Biomimetic Grapefruit-Derived Extracellular Vesicles for Safe and Targeted Delivery of Sodium Thiosulfate against Vascular Calcification.

As the prevalence of vascular calcification (VC), a strong contributor to cardiovascular morbidity and mortality, continues to increase, the need for pharmacologic therapies becomes urgent. Sodium thiosulfate (STS) is a clinically approved drug for therapy against VC; however, its efficacy is hampered by poor bioavailability and severe adverse effects. Plant-derived extracellular vesicles have provided options for VC treatment since they can be used as biomimetic drug carriers with higher biosafety and targeting abilities than artificial carriers. Inspired by natural grapefruit-derived extracellular vesicles (EVs), we fabricated a biomimetic nanocarrier comprising EVs loaded with STS and further modified with hydroxyapatite crystal binding peptide (ESTP) for VC-targeted delivery of STS. In vitro, the ESTP nanodrug exhibited excellent cellular uptake capacity by calcified vascular smooth muscle cells (VSMCs) and subsequently inhibited VSMCs calcification. In the VC mice model, the ESTP nanodrug showed preferentially the highest accumulation in the calcified arteries compared to other treatment groups. Mechanistically, the ESTP nanodrug significantly prevented VC via driving M2 macrophage polarization, reducing inflammation, and suppressing bone-vascular axis as demonstrated by inhibiting osteogenic phenotype trans-differentiation of VSMCs while enhancing bone quality. In addition, the ESTP nanodrug did not induce hemolysis or cause any damage to other organs. These results suggest that the ESTP nanodrug can prove to be a promising agent against VC without the concern of systemic toxicity.

Incremental Benefit of Lipid Lowering in a Large Chinese Population Aged 75 Years and Older With Established Atherosclerotic Cardiovascular Disease.

OBJECTIVE: To explore the optimal low-density lipoprotein cholesterol (LDL-C) level in patients aged 75 years and older with established atherosclerotic cardiovascular disease (ASCVD). PATIENTS AND METHODS: We conducted a retrospective multicenter cohort study of veterans aged 75 years and older with ASCVD who were regularly hospitalized or medically examined in 15 medical institutions in southern China from January 1, 2006, to December 31, 2013. Follow-up continued through October 1, 2021. The time-weighted average (TWA) LDL-C level represented the average LDL-C level during follow-up. Participants were divided into TWA LDL-C groups of 55.0 mg/dL or lower, 55.1 to 70.0 mg/dL, 70.1 to 85.0 mg/dL, 85.1 to 100.0 mg/dL, and greater than 100.0 mg/dL. The subgroup with LDL-C levels lower than 55.0 mg/dL was further subdivided into groups with LDL-C levels from 40.1 to 55.0 mg/dL and 40.0 mg/dL or less. The association of TWA LDL-C levels with outcomes was evaluated with Cox proportional hazards models. RESULTS: Overall, 6387 patients aged 75 years or older with ASCVD were included (mean age, 79.4 years). In total, 4267 major adverse cardiovascular events, 1518 stroke events, and 515 myocardial infarction events occurred during a mean follow-up of 12.7 years. Generally, lower TWA LDL-C level was associated with a lower risk of cardiovascular events but was not associated with a higher risk of adverse events in elderly individuals with ASCVD, with the lowest cardiovascular risk observed for LDL-C levels of less than 55.0 mg/dL. After multivariable adjustment, the risk of a major adverse cardiovascular event was 1.30 (95% CI, 1.26 to 1.34; P<.001) for a per SD increment in TWA LDL-C level. Compared with TWA LDL-C levels of 40.1 to 55.0 mg/dL, TWA LDL-C levels of 40.0 mg/dL or less were associated with an increased risk of hemorrhagic stroke (hazard ratio, 3.71; 95% CI, 1.89 to 7.26). CONCLUSION: Low-density lipoprotein cholesterol levels from 40.1 to 55.0 mg/dL exhibited the maximum cardiovascular benefit in patients aged 75 years and older who had ASCVD. Lowering LDL-C levels to 40.0 mg/dL or less might increase the risk of hemorrhagic stroke.

Cumulative remnant cholesterol predicts cardiovascular outcomes in elderly patients with atherosclerotic cardiovascular disease.

AIMS: Remnant cholesterol (RC) reportedly mediates residual cardiovascular risk in atherosclerotic cardiovascular diseases (ASCVD). However, few studies have characterized long-term cumulative RC exposure among elderly people. The study aimed to evaluate the association between cumulative exposure to RC and incident major adverse cardiovascular events (MACE) by analysing a cohort of elderly patients with ASCVD. METHODS AND RESULTS: This retrospective multicentre cohort study enrolled ASCVD participants aged ≥75 years with baseline visits occurring from 2006 to 2012 followed by four in-person visits. Cumulative RC was estimated as the area under the curve using measurements from the first to fourth visits by using 9-year data. The time-weighted average (TWA) RC was expressed as cumulative exposure to RC averaged by years. All outcomes were follow-up from the fourth visit to the year 2021. Outcomes included a composite of MACE (stroke, unstable angina pectoris, myocardial infarction, and cardiac death). We included 4,680 participants (73.1% male, mean age 79.3 ± 2.5 years). The median follow-up duration was 6.1 years (interquartile range: 3.4-6.6 years). In the multivariable model adjusted for traditional cardiovascular risk factors, low-density lipoprotein cholesterol level, and most recent RC level, the hazard ratios for MACE that compared the high and low tertiles of the RC variables were 1.30 [95% confidence interval (CI), 1.16-1.44] for cumulative RC and 1.36 (95% CI, 1.23-1.52) for TWA RC. Consistent significant associations were observed among most propensity score analyses. CONCLUSIONS: Long-term cumulative RC was independently associated with incident MACE in elderly participants with ASCVD, suggesting that achieving and maintaining optimal RC levels later in life may still improve cardiovascular outcomes.

This retrospective multicentre cohort study, enrolling 4680 participants aged ≥75 years with pre-existing atherosclerotic cardiovascular diseases (ASCVD), found that greater cumulative exposure to remnant cholesterol (RC) across a 9-year span was independently associated with an increased incidence of cardiovascular events, suggesting that cumulative RC may be a powerful predictor of cardiovascular outcomes in patients with ASCVD.

Association of long-term time in target range for systolic blood pressure with cardiovascular risk in the elderly: a Chinese veteran cohort study.

AIMS: Short-term blood pressure (BP) time in target range (TTR) independently predicts cardiovascular (CV) outcomes in adults. However, there are limited data regarding long-term TTR for BP among elderly participants. We aimed to determine whether future CV risk varies for those who can maintain a long-term systolic BP (SBP) target range by assessing TTR in elderly individuals with hypertension. METHODS AND RESULTS: The Chinese veteran cohort study included 943 elderly participants with hypertension aged over 75 years. The primary outcome was the first occurrence of CV events during annual visits. Time in target range was estimated over 15 years of follow-up using linear interpolation. The target range was defined as 120-140 mmHg according to guidelines. The association between SBP TTR and CV outcomes was estimated using multivariable Cox proportional hazards models. During the 15 year follow-up, the probability of CV events gradually decreased with increasing TTR for SBP. After multivariable adjustment for traditional CV risk factors and mean BP, comparing the highest vs. lowest quartiles of TTR for SBP, the hazard ratios (HRs) [95% confidence intervals (CIs)] were 0.424 (0.289-0.624) for the primary outcome. For each 1 SD increase in TTR, the risk of the primary outcome decreased by 25.4% (HR: 0.746; 95% CI: 0.666-0.834). Consistent findings were observed in sensitivity analyses. CONCLUSION: Greater long-term TTR for SBP was associated with a decreased risk of CV events in elderly individuals independent of mean BP, suggesting that SBP TTR might serve as a modifiable risk factor for future CV health in elderly patients with hypertension. LAY SUMMARY: This ongoing Chinese veteran cohort study adds to the understanding of the relationship between higher long-term systolic blood pressure (SBP) time in target range (TTR) and cardiovascular benefits among elderly individuals with hypertension.

Higher long-term systolic blood pressure (SBP) time in target range (TTR) is associated with a significantly decreased risk of cardiovascular events independent of mean SBP, suggesting that TTR might serve as an essential measure for monitoring BP status. It might be helpful for lowering the risk of cardiovascular events when the time in SBP target range is maintained after antihypertensive therapy.

Metastatic patterns and prognosis of patients with primary malignant cardiac tumor.

Background: Distant metastases are independent negative prognostic factors for patients with primary malignant cardiac tumors (PMCT). This study aims to further investigate metastatic patterns and their prognostic effects in patients with PMCT. Materials and methods: This multicenter retrospective study included 218 patients with PMCT diagnosed between 2010 and 2017 from Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was utilized to identify metastatic risk factors. A Chi-square test was performed to assess the metastatic rate. Kaplan-Meier methods and Cox regression analysis were used to analyze the prognostic effects of metastatic patterns. Results: Sarcoma (p = 0.002) and tumor size¿4 cm (p = 0.006) were independent risk factors of distant metastases in patients with PMCT. Single lung metastasis (about 34%) was the most common of all metastatic patterns, and lung metastases occurred more frequently (17.9%) than bone, liver, and brain. Brain metastases had worst overall survival (OS) and cancer-specific survival (CSS) among other metastases, like lung, bone, liver, and brain (OS: HR = 3.20, 95% CI: 1.02-10.00, p = 0.046; CSS: HR = 3.53, 95% CI: 1.09-11.47, p = 0.036). Conclusion: Patients with PMCT who had sarcoma or a tumor larger than 4 cm had a higher risk of distant metastases. Lung was the most common metastatic site, and brain metastases had worst survival among others, such as lung, bone, liver, and brain. The results of this study provide insight for early detection, diagnosis, and treatment of distant metastases associated with PMCT.

Grape exosome-like nanoparticles: A potential therapeutic strategy for vascular calcification.

Vascular calcification (VC) is prevalent in hypertension, diabetes mellitus, chronic kidney disease, and aging and has been identified as an important predictor of adverse cardiovascular events. With the complicated mechanisms involved in VC, there is no effective therapy. Thus, a strategy for attenuating the development of VC is of clinical importance. Recent studies suggest that grape exosome-like nanoparticles (GENs) are involved in cell-cell communication as a means of regulating oxidative stress, inflammation, and apoptosis, which are known to modulate VC development. In this review, we discuss the roles of GENs and their potential mechanisms in the development of VC.

Long-term risk of cardiovascular disease mortality among classic Hodgkin lymphoma survivors.

BACKGROUND: The temporal trend of cardiovascular disease (CVD) mortality in patients with classic Hodgkin lymphoma (cHL) throughout follow-up remains unclear. This study aimed to assess this temporal trend in patients with cHL. METHODS: This multicenter cohort included 15,889 patients with cHL diagnosed between 1983 and 2015, covering all ages. The proportional mortality ratio, cumulative incidence of cause-specific mortality accounting for competing risk, standard mortality ratio, and absolute excess risk were analyzed. RESULTS: Among patients in stage I and stage II cHL, the proportional mortality ratio for CVD exceeded that for cHL, after approximately 60 or 120 months of follow-up, respectively. For almost all the patients with stage I or stage II disease, the cumulative incidence of CVD mortality exceeded that of cHL and other neoplasms over time. In recent decades, the risk of cHL mortality declined sharply, but the risk of CVD mortality among patients with cHL declined quite slowly or even remained unchanged among some populations. Patients with stage I or stage II disease experienced a higher risk of CVD mortality than the general population in almost all follow-up intervals. The absolute excess CVD risk among patients in stage I reached 48.5. CONCLUSIONS: The risk of CVD mortality exceeded that of cHL and other neoplasms and became the leading cause of death over time, among patients with stage I or stage II disease. More effective measures should be taken to reduce the risk of CVD mortality. LAY SUMMARY: Among patients with stage I and stage II classic Hodgkin lymphoma (cHL), the proportional mortality ratio of cardiovascular disease (CVD) exceeded that of cHL after approximately 60 or 120 months of follow-up, respectively. For almost all the patients with stage I or stage II disease, the cumulative incidence of CVD mortality exceeded that of cHL and other neoplasms over time. In the past several decades, the risk of cHL mortality declined sharply, but the risk of CVD mortality among patients with cHL declined quite slowly or even unchanged among some populations. CVD exceeded cHL and has become the leading cause of death over time.

Association of Chronic Respiratory Symptoms With Incident Cardiovascular Disease and All-Cause Mortality: Findings From the Coronary Artery Risk Development in Young Adults Study.

BACKGROUND: Respiratory and cardiovascular diseases (CVDs) frequently coexist; however, there is limited evidence on the relationship between chronic respiratory symptoms in young adulthood and late-onset CVD. RESEARCH QUESTION: Are chronic respiratory symptoms in young adulthood associated with CVD and all-cause mortality in later life? STUDY DESIGN AND METHODS: A total of 4,621 participants from the Coronary Artery Risk Development in Young Adults Study (CARDIA) cohort study aged 18 to 30 years were included. Chronic respiratory symptoms were identified through respiratory symptom questionnaires in two consecutive examinations. Incident CVD and all-cause mortality were adjudicated over 30-year follow-up. Multivariable Cox proportional hazards models were used to explore the association of chronic respiratory symptoms with incident CVD and all-cause mortality. RESULTS: During a median follow-up of 30.9 years, 284 CVD events (6.15%) and 378 deaths (8.18%) occurred. Following multivariable adjustment for demographic characteristics, cardiovascular risk factors, smoking, and lung function, the hazard ratios (95% CIs) for CVD events were 1.51 (1.18-1.93) for any respiratory symptom, 1.57 (1.18-2.09) for cough or phlegm, 1.31 (1.01-1.68) for wheeze, 1.73 (1.25-2.41) for shortness of breath, and 1.32 (1.01-1.71) for chest illnesses. Similar findings were also observed in all-cause mortality. Comparing zero vs three to four respiratory symptoms, the hazard ratios (95% CIs) were 1.97 (1.34-2.91) for CVD and 1.75 (1.23-2.47) for all-cause mortality. Similar results were observed in various sensitivity analyses. INTERPRETATION: Chronic respiratory symptoms in young adulthood are associated with an increased risk of CVD and all-cause mortality in midlife independent of established cardiovascular risk factors, smoking, and lung function. Identifying chronic respiratory symptoms in young adulthood may help provide prognostic information regarding future cardiovascular health. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT00005130; URL: https://www. CLINICALTRIALS: gov.

SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease.

Vascular calcification (VC) is regarded as an important pathological change lacking effective treatment and associated with high mortality. Sirtuin 6 (SIRT6) is a member of the Sirtuin family, a class III histone deacetylase and a key epigenetic regulator. SIRT6 has a protective role in patients with chronic kidney disease (CKD). However, the exact role and molecular mechanism of SIRT6 in VC in patients with CKD remain unclear. Here, we demonstrated that SIRT6 was markedly downregulated in peripheral blood mononuclear cells (PBMCs) and in the radial artery tissue of patients with CKD with VC. SIRT6-transgenic (SIRT6-Tg) mice showed alleviated VC, while vascular smooth muscle cell-specific (VSMC-specific) SIRT6 knocked-down mice showed severe VC in CKD. SIRT6 suppressed the osteogenic transdifferentiation of VSMCs via regulation of runt-related transcription factor 2 (Runx2). Coimmunoprecipitation (co-IP) and immunoprecipitation (IP) assays confirmed that SIRT6 bound to Runx2. Moreover, Runx2 was deacetylated by SIRT6 and further promoted nuclear export via exportin 1 (XPO1), which in turn caused degradation of Runx2 through the ubiquitin-proteasome system. These results demonstrated that SIRT6 prevented VC by suppressing the osteogenic transdifferentiation of VSMCs, and as such targeting SIRT6 may be an appealing therapeutic target for VC in CKD.

Receptor-Interacting Protein Kinase 3 Inhibition Prevents Cadmium-Mediated Macrophage Polarization and Subsequent Atherosclerosis via Maintaining Mitochondrial Homeostasis.

Chronic cadmium (Cd) exposure contributes to the progression of cardiovascular disease (CVD), especially atherosclerosis (AS), but the underlying mechanism is unclear. Since mitochondrial homeostasis is emerging as a core player in the development of CVD, it might serve as a potential mechanism linking Cd exposure and AS. In this study, we aimed to investigate Cd-mediated AS through macrophage polarization and know the mechanisms of Cd-caused mitochondrial homeostasis imbalance. In vitro, flow cytometry shows that Cd exposure promotes M1-type polarization of macrophages, manifested as the increasing expressions of nuclear Factor kappa-light-chain-enhancer of activated B (NF-kB) and NLR family pyrin domain containing 3 (NLRP3). Mitochondrial homeostasis tests revealed that decreasing mitochondrial membrane potential and mitophage, increasing the mitochondrial superoxide (mROS), and mitochondrial fission are involved in the Cd-induced macrophage polarization. The upregulated expressions of receptor-interacting protein kinase 3 (RIPK3) and pseudokinase-mixed lineage kinase domain-like protein (p-MLKL) were observed. Knocking out RIPK3, followed by decreasing the expression of p-MLKL, improves the mitochondrial homeostasis imbalance which effectively reverses macrophage polarization. In vivo, the oil red O staining showed that Cd with higher blood significantly aggravates AS. Besides, M1-type polarization of macrophages and mitochondrial homeostasis imbalance were observed in the aortic roots of the mice through immunofluorescence and western blot. Knocking out RIPK3 restored the changes above. Finally, the administered N-acetyl cysteine (NAC) or mitochondrial division inhibitor-1 (Mdivi-1), which decreased the mROS or mitochondrial fission, inhibited the expressions of RIPK3 and p-MLKL, attenuating AS and macrophage M1-type polarization in the Cd-treated group. Consequently, the Cd exposure activated the RIPK3 pathway and impaired the mitochondrial homeostasis, resulting in pro-inflammatory macrophage polarization and subsequent AS. Knocking out RIPK3 provided a potential therapeutic target for Cd-caused macrophage polarization and subsequent AS.

Olanzapine: Association Between a Typical Antipsychotic Drug and Aortic Calcification.

Aims: This study concentrates on the relationship between antipsychotic drugs (APDs) and aortic calcification. Methods: All 56 patients with schizophrenia were divided into two groups according to aortic calcification index. APD equivalent dose was calculated via defined daily doses method. Results: In schizophrenia patients with higher aortic calcification index scores, APD equivalent doses were lower. APD equivalent dose was negatively related to aortic calcification index. Although equivalent APD dose in patients without olanzapine treatment was negatively related to aortic calcification index, it seems that equivalent APD dose did not associate with aortic calcification. Conclusion: Aortic calcification is negatively associated with APD dose in schizophrenia patients. Olanzapine seems to be vital to the relationship between aortic calcification and APD treatment.

LncRNA H19 abrogates the protective effects of curcumin on rat carotid balloon injury via activating Wnt/ß-catenin signaling pathway.

Intimal hyperplasia-induced restenosis is a common response to vascular endothelial damage caused by mechanical force or other stimulation, and is closely linked to vascular remodeling. Curcumin, a traditional Chinese medicine, exhibits potent protective effects in cardiovascular diseases; for example, it attenuates vascular remodeling. Although the suppressive effects of curcumin on diseases caused by vascular narrowing have been investigated, the underlying mechanisms remain unknown. Long non-coding RNAs (lncRNAs) regulate various pathological processes and affect the action of drugs. In the present study, we found that the curcumin remarkably downregulated the expression of lncRNA H19 and thereby inhibited intimal hyperplasia-induced vascular restenosis. Furthermore, the inhibition of the expression of H19 by curcumin resulted in the inactivation of the Wnt/ß-catenin signaling. Overall, we show that curcumin suppresses intimal hyperplasia via the H19/Wnt/ß-catenin pathway, implying that H19 is a critical molecule in the suppression of intimal hyperplasia after balloon injury by curcumin. These insights should be useful for potential application of curcumin as a therapeutic intervention in vascular stenosis.

Supramolecular Self-Assembled Nanofibers Efficiently Activate the Precursor of Hepatocyte Growth Factor for Angiogenesis in Myocardial Infarction Therapy.

The reconstruction of blood perfusion is a crucial therapeutic method to save and protect cardiac function after acute myocardial infarction (AMI). The activation of the hepatocyte growth factor precursor (pro-HGF) has a significant effect on promoting angiogenesis and antiapoptosis. The oxygen/glucose deprivation (OGD) caused by AMI could induce vascular adventitia fibroblasts to differentiate into myofibroblasts and secrete the pro-HGF. Meanwhile, the specific Met receptor of the hepatocyte growth factor (HGF) is upregulated in endothelial cells during AMI. However, the poor prognosis of AMI suggests that the pro-HGF is not effectively activated. Improving the activation efficiency of the pro-HGF may play a positive role in the treatment of AMI. Herein, we designed supramolecular nanofibers self-assembled by compound 1 (Comp.1, Nap-FFEG-IVGGYPWWMDV), which can strongly activate the pro-HGF and initiate HGF-Met signaling. Studies have proven that Comp.1 possesses a better ability to activate the pro-HGF to perform antiapoptosis and pro-angiogenesis. In vivo results have confirmed that the retention time of Comp.1 and its accumulation in the infarct area of the heart are promoted. Moreover, Comp.1 plays an effective role in promoting angiogenesis in the marginal area of AMI, reducing myocardial fibrosis, and protecting cardiac function. Herein, we will optimize the structure of bioactive peptides through supramolecular self-assembly and amplify their therapeutic effect by improving their efficiency, providing a new strategy for the therapy of AMI.

Osteomodulin is a Potential Genetic Target for Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases. Its features include abnormal cardiomyocyte hypertrophy, microvascular dysfunction, and increased accumulation of intercellular matrix. We aim to unravel genes associated with the pathogenesis of HCM and provide a potential target for diagnosis and treatment. Key modules were identified by weighted gene co-expression network analysis (WGCNA). A miRNA-mRNA network was constructed with the predicted miRNA and the most likely hub gene was screened out for gene set enrichment analysis (GSEA). The diagnostic capacity of hub gene was verified by receiver operating characteristic (ROC) curves. Single-cell sequencing (sc-RNA seq) data of normal adult hearts were used to further predict the specific cell types expressing the hub gene. WGCNA assigned genes into different modules and found that the genes contained in the red module had the strongest positive correlation with HCM disease. 2.5% of the genes were common between DEG and hub genes. With the miRNA-mRNA network, osteomodulin (OMD) was identified as the most potential hub gene. GSEA showed that OMD was mainly involved in the synthesis of extracellular matrix and had a certain inhibitory effect on the immune system. The expression of OMD in HCM was validated and ROC curve analysis showed that OMD could distinguish HCM from controls with the area under the curve (AUC) > 0.7. The sc-RNA seq revealed that OMD was mainly expressed in the later stages of cardiac fibroblasts, suggesting that OMD may have an effect on fibroblasts, participating in the pathogenesis of HCM. OMD may serve as a biomarker and therapeutic target for HCM in the future.

Circadian rhythm disorder: a potential inducer of vascular calcification?

Over the past decades, circadian rhythm has drawn a great attention in cardiovascular diseases. The expressions of rhythm genes fluctuate in accordance with the diurnal changes of vascular physiology, which highlights the pivotal effect of vascular clock. Recent researches show that the circadian clock can directly regulate the synthetic and secretory function of endothelial cells and phenotypic switch of vascular smooth muscle cells to adjust vascular relaxation and contraction. Importantly, dysfunction of vascular cells is involved in vascular calcification. Secretion of osteogenic cytokines and calcified vesicles in the vessel, osteogenic phenotype switch of vascular smooth muscle cells are all implicated in the calcification process. Moreover, circadian rhythm disorder can lead to abnormal hormone secretion, oxidative stress, inflammatory reaction, and autophagy, all of which should not be ignored in vascular calcification. Vascular senescence is another pathogenetic mechanism in vascular calcification. Accelerated vascular senescence may act as an important intermediate factor to promote vascular calcification in circadian rhythm disorders. In this review, we elaborate the potential effect of circadian rhythm disorder in vascular calcification and try to provide a new direction in the prevention of vascular calcification.

Statins ameliorate cholesterol-induced inflammation and improve AQP2 expression by inhibiting NLRP3 activation in the kidney.

Background: Chronic kidney diseases (CKD) are usually associated with dyslipidemia. Statin therapy has been primarily recommended for the prevention of cardiovascular risk in patients with CKD; however, the effects of statins on kidney disease progression remain controversial. This study aims to investigate the effects of statin treatment on renal handling of water in patients and in animals on a high-fat diet. Methods: Retrospective cohort patient data were reviewed and the protein expression levels of aquaporin-2 (AQP2) and NLRP3 inflammasome adaptor ASC were examined in kidney biopsy specimens. The effects of statins on AQP2 and NLRP3 inflammasome components were examined in nlrp3-/- mice, 5/6 nephroectomized (5/6Nx) rats with a high-fat diet (HFD), and in vitro. Results: In the retrospective cohort study, serum cholesterol was negatively correlated to eGFR and AQP2 protein expression in the kidney biopsy specimens. Statins exhibited no effect on eGFR but abolished the negative correlation between cholesterol and AQP2 expression. Whilst nlrp3+/+ mice showed an increased urine output and a decreased expression of AQP2 protein after a HFD, which was moderately attenuated in nlrp3 deletion mice with HFD. In 5/6Nx rats on a HFD, atorvastatin markedly decreased the urine output and upregulated the protein expression of AQP2. Cholesterol stimulated the protein expression of NLRP3 inflammasome components ASC, caspase-1 and IL-1ß, and decreased AQP2 protein abundance in vitro, which was markedly prevented by statins, likely through the enhancement of ASC speck degradation via autophagy. Conclusion: Serum cholesterol level has a negative correlation with AQP2 protein expression in the kidney biopsy specimens of patients. Statins can ameliorate cholesterol-induced inflammation by promoting the degradation of ASC speck, and improve the expression of aquaporin in the kidneys of animals on a HFD.

Association Between Fasting Glucose Variability in Young Adulthood and the Progression of Coronary Artery Calcification in Middle Age.

OBJECTIVE: To investigate whether intraindividual variability of fasting glucose (FG) in young adulthood is associated with coronary artery calcification (CAC) progression in middle age. RESEARCH DESIGN AND METHODS: We included 2,256 CARDIA (Coronary Artery Risk Development Study in Young Adults) participants with CAC assessment by computed tomography scanner at baseline (2000-2001) and 10 years later (2010-2011). CAC progression was assessed for each individual as the difference of logarithmic CAC scores at follow-up and baseline (log[CAC (follow-up) + 1] - log[CAC (baseline) + 1]). FG variability was defined by the coefficient of variation about the mean FG (FG-CV), the SD of FG (FG-SD), and the average real variability of FG (FG-ARV) during the 10-year follow-up. We investigated the association between FG variability and CAC progression with adjustment for demographics, clinical risk factors, mean FG level, change in FG level, diabetes incidence, and medication use. RESULTS: After multivariable adjustment, 1-SD increment in FG-CV was associated with worse progression of CAC as demonstrated as percent change in CAC, with incident CAC 5.9% (95% CI 1.0, 10.7) and any CAC progression 6.7% (95% CI 2.3, 11.1) during 10 years. Similar findings were also observed in FG-SD and FG-ARV. CONCLUSIONS: Higher FG variability during young adulthood was associated with greater CAC progression in middle age, suggesting its value in predicting risk for subclinical coronary artery diseases.

Erratum: Ion Therapy: A Novel Strategy for Acute Myocardial Infarction.

[This corrects the article DOI: 10.1002/advs.201801260.].

LncRNA SOX2 overlapping transcript acts as a miRNA sponge to promote the proliferation and invasion of Ewing's sarcoma.

Long non-coding RNAs (lncRNAs) function as critical regulator in human cancers. However, the biological regulatory mechanisms of lncRNAs in Ewing's sarcoma are still elusive. This study tries to investigate the clinical significance and pathological role of lncRNA SOX2 overlapping transcript (SOX2OT) in Ewing's sarcoma progression. SOX2OT was identified to be up-regulated in Ewing's sarcoma tissue and cells. In vitro, SOX2OT knockdown suppressed Ewing's sarcoma cells proliferation and invasion, and triggered apoptosis. In vivo xenograft assays, SOX2OT knockdown significantly inhibited Ewing's sarcoma growth. With the help of bioinformatics analysis and luciferase assay, SOX2OT was validated to harbor miR-363, acting as miRNA sponge or competing endogenous RNA (ceRNA). Furthermore, FOXP4 was validated to be the target protein of miR-363. Western blot and RT-PCR confirmed that SOX2OT was positively correlated with FOXP4 protein via sponging miR-363, forming a negative cascade regulation. In conclusion, our study realizes that SOX2OT acted as oncogene in the tumorigenesis of Ewing's sarcoma, suggesting the SOX2OT/miR-363/FOXP4 pathway in Ewing's sarcoma.

Ion Therapy: A Novel Strategy for Acute Myocardial Infarction.

Although numerous therapies are widely applied clinically and stem cells and/or biomaterial based in situ implantations have achieved some effects, few of these have observed robust myocardial regeneration. The beneficial effects on cardiac function and structure are largely acting through paracrine signaling, which preserve the border-zone around the infarction, reduce apoptosis, blunt adverse remodeling, and promote angiogenesis. Ionic extracts from biomaterials have been proven to stimulate paracrine effects and promote cell-cell communications. Here, the paracrine stimulatory function of bioactive ions derived from biomaterials is integrated into the clinical concept of administration and proposed "ion therapy" as a novel strategy for myocardial infarction. In vitro, silicon- enriched ion extracts significantly increase cardiomyocyte viability and promote cell-cell communications, thus stimulating vascular formation via a paracrine effect under glucose/oxygen deprived conditions. In vivo, by intravenous injection, the bioactive silicon ions act as "diplomats" and promote crosstalk in myocardial cells, stimulate angiogenesis, and improve cardiac function post-myocardial infarction.