Low-Shear Stress Promotes Atherosclerosis via Inducing Endothelial Cell Pyroptosis Mediated by IKKε/STAT1/NLRP3 Pathway.

Atherosclerosis is initiated by vascular endothelial dysfunction, and low-shear stress (LSS) of blood flow is a key factor leading to endothelial dysfunction. Growing evidence suggests that endothelial cell pyroptosis plays an important role in the development of atherosclerosis. Studies have shown that low-shear stress can induce endothelial cell pyroptosis, but the exact mechanism remains unclear. Our experiments demonstrated that low-shear stress induced endothelial cell pyroptosis and the phosphorylation of IκB kinase ε (IKKε). IKKε knockdown not only significantly attenuated atherosclerosis lesions of aortic arch areas in ApoE-/- mice fed with high cholesterol diets, but also markedly reduced endothelial cell pyroptosis and NLRP3 expression triggered by low-shear stress. Further mechanism studies showed that IKKε promoted the expression of NLRP3 via activating signal transducer and activator of transcription 1 (STAT1) and the subsequent binding of STAT1 to NLRP3 promoter region. These results suggest that low-shear stress plays a pro-atherosclerotic role by promoting endothelial cell pyroptosis through the IKKε/STAT1/NLRP3 pathway, which provides new insights into the formation of atherosclerosis.

USP36-mediated PARP1 deubiquitination in doxorubicin-induced cardiomyopathy.

Doxorubicin (Dox) is a potent antineoplastic agent, but its use is curtailed by severe cardiotoxicity, known as Dox-induced cardiomyopathy (DIC). The molecular mechanism underlying this cardiotoxicity remains unclear. Our current study investigates the role of Ubiquitin-Specific Protease 36 (USP36), a nucleolar deubiquitinating enzyme (DUB), in the progression of DIC and its mechanism. We found increased USP36 expression in neonatal rat cardiomyocytes and H9C2 cells exposed to Dox. Silencing USP36 significantly mitigated Dox-induced oxidative stress injury and apoptosis in vitro. Mechanistically, USP36 upregulation positively correlated with Poly (ADP-ribose) polymerase 1 (PARP1) expression, and its knockdown led to a reduction in PARP1 levels. Further investigation revealed that USP36 could bind to and mediate the deubiquitination of PARP1, thereby increasing its protein stability in cardiomyocytes upon Dox exposure. Moreover, overexpression of wild-type (WT) USP36 plasmid, but not its catalytically inactive mutant (C131A), stabilized PARP1 in HEK293T cells. We also established a DIC model in mice and observed significant upregulation of USP36 in the heart. Cardiac knockdown of USP36 in mice using a type 9 recombinant adeno-associated virus (rAAV9)-shUSP36 significantly preserved cardiac function after Dox treatment and protected against Dox-induced structural changes within the myocardium. In conclusion, these findings suggest that Dox promotes DIC progression by activating USP36-mediated PARP1 deubiquitination. This novel USP36/PARP1 axis may play a significant regulatory role in the pathogenesis of DIC.

Prospective evaluation of cardiovascular risk and mortality in patients with psoriasis: An American population-based study.

The association between psoriasis and cardiovascular disease (CVD) has long been discussed and continually refined. However, there is currently a lack of prospective studies on the cardiovascular risk attributed to psoriasis in the United States general population. Representative adult participants were selected from the National Health and Nutrition Examination Survey (NHANES). Risks of cardiovascular symptoms and diseases prevalence were evaluated between participants with and without psoriasis. The hazards for all-cause mortality and CVD mortality were stratified by psoriasis status. Mediation analysis was then conducted to identify potential mediators between psoriasis and cardiac death. Overall, 19 741 participants were included in the current study, 542 (2.7%) had psoriasis and 19 199 (97.3%) did not have psoriasis. After adjusting for known CVD risk factors, odds for hypertension (OR = 1.37, 95% CI: 1.13-1.66, p = 0.001), hypercholesterolemia (OR = 1.37, 95% CI: 1.13-1.64, p < 0.001) and angina pectoris (OR = 1.74, 95% CI: 1.11-2.60, p = 0.011) were higher in psoriasis patients. Compared with participants without psoriasis, moderate/severe but not mild patients showed significantly higher CVD mortality (HR = 2.55, 95% CI: 1.27-5.15, p = 0.009). This result was supported by subgroup analyses. Mediation analysis further suggested that the direct effect of moderate/severe psoriasis on CVD mortality accounted for 81.4% (65.8%-97.1%). Besides, the indirect effect might derive from disturbance of serum albumin, urea nitrogen and uric acid. Moderate-to-severe psoriasis is an independent risk factor for cardiovascular disease, making it necessary to regularly conduct cardiovascular disease-related examinations for patients with higher severity of psoriasis in clinical settings.

PCAF Accelerates Vascular Senescence via the Hippo Signaling Pathway.

P300/CBP-Associated Factor (PCAF), one of the histone acetyltransferases (HATs), is known to be involved in cell growth and/or differentiation. PCAF is reported to be involved in atherosclerotic plaques and neointimal formation. However, its role in cellular senescence remains undefined. We investigated the potential mechanism for PCAF-mediated cellular senescence. Immunohistochemical (IHC) analysis showed PCAF was distinctly increased in the endothelia of aorta in aged mice. Palmitate acid (PA) or X radiation significantly induced the expression of senescence-associated markers and PCAF in human umbilical vein endothelial cells (HUVECs). PCAF silence in PA-treated HUVECs significantly rescued senescence-associated phenotypes, while PCAF overexpression accelerated it. Additionally, our results showed that Yes1 Associated Transcriptional Regulator (YAP) that acts as end effector of the Hippo signaling pathway is crucial in PCAF-mediated endothelial senescence. YAP activity declining was observed in aged vascular endothelia. Overexpression of YAP partially ameliorated PCAF-induced endothelial senescence. In vivo, endothelial-(EC-) specific PCAF downregulation in aged mice using adeno-associated virus revealed less vascular senescence-associated phenotypes. These results suggested that PCAF mediated endothelial senescence through the Hippo signaling pathway, implying that PCAF may become a potential target for the prevention and treatment of vascular aging.

Berberine inhibits low shear stress-induced vascular endothelial inflammation via decreasing phosphorylation of Akt and IRF3.

BACKGROUND: Low shear stress (LSS) is closely related to vascular endothelial inflammation and the development of atherosclerosis. Berberine (BBR), a natural compound isolated from Coptis chinensis, has been reported to exert anti-inflammatory and antiatherosclerotic effects. However, the role of berberine in low shear stress-induced endothelial inflammation remains unclear. METHODS: The role of berberine in low shear stress-induced vascular endothelial inflammation was investigated in human umbilical vein endothelial cells (HUVECs) using a plate flow chamber in vitro and in mice with an established LSS model by partial ligation of the carotid artery in vivo. RESULTS: First, in vitro experiments demonstrated that BBR significantly decreased the expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and the phosphorylation of Akt in HUVECs induced by low shear stress. Moreover, BBR significantly inhibited the low shear stress-mediated phosphorylation of IRF3 and its translocation to the nucleus. Notably, Akt overexpression markedly reversed the inhibitory effects of BBR on LSS-induced IRF3 activation and ICAM-1 expression. Moreover, in vivo experiments showed that BBR markedly decreased intimal ICAM-1 and IRF3 in the LSS areas of partially ligated carotid arteries in mice; however, EC-specific Akt overexpression mediated by adeno-associated viruses abolished the anti-inflammatory effect of BBR. CONCLUSION: Taken together, our findings suggest that BBR treatment attenuates LSS-induced vascular endothelial inflammation by decreasing the activation of the Akt/IRF3 signalling pathway.

Bioactive Compounds From Coptidis Rhizoma Alleviate Pulmonary Arterial Hypertension by Inhibiting Pulmonary Artery Smooth Muscle Cells' Proliferation and Migration.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by excessive proliferation and vasoconstriction of small pulmonary artery vascular smooth muscle cells (PASMCs). Coptidis rhizoma (CR) because of the complexity of the components, the underlying pharmacological role and mechanism of it on PAH remains unknown. In this article, the network pharmacological analysis was used to screen the main active constituents of CR and the molecular targets that these constituents act on. Then, we evaluated the importance of berberine and quercetin (biologically active components of CR) on the proliferation and migration of PASMCs and vascular remodeling in experimental models of PAH. Our results showed that berberine and quercetin effectively inhibited the proliferation and migration of hypoxia-induced PASMCs in a manner likely to be mediated by the suppression of MAPK1, NADPH oxidase 4 (NOX4), and cytochrome P450 1B1 (CYP1B1) expression. Furthermore, berberine and quercetin treatment attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension in rat models. In conclusion, this research demonstrates CR might be a promising treatment option for PAH, and the network pharmacology approach can be an effective tool to reveal the potential mechanisms of Chinese herbal medicine.

Mitoferrin 2 deficiency prevents mitochondrial iron overload-induced endothelial injury and alleviates atherosclerosis.

Endothelial dysfunction is an early step in the development of atherosclerotic cardiovascular disease. Iron overload can lead to excessive mitochondrial reactive oxygen species (mtROS) production, resulting in mitochondrial dysfunction and vascular endothelial cell (EC) damage. Mitoferrin 2 (Mfrn2) is an iron transporter in the inner mitochondrial membrane. This study aimed to assess whether Mfrn2 and mitochondrial iron overload were involved in atherosclerosis progression and to explore the potential mechanism. We observed significant upregulation of Mfrn2 in the arteries of high-fat diet (HFD)-fed Apolipoprotein E-/- (ApoE-/-) mice and in TNF-α-induced mouse aortic endothelial cells (MAECs). Mfrn2 gene silencing inhibited mitochondrial iron overload, stabilized mitochondrial membrane potential and improved mitochondrial function in TNF-α-induced MAECs. Vascular EC-specific knockdown of Mfrn2 in ApoE-/- mice markedly decreased atherosclerotic lesion formation and the levels of ICAM-1 in aortas and reduced monocyte infiltration into the vascular wall. Furthermore, TNF-α increased the binding of 14-3-3 epsilon (ε) and Mfrn2, preventing Mfrn2 degradation and leading to mitochondrial iron overload in ECs, while 14-3-3ε overexpression increased Mfrn2 stability by inhibiting its ubiquitination. Together, our results reveal that Mfrn2 deficiency attenuates endothelial dysfunction by decreasing iron levels within the mitochondria and mitochondrial dysfunction. These findings may provide new insights into preventive and therapeutic strategies against vascular endothelial dysfunction in atherosclerotic disease.

All-inorganic silicon white light-emitting device with an external quantum efficiency of 1.0.

With low toxicity and high abundance of silicon, silicon nanocrystal (Si-NC) based white light-emitting device (WLED) is expected to be an alternative promising choice for general lighting in a cost-effective and environmentally friendly manner. Therefore, an all-inorganic Si-NC based WLED was reported for the first time in this paper. The active layer was made by mixing freestanding Si-NCs with hydrogen silsesquioxane (HSQ), followed by annealing and preparing the carrier transport layer and electrodes to complete the fabrication of an LED. Under forward biased condition, the electroluminescence (EL) spectrum of the LED showed a broadband spectrum. It was attributed to the mechanism of differential passivation of Si-NCs. The performance of LED could be optimized by modifying the annealing temperature and ratio of Si-NCs to HSQ in the active layer. The external quantum efficiency (EQE) peak of the Si WLED was 1.0% with a corresponding luminance of 225.8 cd/m2, and the onset voltage of the WLED was 2.9V. The chromaticity of the WLED indicated a warm white light emission.

Symmetric guided-mode resonance sensors in aqueous media with ultrahigh figure of merit.

Optical sensors with a high figure of merit (FOM) for refractive index measurement can substantially enhance detection performance. For guided mode resonance (GMR) sensors, previous works mainly focused on the sensitivity enhancement rather than FOM optimization; therefore, the state-of-the-art FOM is limited within the range of 100. To address this, we propose a low-index, ultraviolet-curable resin (n = 1.344) to form a simple, stable, symmetric, GMR sensor, with enhanced sensitivity, narrowed resonant linewidth, and substantially improved FOM, in aqueous media. The influence of structural parameters was systematically investigated, and optimized FOM values as high as tens of thousands were obtained using numerical calculation. Using low-cost, nanoimprinting technology, we experimentally demonstrated a spectral linewidth as narrow as 56 pm, a bulk refractive index sensitivity of 233.35 nm / RIU, and a low detection limit 1.93 × 10-6, resulting in a FOM value up to 4200 (48 times typical GMR sensors). The proposed symmetric GMR sensor exhibits great potential in a variety of applications, including label-free biosensing, bio-imaging, and optical filters.

White light emission and optical gains from a Si nanocrystal thin film.

We report a Si nanocrystal thin film consisting of free-standing Si nanocrystals, which can emit white light and show positive optical gains for its red, green and blue (RGB) components under ultraviolet excitation. Si nanocrystals with ϕ = 2.31 ± 0.35 nm were prepared by chemical etching of Si powder, followed by filtering. After being mixed with SiO2 sol-gel and thermally annealed, a broadband photoluminescence (PL) from the thin film was observed. The RGB ratio of the PL can be tuned by changing the annealing temperature or atmosphere, which is 1.00/3.26/4.59 for the pure white light emission. The origins of the PL components could be due to differences in oxygen-passivation degree for Si nanocrystals. The results may find applications in white-light Si lasing and Si lighting.

Ensemble learning for spatial interpolation of soil potassium content based on environmental information.

One important method to obtain the continuous surfaces of soil properties from point samples is spatial interpolation. In this paper, we propose a method that combines ensemble learning with ancillary environmental information for improved interpolation of soil properties (hereafter, EL-SP). First, we calculated the trend value for soil potassium contents at the Qinghai Lake region in China based on measured values. Then, based on soil types, geology types, land use types, and slope data, the remaining residual was simulated with the ensemble learning model. Next, the EL-SP method was applied to interpolate soil potassium contents at the study site. To evaluate the utility of the EL-SP method, we compared its performance with other interpolation methods including universal kriging, inverse distance weighting, ordinary kriging, and ordinary kriging combined geographic information. Results show that EL-SP had a lower mean absolute error and root mean square error than the data produced by the other models tested in this paper. Notably, the EL-SP maps can describe more locally detailed information and more accurate spatial patterns for soil potassium content than the other methods because of the combined use of different types of environmental information; these maps are capable of showing abrupt boundary information for soil potassium content. Furthermore, the EL-SP method not only reduces prediction errors, but it also compliments other environmental information, which makes the spatial interpolation of soil potassium content more reasonable and useful.

Association between metabolic syndrome and osteoporotic fracture in middle-aged and elderly Chinese peoples.

Associations between metabolic syndrome (MetS) and osteoporotic fracture have been reported. However, the epidemiological studies are not conclusive. The objective of the study was to determine whether MetS associates with osteoporotic fracture. This was a cross-sectional study of 9,930 Chinese adults aged 40 years or older in the Chongming District, Shanghai, China. A questionnaire, anthropometric measurements and laboratory tests were conducted. Metabolic syndrome was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. A history of fractures was collected with an interviewer-assisted questionnaire. Osteoporotic fractures were defined as fractures that occurred due to low trauma in 2 years prior to the study. Among women, the prevalence of osteoporotic fractures was significantly higher in those with MetS (3.5 vs. 2.6 %, = 0.028). However, the difference was not found in men (2.6 vs. 2.4 %, P = 0.737). The presence of MetS was significantly associated with increased odds of osteoporotic fracture among women (odds ratio 1.22; 95 % confidence interval 1.12-1.54; P = 0.039) after controlling for potential confounders. The significant associations were not detected in men. The presence of MetS was significantly associated with a recent history of osteoporotic fracture in middle-aged and elderly Chinese women.