Analysis of the effect of CYP2C19 gene properties on the anti-platelet aggregation of clopidogrel after carotid artery stenting under network pharmacology.

Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count.

Endometriosis and epithelial ovarian cancer: a two-sample Mendelian randomization analysis.

Endometriosis, a prevalent condition, has long been recognized as a chronic and debilitating ailment affecting an estimated 1790 million women worldwide. Observational studies have established a correlation between endometriosis and ovarian cancer. Thus, we endeavored to employ Two-Sample Mendelian Randomization, utilizing summary statistics from a Genome-Wide Association Study of endometriosis and epithelial ovarian cancer, with genetic markers serving as proxies for epithelial ovarian cancer. The analysis revealed a significant correlation between these entities, with an odds ratio (OR) of 1.23 (95% CI 1.11-1.36). Upon histotype-specific examination, robust evidence emerged for an association of endometriosis with the risk of endometrioid carcinoma (OR 1.49, 95% CI 1.24-1.81), clear cell carcinoma (OR 2.56, 95% CI 1.75-3.73), and low malignant potential tumors (OR 1.28, 95% CI 1.08-1.53). These findings provide a theoretical framework for prospective investigations aimed at enhancing the potential therapeutic efficacy of managing endometriosis in averting the onset and progression of ovarian cancer.

Association between Cardiovascular Response and Inflammatory Cytokines in Non-Small Cell Lung Cancer Patients.

Cardiovascular disease is an essential comorbidity in patients with non-small cell lung cancer (NSCLC) and represents an independent risk factor for increased mortality. Therefore, careful monitoring of cardiovascular disease is crucial in the healthcare of NSCLC patients. Inflammatory factors have previously been associated with myocardial damage in NSCLC patients, but it remains unclear whether serum inflammatory factors can be utilized to assess the cardiovascular health status in NSCLC patients. A total of 118 NSCLC patients were enrolled in this cross-sectional study, and their baseline data were collected through a hospital electronic medical record system. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of leukemia inhibitory factor (LIF), interleukin (IL)-18, IL-1ß, transforming growth factor-ß1 (TGF-ß1), and connective tissue growth factor (CTGF). Statistical analysis was performed using the SPSS software. Multivariate and ordinal logistic regression models were constructed. The data revealed an increased serum level of LIF in the group using tyrosine kinase inhibitor (TKI)-targeted drugs compared to non-users (p < 0.001). Furthermore, serum TGF-ß1 (area under the curve, AUC: 0.616) and cardiac troponin T (cTnT) (AUC: 0.720) levels were clinically evaluated and found to be correlated with pre-clinical cardiovascular injury in NSCLC patients. Notably, the serum levels of cTnT and TGF-ß1 were found to indicate the extent of pre-clinical cardiovascular injury in NSCLC patients. In conclusion, the results suggest that serum LIF, as well as TGFß1 together with cTnT, are potential serum biomarkers for the assessment of cardiovascular status in NSCLC patients. These findings offer novel insights into the assessment of cardiovascular health and underscore the importance of monitoring cardiovascular health in the management of NSCLC patients.

Cannabinoid Receptor 2-Centric Molecular Feedback Loop Drives Necroptosis in Diabetic Heart Injuries.

BACKGROUND: Diabetic heart dysfunction is a common complication of diabetes. Cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise time to intervene of particular cell death type remain largely unknown in the diabetic heart. This study aims to identify the particular cell death type that is responsible for diabetic heart dysfunction and to propose a promising therapeutic strategy by intervening in the cell death pathway. METHODS: Type 2 diabetes models were established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. The type 1 diabetes model was established in streptozotocin-induced mice. Apoptosis and programmed cell necrosis (necroptosis) were detected in diabetic mouse hearts at different ages. G protein-coupled receptor-targeted drug library was searched to identify potential receptors regulating the key cell death pathway. Pharmacological and genetic approaches that modulate the expression of targets were used. Stable cell lines and a homemade phosphorylation antibody were prepared to conduct mechanistic studies. RESULTS: Necroptosis was activated after apoptosis at later stages of diabetes and was functionally responsible for cardiac dysfunction. Cannabinoid receptor 2 (CB2R) was a key regulator of necroptosis. Mechanically, during normal glucose levels, CB2R inhibited S6 kinase-mediated phosphorylation of BACH2 at serine 520, thereby leading to BACH2 translocation to the nucleus, where BACH2 transcriptionally repressed the necroptosis genes Rip1, Rip3, and Mlkl. Under hyperglycemic conditions, high glucose induced CB2R internalization in a ß-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. Cardiac re-expression of CB2R rescued diabetes-induced cardiomyocyte necroptosis and heart dysfunction, whereas cardiac knockout of Bach2 diminished CB2R-mediated beneficial effects. In human diabetic hearts, both CB2R and BACH2 were negatively associated with diabetes-induced myocardial injuries. CONCLUSIONS: CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. Our study provides the integrative view of a novel molecular mechanism loop for regulation of necroptosis centered by CB2R, which represents a promising alternative strategy for controlling diabetic heart dysfunction.

Protections of transcription factor BACH2 and natural product myricetin against pathological cardiac hypertrophy and dysfunction.

Pathological hypertrophic myocardium under consistent adverse stimuli eventually can cause heart failure. This study aims to explore the role of BACH2, a member of the basic region leucine zipper transcription factor family, in cardiac hypertrophy and failure. Transverse aortic constriction surgery was operated to induce cardiac hypertrophy and failure in mice. BACH2 was overexpressed in mice through tail vein injection of AAV9-Bach2. Mice with systemic or cardiac-specific knockdown of Bach2 were adopted. Neonatal rat ventricular myocytes (NRVMs) were isolated and infected with lentivirus to overexpress Bach2 or transfected with siRNA to knock down Bach2. Our data showed that overexpression of BACH2 ameliorated TAC-induced cardiac hypertrophy and failure in mice and decreased isoproterenol (ISO)-triggered myocyte hypertrophy in NRVMs. Systemic or cardiac-specific knockdown of Bach2 worsened the cardiac hypertrophy and failure phenotype in mice. Further assays showed that BACH2 bound to the promotor region of Akap6 at the -600 to -587 site and repressed its expression, which functioned as a crucial scaffold for cardiac hypertrophy and failure signaling pathways. Small molecular natural product library screening suggested that myricetin could up-regulate expression of Bach2 and simultaneously suppress the transcriptional levels of hypertrophic marker genes Bnp and Myh7. Further studies showed that myricetin exerted a BACH2-dependent protective effect against cardiac hypertrophy in vivo and in vitro. Taken together, our findings demonstrated that BACH2 plays a crucial role in the regulation of cardiac hypertrophy and failure and can be a potential therapeutic target in the future.

CB1R-stabilized NLRP3 inflammasome drives antipsychotics cardiotoxicity.

Long-term use of antipsychotics is a common cause of myocardial injury and even sudden cardiac deaths that often lead to drug withdrawn or discontinuation. Mechanisms underlying antipsychotics cardiotoxicity remain largely unknown. Herein we performed RNA sequencing and found that NLRP3 inflammasome-mediated pyroptosis contributed predominantly to multiple antipsychotics cardiotoxicity. Pyroptosis-based small-molecule compound screen identified cannabinoid receptor 1 (CB1R) as an upstream regulator of the NLRP3 inflammasome. Mechanistically, antipsychotics competitively bond to the CB1R and led to CB1R translocation to the cytoplasm, where CB1R directly interacted with NLRP3 inflammasome via amino acid residues 177-209, rendering stabilization of the inflammasome. Knockout of Cb1r significantly alleviated antipsychotic-induced cardiomyocyte pyroptosis and cardiotoxicity. Multi-organ-based investigation revealed no additional toxicity of newer CB1R antagonists. In authentic human cases, the expression of CB1R and NLRP3 inflammasome positively correlated with antipsychotics-induced cardiotoxicity. These results suggest that CB1R is a potent regulator of the NLRP3 inflammsome-mediated pyroptosis and small-molecule inhibitors targeting the CB1R/NLRP3 signaling represent attractive approaches to rescue cardiac side effects of antipsychotics.

Fine particulate matter air pollution and subclinical cardiovascular outcomes: A longitudinal study in 15 Chinese cities.

AIMS: Although previous studies have linked short-term exposure to fine particulate matter (PM2.5) air pollution with various molecular biomarkers of cardiovascular system, limited evidence is available for indicators at clinical or subclinical levels. We examined the associations between short-term PM2.5 exposure and a range of clinical or subclinical indicators of cardiovascular health in general population. METHODS AND RESULTS: A longitudinal repeated-measure study was conducted among 247,640 participants who repeatedly visited health examination centers in 15 typical cities across China from 2013 to 2020. A total of 19 well-established indicators of cardiovascular risk or injury were evaluated and air quality data at nearest fixed-site monitors were collected. Linear mixed-effects models with distributed lag models were used to analyze the potentially lagged effects of PM2.5. The average daily PM2.5 concentration was 48 µg/m3 during the study period. PM2.5 exposure was associated with significant changes of 16 indicators with the effects generally peaked on lag 0 to 3 day. For an interquartile range (IQR) elevation (37 µg/m3) in PM2.5 concentrations over lag 0-7 day, the cumulative percentage changes were 0.50% to 1.27% in heart rates and blood pressure, 0.10% to 5.04% in inflammatory markers, -0.29% to 1.39% in blood viscosity parameters, -0.67% to 3.45% in blood lipids, 0.89% in blood homocysteine, 0.13% to 0.78% in myocardial enzymes, and 3.03% in pulse wave velocity. These associations were not substantially changed after adjusting concomitant exposures to gaseous pollutants. CONCLUSION: Short-term exposure to PM2.5 may induce early cardiovascular effects in general population, including acute inflammation, myocardial injury, increased blood viscosity, vascular stiffness and hyperlipidemia.

Inverse Associations Between Circulating Secreted Frizzled Related Protein 2 (sFRP2) and Cardiometabolic Risk Factors.

Background: Secreted frizzled-related protein 2 (sFRP2) plays an important role in metabolic syndrome and cardiovascular diseases (CVDs); However, its relevance with cardiometabolic diseases remains to be elucidated. We aimed to determine the serum levels of sFRP2 in patients at different stages of heart failure (HF) with or without type 2 diabetes mellitus (T2DM), and assess the correlation between circulating sFRP2 levels and cardiometabolic risk factors. Methods: In this study, serum samples from 277 patients visiting Zhongshan Hospital affiliated to Fudan University were collected. These patients were clinically diagnosed and categorized as five groups, including the control group, pre-clinical HF group, pre-clinical HF+T2DM group, HF group and HF+T2DM group. Serum sFRP2 levels were measured with enzyme-linked immunosorbent assay (ELISA) tests and the clinical characteristics of each patient were recorded. Spearman rank correlation analysis and multiple stepwise linear regression analysis were conducted. Univariate and multivariate logistic regression analysis were performed to screen risk factors for HF in patients with CVDs. Results: Serum sFRP2 levels were significantly lower in the HF+T2DM group compared with the other four groups. Spearman rank correlation analysis showed that sFRP2 was negatively correlated with parameters including patients' age, fasting plasma glucose (FPG), glycated hemoglobin A1c (HbA1c), cardiac troponin T (cTNT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), left atrial dimension (LAD) and left ventricular posterior wall (LVPW), and positively correlated with hemoglobin, estimated glomerular filtration rate (eGFR), albumin, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and left ventricular ejection fraction (LVEF). However, in multiple regression analysis, significant associations with ln(sFRP2) were observed only in FPG, hs-CRP and LAD. Higher serum sFRP2 was significantly linked to lower odds of HF in patients with CVDs. Conclusion: sFRP2 progressively decreased when glucose homeostasis and cardiac function deteriorated. sFRP2 acted as a risk factor for HF in patients with CVDs, especially in those with concomitant T2DM.

Detection of microalgae objects based on the Improved YOLOv3 model.

Microalgae play a major role in the invasion of alien organisms with ballast water as a carrier, and traditional ballast water detection methods have many limitations in identifying microalgae species. Therefore, this paper proposes a method to identify microalgae in ballast water based on an Improved YOLOv3 model. The method first used a lightweight network MobileNet instead of the Darknet-53 network as the backbone network of feature extraction in the original YOLOv3 model. Secondly, improved spatial pyramid pooling (SPP) is introduced to pool and concatenate the multi-scale regional features so as to reduce the position error when detecting small objects. Then, by considering the overlap area of the bounding box, central point distance and aspect ratio, the Complete IoU (CIoU) algorithm is used to optimize the loss function of the YOLOv3 model. Finally, the proposed method is experimentally compared with other latest methods on the established dataset. The experimental results demonstrated that under the same conditions, this Improved YOLOv3 model achieves an average accuracy of 98.90%, and the detection efficiency is 8.59% higher than that of the original YOLOv3 model and is better than the existing methods. The average time of this method to identify a single image is 0.086 s, and it has a good detection effect on the identification of microalgae species.

Design, synthesis and biological evaluation of 1,4-Diazobicylco[3.2.2]nonane derivatives as α7-Nicotinic acetylcholine receptor PET/CT imaging agents and agonists for Alzheimer's disease.

α7-Nicotinic acetylcholine receptor (α7-nAChR) agonists are promising therapeutic drug candidates for treating the cognitive impairment associated with Alzheimer's disease (AD). Thus, a novel class of derivatives of 1,4-diazobicylco[3.2.2]nonane has been synthesized and evaluated as α7-nAChR ligands. Five of them displayed high binding affinity (Ki = 0.001-25 nM). In particular, the Ki of 14 was 0.0069 nM, which is superior to that of the most potent ligand that was previously reported by an order of magnitude. Four of them had high selectivity for α7-nAChRs over α4ß2-nAChRs and no significant hERG (human ether-a-go-go-related gene) inhibition. Their agonist activity was also discussed preliminarily. One of the compounds, 15 (Ki = 2.98 ±â€¯1.41 nM), was further radiolabeled with 18F to afford [18F]15 for PET imaging, which exhibited high initial brain uptake (11.60 ±â€¯0.14%ID/g at 15 min post injection), brain/blood value (9.57 at 30 min post injection), specific labeling of α7-nAChRs and fast clearance from the brain. Blocking studies demonstrated that [18F]15 was α7-nAChR selective. In addition, micro-PET/CT imaging in normal rats further indicated that [18F]15 had obvious accumulation in the brain. Therefore, [18F]15 was proved to be a potential PET radiotracer for α7-nAChR imaging.

[Relationships of rice canopy PAR interception and light use efficiency to grain yield].

Taking two rice cultivars (Liangyoupeijiu and Wuxiangjing 14) with different plant types as test materials, a 2-year field experiment was conducted to study the relationships of rice canopy photosynthetically active radiation (PAR) interception and light use efficiency to grain yield under three planting densities and five nitrogen (N) application rates. From tillering to maturing stage, the average PAR reflectance in all treatments was 3.45%. The ratio of reflected PAR to the total loss of PAR from tillering to heading stage was 10.90%, which was significantly lower than that (22.06%) from heading to maturiting stage. The PAR conversion efficiency from tillering to maturing stage decreased with increasing planting density but increased with increasing nitrogen rate, and the conversion efficiency was significantly higher from tillering to heading than from heading to maturing stage. The PAR use efficiency from tillering to maturing stage increased with the increase of planting density and nitrogen application rate, and the average PAR use efficiency of Liangyoupeijiu (1.83 g x MJ(-1)) was significantly higher than that of Wuxiangjing 14 (1.42 g x MJ(-1)). Due to the longer growth period of Wuxiangjing 14, its incident PAR and intercepted PAR under midium and high planting densities were higher, as compared with Liangyoupeijiu. The grain yield was significantly positively correlated with the canopy PAR interceptance and use efficiency at different growth stages, but less correlated with the PAR conversion efficiency. To increase the canopy PAR use efficiency and conversion efficiency on the basis of maintaining higher PAR interception rate could be an effective way to increase rice yield.