Notch1 signaling activation alleviates coronary microvascular dysfunction through histone modification of Nrg-1 via the interaction between NICD and GCN5.

The Notch signaling pathway is related to endothelial dysfunction in coronary atherosclerosis. Our objective was to explore the role of Notch signaling in coronary microvascular dysfunction (CMD). CMD models were constructed by sodium laurate injection in vivo and homocysteine (Hcy) stimulation in vitro. The binding ability of Notch Intracellular Domain (NICD)/H3K9Ac/GCN5 (General Control Non-derepressible 5) to Neuregulin-1 (Nrg-1) promoter was examined by chromatin immunoprecipitation. Immunofluorescence staining was conducted to detect CD31 positive cells, NICD localization, and co-localization of NICD and GCN5. Flow cytometry and Tunel staining were conducted to identify the apoptosis. Hematoxylin and eosin staining, quantitative real-time PCR, western blot, immunohistochemical staining, co-immunoprecipitation, and double luciferase report analysis were also conducted. Notch signaling pathway-related protein levels were decreased, levels of Nrg-1 and the phosphorylation of ErbB2 and ErbB4 were enhanced in CMD models. Interference with Nrg-1 further increased the apoptosis in Hcy-induced cardiac microvascular endothelial cells (CMECs). Meanwhile, the activation of the Notch signaling pathway increased the levels of Nrg-1 and the phosphorylation of ErbB2 and ErbB4, as well as inhibited the apoptosis induced by Hcy. Furthermore, NICD and histone acetyltransferase enzyme GCN5 could regulate Nrg-1 promoter activity by affecting the expression of acetylation-modified protein H3K9Ac. In addition, NICD also interacted with GCN5. In vivo results also confirmed that the activation of the Notch signal alleviated CMD. Notch signaling pathway regulates Nrg-1 level through synergistic interaction with GCN5, thereby mitigating CMD.

Non-exercise Estimated Cardiorespiratory Fitness and Mortality Among Adults with Hypertension.

BACKGROUND: The non-exercise estimated cardiorespiratory fitness (eCRF) has been recognized as important predictor of mortality among general population. This study sought to evaluate the relationship between eCRF and mortality from all causes, cardiovascular disease (CVD), and cancer in hypertensive adults. METHODS: We included 27437 adults with hypertension from the National Health and Nutrition Examination Survey (NHANES) III and 10 NHANES cycles from 1999-2018. Multivariate Cox proportional hazards models were used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) of eCRF for mortality. RESULTS: A total of 8023 deaths were recorded throughout a median 8.6-year follow-up, including 2338 from CVD, and 1761 from cancer. The eCRF with per 1 metabolic equivalent increase was linked to decreased risk of all-cause (adjusted HR 0.78, 95% CI: 0.75-0.81) and CVD mortality (adjusted HR 0.79, 95% CI: 0.74-0.84), rather than cancer mortality (adjusted HR 0.94, 95% CI: 0.86-1.03). Moreover, a stronger protective effect of eCRF was observed for females (HR 0.66 (95% CI: 0.62-0.72) versus HR 0.78 (95% CI: 0.73-0.83), Pinteraction < 0.001 for all-cause mortality; HR 0.70 (95% CI: 0.61-0.80;) versus HR 0.82 (95% CI: 0.73-0.92), Pinteraction = 0.026 for CVD mortality) compared with males. Findings did not significantly differ in subgroup analyses and sensitivity analyses. CONCLUSIONS: Among adults with hypertension, eCRF was inversely related to all-cause and CVD mortality, but not cancer mortality. A significant interaction effect existed between sex and eCRF. Further studies are needed to verify this association in different population.

Drug-coated balloons for the treatment of ostial left anterior descending or ostial left circumflex artery lesions: a patient-level propensity score-matched analysis.

BACKGROUND: Controversy exists as to the optimal treatment approach for ostial left anterior descending (LAD) or ostial left circumflex artery (LCx) lesions. Drug-coated balloons (DCB) may overcome some of the limitations of drug-eluting stents (DES). Therefore, we investigated the security and feasibility of the DCB policy in patients with ostial LAD or ostial LCx lesions, and compared it with the conventional DES-only strategy. METHODS: We retrospectively enrolled patients with de novo ostial lesions in the LAD or LCx who underwent interventional treatment. They were categorized into two groups based on their treatment approach: the DCB group and the DES group. The treatment strategies in the DCB group involved the use of either DCB-only or hybrid strategies, whereas the DES group utilized crossover or precise stenting techniques. Two-year target lesion revascularization was the primary endpoint, while the rates of major adverse cardiovascular events, cardiac death, target vessel myocardial infarction, and vessel thrombosis were the secondary endpoints. Using propensity score matching, we assembled a cohort with comparable baseline characteristics. To ensure result analysis reliability, we conducted sensitivity analyses, including interaction, and stratified analyses. RESULTS: Among the 397 eligible patients, 6.25% of patients who were planned to undergo DCB underwent DES. A total of 108 patients in each group had comparable propensity scores and were included in the analysis. Two-year target lesion revascularization occurred in 5 patients (4.90%) and 16 patients (16.33%) in the DCB group and the DES group, respectively (odds ratio = 0.264, 95% CI: 0.093-0.752, P = 0.008). Compared with the DES group, the DCB group demonstrated a lower major adverse cardiovascular events rate (7.84% vs. 19.39%, P = 0.017). However, differences with regard to cardiac death, non-periprocedural target vessel myocardial infarction, and definite or probable vessel thrombosis between the groups were non-significant. CONCLUSIONS: The utilization of the DCB approach signifies an innovative and discretionary strategy for managing isolated ostial lesions in the LAD or LCx. Nevertheless, a future randomized trial investigating the feasibility and safety of DCB compared to the DES-only strategy specifically for de novo ostial lesions in the LAD or LCx is highly warranted.

E3 ubiquitin ligase mind bomb 1 overexpression reduces apoptosis and inflammation of cardiac microvascular endothelial cells in coronary microvascular dysfunction.

BACKGROUND: The apoptosis and inflammation in cardiac microvascular endothelial cells (CMECs) promote the development of coronary microvascular dysfunction (CMD). The present study aimed to explore the role of E3 ubiquitin ligase mind bomb 1 (MIB1) in the apoptosis and inflammation in CMECs during CMD. METHODS: In vivo, CMD in rats was induced by sodium laurate injection. In vitro, rat primary CMECs were stimulated by homocysteine (Hcy). The apoptosis of CMECs was measured using flow cytometry. The inflammation of CMECs was evaluated by the level of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß). The interplay between MIB1 and mitogen-activated protein kinase kinase kinase 5 (map3k5, also called ASK1) was measured using Co-immunoprecipitation. RESULTS: MIB1 expression was decreased and ASK1 expression was increased in the heart tissues of CMD rats and Hcy-treated CMECs. MIB1 overexpression decreased fibrinogen-like protein 2 (FGL2) secretion, inflammation, and apoptosis induced by Hcy in CMECs. Meanwhile, MIB1 overexpression decreased the protein levels of ASK1 and p38, while not affected ASK1 mRNA levels. The following mechanism experiments revealed that MIB1 downregulated ASK1 expression by increasing its ubiquitination. ASK1 overexpression reversed the inhibitory effect of MIB1 on FGL2 secretion, apoptosis, inflammation, and p38 activation in Hcy-treated CMECs. In CMD rats, MIB1 overexpression partly retarded CMD progression, manifesting as increased coronary capillary density and decreased microthrombi formation. CONCLUSION: MIB1 overexpression relieved apoptosis and inflammation of CMECs during CMD by targeting the ASK1/p38 pathway.

Stentless at ostium: a novel approach for treating ostial left anterior descending or left circumflex coronary artery lesions with drug-coated balloons.

BACKGROUND: Currently, there is no optimal treatment strategy for ostial left anterior descending (LAD) or ostial left circumflex artery (LCx) lesions. This study explored effectiveness and safety of drug-coated balloons (DCB) in individuals presenting with ostial LAD or LCx lesions. METHODS: A total of 137 patients with de novo ostial LAD or LCx lesions scheduled for DCB treatment were prospectively recruited into the study. After mandatory lesion preparation, DCB-only or hybrid strategy [DCB + drug-eluting stent (DES)] were performed on 120 patients (87.59%). The primary endpoint was the rate of 2-year target lesion revascularization (TLR). Rates of major adverse cardiovascular events (MACE), cardiac death, target vessel myocardial infarction (TVMI), and vessel thrombosis were explored as the secondary outcomes. Quantitative coronary angiography software was used to analyze coronary angiograms. RESULTS: Of the participants, 58 were treated with DCB-only and 62 with hybrid strategy. Relative to the DCB-only group, patients in the hybrid group had longer target lesions (15.47 ± 10.08 vs. 36.85 ± 9.46 mm, P<0.001) and higher Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) scores (23.47 ± 5.22 vs. 29.98 ± 3.18, P<0.001). During follow-up (731 ± 64 days), neither the primary endpoint (TLR) nor the secondary endpoints (including MACE, cardiac death, TVMI, and vessel thrombosis) differed statistically between the two groups (all P > 0.05). Treatment strategy (DCB-only or hybrid) was not a significant risk factor for TLR. Patients who underwent DCB-only exhibited less late lumen loss compared with the patients who underwent hybrid strategy (-0.26 ± 0.59 vs. 0.42 ± 0.47 mm, P<0.001) at 1-year angiographic follow-up. CONCLUSIONS: With regards to safety and efficacy, the strategy of DCB as a standalone therapy was similar in comparison with the hybrid strategy of DCB + DES for ostial LAD and ostial LCx lesions. This approach might be effective and technically easy in treating ostial LAD and LCx diseases.

Microsurgical treatment of cerebrospinal fluid rhinorrhea in sphenoidal sinus.

OBJECTIVE: To explore the clinical manifestation, diagnosis and surgical treatment of cerebrospinal fluid rhinorrhea in sphenoidal sinus. METHODS: Nine cases of cerebrospinal fluid rhinorrhea in sphenoidal sinus from 2007 to 2009 were retrospectively analyzed consisting of their possible etiological factors, clinical manifestations, localization of the leakage site and treatment methods. Among them, there were 3 cases of traumatic rhinorrhea, 4 postoperative rhinorrhea and 2 spontaneous rhinorrhea. All 9 patients underwent 3-dimensional CT scan in sellar region including all para-nasal sinus. Leakage site was identified and repairing procedure was performed through trans-sphenoidal approach. RESULTS: All cases were cured with the trans-sphenoidal microsurgical procedure. They were followed up for 9 months to 2 years. No recurrence, no infection and epilepsy complications were observed. CONCLUSION: For the cerebrospinal fluid rhinorrhea at sphenoidal sinus, it is critical to identify the leakage site accurately and the trans-sphenoidal approach is a microinvasive and effective way to repair the leakage, which is worthy to be advocated.

Feminizing/demasculinizing effects of polychlorinated biphenyls on the secondary sexual development of Xenopus laevis.

We have previously demonstrated that polychlorinated biphenyls (PCBs) have caused phenotypic feminization/demasculinization of gonadal development in Xenopus laevis. Whether PCBs affect secondary sexual development has remained unknown. In this study, X. laevis tadpoles were exposed to Aroclor1254 and PCB(3) from stage 46/47 (system of Nieuwkoop and Faber) for up to 1 month postmetamorphosis. After 24 months postmetamorphosis, the degree of secondary sexual development was examined. Male oviducts were observed in some of the PCB-exposed male frogs, but not in control males. These male oviducts had not completely developed in histological structure when compared with mature female oviducts. Larynx weight and width of PCB-exposed males were significantly less than those of control males. Laryngeal histology showed that PCBs inhibited cartilaginous and muscular development of male frogs, i.e. elastic cartilages had not completely developed and laryngeal muscle fibers were smaller. In a further study on adult male frogs, a decrease in serum testosterone level was found in PCB-exposed frogs compared with controls, but serum estradiol level was not significantly affected. Our study suggests that PCBs can cause phenotypic feminization/demasculinization of male genital ducts and larynges, and these effects may, in part, result from the decrease in serum testosterone level in X. laevis.

Effects of vitamin D on plasma lipid profiles in statin-treated patients with hypercholesterolemia: A randomized placebo-controlled trial.

BACKGROUND & AIMS: Lipid abnormalities are regarded as a risk factor for cardiovascular disease. Low vitamin D status has been shown to be associated with hyperlipidemia. We planned to research the effects of vitamin D supplementation as an adjuvant therapy for patients with hypercholesterolemia. METHODS: Patients with hypercholesterolemia were enrolled in this single-center, double-blind, placebo-controlled trial in Beijing (39°54' N). Fifty-six patients were randomly assigned to receive vitamin D (n = 28, 2000 IU/d) or a placebo (n = 28) as an add-on to statin, by the method of permutated block randomization. Serum lipid levels were evaluated at baseline, 1, 3 and 6 months. RESULTS: Vitamin D supplementation resulted in increased serum 25-hydroxyvitamin D concentrations compared with placebo (+16.3 ± 11.4 compared with +2.4 ± 7.1 ng/ml; p < 0.001). At 6 months, the primary end point, a difference in the fall of serum total cholesterol levels between the vitamin D and placebo groups after 6 months of treatment was significant -22.1 mg/dl (95% CI -32.3; -12.2) (p < 0.001). The difference between the groups in the fall of serum triglyceride levels after 6 months of treatment was -28.2 mg/dl (95% CI -48.8; -8.4) (p < 0.001). In patients with 25-hydroxyvitamin D level<30 ng/ml at baseline (n = 43), the serum total cholesterol and triglyceride levels were reduced by -28.5 ± 11.9 mg/dl (p < 0.001) and -37.1 ± 19.5 mg/dl (p < 0.001), respectively. CONCLUSIONS: Vitamin D supplementation might improve serum lipid levels in statin-treated patients with hypercholesterolemia, it might be an adjuvant therapy for patients with hypercholesterolemia. Clinical Trials Registration Number - NCT02009787.

Changes of polybrominated diphenyl ether concentrations in ducks with background exposure level and time.

To reveal what degree bioaccumulation of polybrominated diphenyl ethers (PBDEs) depends on exposure time and other factors, we conducted a semi-field experiment for a year (June 2008-June 2009) in a village in an e-waste recycling site in Taizhou, China. Approximately one hundred of juvenile ducks (Anas domestica Linnaeus) were entrusted to a villager. The ducks lived and forged in a PBDE-polluted pond from the late March to the end of November. Fish and mudsnails that were heavily polluted by PBDEs were main food. In cold days (from December to the middle March), the ducks lived in the villager' house, and mainly fed on paddy, which contained lower concentrations of PBDEs than fish and mudsnails. The female ducks were sampled for PBDE analysis every three months. We found that the ∑PBDE concentrations in duck liver, muscle, lung and brain fluctuated greatly with the changes of exposure levels that were determined by the environment and diets, but the ∑PBDE concentrations in fat tissue increased successively with time. Congener analysis demonstrated that the successive increase in the ∑PBDE concentrations with time in fat tissue was due to the successive increase in BDE-209, -183 and -153 concentrations, with large fluctuations of low brominated congeners. The results show that PBDE concentrations in liver, muscle, lung and brain tissues heavily depends on exposure levels rather than exposure time. In fat tissue, by contrast, PBDE concentrations (mainly high brominated congeners) slightly depends on exposure levels but heavily depend on time relative to other tissues, implying that high brominated congeners seem to have longer half-lives than low brominated congeners in fat tissue.

Determination of polybrominated diphenyl ethers in human semen.

Some persistent organic pollutants (POPs) have been found in human semen but until this point it was unclear whether polybrominated diphenyl ethers (PBDEs) could be detected in human semen. In this study, PBDEs were found for the first time in human semen samples (n=101) from Taizhou, China. The concentrations of total PBDEs (∑PBDEs) varied from 15.8 to 86.8 pg/g ww (median=31.3 pg/g ww) and 53.2 to 121 pg/g ww (median=72.3 pg/g ww) in semen and blood samples, respectively. The ∑PBDE level in semen was about two times lower than in human blood, which was different in the distribution in the two matrices from other POPs. A correlation of ∑PBDE concentration was found between paired semen and in blood. The results suggest that semen could be used to detect PBDE burden in human body as a non-invasive matrix. In addition, the levels of BDE-209 and BDE-153, especially the latter, were much higher in blood than in semen, while the levels of BDE-28, BDE-47 and BDE-99 were comparable in the two matrices, suggesting that low brominated congeners could be more easily transferred to semen than high brominated congeners. Considering different toxicities among the PBDE congeners, it might be more significant to measure PBDEs in semen than in blood for evaluating male reproduction risks of PBDEs.

Bioaccumulation, maternal transfer and elimination of polybrominated diphenyl ethers in wild frogs.

To investigate bioaccumulation, maternal transfer and elimination of polybrominated diphenyl ethers (PBDEs) in amphibians, we collected adult frogs (Rana limnocharis) from a rice field in an e-waste recycling site in China. We found that ∑PBDEs in the whole frogs and various tissues (brain, liver, testis and egg) ranged from 17.10 to 141.11 ng g(-1) wet weight. Various tissues exhibited a similar PBDE congener profile, which was characterized by intermediate brominated congeners (BDE-99 and BDE-153) as the largest contributors, with less lower brominated congeners (BDE-28 and BDE-47) and higher brominated congeners (BDE-209). The maternal transfer capacity of PBDEs declined with the increase in bromine numbers of PBDE congeners. We suggest that the bromine atom number (the molecular size, to some degree) might be a determining factor for the maternal transport of a PBDE congener rather than K(ow) (Octanol-Water partition coefficient), which expresses a compound's lipophilicity. ∑PBDEs concentrations in frogs decreased over time during a depuration period of 54 days when these wild frogs were brought to the lab from the e-waste recycling site. The half-life of ∑PBDEs was 35 days, with about 14 days for BDE-47, and 36 and 81 days for BDE-99 and BDE-153, respectively. The data shows that the elimination of PBDEs has no essential difference from aquatic and terrestrial species.

Dual body burdens of polychlorinated biphenyls and polybrominated diphenyl ethers among local residents in an e-waste recycling region in Southeast China.

E-waste recycling resulted in serious pollution of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in Taizhou of Zhejiang Province, China. The aims of this study were to assess dual body burdens of the two pollutants and potential health risk for local residents. Blood samples were collected from two e-waste recycling sites, Luqiao (where PCBs-containing e-wastes were recycled) and Wenling (where PBDEs-containing e-wastes were recycled). The mean summation SigmaPCBs (CB-105, 118, 153, 183, and 180) and summation SigmaPBDEs (BDE-28, 47, 99, 100, 153, 154, 180, and 209) were 204.20 and 117.58 ng g(-1) lipid in the blood from Luqiao, respectively, while they were 83.80 and 357.44 ng g(-1) lipid from Wenling, respectively. The PCBs levels among Luqiao residents were comparable to the values reported for US populations, while the PBDEs levels among two study populations were higher than the values from US populations. This is the first report to present dual body burdens of PCBs and PBDEs at so high levels. Based on previous epidemiologic data, it is suggested that dual burdens of PCBs and PBDEs at so high levels might pose health risk for local residents. In addition, no correlation between PCBs or PBDEs concentrations and the ages of the volunteers was observed in the two populations, which was explained by similar exposure time. No correlation of PBDEs with PCBs concentrations suggested different pathways of human exposures to PCBs and PBDEs. Our findings have raised concern about human health risk of dual exposure to PCBs and PBDEs resulting from e-waste recycling.

Determination of environmentally relevant exposure concentrations of polybrominated diphenyl ethers for in vitro toxicological studies.

Toxicological studies at environmentally relevant concentrations are essential for understanding ecotoxic and health risks of pollutants such as polybrominated diphenyl ethers (PBDEs). However, no information is available on what exposure levels of PBDEs in vitro studies are environmentally relevant. We exposed MCF-7, HepG2, H295R and PC12 cells to BDE-47, and measured BDE-47 concentrations in the cells after exposure. We also used the percentile method to summarize literature data on environmental exposure levels of biotic tissues to PBDEs. The exposure concentration that resulted in a BDE-47 burden in cells close to the 90th percentile of PBDEs levels in tissues was assigned as the upper limit for the environmentally relevant concentration. Exposure to 1nM BDE-47 resulted in PBDEs burdens in MCF-7, HepG2 and H295R cells close to the 90th percentile but PBDEs burdens in PC12 cells were higher than the 90th percentile. In consideration of the high exposure levels in PBDE-polluted areas, we concluded that the highest environmentally relevant exposure concentration of PBDEs in culture media should be approximately 10nM for MCF-7, HepG2 and H295R cells, and<10nM for PC12 cells. These results provide an approximate reference for setting environmentally relevant exposure concentrations of PBDEs for studies in vitro.

Diffusion of polybrominated diphenyl ether (PBDE) from an e-waste recycling area to the surrounding regions in Southeast China.

Using Cinnamomum camphora (C. camphora) leaves as biomonitors, we investigated that the diffusion of polybrominated diphenyl ethers (PBDEs) from an e-waste recycling area to the surrounding regions. Variance in sigma(32)PBDEs concentrations (0.46-399.93 ng g(-1) dry weight) in the leaves showed that PBDEs from the e-waste recycling area diffused into the surrounding regions, and resulted in a halo of PBDEs contamination, at least 74 km in radius. The attenuation of sigma(32)PBDEs in the diffusing process fitted in log-linear regression. The difference in the attenuating slopes of linear equations among different directions can be explained by terrain and wind direction. The attenuation of PBDE congeners also fitted well in log-linear regression. The findings that similar attenuating slopes and characteristic travel distance among congeners suggest that the transport behavior of lower brominated congeners might not differ from that of higher brominated congeners in short-range scale.