A device-related fistula between coronary artery and left atrial appendage following left atrial appendage closure: Case presentation.

INTRODUCTION: Left atrial appendage (LAA) closure (LAAC) is considered a viable alternative to anticoagulation therapy for stroke prevention in nonvalvular atrial fibrillation, we report a case with a less common shunt resulting from a device-related coronary artery-appendage fistula (CAAF) following LAAC. METHODS AND RESULTS: A 67-year-old male with a history of LAAC was referred to our emergency room with recurrent chest pain and palpitations and was diagnosed with ischemic angina pectoris. Subsequent coronary angiography (CAG) revealed 70% in-stent restenosis and an abnormal shunt of contrast originating from the left circumflex artery (LCA) to the LAA tip which did not exist before. The restenosis was successfully dilated using a drug-coated balloon, the procedure was safely completed without pericardial effusion. The patient had been implanted with a LAmbre occluder (Lifetech Scientific Corp.) in the previous LAAC procedure. This occluder had a lobe-disk design, and the distal umbrella was not fully opened after release, particularly in the lower portion. This could make the hooks embedded on the umbrella contact the LAA wall more tightly, possibly resulting in microperforation and coincidental impingement of the LCA. The epicardial adipose and hyperplastic tissue then chronically wrapped the perforated site, prevented blood outflow into the epicardium, and ultimately formed a CAAF. CONCLUSION: CAAF is a rare complication after LAAC but may be underestimated, especially for lobe-disk designed occluders. Therefore, CAG is perhaps necessary to detect this complication.

The individuals' awareness and adoption of electronic health records in China: a questionnaire survey of 1,337 individuals.

BACKGROUND: Electronic health records (EHRs) are digital records of individual health information. However, their adoption and utilization remain low. This study explores the factors influencing the implementation of EHRs through a questionnaire survey to enhance individual awareness and adoption of EHRs. METHODS: A questionnaire and an expert rating scale were developed sequentially, and the consistency of the scores from five experts was calculated using Kendall's W to generate a final questionnaire. A non-parametric test was utilized to analyze differences in continuous data that did not follow a normal distribution. Categorical variables were expressed as percentages (%), the chi-square test was employed for group comparisons, and multiple logistic regression was implemented to assess individuals' awareness and adoption of EHRs. RESULTS: In total, 1,341 survey questionnaires were distributed between January and December 2022, with 1,337 valid responses (99.7%). The results indicated that the proportion of participants who were aware of EHRs and had a bachelor's degree or higher education, an income of ≥$700 per month, residence in urban areas, possessed self-care abilities, and underwent annual physical examinations was significantly higher than that without awareness of EHRs (P < 0.05), while in hearing problems and walking abilities was markedly lower than that of participants without awareness of EHRs (P < 0.05). Additionally, the proportion of individuals willing to self-manage EHRs was significantly higher than those reluctant to do so (P < 0.05) among participants with a bachelor's degree or higher education, an income of ≥$700 per month, residence in urban areas, possession of self-care abilities, annual physical examinations, hearing problems, and poor walking abilities. Age (Odds Ratio [OR] = 1.104, 95% Confidence Interval [CI] 1.001-1.028, P = 0.033), hearing problems (OR = 0.604, 95% CI 0.377-0.967, P = 0.036), self-care ability (OR = 5.881, 95% CI 1.867-18.529, P = 0.002), and annual physical examinations (OR = 3.167, 95% CI 2.31-4.34, P < 0.001) were independently associated with willingness to self-manage EHRs. Annual physical examination (OR = 2.507, 95%CI 1.585-2.669, P < 0.001) also independently made a difference to the awareness of EHRs. CONCLUSIONS: Our findings suggest that annual physical examinations, age, hearing problems, and self-care abilities are significant factors in assessing individuals' awareness and adoption of EHRs. Understanding the characteristics of individuals who are aware of or are willing to take advantage of EHRs plays a positive role in promoting their popularization and application.

TNFSF14/LIGHT promotes cardiac fibrosis and atrial fibrillation vulnerability via PI3Kγ/SGK1 pathway-dependent M2 macrophage polarisation.

BACKGROUND: Tumour necrosis factor superfamily protein 14 (TNFSF14), also called LIGHT, is an important regulator of immunological and fibrosis diseases. However, its specific involvement in cardiac fibrosis and atrial fibrillation (AF) has not been fully elucidated. The objective of this study is to examine the influence of LIGHT on the development of myocardial fibrosis and AF. METHODS: PCR arrays of peripheral blood mononuclear cells (PBMCs) from patients with AF and sinus rhythm was used to identify the dominant differentially expressed genes, followed by ELISA to evaluate its serum protein levels. Morphological, functional, and electrophysiological changes in the heart were detected in vivo after the tail intravenous injection of recombinant LIGHT (rLIGHT) in mice for 4 weeks. rLIGHT was used to stimulate bone marrow-derived macrophages (BMDMs) to prepare a macrophage-conditioned medium (MCM) in vitro. Then, the MCM was used to culture mouse cardiac fibroblasts (CFs). The expression of relevant proteins and genes was determined using qRT-PCR, western blotting, and immunostaining. RESULTS: The mRNA levels of LIGHT and TNFRSF14 were higher in the PBMCs of patients with AF than in those of the healthy controls. Additionally, the serum protein levels of LIGHT were higher in patients with AF than those in the healthy controls and were correlated with left atrial reverse remodelling. Furthermore, we demonstrated that rLIGHT injection promoted macrophage infiltration and M2 polarisation in the heart, in addition to promoting atrial fibrosis and AF inducibility in vivo, as detected with MASSON staining and atrial burst pacing respectively. RNA sequencing of heart samples revealed that the PI3Kγ/SGK1 pathway may participate in these pathological processes. Therefore, we confirmed the hypothesis that rLIGHT promotes BMDM M2 polarisation and TGB-ß1 secretion, and that this process can be inhibited by PI3Kγ and SGK1 inhibitors in vitro. Meanwhile, increased collagen synthesis and myofibroblast transition were observed in LIGHT-stimulated MCM-cultured CFs and were ameliorated in the groups treated with PI3Kγ and SGK1 inhibitors. CONCLUSION: LIGHT protein levels in peripheral blood can be used as a prognostic marker for AF and to evaluate its severity. LIGHT promotes cardiac fibrosis and AF inducibility by promoting macrophage M2 polarisation, wherein PI3Kγ and SGK1 activation is indispensable.

Alterations in gut microbiota and host transcriptome of patients with coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a widespread heart condition caused by atherosclerosis and influences millions of people worldwide. Early detection of CAD is challenging due to the lack of specific biomarkers. The gut microbiota and host-microbiota interactions have been well documented to affect human health. However, investigation that reveals the role of gut microbes in CAD is still limited. This study aims to uncover the synergistic effects of host genes and gut microbes associated with CAD through integrative genomic analyses. RESULTS: Herein, we collected 52 fecal and 50 blood samples from CAD patients and matched controls, and performed amplicon and transcriptomic sequencing on these samples, respectively. By comparing CAD patients with health controls, we found that dysregulated gut microbes were significantly associated with CAD. By leveraging the Random Forest method, we found that combining 20 bacteria and 30 gene biomarkers could distinguish CAD patients from health controls with a high performance (AUC = 0.92). We observed that there existed prominent associations of gut microbes with several clinical indices relevant to heart functions. Integration analysis revealed that CAD-relevant gut microbe genus Fusicatenibacter was associated with expression of CAD-risk genes, such as GBP2, MLKL, and CPR65, which is in line with previous evidence (Tang et al., Nat Rev Cardiol 16:137-154, 2019; Kummen et al., J Am Coll Cardiol 71:1184-1186, 2018). In addition, the upregulation of immune-related pathways in CAD patients were identified to be primarily associated with higher abundance of genus Blautia, Eubacterium, Fusicatenibacter, and Monoglobus. CONCLUSIONS: Our results highlight that dysregulated gut microbes contribute risk to CAD by interacting with host genes. These identified microbes and interacted risk genes may have high potentials as biomarkers for CAD.

Nano hydrogel-based oxygen-releasing stem cell transplantation system for treating diabetic foot.

The employment of stem cells and hydrogel is widespread in contemporary clinical approaches to treating diabetic foot ulcers. However, the hypoxic conditions in the surrounding lesion tissue lead to a low stem cell survival rate following transplantation. This research introduces a novel hydrogel with superior oxygen permeability and biocompatibility, serving as a vehicle for developing a stem cell transplantation system incorporating oxygen-releasing microspheres and cardiosphere-derived stem cells (CDCs). By optimizing the peroxidase fixation quantity on the microsphere surface and the oxygen-releasing microsphere content within the transplantation system, intracellular oxygen levels were assessed using electron paramagnetic resonance (EPR) under simulated low-oxygen conditions in vitro. The expression of vascularization and repair-related indexes were evaluated via RT-PCR and ELISA. The microspheres were found to continuously release oxygen for three weeks within the transplantation system, promoting growth factor expression to maintain intracellular oxygen levels and support the survival and proliferation of CDCs. Moreover, the effect of this stem cell transplantation system on wound healing in a diabetic foot mice model was examined through an in vivo animal experiment. The oxygen-releasing microspheres within the transplantation system preserved the intracellular oxygen levels of CDCs in the hypoxic environment of injured tissues. By inhibiting the expression of inflammatory factors and stimulating the upregulation of pertinent growth factors, it improved the vascularization of ulcer tissue on the mice's back and expedited the healing of the wound site. Overall, the stem cell transplantation system in this study, based on hydrogels containing CDCs and oxygen-releasing microspheres, offers a promising strategy for the clinical implementation of localized stem cell delivery to improve diabetic foot wound healing.

Predictive value of coronary artery computed tomography-derived fractional flow reserve for cardiovascular events in patients with coronary artery disease.

BACKGROUND: Coronary computed tomography-derived fractional flow reserve (FFR-CT) assesses whether coronary artery lesions will result in myocardial ischemia. This study aimed to evaluate the predictive value of FFR-CT for cardiovascular events in patients with coronary artery disease (CAD). METHODS: Data were collected retrospectively from patients with CAD who underwent FFR-CT at our hospital from January 2020 to February 2022 (1-year average follow-up). Patients were divided into ischemic (FFR-CT ≤ 0.80) and non-ischemic (FFR-CT > 0.80) groups. The incidence of endpoint events (cardiac death, acute myocardial infarction, unplanned revascularization, unstable angina, and stable angina) was calculated. The FFR-CT value was correlated with endpoint events using Cox regression models and Kaplan-Meier survival curves. RESULTS: We recruited 134 patients (93 [69.4%] and 41 [30.6%] patients in the ischemic and non-ischemic groups, respectively). The ischemic group had a higher proportion of men, patients with type 2 diabetes and hypertension, and patients taking antiplatelet drugs and ß­blockers than did the non-ischemic group (all p < 0.05), whereas other parameters were comparable. Multivariate Cox regression analysis revealed no significant differences in cardiac death, acute myocardial infarction, unplanned revascularization, and unstable angina between the groups. The incidence of stable angina events (hazard ratio: 3.092, 95% confidence interval: 1.362-7.022, p = 0.007) was significantly higher in the ischemic group. Kaplan-Meier survival analysis revealed a significant difference in event-free survival for stable angina between the groups (p = 0.002). CONCLUSION: In patients with CAD, FFR-CT showed an independent predictive value for stable angina within 1 year of examination.

Atractylenolide-III alleviates osteoarthritis and chondrocyte senescence by targeting NF-κB signaling.

Atractylenolide-III (AT-III) is well known as its role in antioxidant and anti-inflammatory. Present study was aimed to figure out its effects on osteoarthritis and potential mechanisms. Rat model, human osteoarthritis cartilage explants as well as rat/human chondrocyte cultures were prepared to test AT-III's effects on osteoarthritis progression and chondrocyte senescence. Potential targeted molecules of AT-III were predicted using network pharmacology and molecular docking, assessed by Western blotting and then verified with rescue experiments. AT-III treatment alleviated osteoarthritis severity (shown by OARSI grading score and micro-CT) and chondrocyte senescence (indexed by levels of SA-ß-gal, P16, P53, MMP13, ROS and ratio of healthy/collapsed mitochondrial membrane potentials). Network pharmacology and molecular docking suggested that AT-III might play role through NF-κB pathway. Further experiments revealed that AT-III reduced phosphorylation of IKKα/ß, IκBα and P65 in NF-κB pathway. As well as nuclear translocation of p65. Both in vivo and in vitro experiments indicated that AT-III's effects on osteoarthritis and anti-senescence were reversed by an NF-κB agonist. AT-III could alleviate osteoarthritis by inhibiting chondrocyte senescence through NF-κB pathway, which indicated that AT-III is a prospective drug for osteoarthritis treatment.

The structure, antioxidant activity, and stability of fish gelatin/chitooligosaccharide nanoparticles loaded with apple polyphenols.

BACKGROUND: Apple polyphenols (APs) with multiple biological effects have attracted extensive attention due to their broad opportunities for application. However, the use of APs is hampered by their instability in the face of environmental changes. Designing efficient carriers to improve the bioavailability of APs is the key to solving these problems. In this study, gelatin-chitooligosaccharide nanoparticles produced by the Maillard reaction (GCM) were fabricated to encapsulate AP, and the structure, antioxidant activity, and stability of the GMM-AP nanoparticle system were evaluated. RESULTS: The results of endogenous fluorescence spectrum, Fourier-transform infrared (FTIR) spectroscopy, X-ray diffraction, and simultaneous thermal analysis confirmed structural changes and interactions between GCM and AP. Combination with GCM did not adversely affect the antioxidant properties of AP, and the GCM-AP nanoparticles possessed superior temperature and storage stability. In comparison with fish gelatin-apple polyphenol nanoparticles, the GCM-AP nanoparticles were more stable at a wider pH range, and were more resistant to the electrostatic shielding effect of NaCl. After simulating gastric digestion, the particle size and polydispersity index (PDI) of GCM-AP nanoparticles were almost unchanged. CONCLUSION: The findings suggest that GCM nanoparticles loaded with AP could be used as good carriers with good antioxidant activity and stability. This study therefore provides a theoretical foundation for the development and industrial application of food functional factors. © 2023 Society of Chemical Industry.

Utilizing a Combination of Network Pharmacology and Experimental Validation to Unravel the Mechanism by Which Kuanxiongzhuyu Decoction Ameliorates Myocardial Infarction Damage.

Background and Objectives: With the growing incidence and disability associated with myocardial infarction (MI), there is an increasing focus on cardiac rehabilitation post-MI. Kuanxiongzhuyu decoction (KXZY), a traditional Chinese herbal formula, has been used in the rehabilitation of patients after MI. However, the chemical composition, protective effects, and underlying mechanism of KXZY remain unclear. Materials and Methods: In this study, the compounds in KXZY were identified using a high-performance liquid chromatography-mass spectrometry (HPLC-MS) analytical method. Based on the compounds identified in the KXZY, we predictively selected the potential targets of MI and then constructed a protein-protein interaction (PPI) network to identify the key targets. Furthermore, the DAVID database was used for the GO and KEGG analyses, and molecular docking was used to verify the key targets. Finally, the cardioprotective effects and mechanism of KXZY were investigated in post-MI mice. Results: A total of 193 chemical compounds of KXZY were identified by HPLC-MS. In total, 228 potential targets were obtained by the prediction analysis. The functional enrichment studies and PPI network showed that the targets were largely associated with AKT-pathway-related apoptosis. The molecular docking verified that isoguanosine and adenosine exhibited excellent binding to the AKT. In vivo, KXZY significantly alleviated cardiac dysfunction and suppressed AKT phosphorylation. Furthermore, KXZY significantly increased the expression of the antiapoptotic proteins Bcl-2 and Bcl-xl and decreased the expression of the proapoptotic protein BAD. Conclusions: In conclusion, the network pharmacological and experimental evidence suggests that KXZY manifests anti-cardiac dysfunction behavior by alleviating cardiomyocyte apoptosis via the AKT pathway in MI and, thus, holds promising therapeutic potential.

Natural products from traditional Chinese medicine for the prevention and treatment of heart failure: progress and perspectives.

Heart failure (HF) is the end stage of several cardiovascular diseases with high mortality worldwide; however, current chemical drugs have not beneficial effect on reducing its mortality rate. Due to its properties of multiple targets components with multiple targets, natural products derived from traditional Chinese medicine (TCM) have exerts unique effects on the amelioration of the clinical symptoms of HF, yet, TCM is not widely used in the clinic since the potential therapeutic targets have not been fully investigated. Therefore, in this review, we briefly summarized the pathophysiological mechanism of HF and reviewed the published clinical evaluations of TCM and natural products from Chinese herbs to treat HF. Then, the therapeutic potential and the underlying mechanisms by which the natural products from Chinese herb exert their protective effects were further summarized. We concluded from this review that natural products from Chinese herbs have been shown to be more effective in treating HF by targeting multiple signaling pathways, including anticardiac hypertrophy, antifibrotic, anti-inflammatory, antioxidative and antiapoptotic activities. However, the major limitations of these compounds is that there are a lack of large scale, multicenter, randomized and controlled clinical trials for their use in treatment of HF, and the toxic effects of natural products from Chinese herbs also needed further investigation. Despite these limitations, further clinical trials and experimental studies will provide a better understanding of the mechanism of natural products from Chinese herbs and promote their wide use to treat HF.

Heparin-induced thrombocytopenia post-cardiovascular interventional therapy: a case report.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction characterized by thrombocytopenia and thromboembolism. Herein, we present a case of HIT with subcutaneous hemorrhage after cardiovascular interventional therapy. CASE PRESENTATION: A 74-year-old man was admitted to the hospital for elective atrial fibrillation (AF) catheter ablation and left atrial appendage closure because of intermittent dizziness and palpitations. At presentation, the routine laboratory test results showed no abnormalities. He received subcutaneous enoxaparin for stroke prevention and unfractionated heparin for intraprocedural anticoagulation during coronary angiography and the AF procedure. On the second day after the AF procedure, the patient developed profound thrombocytopenia, moderate anemia, and mild subcutaneous hematoma. Blood tests and imaging examinations excluded acute hemolysis and other active bleeding. A 4Ts score of 5 and markedly positive platelet factor 4 IgG antibody established the diagnosis of HIT. Due to progressive subcutaneous hemorrhage in the thighs that could not be suppressed by pressure dressing, the patient received platelet transfusion and rivaroxaban for anticoagulation. The following days, the patient remained clinically stable from the hemorrhage, and his platelet count recovered. No thrombotic events occurred during hospitalization or follow-up. CONCLUSION: This case emphasizes the significance of suspecting HIT in patients with unexplained rapid thrombocytopenia after frequent heparin exposure. Decision-making regarding alternative anticoagulation and platelet transfusion in HIT with hemorrhage must be based on unique patient characteristics.

Clinical impact of posterior wall isolation in catheter ablation for persistent atrial fibrillation: A systematic review and meta-analysis.

BACKGROUND: The clinical outcomes of pulmonary venous isolation alone for persistent atrial fibrillation (PerAF) remain unclear. Adjuvant posterior wall isolation (PWI) has become a potential supplementary strategy for improving the outcome of PerAF ablation. This meta-analysis aimed to evaluate the effect of PWI added to catheter ablation for PerAF. METHODS: PubMed, EMBASE, and Cochrane Library databases were searched for studies comparing the outcomes of PerAF ablation with and without PWI. The efficacy outcomes were recurrence of atrial arrhythmia (AA), atrial fibrillation (AF), and atrial tachycardia (AT), and the safety outcome was adverse events. RESULTS: In total, eight studies with 1428 patients were included in the pooled analyses. The results showed that PWI significantly reduced the recurrence of AA (RR = 0.69, 95% CI = 0.55-0.87, p = .002, I2  = 63%) and AF (RR = 0.57, 95% CI = 0.40-0.80, p = .001, I2  = 70%). AT recurrence (RR = 0.92, 95% CI = 0.67-1.27, p = .63, I2  = 42%) and adverse events (RR = 1.11, 95% CI = 0.67-1.84, p = .70, I2  = 0%) were comparable between the two groups. In the sub-analyses, the efficacy of PWI in reducing AA recurrence was consistent in patients who underwent cryoablation or debulking ablation. CONCLUSION: PWI effectively decreased AA recurrence after PerAF ablation without increasing the risk of AT or procedure-related complications. However, more randomized studies are needed to confirm these results.

Safety and efficacy of high power shorter duration ablation for atrial fibrillation: A systematic review and meta-analysis.

BACKGROUND: Radiofrequency ablation in patients with atrial fibrillation (AF) is effective but hampered by pulmonary veins reconnection because of insufficient lesions. High power shorter duration ablation (HPSD) was seen to increase efficacy and safety. This analysis aimed to evaluate the clinical benefits of HPSD in patients with AF. METHODS: The Medline, PubMed, Embase, and the Cochrane Library databases were searched for studies comparing HPSD and Low power longer duration (LPLD) ablation. RESULTS: A total of seven trials with 2023 patients were included in the analysis. Pooled analyses demonstrated that HPSD showed a benefit of first-pass pulmonary vein isolation (PVI) [risk ratio (RR): 1.27; 95% confidence interval (CI): 1.18-1.37, P < .001]. HPSD could reduce recurrence of atrial arrhythmias (RR: 0.70; 95% CI: 0.50-0.98, P = .04). Additionally, HPSD was more beneficial in terms of procedural time [Weighted Mean Difference, (WMD): -44.62; 95% CI, -63.00 to -26.23, P < .001], ablation time (WMD: -21.25; 95% CI: -25.36 to -17.13, P < .001), and fluoroscopy time (WMD: -4.13; 95% CI: -7.52 to -0.74, P < .001). Moreover, major complications and esophageal thermal injury (ETI) were similar between two groups (RR: 0.75; 95% CI: 0.44-1.30, P = .31) and (RR: 0.64; 95% CI: 0.17-2.39, P = .51). CONCLUSION: HPSD was safe and efficient for treating AF with clear advantages of procedural features, it also showed benefits of higher first-pass PVI and reducing recurrence of atrial arrhythmias compared with the LPLD. Moreover, major complications and ETI were similar between two groups.

Value of microalbuminuria in the diagnosis of heart failure with preserved ejection fraction.

OBJECTIVE: Elevated microalbuminuria (MAU) levels have been demonstrated in patients with heart failure with reduced ejection fraction (HFrEF). However, nothing is known about MAU levels in patients with heart failure with preserved ejection fraction (HFpEF). Therefore, the aim of our study was to explore the relationship between MAU levels and HFpEF. METHODS: The MAU and N­terminal B­type natriuretic peptide (NT-proBNP) concentrations were examined in 260 participants, including 160 patients with HFpEF and 100 control subjects without HF. Echocardiography was performed on all study participants. The patients with HFpEF were divided into class II, III, or IV according to the New York Heart Association (NYHA) classification. RESULTS: The MAU levels in the HFpEF group were significantly higher than those in the non-HF group (58.97 ± 89.84 vs. 19.56 ± 29.34, p > 0.05). However, there was no significant difference in the levels of MAU among NYHA class II-IV patients in the HFpEF group (p > 0.05). In Pearson linear correlation analysis, MAU levels in the HFpEF group were positively correlated with left atrial diameter (LAD; r = 0.344, p < 0.05), but negatively correlated with hemoglobin (r = - 0.233, p < 0.05). The area under the ROC curve (AUC) of MAU for the diagnosis of HFpEF was 0.83 (95% CI [0.76, 0.90], p < 0.05), the sensitivity was 72.50%, and the specificity was 82.0%. The AUC of NT-proBNP was 0.88 (95% CI [0.83, 0.94], p < 0.05), the sensitivity was 82%, and the specificity was 73.8%. The AUC of MAU combined with NT-proBNP was 0.91 (95% CI [0.86, 0.96], p < 0.05). CONCLUSION: Our results show that MAU can be used as a biomarker for the diagnosis of HFpEF. Combined detection of MAU with NT-proBNP has clinical value in improving the accuracy of diagnosis of HFpEF. However, there is no significant correlation between MAU levels and the severity of HFpEF.

Suppression of CHOP Reduces Neuronal Apoptosis and Rescues Cognitive Impairment Induced by Intermittent Hypoxia by Inhibiting Bax and Bak Activation.

Our previous study showed that growth arrest- and DNA damage-inducible gene 153 (GAD153/CHOP) plays an important role in intermittent hypoxia- (IH-) induced apoptosis and impaired synaptic plasticity. This study is aimed at determining which signaling pathway is activated to induce CHOP and the role of this protein in mitochondria-dependent apoptosis induced by IH. In the in vivo study, mice were placed in IH chambers for 8 h daily over a period of 2 weeks; the IH chambers had oxygen (O2) concentrations that oscillated between 10% and 21%, cycling every 90 s. In the in vitro study, PC12 cells were exposed to 21% O2 (normoxia) or 8 IH cycles (25 min at 21% O2 and 35 min at 0.1% O2 for each cycle). After 2 weeks of IH treatment, we observed that the expression levels of phosphorylated protein kinase-like endoplasmic reticulum kinase (p-PERK), activating transcription factor 4 (ATF-4) and phosphorylated eukaryotic initiation factor 2 alpha (p-elf2α), were increased, but the levels of activating transcription factor 6 (ATF-6) and inositol-requiring enzyme 1 (IRE-1) were not increased. GSK2606414, a specific chemical inhibitor of the PERK pathway, reduced the expression of p-PERK, ATF-4, p-elf2α, and CHOP and rescued ER structure. In addition, Bax and Bak accumulated in the mitochondria after IH treatment, which induced cytochrome c release and initiated apoptosis. These effects were prevented by GSK2606414 and CHOP shRNA. Finally, the impaired long-term potentiation and long-term spatial memory in the IH group were rescued by GSK2606414. Together, the data from the in vitro and in vivo experiments indicate that IH-induced apoptosis and impaired synaptic plasticity were mediated by the PERK-ATF-4-CHOP pathway. Suppressing PERK-ATF-4-CHOP signaling pathway attenuated mitochondria-dependent apoptosis by reducing the expression of Bax and Bak in mitochondria, which may serve as novel adjunct therapeutic strategy for ameliorating obstructive sleep apnea- (OSA-) induced neurocognitive impairment.

Oridonin inhibits the migration and epithelial-to-mesenchymal transition of small cell lung cancer cells by suppressing FAK-ERK1/2 signalling pathway.

Small cell lung cancer (SCLC) is a severe malignant with high morbidity; however, few effective and secure therapeutic strategy is used in current clinical practice. Oridonin is a small molecule from the traditional Chinese herb Rabdosia rubescens. This study mainly aimed to investigate the role of oridonin on inhibiting the process of H1688, a kind of small cell lung cancer cells from human. Oridonin could suppress H1688 cell proliferation and induce their apoptosis in a high dosage treatment (20 µmol/L). Meanwhile, cell migration was suppressed by oridonin (5 and 10 µmol/L) that did not affect cell proliferation and apoptosis. The expression level of E-cadherin was significantly increased, and the expression of vimentin, snail and slug was reduced after administration of oridonin. These expression changes were associated with the suppressed integrin ß1, phosphorylation of focal adhesion kinase (FAK) and ERK1/2. In addition, oridonin (5 and 10 mg/kg) inhibited tumour growth in a nude mouse model; however, HE staining revealed a certain degree of cytotoxicity in hepatic tissue after treatment oridonin (10 mg/kg). Furthermore, the concentration of alanine aminotransferase (ALP) was significantly increased and lactate dehydrogenase (LDH) was reduced after oridonin treatment (10 mg/kg). Immunohistochemical analysis further revealed that oridonin increased E-cadherin expression and reduced vimentin and phospho-FAK levels in vivo. These findings indicated that oridonin can inhibit the migration and epithelial-to-mesenchymal transition (EMT) of SCLC cells by suppressing the FAK-ERK1/2 signalling pathway. Thus, oridonin may be a new drug candidate to offer an effect of anti-SCLC with relative safety.

LncRNA KCNQ1OT1 contributes to cardiomyocyte apoptosis by targeting FUS in heart failure.

Long noncoding RNAs (lncRNAs) have recently been recognized as the important regulators in cardiac diseases. This study was aimed to investigate the role and molecular mechanism of lncRNA KCNQ1OT1 in regulating cardiomyocyte apoptosis in heart failure (HF). The mouse model of HF was induced by doxorubicin (ADR). Cell apoptosis was detected by Hoechst and TUNEL staining. Molecule expressions were determined by qRT-PCR and western blot. The interaction between KCNQ1OT1 and Fused in sarcoma (FUS) was assessed by RNA immunoprecipitation (RIP) and RNA pull-down assays. KCNQ1OT1 was up-regulated in the myocardial tissues of HF mice and the ADR-stimulated mouse myocardial cell line (HL-1). KCNQ1OT1 overexpression promoted apoptosis of ADR-stimulated HL-1 cells, while KCNQ1OT1 knockdown caused the opposite effect. The RIP and RNA pull-down results showed that KCNQ1OT1 - bound to FUS and negatively regulated its protein level. Knockdown of FUS inhibited apoptosis of ADR-stimulated HL-1 cells and reversed the effect of KCNQ1OT1 overexpression on cardiomyocyte apoptosis. In vivo experiment showed that KCNQ1OT1 ovexpression improved myocardial histopathological changes, reduced myocardial fibrosis areas, down-regulated FUS expression, and inhibited cell apoptosis of HF mice. In conclusion, KCNQ1OT1 facilitates cardiomyocyte apoptosis by - targeting FUS in ADR-induced HF.

Genetic and Epigenetic Analysis Revealing Variants in the NCAM1-TTC12-ANKK1-DRD2 Cluster Associated Significantly With Nicotine Dependence in Chinese Han Smokers.

BACKGROUNDS: Although studies have demonstrated that the NCAM1-TTC12-ANKK1-DRD2 gene cluster plays essential roles in addictions in subjects of European and African origin, study of Chinese Han subjects is limited. Further, the underlying biological mechanisms of detected associations are largely unknown. METHODS: Sixty-four single-nucleotide polymorphisms (SNPs) in this cluster were analyzed for association with Fagerstrom Test for Nicotine Dependence score (FTND) and cigarettes per day (CPD) in male Chinese Han smokers (N = 2616). Next-generation bisulfite sequencing was used to discover smoking-associated differentially methylated regions (DMRs). Both cis-eQTL and cis-mQTL analyses were applied to assess the cis-regulatory effects of these risk SNPs. RESULTS: Association analysis revealed that rs4648317 was significantly associated with FTND and CPD (p = .00018; p = .00072). Moreover, 14 additional SNPs were marginally significantly associated with FTND or CPD (p = .05-.01). Haplotype-based association analysis showed that one haplotype in DRD2, C-T-A-G, formed by rs4245148, rs4581480, rs4648317, and rs11214613, was significantly associated with CPD (p = .0005) and marginally associated with FTND (p = .003). Further, we identified four significant smoking-associated DMRs, three of which are located in the DRD2/ANKK1 region (p = .0012-.00005). Finally, we found five significant CpG-SNP pairs (p = 7.9 × 10-9-6.6 × 10-6) formed by risk SNPs rs4648317, rs11604671, and rs2734849 and three methylation loci. CONCLUSIONS: We found two missense variants (rs11604671; rs2734849) and an intronic variant (rs4648317) with significant effects on ND and further explored their mechanisms of action through expression and methylation analysis. We found the majority of smoking-related DMRs are located in the ANKK1/DRD2 region, indicating a likely causative relation between non-synonymous SNPs and DMRs. IMPLICATIONS: This study shows that there exist significant association of variants and haplotypes in ANKK1/DRD2 region with ND in Chinese male smokers. Further, this study also shows that DNA methylation plays an important role in mediating such associations.

Thromboembolism and bleeding risk in atrial fibrillation ablation with uninterrupted anticoagulation between new oral anticoagulants and vitamin K antagonists: insights from an updated meta-analysis.

Cumulative reports comparing the efficacy and safety outcomes between uninterrupted NOACs and vitamin K antagonists (VKA) in AF ablation had been freshly published. This meta-analysis aimed at offering a more comprehensive evaluation between these two anticoagulants in uninterrupted strategy. We searched in PUBMED, EMBASE, and Cochrane Library (inception to June 10, 2019) for eligible studies. Fixed-effects model was preferred in pooled analysis if I2 < 50%. Publication bias was also evaluated. A total of 23 studies involving 12,725 individuals were analyzed in this literature. There were no difference between uninterrupted NOACs and VKA groups in incidence of Stroke/TIA (RR 0.98, 95% CI 0.54-1.77, P = 0.93, I2 = 0%), silent cerebral embolism (RR 1.09, 95% CI 0.82-1.43, P = 0.56, I2 = 0%), minor bleeding complication (RR 0.97, 95% CI 0.83-1.14, P = 0.73, I2 = 0%), cardiac tamponade (RR 0.95, 95% CI 0.63-1.42, P = 0.80, I2 = 0%). Uninterrupted NOACs was associated with significantly lower major bleeding incidence (RR 0.67, 95% CI 0.49-0.92, P = 0.01, I2 = 0%), pericardial effusion (RR 0.75, 95% CI 0.56-1.00, P = 0.048, I2 = 9%). In sub-analysis, no difference was found in all sub-analyses for Stroke/TIA while significant major bleeding risk reduction in uninterrupted NOACs was identified in the subgroup of CHA2DS2-VASc score ≥ 2 and target activated clotting time (ACT) > 300 s. In conclusions, uninterrupted NOACs was more effective than uninterrupted VKA in reducing major bleeding and pericardial effusion risk without increasing thromboembolism risk, and the benefits of uninterrupted NOACs on major bleeding complication could be more pronounced if CHA2DS2-VASc score ≥ 2 or target ACT > 300 s.

Circulating MicroRNA-30e Predicts Left Ventricular Hypertrophy In Essential Hypertensive Patients.

BACKGROUND: The biomarker for left ventricular hypertrophy (LVH) in patients with essential hypertension (EH) remains an unmet clinical need. The microRNA-30 (miR-30) family has been associated with LVH in cellular and animal studies, but not in a clinical setting. OBJECTIVE: The objective of the study was to investigate the clinical significance of circulating levels of miR-30 family as a biomarker for LVH in EH patients. METHODS: A total of 239 EH patients and 239 healthy controls were enrolled in this study. Circulating levels of miR-30 family members, namely, miR-30a, miR-30b, miR-30c-1, miR-30c-2, miR- 30d, and miR-30e, were evaluated using real-time polymerase chain reaction assays. RESULTS: The circulating miR-30a, miR-30b, and miR-30e were significantly reduced in EH patients in contrast to controls. EH patients with LVH (EH-LVH) had substantially lower circulating miR-30b and miR-30e levels compared to EH patients without LVH (EH-nLVH). Moreover, the expression levels of miR-30b and miR-30e were positively related to LVMI, respectively. Receiver operating curve analysis showed that circulating miR-30e levels distinguished EH patients from controls, and EH-LVH from EH-nLVH patients. Logistic regression analysis identified the circulating miR-30e as a risk factor for LVH in EH patients. CONCLUSION: Circulating miR-30e level can be used as a biomarker in distinguishing EH-LVH from EH-nLVH. A further prospective study is warranted to validate this finding.