be through the inhibition of HIF-1α/VEGF/VEGFR2/Akt pathway, which suppressed the downstream signaling molecules, including Akt1/mTOR/p70S6K and Akt2/PKCζ/integrin ß1 pathways. Taken together, chiral ionone alkaloid derivative 11 g has the potential to be developed into an antitumor metastatic agent for breast cancer.

Elevated triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio increased risk of hyperuricemia: a 4-year cohort study in China.

PURPOSE: Previous studies revealed that high serum uric acid (SUA) levels correlated with increased triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio. However, evidence is lacking regarding whether TG/HDL-C is an independent risk factor or just a simple marker of hyperuricemia. We aimed to investigate the relationship between TG/HDL-C and the risk of hyperuricemia in Chinese population. METHODS: This retrospective cohort study involved 15,198 subjects (43.14 ± 13.13 years, 54.9% men) who were free of hyperuricemia at baseline. The association between TG/HDL-C and the risk of hyperuricemia, in the total sample and stratified by subgroups, was examined by multiple logistic regression analyses. RESULTS: During 4 years follow-up, hyperuricemia occurred in 2365 (15.6%) participants. The cumulative incidence of hyperuricemia was significantly elevated with increasing TG/HDL-C quartiles (5.9, 10.8, 18.4, and 27.5%, respectively). After multivariate adjustment, the odds ratio for hyperuricemia in the highest compared with the lowest quartile of TG/HDL-C was 1.80 (95% confidence interval [CI] 1.49, 2.18), and each SD increment of TG/HDL-C ratio caused a 10% additional risk for hyperuricemia. Moreover, subgroup analyses showed that the association between TG/HDL-C and the risk of hyperuricemia was more pronounced in women and normal-weight adults. The results were consistent when analyses were restricted to participants without metabolic syndrome. CONCLUSIONS: TG/HDL-C ratio was positively related to the risk of hyperuricemia in Chinese population, particularly in women and normal-weight individuals. These findings suggested the potential of TG/HDL-C ratio to serve as an independent risk indicator in the prevention of hyperuricemia.

Differences of Matrix Metalloproteinase 2 Expression between Left and Right Ventricles in Response to Nandrolone Decanoate and/or Swimming Training in Mice.

BACKGROUND: Matrix metalloproteinase (MMP)-2 plays an important role in the remodeling of left ventricles (LVs) and right ventricles (RVs). We investigated the differences of MMP-2 expression between LV and RV in response to nandrolone decanoate (ND), swimming training (ST), and combined ND and ST (NS) in mice, based on their structural, functional, and biochemical characteristics. METHODS: Totally 28 male C57B1 mice (6 weeks old; 20-23 g) were divided into four groups, including the control (n = 7), ND (n = 6), ST (n = 8), and NS (n = 7) groups. After respective treatments for 8 weeks, echocardiographic examination was used to assess the cardiac structure and function. Van Gieson stain was used to examine the fibrosis of LV and RV in response to different treatments, and Western blotting analysis was performed to explore different MMP-2 expressions between LV and RV in response to ND and/or ST. Analysis of variance was used for comparing the four groups. RESULTS: At 8 weeks, right ventricular dimension/body weight in the ND group was larger than the other three groups (F = 7.12, P < 0.05) according to the echocardiographic examination. Fibrosis induced by ND administration was increased more in RV (2.59%) than that in LV (2.21%). MMP-2 expression of the ND group in RV was significantly greater than the control and NS groups in RV and the corresponding ND group in LV. CONCLUSION: The experimental data support the hypothesis that ND administration induces greater MMP-2 expression increase in RV compared to LV, leading to consequent RV dilation.

Safety of antithrombotic drugs in patients with atrial fibrillation and non-end-stage chronic kidney disease: Meta-analysis and systematic review.

OBJECTIVE: To evaluate the safety of antithrombotic drugs used in patients with both atrial fibrillation (AF) and non-end-stage chronic kidney disease (NECKD). METHODS: A search was performed for studies on major bleeding outcomes in patients with concurrent AF and NECKD using Medline and Cochrane databases on 19th February, 2015. Fixed- or random-effects meta-analysis was adopted for evaluating pooled effect sizes according to whether heterogeneity existed. RESULTS: Twelve articles were included for analysis. Three studies evaluated AF patients who took warfarin vs. placebo/antiplatelet drugs in the presence of NECKD. No significant difference in major bleeding risk was observed according to the pooled analysis using the random-effects model (RR: 1.05, 95% CI: 0.74-1.36). The risk of a composite of major bleeding outcomes was reduced by 19% in patients randomized to direct oral anticoagulants (DOACs) compared to dose-adjusted warfarin from pooled data of three randomized controlled trials with regard to AF and NECKD (RR: 0.81, 95% CI: 0.75-0.88). This superiority of DOACs to warfarin maintained until the renal function was severely impaired. CONCLUSIONS: In patients with AF and NECKD, no significant increase in the incidence of major bleeding outcomes was observed in warfarin use compared with placebo/antiplatelet drugs. DOACs reduced the risk of major bleeding by 19% compared to warfarin and further data-exploration indicated that the risk did not increase as renal function deteriorated during the renal status of mild to moderate impairment.

Value of Neutrophil Counts in Predicting Surgery-Related Acute Kidney Injury and the Interaction of These Counts With Diabetes in Chronic Kidney Disease Patients With Hypertension: A Cohort Study.

As a component of routine blood cell analyses, the quantity of neutrophils present is a proven predictor of morbidity and mortality in several clinical settings. However, whether episodes of acute kidney injury (AKI) are associated with higher neutrophil counts in vulnerable groups, such as chronic kidney disease (CKD) patients with hypertension, are unknown. This study was conducted to investigate the relationship between neutrophil counts and the incidence of surgery-related AKI in CKD patients with hypertension.This was a retrospective cohort study of the relationship between neutrophils and surgery-related AKI. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression models.In total, 119 (11.9%) of 998 patients experienced surgery-related AKI during hospitalization from October 2008 to February 2013. We divided patients into 4 quartiles according to their neutrophil counts. After adjusting for multiple covariates, the patients in the 4th quartile of neutrophil counts had greater ORs for AKI compared to those in the 1st quartile. The incidence of AKI increased 1.59-fold for those patients with neutrophil counts ≥6.30 × 10/L. There was a positive linear association between the neutrophil count upon admission and the predicted probability of AKI. The cross-validation revealed a statistically significant predictive accuracy for AKI (area under the curve (AUC) = 0.68, 95% CI, 0.67-0.69). The interaction analyses revealed that higher neutrophil counts are associated with a heightened risk of AKI in the presence of diabetes (OR = 3.38, 95% CI, 1.06-10.80). There were no interactions between neutrophil counts and age (P = 0.371), sex (P = 0.335), estimated glomerular filtration rate (P = 0.487), systolic blood pressure (P = 0.950), diastolic blood pressure (P = 0.977), the presence of chronic heart failure (P = 0.226), or sepsis (P = 0.796).The neutrophil count upon admission, an index that is easily and rapidly measured, is valuable for the prediction of surgery-related AKI in CKD patients with hypertension, especially in those with diabetes.

Differences in Quality of Life Between Atrial Fibrillation Patients with Low Stroke Risk Treated With and Without Catheter Ablation.

BACKGROUND: Impacts of a single radiofrequency ablation (RFA) on quality of life (QoL) were not well investigated in atrial fibrillation (AF) patients with low stroke risk. METHODS AND RESULTS: Nine hundred AF patients with low CHADS2 score (ie, CHADS2 ≤1) who completed both a baseline and 6-month Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) questionnaire were selected from The Chinese Atrial Fibrillation Registry between 2011 and 2013. A final cohort of 222 patients was constructed after a propensity score matching with 74 in the RFA group and 148 in the non-RFA group. Domains of AFEQT were balanced at baseline between the 2 groups. No statistically significant differences were noted in QoL (all P>0.05) when AFEQT at 6 months was compared between groups, except for the symptoms domain (83.07±12.37 units in the RFA group vs. 77.68±17.14 units in the non-RFA group; P=0.008) and treatment satisfaction domain (76.34±14.92 units in the RFA group vs. 70.38±16.81 units in the non-RFA group; P=0.01). Within-group changes in all domains and the global score of the questionnaire were moderate to large, whereas between-group comparisons in baseline to 6-month changes and QoL at 6 months were small to moderate according to Cohen effect sizes. CONCLUSIONS: QoL was balanced at baseline and improved at 6 months in both groups from this observational propensity-matched cohort based on the AFEQT questionnaire. However, RFA treatment was only associated with small-to-moderate superiorities over non-RFA treatment. The role of RFA in QoL improvement among AF patients with low stroke risk requires further research.

Every patient with atrial fibrillation has his (her) own optimal heart rate.

Heart rate control is an important part of atrial fibrillation (AF) treatment and the recommendation for the target rate has become lenient in the recent guideline. Since heart rhythm of AF patients is irregularly irregular with great rate variation, the number of effective ventricular contractions may be different within a given time period among patients with similar heart rates and it may further lead to different levels of cardiac output. Therefore, we propose that every AF patient has his (her) own optimal heart rate, or to say that, the target for rate control in each AF patient should be individualized. This optimal heart rate can be defined by pulse counting, echocardiography or cardiopulmonary exercise test. With this new target, patients will achieve higher cardiac output with better exercise tolerance and life quality, even an improved prognosis.