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Zhong-guo Fan,1 Yang Xu,1 Xi Chen,1 Ming-yue Ji,1,2 Gen-shan Ma1 1Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 2Department of Cardiology, Lianshui People’s Hospital, Huaian, People’s Republic of ChinaCorrespondence: Gen-shan Ma, Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China, Tel +86-13002580569, Email magenshan_D@163.comObjective: Dapagliflozin (DAPA) has been reported to have significant cardiac protective effects on heart failure (HF). However, the dose and time, as well as the underlying mechanisms, for DAPA treatment in acute myocardial infarction (AMI) remain controversial. The aim of this study aimed to assess the efficacy and safety of DAPA treatment along with an increased concentration gradient for AMI and explore the potential mechanisms.Methods: Non-diabetic Sprague-Dawley rats were used for establishing AMI models and then were treated with three different concentrations of DAPA [0.5 mg/kg, 1 mg/kg and 1.5 mg/kg, described as AMI+DAPA Low, AMI+DAPA Medium (Med) and AMI+DAPA High, respectively] for six weeks from the onsetting of AMI. Echocardiography, histological staining and Western blot were performed to assess the relevant cardiac protective effects. Mitochondrial biogenesis and myocardial apoptosis were evaluated via the electron microscopy and TUNEL assay, respectively, as well as the Immunoblotting. In vitro, H9c2 cells were subjected to hypoxic treatment to assess the efficacy of DAPA on mitochondrial biogenesis and apoptosis.Results: The medium dose of DAPA treatment could significantly reduce the infarct size (P < 0.01) and the echocardiography results showed that the MI-induced damage in cardiac function got partly repaired, showing no significant difference in left ventricle ejection fraction (LVEF) versus the Sham group (Sham vs AMI+DAPA Med group: 70.47% vs 61.73%). The Western blotting results confirmed the relevant benefits and the underlying mechanisms might be through the activation of PGAM5/Drp1 signaling pathway to normalize the mitochondrial fission and reduce cardiomyocyte apoptosis. Moreover, a medium dose of DAPA treatment could avoid increased damage to the bladder endothelium following higher treatment doses.Conclusion: Appropriate dose of DAPA treatment could improve the cardiac remodeling and reduce the cardiomyocyte apoptosis after AMI, without increased damage to bladder endothelium, which might be more preferred for MI patients without diabetes.Keywords: Dapagliflozin, acute myocardial infarction, mitochondrial fission, cardiomyocyte apoptosis

Yefei Li*, Yuyu Yao*, Zulong Sheng, Yanxiaoxiao Yang, Genshan Ma,Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu, China*These two authors contributed equally to this work.Purpose: Results for implantation efficiency and effective improvement of cardiac function in the field of mesenchymal stem cells (MSCs) are controversial. To attempt to clarify this debate, we utilized magnetic resonance imaging (MRI) and near-infrared optical imaging (OI) to explore the effects of different delivery modes of mesenchymal stem cells on cell retention time and cardiac function after myocardial infarction (MI).Methods: Rat MSCs were labeled with superparamagnetic iron oxide nanoparticles and 1, 1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt (DiD) for noninvasive cell tracking in a rat MI model. Rats underwent coronary artery ligation and were randomized into three experimental groups: intravenous (IV), intramyocardial (IM), and a control group. The first two groups referred to the route of delivery of the transplanted dual-labeled MSCs; whereas the control group was given an IV injection of serum-free medium one day post-MI. Cellular engraftment was determined 1 day and 7 days post cell delivery by measuring the iron and optical signals in explanted organs. Prussian blue staining and fluorescent microscopy were performed on histological sections for iron and DiD, respectively. Cardiac function was measured by echocardiography on day 7.Results: The cardiac function of the IM group increased significantly compared to the IV and control groups at day 7. In the IM group, labeled cells were visualized in the infracted heart by serial MRI, and the intensity by OI was significantly higher on day 1. In the IV group, the heart signals were significantly attenuated by dual-modal tracking at two time points, but the lung signals in OI were significantly stronger than the IM group at both time points.Conclusion: IM injection of MSCs increased cell engraftment within infarcted hearts and improved cardiac function after MI. However, IV infusion has a low efficacy due to the cell trapping in the lung. Therefore, direct injection may provide an advantage over IV, with regard to retention of stem cells and protection of cardiac function.Keywords: stem cell tracking, superparamagnetic iron oxide, DiD, cardiac function, myocardial infarction

Objective: Studies have found that high expression of human Kallistatin (HKS) in adipose tissue can improve obesity and its associated comorbidities, but the underlying mechanism of specific regulation is unclear. Methods: An obesity model was built by injecting 8-week-old C57BL/6 mice ( n  = 6 mice per group) with (Ad.Null and (Ad.HKS adenovirus into epididymal adipose tissue and fed with a high-fat diet (HFD). Insulin resistance-related proteins, AKT and IRS1, were detected in the liver, subcutaneous fat, and skeletal muscle by western blotting after one month of HFD. Epididymal adipose tissue was isolated after 24 h for culture, and exosomes were extracted by differential centrifugation. Enzyme-linked immunosorbent assay detected the expression of HKS protein in serum and exosomes. To examine the role of exosomes in AML12 insulin resistance, we used epididymal adipose tissue-derived exosomes or transfected (Ad.HKS into mature 3T3L1-derived exosomes to interfere with palmitic acid (PA)-induced mouse AML12 insulin resistance model. GW4869 was used to inhibit exosome biogenesis and release. Results: Our results showed that HFD-induced mice with high expression of HKS in epididymal adipose tissue had slower weight gain, lower serum triglycerides, reduced free fatty acids, and improved liver insulin resistance compared with the (Ad.Null group. We also demonstrated that HKS was enriched in epididymal adipose tissue-derived exosomes and released through the exosome pathway. In PA-induced AML12 cells, insulin resistance was alleviated after incubation of the HKS-related exosome; this effect was reversed with GW4869. Conclusion: High expression of HKS in epididymal adipose tissue could lead to its exocrine secretion in the form of exosomes and improve liver insulin resistance by promoting the phosphorylation of AKT. Production of high HKS vesicles might be a possible way to alleviate insulin resistance associated with obesity.

Mitochondrial dysfunction plays a critical role in the development and exacerbation of heart failure (HF). Dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fission, influences cardiac energy metabolism. The present study investigated the relationship between serum Drp1 levels and the prognosis of patients with HF across a broad spectrum. Serum Drp1 concentrations were measured using ELISA. The primary outcome was the risk of composite major adverse cardiac events (MACEs), which included instances of cardiac death and HF-related readmissions. To assess the prognostic significance of serum Drp1, a receiver operating characteristic curve was constructed to predict MACE-free survival. Additionally, an optimal threshold value for Drp1 was determined and was used to stratify patients into different risk categories. A total of 256 HF patients were finally included and categorized into two groups based on their serum Drp1 levels, labeled as the low (Drp1 ≤2.66 ng/ml, n=101) and high group (Drp1 >2.66 ng/ml, n=155). Patients with low serum Drp1 concentrations showed impaired heart structure and function, as assessed by echocardiography. The 6-month follow-up results indicated that patients with reduced Drp1 concentrations faced a substantially increased risk of MACEs (21.1% vs. 2.8%; P<0.001). The present study revealed that diminished serum Drp1 concentrations could potentially act as a predictive marker for the prognosis of HF in a broad patient population., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Cheng et al.)

High-fat diet (HFD) can cause obesity, inducing dysregulation of the visceral adipose tissue (VAT). This study aimed to explore potential biological pathways and hub genes involved in obese VAT, and for that, bioinformatic analysis of multiple datasets was performed. The expression profiles (GSE30247, GSE167311 and GSE79434) were downloaded from Gene Expression Omnibus. Overlapping differentially expressed genes (ODEGs) between normal diet and HFD groups in GSE30247 and GSE167311 were selected to run protein-protein interaction network, GO and KEGG analysis. The hub genes in ODEGs were screened by Cytoscape software and further verified in GSE79434 and obese mouse model. A total of 747 ODEGs (599 up-regulated and 148 down-regulated) were screened, and the GO and KEGG analysis showed that the up-regulated ODEGs were significantly enriched in inflammatory response and extracellular matrix receptor interaction pathways. On the other hand, the down-regulated ODEGs were involved in metabolic pathways; however, there were no significant KEGG pathways. Furthermore, six hub genes, Mki67, Rac2, Itgb2, Emr1, Tyrobp and Csf1r were acquired. These pathways and genes were verified in GSE79434 and VAT of obese mice. This study revealed that HFD induced VAT expansion, inflammation and fibrosis, and the hub genes could be used as therapeutic biomarkers in obesity.

Purpose of Review: Lipoprotein(a) is an independent risk factor for cardiovascular disease. We review the ongoing shifts in consensus guidelines for the testing and management of Lp(a) and provide insight into whether current evidence suggests that awareness and testing of Lp(a) is clinically actionable., Recent Findings: GWAS and Mendelian randomization studies have established causal links between elevated Lp(a) and forms of CVD, including CAD and calcific aortic valve disease. Testing of Lp(a) identifies patients with similar risk to that of heterozygous FH, enhances risk stratification in patients with borderline/intermediate risk as determined through traditional factors, and facilitates the assessment of inherited CVD risk through cascade screening in patients with known family history of elevated Lp(a). Reductions in Lp(a) through non-targeted therapies including PCSK9 inhibition and lipoprotein apheresis have demonstrated reductions in ASCVD risk that are likely attributable to lowering Lp(a). Targeted therapies to potently lower Lp(a) are in clinical development. Lp(a) is actionable, and can be used to identify high risk patients for primary prevention and their family members through cascade screening, and to guide intensification of therapy in primary and secondary prevention of ASCVD., (© 2023. The Author(s).)

Objective: Adipose tissue remodeling is a dynamic process that is pathologically expedited in the obese state and is closely related to obesity-associated disease progression. This study aimed to explore the effects of human kallistatin (HKS) on adipose tissue remodeling and obesity-related metabolic disorders in mice fed with a high-fat diet (HFD)., Methods: Adenovirus-mediated HKS cDNA (Ad.HKS) and a blank adenovirus (Ad.Null) were constructed and injected into the epididymal white adipose tissue (eWAT) of 8-weeks-old male C57B/L mice. The mice were fed normal or HFD for 28 days. The body weight and circulating lipids levels were assessed. Intraperitoneal glucose tolerance test (IGTT) and insulin tolerance test (ITT) were also performed. Oil-red O staining was used to assess the extent of lipid deposition in the liver. Immunohistochemistry and HE staining were used to measure HKS expression, adipose tissue morphology, and macrophage infiltration. Western blot and qRT-PCR were used to evaluate the expression of adipose function-related factors., Results: At the end of the experiment, the expression of HKS in the serum and eWAT of the Ad.HKS group was higher than in the Ad.Null group. Furthermore, Ad.HKS mice had lower body weight and decreased serum and liver lipid levels after four weeks of HFD feeding. IGTT and ITT showed that HKS treatment maintained balanced glucose homeostasis. Additionally, inguinal white adipose tissue (iWAT) and eWAT in Ad.HKS mice had a higher number of smaller-size adipocytes and had less macrophage infiltration than Ad.Null group. HKS significantly increased the mRNA levels of adiponectin, vaspin, and eNOS. In contrast, HKS decreased RBP4 and TNFα levels in the adipose tissues. Western blot results showed that local injection of HKS significantly upregulated the protein expressions of SIRT1, p-AMPK, IRS1, p-AKT, and GLUT4 in eWAT., Conclusions: HKS injection in eWAT improves HFD-induced adipose tissue remodeling and function, thus significantly improving weight gain and dysregulation of glucose and lipid homeostasis in mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Dynamin-related protein 1 (Drp1) has been demonstrated as a crucial role in mediating the programed cell death and cardiac metabolism through its regulatory of mitophagy in animal studies. However, the clinical values of Drp1 for human cardiac disease remain unknown. This study is aimed to evaluate the diagnostic and prognostic values of serum Drp1 in these patients with heart failure (HF)., Methods: The enzyme linked immunosorbent assay (ELISA) was used for measuring serum Drp1 concentrations in 85 cases of HF with preserved ejection fraction (HFpEF) and 86 cases of HF with reduced ejection fraction (HFrEF). The diagnostic value of Drp1 was evaluated using the receiver operating characteristic (ROC) analysis. The composite endpoint was consisted of cardiac death and rehospitalization for HF, and the association between Drp1 and clinical outcomes were further determined., Results: Serum Drp1 concentrations were much higher in HFpEF than that in HFrEF (4.2 ± 3.7 ng/mL vs. 2.6 ± 2.2 ng/mL, p = 0.001) and the ROC analysis demonstrated it as a potential diagnostic biomarker for distinction of the HF phenotypes, with an optimal cutoff point of 3.5 ng/mL (area under the curve (AUC) = 0.659, sensitivity: 45.9%, specificity: 83.7%). Kaplan-Meier survival analysis indicated that a low serum concentration of Drp1 (cut-off value = 2.5 ng/mL, AUC = 0.738) was in relation to poor prognosis of HF. Moreover, binary logistic regression analysis identified the low serum concentration of Drp1 as an independent risk predictor for rehospitalization (odds ratio (OR) = 6.574, p = 0.001) and a composite endpoint (OR = 5.927, p = 0.001)., Conclusions: Our findings suggested that low serum concentrations of Drp1 might serve as a predicting biomarker for distinction of HF phenotypes and overall prognosis of HF., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)

Background: Fibrotic remodeling is an essential aspect of heart failure. Human kallistatin (KS, mouse Serpina3c homologs) inhibits fibrosis after myocardial infarction (MI) but the specific underlying mechanism is unknown., Methods: A total of 40 heart failure patients (HFPs) were enrolled and their plasma KS was measured using ELISA. Serpina3c -/- and C57BL/6 mice were used to construct the MI model. TGF-β1 or a hypoxic condition was established to interfere with the functioning of cardiac fibroblasts (CFs). RNA-seq was performed to assess the effect of Serpina3c on the transcriptome., Findings: The levels of KS were used as a predictor of readmission among the HFPs. Serpina3c expression decreased in MI hearts and CFs. Serpina3c -/- led to the aggravation of MI fibrosis, and increased the proliferation of CFs. The overexpression of Serpina3c in CFs had the opposite effect. Glycolysis-related genes were significantly increased in Serpina3c -/- group by RNA-seq. Enolase (ENO1), which is a key enzyme in glycolysis, increased most significantly. Inhibition of ENO1 could antagonize the promotion of Serpina3c -/- on the proliferation of CFs. Co-IP was performed to verify the interaction between Serpina3c and Nr4a1. Serpina3c -/- inhibited the acetylation of Nr4a1 and increased the degradation of Nr4a1. Activation of Nr4a1 could negatively regulate the expression of ENO1 and inhibited the proliferation of Serpina3c -/- CFs in Serpina3c -/- MI mice., Interpretation: Serpina3c inhibits the transcriptional activation of ENO1 by regulating the acetylation of Nr4a1, thereby reducing the fibrosis after MI by inhibiting glycolysis. Serpina3c is a potential target for prevention and treatment of heart failure after MI., (Copyright © 2022 Elsevier B.V. All rights reserved.)

What Is Known and Objective: It is well known that high in-stent thrombotic risk due to the superimposition of a platelet-rich thrombus was considered as the main origin of major adverse cardiac events after stent implantation. The clinical management of antiplatelet therapy strategy after percutaneous coronary intervention (PCI) remains controversial. This study is sought to explore the efficacy and safety of a maintained P2Y 12 inhibitor monotherapy after shorter-duration of dual antiplatelet therapy (DAPT) in these patients., Methods: Medline, Google Scholar, Web of Science, and the Cochrane Controlled Trials Registry were searched online for retrieving eligible citations. A composite of all-cause death, myocardial infarction (MI) and stroke was defined as major adverse cardio- and cerebro-vascular events (MACCE), which is analysed as the primary efficacy endpoint. The risk of bleeding events was chosen as safety endpoint., Results: Five randomized clinical trials (RCT) with 32,143 patients were finally analysed. A maintained P2Y 12 inhibitor monotherapy after shorter-duration of DAPT cloud not only reduce the incidence of MACCE [odds ratios (OR): 0.89, 95% confidence intervals (CI): 0.79-0.99, p = 0.037], but also the bleeding risk (OR 0.61, 95% CI: 0.44-0.85, p = 0.003). No higher incidence of any ischaemic events, including MI, stroke or definite stent thrombosis (ST) was observed with respect to this new antiplatelet therapy option., Conclusions: A maintained P2Y 12 inhibitor monotherapy after shorter-duration of DAPT was suggested as a more preferable antiplatelet therapy option in patients undergoing coronary drug-eluting stents (DES) placement. Larger and more powerful randomized trials with precise sub-analyses are still necessary for further confirming these relevant benefits., (© 2022 John Wiley & Sons Ltd.)

Background and Aims: Lipoprotein(a) [Lp(a)] is causally associated with aortic valve stenosis (AS) but Lp(a) testing among AS patients is not broadly incorporated into clinical practice. We evaluated trends in Lp(a) testing in an academic medical center., Methods: Educational efforts and adding Lp(a) to the lipid panel on the electronic medical record (EMR) and pre-procedure order sets were used to increase awareness of Lp(a) as a risk factor in AS. Medical records at University of California San Diego Health (UCSDH) were analyzed from 2010 to 2020 to define the yearly frequency of first time Lp(a) testing in patients with diagnosis codes for AS or undergoing transcatheter aortic valve replacement (TAVR)., Results: Lp(a) testing for any indication increased over 5-fold from 2010 to 2020. A total of 3808 patients had a diagnosis of AS and 417 patients had TAVR. Lp(a) levels >30 mg/dL were present in 37% of AS and 35% of TAVR patients. The rates of Lp(a) testing in AS and TAVR were 14.0% and 65.7%, respectively. In AS, Lp(a) testing increased over time from 8.5% in 2010, peaking at 24.2% in 2017, and declining to 13.9% in 2020 (p < 0.001 for trend). Following implementation of EMR order-sets in 2016, Lp(a) testing in TAVR cases increased to a peak of 88.5% in 2018., Conclusions: Elevated Lp(a) is prevalent in AS and TAVR patients. Implementation of educational efforts and practice pathways resulted in increased Lp(a) testing in patients with AS. This study represents a paradigm that may allow increased global awareness of Lp(a) as a risk factor for AS., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is a public health challenge and an increasing cause of chronic liver disease worldwide. However, the underlying molecular mechanism remains unclear. The aim of this study was to determine the precise role of serpina3c in the process of NAFLD. Male Apoe -/- /serpina3c -/- double knockout (DKO) and Apoe -/- mice were fed a high-fat diet (HFD) for 12 weeks. Several markers of steatosis and inflammation were evaluated. In vitro cell models induced by palmitic acid (PA) treatment were used to evaluate the beneficial effect of serpina3c on necroptosis and the underlying molecular mechanism. Compared with Apoe -/- mice, DKO mice exhibited a significantly exacerbated hepatic steatosis, increased hepatic triglyceride content and expression of genes involved in lipid metabolism (SREBP1c and SCD1), promoted hepatic inflammation and fibrosis, promoted necroptosis by increasing expression of receptor-interacting protein 3 (RIP3), phosphorylated mixed lineage kinase domain-like (MLKL) and high mobility group box 1 (HMGB1). Notably, serpina3c deficiency increased β-catenin, Foxo1, and Toll-like receptor 4 (TLR4) protein expression. In vitro , serpina3c knockdown promoted necroptosis and lipid droplet formation under condition of lipotoxicity. However, these phenomena were reversed by the overexpression of serpina3c. Mechanistically, downregulation of serpina3c expression promoted Foxo1 and β-catenin colocalized in the nucleus under condition of lipotoxicity, consequently upregulating the expression of TLR4. Conversely, disruption of Foxo1-β/catenin by Foxo1 and β-catenin inhibitors decreased TLR4 expression and ameliorated hepatic necroptosis in vitro. This study highlights a novel mechanism that serpina3c modulates NAFLD development by inhibiting necroptosis via β-catenin/Foxo1/TLR4., (© 2022 Federation of American Societies for Experimental Biology.)

Background: There are some controversies on the utilization and benefits of thrombus aspiration in patients with ST-segment elevation myocardial infarction (STEMI). However, a few studies investigated this issue and the age-associated effects among the large population in China. Hence, we aimed to figure out the age-associated utilization and in-hospital outcomes of thrombus aspiration to improve therapeutic decisions in clinical routine., Methods: We retrospectively recruited 13,655 eligible STEMI patients from the database of the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. These subjects were allocated into primary percutaneous coronary intervention (PPCI)-only group and thrombus aspiration group after being subdivided into three age groups (G 21-50 , G 51-75 , and G 76-95 ). After 1:1 propensity score matching for PPCI-only and thrombus aspiration groups, a total of 8,815 matched patients were enrolled for the subsequent analysis. The primary outcome was in-hospital cardiovascular death, and the key safety outcome was in-hospital stroke., Results: We observed that the ratio of STEMI patients undergoing thrombus aspiration to PPCI-only reduced with aging. For patients ≤ 75 years, the culprit lesion suffered from thrombus aspiration was mainly located in the left anterior descending branch, and left-ventricular ejection fraction (LVEF) was lower (G 21-50 : 54.9 ± 8.9 vs. 56.0 ± 8.7%, P = 0.01; G 51-75 : 53.9 ± 9.6 vs. 54.8 ± 9.0%, P = 0.001) and the rate of regional wall motion abnormality was higher (G 21-50 : 75.7 vs. 66.5%, P < 0.001; G 51-75 : 75.4 vs. 69.1%, P < 0.001) in the thrombus aspiration group. By contrast, for patients > 75 years, the right coronary artery was the predominant culprit lesion undergoing thrombus aspiration, LVEF (63.1 ± 10.5 vs. 53.1 ± 9.5%, P = 0.985) and the regional wall motion abnormality (79.2 vs. 74.2%, P = 0.089) were comparable between the two treatment groups. Thrombus aspiration neither reduced the in-hospital risk of cardiovascular death, all-cause death, recurrent myocardial infarction, acute stent thrombosis, heart failure, cardiogenic shock, and sudden cardiac arrest nor increased stroke risk compared with the PPCI-only group. However, after adjustment for age, thrombus aspiration presented the tendency to reduce the incidence of sudden cardiac arrest (4.9 vs. 2.5%, P = 0.06) and in-hospital cardiovascular death at 3 days (hazard ratio 0.46; 95% CI, 0.20-1.06; log-rank P = 0.08) in G 76-95 group and tended to increase the incidence of heart failure in G 51-75 (5.7 vs. 6.9%, P = 0.07)., Conclusion: The thrombus aspiration neither significantly reduced the in-hospital incidence of major adverse cardiac events nor increased stroke risk. However, it might play a protective role in reducing in-hospital sudden cardiac arrest and increasing survival from cardiovascular death at 3 days for the elderly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qu, Zhang, Ju, Su, Zhang, Zuo, Ji, Chen and Ma.)

Background Myocardial strain can identify subclinical left ventricular dysfunction in various cardiac diseases, but its association with clinical outcomes in genetic cardiomyopathies remains unknown. Herein, we assessed myocardial strain in patients with Danon disease (DD), a rare X-linked autophagic disorder that causes severe cardiac manifestations. Methods and Results Echocardiographic images were reviewed and used to calculate myocardial strain from a retrospective, international registry of patients with DD. Regression analyses were performed to evaluate for an association of global longitudinal strain (GLS) and ejection fraction with the composite outcome (death, ventricular assist device, heart transplantation, and implantable cardioverter defibrillator for secondary prevention). A total of 22 patients with DD (male 14 [63.6%], median age 16.5 years) had sufficient echocardiograms for analysis. Absolute GLS was reduced with a mean of 12.2% with an apical-sparing pattern observed. Univariable regression for GLS and composite outcome showed an odds ratio of 1.32 (95% CI, 1.02-1.71) with P =0.03. For receiver operating characteristic analysis, the areas under the curve for GLS and ejection fraction were 0.810 ( P =0.02) and 0.605 ( P =0.44), respectively. An absolute GLS cutoff of 10.0% yielded a true positive rate of 85.7% and false positive rate of 13.3%. Conclusions In this cohort of patients with DD, GLS may be a useful assessment of myocardial function and may predict clinical outcomes. This study highlights the potential use of myocardial strain phenotyping to monitor disease progression and potentially to predict clinical outcomes in DD and other genetic cardiomyopathies.

Background: Left and right atrium (LA and RA) exert an essential and dynamic role in ventricular filling and hence affect heart performance. Strain quantification has been reported as a novel parameter to assess function. However, the assessment of bi-atrial strains with cardiovascular magnetic resonance (CMR) based techniques is still limited and gender- and age-specific normal values in a healthy population are missing. Methods: One hundred and fifty healthy volunteers (49.8 ± 17.3 years, 75 males) undergoing 1.5 Tesla CMR examination were retrospectively and consecutively recruited. LA and RA free wall (RAFW) radial and longitudinal strains (RS and LS) associated with atrial reservoir, conduit and booster pump functions were evaluated with CMR based tissue tracking (CMR-TT) technique. Results: The reservoir, conduit and pump LS resulted as 30.7 ± 10.2%, 19.5 ± 8.2%, 10.9 ± 3.7% for LA, and 52.2 ± 17.6%, 33.3 ± 14.2%, 19.1 ± 8.5% for RAFW, respectively. The amplitude of RA strains was significantly larger than that of LA strains, except for conduit RS. With the increase of age, the decrement of majority of reservoir and conduit strains were observed, while pump strains remained unaffected. Females presented with significantly larger RAFW strains compared with males, especially in the elderly. In addition to the positive correlation between atrial strains and emptying fraction, the negative correlation between atrial strains and volume index was also confirmed. Intra-observer reproducibility of LA strains was superior to RAFW strains (coefficient of variation: 10.12-17.04% vs. 10.80-27.36%, respectively), and the measurement of reservoir and conduit strains was more reproducible in comparison with pump strain. Conclusion: CMR-TT is a feasible and reproducible technique to quantify LA and RA strains and determine atrial phasic functions. The existence of age- and gender-related difference of strains suggests the necessity to establish specific normal values for individual populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Qu, Buckert, Ma and Rasche.)

Purpose: Microplastics have been widely detected in the environment and marine organisms. However, few studies have investigated the presence of microplastics in humans. This preliminary study identified and quantified the microplastic content in human feces., Methods: A total of 26 young male students aged 18-25 years were recruited from Beijing, China. A self-administered 7-day 24-h fluid intake record was used to document fluid intake, and food intake was recorded for 3 days. Feces were collected by participants using a sterile fecal collector. Microplastics in the remaining fecal residues were measured and identified using fourier transform infrared micro-spectroscopy., Results: Eventually, twenty-four participants completed the study. The fecal samples of 23 (95.8%) participants tested positive for microplastics. In these 23 samples, the abundance of microplastics varied from 1 particle/g to 36 particles/g (size 20 to 800 μm). The summed mass of all microplastic particles per participant ranged from 0.01 to 14.6 mg. Qualitative analysis of the microplastics indicated the presence of one to eight types of microplastics in each sample, with polypropylene (PP) being the most abundant; it was found in 95.8% of fecal samples. We examined associations between water intake habits and the abundance of microplastics in their feces. A moderate correlation was observed between packaged water and beverage intake and microplastic abundance in feces (r = 0.445, P = 0.029)., Conclusion: Various types of microplastics were detected in human feces, with PP being found in the highest proportion. There may be an association between water intake habits and microplastic abundance in feces., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To develop a three-dimensional body image stimuli suitable for middle-aged people in China, and verify the validity and reliability of the body image stimuli. Method: According to China and World Health Organization body mass index classification standards of adults, a set of three-dimensional body image stimuli of Chinese middle-aged males and females with different body size was developed by using 3D Studio Max and Adobe Photoshop CC based on the literature and expert consultation method. Forty-two 45- and 59-year-old middle-aged people in Zhengzhou City, Henan Province were recruited to verify the three-dimensional body image stimuli. Through questionnaire survey and physical examination, the coincidence between the selected body type and the actual body type was tested; the body composition was measured by dual-energy absorptiometry (DXA), and the structure validity of the image was tested; the body size satisfaction was investigated by the body image stimuli and the standard questionnaire, and the empirical validity of the image was tested. The repeated survey was conducted 14 days after the initial survey, and three experts were invited to score the current somatotype of the subjects to test the test-retest reliability and inter-rater reliability of the body image stimuli. Pearson, Spearman, Kendall correlation and Kappa consistency analysis were used to evaluate the validity and reliability of the body image stimuli. Results: The average age of 42 subjects was 52.7 years old, including 13 males and 29 females. A group of three-dimensional body image stimuli of middle-aged men and women were developed, and each group included 8 images. 73.8% of the subjects chose the body size consistent with the actual body type, and the weighted Kappa coefficient was 0.755 ( P <0.01). The selected somatotype was positively correlated with body weight and body composition indexes such as fat content, and the Pearson correlation coefficient of construct validity was 0.623-0.717 ( P <0.05). The results of the two surveys were positively correlated, and the Spearman correlation coefficient of test-retest reliability was 0.784-0.821 ( P <0.05). The scores of the three experts on the current somatotype of the subjects were positively correlated, and the Kendall correlation coefficient of inter-rater reliability was 0.818-0.878 ( P <0.05). Conclusion: The development of principle and reference basis of three-dimensional body image stimuli of middle-aged people is reliable, and the validity and reliability of the body image stimuli are good.

Background: Cardiovascular magnetic resonance based tissue tracking (CMR-TT) was reported to provide detailed insight into left ventricular (LV) contractile function and deformation with both of two- and three-dimensional (2/3D) algorithms. This study was designed to investigate the feasibility and reproducibility of these two techniques for measuring LV global and segmental strain, and establish gender- and age-related reference values of global multi-dimensional peak strains among large healthy population., Methods: We retrospectively recruited 150 healthy volunteers (75 males/females) and divided them into three age groups (G 20-40 , G 41-60 and G 61-80 ). LV global mean and peak strains as well as segmental strains in radial, circumferential and longitudinal directions were derived from post-hoc 2/3D CMR-TT analysis of standard steady-state free precession (SSFP) cine images acquired at 1.5T field strength., Results: Both 2D and 3D CMR-TT modalities enable the tracking of LV myocardial tissues and generate global and segmental strain data. By comparison, 3D CMR-TT was more feasible in measuring segmental deformation since it could generate values at all segments. The amplitudes of LV 3D global peak strain were the smallest among those of 2/3D corresponding global mean or peak strains except in the radial direction, and was highly correlated with 2D global mean strains (correlation coefficient r=0.71-0.90), 2D global peak strains (r=0.75-0.89) and 3D global mean strains (all r=0.99). In healthy cohort, LV 3D global peak values were 44.4%±13.0% for radial, -17.0%±2.7% for circumferential and -15.4%±2.3% for longitudinal strain. Females showed significantly larger amplitude of strains than males, especially in G 61-80 (P<0.05). The subjects in G 61-80 showed larger amplitude of strains than the volunteers in younger groups. The intra- and inter-observer agreement of 2/3D CMR-TT analysis in evaluating LV myocardial global deformation was better than segmental measurement., Conclusions: CMR-TT is a feasible and reproducible technique for assessing LV myocardial deformation, especially at the global level. The establishment of specific reference values of LV global and segmental systolic strains and the investigation of dimension-, gender- and age-related differences provide a fundamental insight into the features of LV contraction and works as an essential step in clinical routine., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-635). The authors have no conflicts of interest to declare., (2021 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Objective: To investigate the effect of remote ischemic preconditioning (RIPC) on contrast-induced acute kidney injury (CI-AKI) in patients with chronic total occlusion (CTO) after percutaneous coronary intervention (PCI). Methods: A total of 282 patients undergoing PCI at Zhongda Hospital Affiliated to Southeast University between June 2017 and January 2019 were prospectively enrolled. The patients were randomly divided into RIPC group ( n =142) and control group ( n =140). CI-AKI was defined as an increase in level of cystatin C (CysC)≥10% above baseline at 24 h after contrast administration. Baseline characteristics and the incidence of CI-AKI were compared between the two groups. The multivariate logistic regression analysis was further used to analyze the independent risk factors of CI-AKI. Results: There were no significant differences in age, gender, smoking, hypertension, diabetes, stroke and old myocardial infarction, coronary artery bypass graft surgery, previous PCI history and laboratory test indicators, target vessel and pathological characteristics of CTO lesions, contrast agent dosage, J-CTO (Multicenter CTO Registry in Japan) score, SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score, PCI success rate and stent number between the two groups ( P >0.05). The incidence of CI-AKI was significantly lower (18.3% vs 29.3%, P =0.036) in RIPC group than that of control group. Multivariate logistic analysis found that creatinine [odds ratio ( OR )=1.018,95% CI : 1.006-1.030, P =0.003], CysC ( OR =5.200, 95% CI :2.714-9.963, P< 0.001),contrast agent dosage ( OR =1.013,95% CI : 1.007-1.019, P< 0.001) and J-CTO score ( OR =1.834, 95% CI : 1.145-2.939, P =0.012) were independent risk factors of CI-AKI. However, RIPC was an independent protective factor of CI-AKI ( OR =0.391, 95% CI : 0.199-0.765, P =0.006). Conclusion: RIPC before contrast agent administration prevents CI-AKI in CTO patients undergoing PCI.

Abnormal vascular smooth muscle cell (VSMC) proliferation is a critical step in the development of atherosclerosis. Serpina3c is a serine protease inhibitor (serpin) that plays a key role in metabolic diseases. The present study aimed to investigate the role of serpina3c in atherosclerosis and regulation of VSMC proliferation and possible mechanisms. Serpina3c is down-regulated during high-fat diet (HFD)-induced atherosclerosis. An Apoe-/-/serpina3c-/--double-knockout mouse model was used to determine the role of serpina3c in atherosclerosis after HFD for 12 weeks. Compared with Apoe-/- mice, the Apoe-/-/serpina3c-/- mice developed more severe atherosclerosis, and the number of VSMCs and macrophages in aortic plaques was significantly increased. The present study revealed serpina3c as a novel thrombin inhibitor that suppressed thrombin activity. In circulating plasma, thrombin activity was high in the Apoe-/-/serpina3c-/- mice, compared with Apoe-/- mice. Immunofluorescence staining showed thrombin and serpina3c colocalization in the liver and aortic cusp. In addition, inhibition of thrombin by dabigatran in serpina3c-/- mice reduced neointima lesion formation due to partial carotid artery ligation. Moreover, an in vitro study confirmed that thrombin activity was also decreased by serpina3c protein, supernatant and cell lysate that overexpressed serpina3c. The results of experiments showed that serpina3c negatively regulated VSMC proliferation in culture. The possible mechanism may involve serpina3c inhibition of ERK1/2 and JNK signaling in thrombin/PAR-1 system-mediated VSMC proliferation. Our results highlight a protective role for serpina3c as a novel thrombin inhibitor in the development of atherosclerosis, with serpina3c conferring protection through the thrombin/PAR-1 system to negatively regulate VSMC proliferation through ERK1/2 and JNK signaling., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Serpina3 is a member of the serine protease inhibitor family and is involved in the inflammatory response. In this study, we investigated the effect of Serpina3c on pancreatic function in hypercholesterolemic mice., Methods: To investigate the role of Serpina3c in hyperlipidaemia, Serpina3c knockout mice were bred with Apoe-knockout mice (on a C57BL/6 background) to generate heterozygous Serpina3c-Apoe double knockout (Serpina3c +/- /Apoe +/- ) mice and were then bred to obtain homozygotes. C57BL/6, Serpina3c -/- , Apoe -/- , and Apoe -/- Serpina3c -/- mice were fed normal chow, and Apoe -/- and Apoe -/- Serpina3c -/- mice were fed a high-fat diet (HFD). After feeding for 3 months, the mice were monitored for body weight, blood glucose, glucose tolerance, and insulin tolerance test (ITT). ELISA and immunohistochemistry were used to detect insulin levels and glucagon expression. Immunohistochemical staining for macrophages in the pancreas was also performed. Western blot analysis was performed on pancreatic tissues to detect the protein levels of insulin-associated molecules, the metalloproteinase MMP2, the tissue inhibitor TIMP2 and components of the JNK-related pathway., Results: Blood glucose levels, glucose tolerance, and ITT were not significantly different among the groups. Serpina3c knockout resulted in blood lipid abnormalities in mice under HFD conditions. Insulin secretion was decreased in Apoe -/- Serpina3c -/- mice compared with Apoe -/- mice under normal chow conditions. In addition, Apoe -/- Serpina3c -/- mice exhibited increased insulin and glucagon secretion and expression after three months of HFD feeding, but insulin secretion was decreased in Apoe -/- Serpina3c -/- mice compared with Apoe -/- mice after the fifth month of HFD feeding. Serpina3c knockout increased MMP2 protein levels, whereas TIMP2 levels in the pancreas were decreased. Furthermore, Serpina3c knockout significantly upregulated the number of macrophages in the pancreas under HFD conditions. The JNK/AKT/FOXO1/PDX-1 axis was found to be involved in Serpina3c-regulated insulin secretion., Conclusion: These novel findings show that Serpina3c could play a protective role in insulin secretion partly through the JNK-related pathway under HFD conditions., Competing Interests: Declaration of Competing interest The authors have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Nutrition literacy is an important part of health literacy, as well as an significant factor to enhance the quality of population, improving the nutritional status of residents and preventing nutrition-related diseases. In 2010, China developed an evaluation tool for health literacy and began to monitor residents' health literacy. So far, eight national surveys on health literacy have been completed, providing an important basis for health promotion intervention strategies and related policies. However, in health literacy evaluation system, there is neither evaluation content of nutrition literacy, nor evaluation tools. In order to achieve the goals of "national nutrition plan (2017-2030)"and evaluate the implementation effect, it is urgent to carry out the assessment and monitoring of nutrition literacy. According to the nutritional characteristics of different populaitons, this research organizes national experts in related fields, following the principles of scientificity, conciseness and generality and through the scientific formulation procedures to construct the nutrition literacy assessment tools for different populations. This assessment tool can enhance the pertinence and scientificity of nutrition education and improve nutrition development strategy. The establishment of the nutrition literacy assessment tool is the premise of gradually establishing the nutrition literacy assessment system of the residents, and also lays a solid foundation for further conducting the national nutrition literacy evaluation work.

Cardiovascular magnetic resonance based tissue tracking (CMR-TT) was reported to provide detailed insight into left ventricular mechanical features. However, inadequate knowledge of the right ventricle (RV) mechanical deformation has been acquired by this advanced technique so far. It was the aim of this study to establish reference values of RV free wall (RVFW) global, regional and segmental longitudinal peak strain and strain rate (LS and LSR), and to investigate the gender- and age-related difference as well as the base-to-apex gradient of RVFW-LS and LSR with CMR-TT. 150 healthy volunteers (75 males/females) were retrospectively and continuously recruited and subdivided into three age groups (G 20-40 , G 41-60 and G 61-80 ). RVFW global, regional (basal, middle-cavity and apical) and segmental LS (GLS, RLS, SLS) along with systolic and diastolic LSR were generated by post-hoc CMR-TT analysis of standard steady-state free precession long-axis four-chamber view cine images acquired at 1.5T field strength. The reference value of myocardial RVFW-GLS was - 24.9 ± 5.2%. We found that females showed more negative GLS than males except in the youngest group, and no age-related difference of GLS was observed in both gender groups. RLS and SLS presented with the same age-related tendency as GLS. The basal and middle-cavity LS were similar between each other and significantly larger than apical LS. RVFW-GLSR resulted as - 1.73 ± 0.58 s -1 and 1.69 ± 0.65 s -1 during systolic and diastolic phases, respectively. The diastolic GLSR of males tended to decline with the ageing and was significantly lower than that of females in G 61-80 group. Regional and segmental LSR showed significant gender-related differences in certain basal and apical region/segments without any age-related effects. CMR-TT overcomes the difficulty in measuring RV global and segmental deformation. The establishment of the vendor-, gender- and segment-specific reference values of RVFW-LS and LSR is essential for the rapid and efficient utilization of CMR-TT modality in the clinical routine.

The current study aimed to investigate the effects of tetramethylprazine (TMP) on myocardial ischemia/reperfusion (MI/R) injury and its underlying mechanisms. MI/R rat model and hypoxia/reoxygenation (H/R) cardiomyocytes model were established. CK level and LDH activity were detected to evaluate MI/R and H/R injury. Cell viability was determined by cell counting kit-8 (CCK-8) assay. Cell apoptosis were identified by flow cytometry and autophagy were detected by western blot. Treatment with TMP significantly reduced CK level and LDH activity and decreased myocardial infarct size in MI/R rats. TMP reduced autophagy dysfunction induced by MI/R. Moreover, TMP treatment decreased H/R-induced injury and attenuated autophagy dysfunction in cardiomyocytes. Inhibiting autophagic flux with chloroquine (CQ) decreased the cardioprotection exerted by TMP in vivo and in vitro. Additionally, the effects of TMP on the modulation of autophagy were inhibited by LY294002 (a PI3K inhibitor) in H/R cardiomyocytes. Our findings suggested TMP exerted cardioprotection against MI/R injury by decreasing Beclin-1 associated autophagy dysfunction through PI3K pathway., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: It is clinically important to identify high-risk patients with acute coronary syndrome (ACS) who may require repeat revascularization. This retrospective study identified risk factors for repeat revascularization among ACS patients after first-time successful percutaneous coronary interventions (PCIs). The predictive value of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio for repeat revascularization was also evaluated., Methods: We enrolled consecutive ACS patients who had coronary angiography performed during the period from 6 to 12 months after a first-time successful PCI. The primary outcome of the study was to identify the risk factors of repeat revascularization. The subjects were stratified based on repeat PCI events. After comparing various clinical characteristics, univariate and multivariate Cox proportional hazard model analyses were adopted to evaluate the effects of risk factors on repeat revascularization., Results: The patients (n=271) were divided into the event (+) group (n=101) and the event (-) group (n=170). In the event (+) group, target lesion revascularization (TLR) accounted for 20.79% and target vessel revascularization (TVR) accounted for 50.49% of the patients. In contrast, 52.47% of the patients required de novo vessel revascularization (DVR). After adjustment for confounding factors, the TG/HDL-C ratio [hazard ratio (HR) =1.206, 95% confidence interval (CI): 1.016-1.431, P=0.032 for each higher TG/HDL-C ratio unit] and the Gensini score (HR =1.012, 95% CI: 1.005-1.018, P<0.001 for each higher Gensini score unit) were independent risk factors for a repeat PCI. Subgroup analyses showed that higher TG/HDL-C ratios were associated with a significantly higher risk of repeat PCIs in the male, hypertensive, and diabetes mellitus subgroups., Conclusions: The TG/HDL-C ratio and Gensini score could serve as risk factors for repeat revascularization in ACS patients after a first-time successful PCI., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Journal of Thoracic Disease. All rights reserved.)

Background: Evidence-based data on percutaneous coronary intervention in elderly patients with chronic total occlusion (CTO) and comparison among different scoring systems have not been well established., Patients and Methods: A total of 246 consecutive patients were stratified into two groups according to the age: elderly group (age≥ 75 years, n = 68) and nonelderly group (age < 75 years, n = 178). Clinical and angiographic characteristics including the Synergy Between PCI With TAXUS and Cardiac Surgery score, in-hospital major adverse cardiac events, procedural success rates, and predictive capacity of four scoring systems [J-CTO, Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS CTO), clinical and lesion-related (CL), and ostial location, Rentrop grade < 2, age ≥ 75 years (ORA) scores] were examined., Results: Triple-vessel disease and the Synergy Between PCI With TAXUS and Cardiac Surgery score in the elderly group were significantly higher than those in the nonelderly group (73.53 vs. 53.93%, P = 0.005; 31.39 ± 7.68 vs. 27.85 ± 7.16, P = 0.001, respectively). The in-hospital major adverse cardiac event rates, vascular access complication rates, and major bleeding rates were similar between the elderly and the nonelderly group (2.94 vs. 2.25%, P = 0.669; 1.47 vs. 0.56%, P = 0.477; 2.94 vs. 1.12%, P = 0.306, respectively). By contrast, the procedural success rate was statistically lower in the elderly group than that in the nonelderly group (73.53 vs. 84.83%, P = 0.040). All the four scoring systems showed a moderate predictive capacity [area under the curve (AUC) for J-CTO score: 0.806, P < 0.0001; AUC for PROGRESS CTO score: 0.727, P < 0.0001; AUC for CL score: 0.800, P < 0.0001; AUC for ORA score: 0.672, P < 0.0001, respectively]. Compared with the ORA score, the J-CTO score, and the CL score showed a significant advantage in predicting procedural success among overall patients (ΔAUC = 0.134, P = 0.0122; ΔAUC = 0.128, P = 0.0233, respectively)., Conclusion: Despite the lower procedural success rate, percutaneous coronary intervention in elderly patients with CTO is feasible and safe. J-CTO, PROGRESS, ORA, and CL scoring systems have moderate discriminatory capacity.

Objective: To investigate the effect of gene polymorphisms in hypoxia-inducible factor 1α (HIF-1α) in left ventricular hypertrophy of hypertensive patients., Patients and Methods: A total of 583 hypertensive patients were divided into two groups, with left ventricular hypertrophy (LVH (+), 198 cases) and without left ventricular hypertrophy (LVH (-), 385 cases). Polymerase Chain Reaction restriction fragment length polymorphism was used to detect the single nucleotide gene polymorphisms rs11549465, rs11549467 and rs1957757 in HIF-1α., Results: The distribution differences of gene frequencies for rs11549465, rs11549467 and rs1957757 in HIF1A single nucleotide gene polymorphisms for LVH (+) and LVH (-) were statistically significant (p<0.05). The T allele of rs11549465 loci and the G allele of rs11549467 loci increased the risk of LVH, related to the increased plasma expression of HIF-1α (p<0.05)., Conclusions: Gene polymorphism of HIF-1α were related to primary hypertensive left ventricular hypertrophy, and the expression of rs11549467 correlated with the increasing concentration of plasma HIF-1α.

Water accounts for 75% of brain mass. Associations may exist between hydration and cognitive performance. The objective of this study was to investigate the effects of dehydration and rehydration on cognitive performance and mood. In this self-control trial, 12 men were recruited from a medical college in Cangzhou, China. After 12 h of overnight fasting, the participants took baseline tests at 8:00 AM on day 2. First morning urine and blood osmolality were analyzed to determine hydration state. Height, weight, and blood pressure were measured following standardized procedures. A visual analog scale for the subjective sensation of thirst was applied, and a profile of mood states questionnaire was applied. Tests were conducted for cognitive performance, including a test of digit span forward and backward, digit-symbol substitutions, dose-work, and stroop effects. Participants were required not to drink water for 36 h but were given three meals on day 3. On day 4, the same indexes were tested as a baseline test. At 8:30 AM, participants drank 1500 mL of purified water over 15 min. After a 1 h interval, the same measurements were performed. Compared with baseline test results, during the dehydration test, participants had lower scores of vigor (11.9 vs. 8.8, %, p = 0.007) and esteem-related affect (8.2 vs. 5.7, %, p = 0.006), lower total scores of digit span (14.3 vs. 13.3, %, p = 0.004), and higher error rates for dose-work (0.01 vs. 0.16, %, p = 0.005). Compared with the dehydration test scores, rehydration test scores showed that fatigue (4.3 vs. 2.1, %, p = 0.005) and total mood disturbance (TMD) (99.0 vs. 90.2, %, p = 0.008) improved, and scores of forward, backward, and total digit span increased (7.7 vs. 8.6, p = 0.014; 5.7 vs. 1.2, p = 0.019; 13.3 vs. 15.4, p = 0.001). Increases were also noted in correct number of digit symbol substitutions, reading speed, and mental work ability (70.8 vs. 75.4, p < 0.001; 339.3 vs. 486.4, n/min, p < 0.001; 356.1 vs. 450.2, p < 0.001), and reaction time decreased (30.2 vs. 28.7, s, p = 0.002). As a conclusion, dehydration had negative effects on vigor, esteem-related affect, short-term memory, and attention. Rehydration after water supplementation alleviated fatigue and improved TMD, short-term memory, attention, and reaction.

Objectives: To investigate the total fluids intake, volume of urine and hydration status among college students from Hebei Province in spring. Methods: In March 2017, the subjects were recruited in a college in Baoding, Hebei Province. 156 students completed the investigation. Total drinking fluids was assessed by 7-day 24-hour fluid intake questionnaire, with a quantitative tool. The water from food was assessed by the duplicate portion method. The urine samples of 24-hour was collected for 3 consecutive days, and the volume, osmolality, pH and specific gravity of urine were measured. Hydration status was grouped to three types according to the urine osmolality (mOsm/kg), namely, optimal hydration (urine osmolality ≤500), middle hydration (500< urine osmolality ≥800) and dehydration (urine osmolality >800), and the differences among subjects in different genders and hydration statuses were compared. Results: The age of all subjects was (19.8±1.1) years old, including 80 male students. The median amounts of total fluids intake, total drinking fluids, water from food and urine volume were 2 324, 1 135, 1 174 and 1 279 ml/d, respectively. The volume of urine among males was 1 272 ml/d, which was not significantly different from that of females (1 304 ml/d) ( P> 0.05). The osmolality and specific gravity of urine among males were 688 mOsm/kg and 1.017, which were higher than those of females (493 mOsm/kg, 1.014) ( P< 0.05). But the pH of males was 6.6±0.3, which was lower than that of females (6.7±0.3) ( P< 0.05). Only 37.2% ( n =58) of college students were in optimal hydration status. The median of the amount of total drinking fluids among subjects in optimal hydration status was 301, 448 ml/d higher than that in middle hydration status and dehydration, respectively ( P< 0.05). The proportion of females in optimal hydration status was 51.3% ( n= 39), which was higher than that of males 23.8% ( n= 19) ( P< 0.05). Conclusion: Large proportion of college students in Hebei had lower total drinking fluids than the recommended intake of China, and the volume of urine was equal to the amount of total drinking fluids among the college students. Only 37.2% of college students were in optimal hydration status, and the proportion of female college students in optimal hydration status was larger than that of males.

Objectives: To investigate the total fluids intake among college students in spring from Hebei. Methods: In March 2017, the subjects were recruited in a college in Baoding, Hebei Province. 156 students completed the investigation. Total drinking fluids was assessed by 7-day 24-hour fluid intake questionnaire, with a quantitative tool. The water from food was assessed by duplicate portion method. The sources of total fluids intake among subjects were analysed. Results: The age of subjects was (19.8±1.1) years old, including 80 male students. The median amounts of total fluids intake, total drinking fluids and water from food were 2 324, 1 135 and 1 174 ml, respectively. The proportions of total drinking fluids and water from food in total fluids intake were 51%±9% and 49%±10%. Only 19.9% ( n =31) and 18.6% ( n =29) of college students had adequate total fluids intake and total drinking fluids, according to the recommendation of China. The median amounts of total fluids intake, total drinking fluids and water from food were 3 210, 1 860 and 1 093 ml/d, respectively. The proportion of total drinking fluids in total fluids intake was 61%±7%, which were all higher than those who did not reach the recommended intake (2 158, 1 000, 1 149 ml/d; drinking fluids accounting for 46%±8% of total fluids intake) ( P< 0.05). Conclusion: The amounts of total fluids intake and total drinking fluids of college students in Hebei Province are lower than the recommended intake in China. The contributions of total drinking fluids and water from food to total fluids intake were nearly same.

Water is an important component of human body and plays a variety of important physiological roles. The intake and discharge of human water is in a dynamic equilibrium. Insufficient water intake will affect the hydration status of human body, which in turn affects cognition and health. Therefore, maintaining proper hydration status is of great importance for maintaining and promoting the health of the body. There were many indicators to evaluate the hydration status of body, including urine and blood plasma biomarkers. It is of great significance to evaluate the hydration status of body, keep the body in a suitable hydration status by replenishing water in time. The lack of drinking water in different populations in China is common, but it has not yet received enough attention and needs to carry out corresponding health education.

At present, methods of water-intake survey include government, industry, sector statistics data, dietary survey (24 hours dietary recall, dietary record and food frequency questionnaire), fluid intake survey (retrospective fluid-intake questionnaire, 1-5 days 24 hours fluid-intake survey, 7 days 24 hours fluid-intake record), weighing method with the food composition table, weighing method, duplicate portion method and chemical analysis, and so on. The method of 7 days 24 hours fluid-intake record is an internationally recognized and authoritative method for fluid-intake survey with the highest accuracy, which can reflect the differences of fluid intake between working and non-working days, and can obtain detailed data on behaviors and patterns of fluid water, such as the time, types and places of fluid intake. The method of combining weighing method, duplicate portion method and chemical analysis is used to analyze water intake from food with the highest accuracy, which can be used in an extensive range of population and areas, but with high cost and complex operating steps. It is of great practical significance to compare and evaluate the advantages and disadvantages of different methods about water-intake survey, which will be helpful for researchers to choose appropriate methods for water-intake survey to obtain accurate and representative data in various areas, different population, and complex circumstances.

Objective: To investigate the food source of water of college students from Hebei Province in spring. Methods: In March 2017, the subjects were recruited in a college in Baoding, Hebei Province. 156 students completed the investigation. All foods were collected for 3 consecutive days using duplicate portion study combined with weighing method to test the water content of various foods. To analyze the water content of the food and calculate the proportion to the total amount of food water intake, the edible parts of each meal were divided into staple food, dishes, porridge, soup and snacks. Body mass index (BMI) was grouped according to quartiles, and the differences in food intake and food water sources among subjects of different genders and BMI were compared. Results: The age of subjects was (19.8±1.1) years old, including 80 male students. The median intake of staple food, dishes, porridge, soup and snacks per day was 562 g, 743 g, 111 g, 102 g and 0 g, respectively. The median intake of water from staple food, dishes, porridge, soup and snacks per day was 301 ml/d, 620 ml/d, 97 ml/d, 93 ml/d and 0 ml/d, respectively. The median ratio of water intake to total food water intake of staple food, dishes, porridge, soup and snacks was 27%, 53%, 8%, 8% and 0%, respectively. The median intake of water from staple food and dishes in male students was significantly higher than that of female students ( P< 0.05). The amount of water intake from porridge of female students was significantly higher than that of male students ( P< 0.05). There was no significant difference in the water intake from soup and snacks between different genders. There was no significant difference in food intake and food water sources among college students with different BMI ( P> 0.05). Conclusion: The food source of water of college students from Hebei Province in spring is mainly based on dishes and staple foods. The food source of water for boys and girls is different.

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for calcific aortic valve stenosis (CAVS) for which transcatheter aortic valve replacement (TAVR) is increasingly utilized as treatment. We evaluated the effect of a program to increase testing of and define the prevalence of elevated Lp(a) among patients undergoing TAVR. Educational efforts and incorporation of a "check-box" Lp(a) order to the preoperative TAVR order set were instituted. Retrospective chart review was performed in 229 patients requiring TAVR between May 2013 and September 2018. Of these patients, 57% had an Lp(a) level measured; testing rates increased from 0% in 2013 to 96% in 2018. Lipoprotein(a) testing occurred in 11% of patients before and in 80% of patients after the "check-box" order set ( P < .001). The prevalence of elevated Lp(a) (≥30 mg/dL) was 35%; these patients had a higher incidence of coronary artery disease requiring revascularization compared with patients with normal Lp(a) (65% vs 47%; P = .047). Patients with Lp(a) ≥30 mg/dL also had higher incidence of paravalvular leak compared with those with normal Lp(a) (13% vs 4%; P = .04). This study defines the prevalence of elevated Lp(a) in advanced stages of CAVS and provides a practice pathway to assess procedural complications and long-term outcomes of TAVR in patients with elevated Lp(a) levels.

In patients undergoing percutaneous coronary intervention after acute myocardial infarction, hyperglycaemia on admission is associated with an increased risk of contrast-induced nephropathy (CIN). However, the effects of hyperglycaemia and elevated glycosylated haemoglobin (HbA1c) on CIN have remained to be fully elucidated. Therefore, a prospective cohort study was performed, comprising 258 patients who underwent coronary angiography between May 2017 and November 2017 at Zhongda Hospital affiliated with Southeast University (Nanjing, China). According to the diagnostic criteria for CIN (increase of serum creatinine by >44.2 µmol/l or by 25% within 48-72 h of using contrast agent), the patients were divided into two groups: CIN (45 cases) and non-CIN (213 cases). For all patients, the baseline data, medical history, laboratory parameters, medication history and intraoperative situation were recorded and assessed using single-factor analysis and multiple logistic regression analysis to analyse the risk factors of CIN. The incidence of CIN in the hyperglycaemia group (blood glucose on admission, >11.1 mmol/l) was 25%, compared with 13.8% in the non-hyperglycaemia group (P=0.026). Furthermore, the incidence of CIN in the elevated HbA1c group (HbA1c on admission, upper limit of normal) was 26.1%, compared with 14.3% in the group without elevated HbA1c (P=0.027). Hyperglycaemia was present on hospital admission in 84 of 258 patients (32.6%). The percentage of patients with elevated HbA1c was 26.7%. Age, estimated glomerular filtration rate, pre-operative blood cholesterol, hyperglycaemia on admission and elevated HbA1c were all identified to be associated with CIN. According to the multivariate logistic regression analysis, hyperglycaemia was an independent predictor of CIN (odds ratio, 2.815; 95% confidence interval, 1.042-4.581; P=0.029). In the acute coronary syndrome (ACS) and diabetes subgroups, hyperglycaemia was significantly associated with CIN. In the ACS subgroup, the incidence of CIN was 38.1%. It was indicated that hyperglycaemia is an independent risk factor for CIN, particularly in patients with ACS or diabetes. Trial registration no. ChiCTR-OOC-17011466.

Objective: To investigate the effect of erythropoietin (EPO) on blood glucoseand plasma insulin level, index of insulin resistance (HOMA-IR), introperitoneal glucose tolerance test (IPGTT), the mRNA and protein level of PR domain-containing 16 (PRDM16), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), fibroblast growth factor 21 (FGF21) of brown adipose tissue (BAT) in mice fed with high fat diet (HFD) in order to provide clues for the mechanism of obesity and complication., Methods: Twenty C57BL/6J male mice fed with HFD were randomly divided into control group (HFD-Con) and EPO group (HFD-EPO), mice in the two groups were injected intraperitoneally normal saline and EPO (200 IU/kg) res pectively, 3 times per week for consecutive 4 weeks.Then the body weight, blood glucose, plasma insulin level, HOMA-IR and IPGTT were detected.The mRNA and protein level of PRDM16, FGF21, p-STAT3/STAT3 in brown adipose tissue were detected by real-time quantitative RT-PCR and Western blot respectively., Results: After intraperitoneal injection of EPO for 4 weeks, the body weight of the mice in HFD-EPO and HFD-Con groups was (26.65±0.85) g and (31.50±1.6 0) g respectively.The blood glucose of the mice in HFD-EPO group[(62.79±8.09) mg/dl]was significantly decreased compared with that in HFD-Con group[(91.06±9.86) mg/dl].The plasmainsulin level in HFD-EPO group[(10.56±1.06)μU/ml]was significantly decreased compared with that in HFD-Con group[(13.2±1.1)μU/ml, P < 0.01].The level of IPGTT in HFD-EPO group was significantly ameliorated and th e HOMA-IR decreased compared with those in HFD-Con group.The mRNA and protein expressions of PRDM16, FGF21 and the level of STAT3 of brown adipose tissue in HFD-E PO group were increased obviously.And there was no difference of FGF21 mRNA content in liver and FGF21 content in plasmabetween the two groups., Conclusions: EPO could promote differentiation of brown adipose tissue by increase in the express ion of PRDM16, and decrease the blood glucose level, ameliorate glucose metabolism in obses mice.

Objective: To analyze the effect of breakfast nutrition quality on the satiety among young white-collar workers. Methods: A total of 278 subjects were recruited from two cities, Shenyang and Chongqing, in June 2015. The inclusion criteria: white-collar workers aged 25-45 years involved mainly in office work, who did not experience major changes, and individuals who should follow the study protocol and sign the informed consent form. The study employed a three-phase crossover design trial. Each participant received nutritional-adequate breakfast, nutritional-inadequate breakfast, and no breakfast treatment on the basis of assignment to one of three sequences. The breakfast time was once a week and then changed, all participants underwent the tests for three successive weeks. At last, we compared the effect of participants to consume different nutritional quality on satiety sense and hunger sense. Results: A total of 232 participants completed three successive breakfast intervention studies, the age of participants was (35.2 ± 7.9) years, comprised of 48.7% male ( n= 113). The numbers of participants of aged 25-35 year-old and aged 36-45 were 118 and 114, respectively. Satiety scores of nutrition-adequate breakfast group, nutrition-inadequate breakfast group and no breakfast group were 63.5±14.7, 53.1±10.2 and 36.4±7.2, respectively ( P< 0.05). In nutrition-inadequate breakfast group and no breakfast group, male subjects scored significantly higher than female subjects (50.9±10.5 vs 46.6±9.4, 35.2±8.3 vs 31.8±5.4) ( P< 0.05). And, participants aged 25-35 year-old. got satiety score significantly higher than aged 36-45 (51.3±11.0 vs 45.6±12.1, 34.1±6.8 vs 32.5±7.9), the difference was statistically significant ( P< 0.05). The scores of hunger in the group of nutrition-adequate breakfast, nutrition-inadequate breakfast and no breakfast were 26.3 ± 8.0, 35.1 ± 11.2 and 57.3 ± 17.0, respectively ( P< 0.05). Conclusion: The nutrition quality of breakfast affects the satiety of young white-collar workers. The better the nutrition quality of breakfast is, the higher the satiety score and the lower the hunger score become. Compared with women and participants aged 36-45 year-old, men and those aged 25-35 year-old get satiety sense more easily.

Lipoprotein(a; Lp[a]) and its associated oxidized phospholipids are causal, genetic risk factors for calcific aortic valve stenosis (CAVS). We determined the prevalence of Lp(a) measurement among 2710 patients with CAVS and 1369 control patients (∼50% of study group) without CAVS with an echocardiogram between January 2010 and February 2016 in an academic echocardiography laboratory. Lipoprotein(a) measurements were performed at a referral laboratory using an isoform-independent assay. The prevalence of any Lp(a) measurement was 4.6% (124 of the 2710) in patients with CAVS and 3.1% (42 of the 1369) in the control group ( P = .021). In patients with CAVS, mean (standard deviation) Lp(a) levels were 38 (54) mg/dL and median (interquartile range) Lp(a) levels were 14 (6-48) mg/dL. Of the 124 patients with CAVS having Lp(a) measurements, 83 (66.9%) had Lp(a) <30 mg/dL and 41 (33.1%) had Lp(a) ≥30 mg/dL. This study reflects low physician testing of Lp(a) levels in CAVS. Given the role of Lp(a) as a causal risk factor for CAVS, and the ongoing development of therapies to normalize Lp(a) levels, our results suggest that Lp(a) measurements in CAVS should be more widely obtained in clinical practice.

Purpose: Enhanced endoplasmic reticulum (ER) stress and down-regulated SERCA2a expression play crucial roles in diabetes. We aimed to verify whether erythropoietin (EPO) attenuates cardiac dysfunction by suppressing ER stress in diabetic rats., Methods: Forty male SD rats were randomly divided into four groups: control, EPO-treated control, vehicle-treated diabetic, and EPO-treated diabetic groups. The animals in the EPO-treated control and diabetic groups were administered recombinant human EPO (1000 U/kg body weight) once per week for 12 weeks. RT-PCR and Western blotting assays were performed to detect the expression of 78-kDa glucose-regulated protein precursor (GRP78) and sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA2a). We cultured neonatal rat cardiomyocytes and investigated the protective effects of EPO against high glucose (HG)-induced apoptosis. Intracellular calcium levels were measured through confocal microscopy., Results: We observed increased myocardial GRP78 expression and decreased myocardial SERCA2a expression in diabetic rats. EPO prevented the changes in GRP78, SERCA2a expression and cardiac dysfunction in diabetic rats. The levels of GRP78 protein were significantly reduced in EPO-treated diabetic rats compared with vehicle-treated diabetic rats (GRP78 protein 0.09 ± 0.03 vs. 0.54 ± 0.04, P < 0.01). The levels of the SERCA2a proteins were significantly increased in EPO-treated diabetic rats compared with vehicle-treated diabetic rats (SERCA2a protein 0.60 ± 0.05 vs. 0.13 ± 0.04, P < 0.01). A reduction in apoptosis was observed in the cardiomyocytes treated with 20 U/mL EPO compared with the cardiomyocytes cultured under HG conditions (apoptosis rate 18.9 ± 1.94 vs. 37.9 ± 1.59%, P < 0.01)., Conclusions: This study demonstrates that EPO treatment improved the parameters of cardiac function following HG-induced injury by suppressing ER stress and inducing SERCA2a expression.

The Report on the Status of Nutrition and Chronic Diseases of Chinese residents (2015) indicated that the prevalence of diabetes was 9.7% among adults aged ⩾18 years, which markedly increased from 2.6% in 2002 within 10 years. In addition to the social economic factors, transitions in food consumption, behavioral and lifestyle playing the important roles in the fast increase of type 2 diabetes mellitus (T2DM). In 2010-2012, the cereal food consumption of Chinese residents was 337 g/d, vegetables consumption 269 g/d, fruit consumption 41 g/d, legume and legume products 11 g/d, dairy and dairy products consumption 25 g/d, meat consumption 90 g/d, edible oil consumption 42 g/d and dietary fiber 10.8 g/d. The traditional Chinese dietary pattern (high consumption of rice, pork and vegetables) is shifting towards a dietary pattern with high consumption of meats and edible oil but low consumption of cereals and vegetables. Smoking, breakfast omitting and high consumption of sugar-sweetened beverages became popular. Insufficient physical activity rate was 31.7%. Less sleep duration and poorer sleep quality was also common for Chinese residents. Concerning early life factors, residents exposed to the Chinese famine (1959-1961) during fetal life and childhood had an increased risk of hyperglycemia. As a conclusion, current unhealthy lifestyle has inversely effect on the incidence and development of T2DM, especially for the increased intake of fat and carbohydrate, the transition of dietary pattern, the extension of sedentary time and the increasing rate of obesity. Lifestyle management should be taken seriously as a part of diabetes prevention.

Mucin-1 (MUC1), a transmembrane glycoprotein is aberrantly expressed on ∼90% of breast cancer and is an excellent target for nanoparticulate targeted imaging. In this study, the development of a dye-doped NIR emitting mesoporous silica nanoparticles platform conjugated to tumor-specific MUC1 antibody (ab-tMUC1-NIR-MSN) for in vivo optical detection of breast adenocarcinoma tissue is reported. The structural properties, the in vitro and in vivo performance of this nanoparticle-based probe were evaluated. In vitro studies showed that the MSN-based optical imaging nanoprobe is non-cytotoxic and targets efficiently mammary cancer cells overexpressing human tMUC1 protein. In vivo experiments with female C57BL/6 mice indicated that this platform accumulates mainly in the liver and did not induce short-term toxicity. In addition, we demonstrated that the ab-tMUC1-NIR-MSN nanoprobe specifically detects mammary gland tumors overexpressing human tMUC1 in a human MUC1 transgenic mouse model.

Objective: To evaluate the incidence and risk factors of postoperative delirium in patients post permanent pacemaker implantation., Methods: Patients underwent permanent pacemaker implantation in our department from September 2013 to February 2015 were included in this study. Delirium was measured by the confusion assessment method on the first three postoperative days. All the patients were divided into the postoperative delirium group and the non-delirium control group according to whether new onset delirium was diagnosed. Risk factors significantly associated with postoperative delirium detected by univariate analysis were entered into multivariable analysis to define the independent predictors of postoperative delirium., Results: A total of 225 patients were enrolled in this study. The incidence of postoperative delirium was 5.3%. Patients developing postoperative delirium were older ((83±5) years vs. (74±11) years, P=0.002), had a significantly higher incidence of blood pressure fluctuations (58.3% (7/12) vs. 4.7% (10/213), P<0.001), hyponatremia (25.0% (3/12) vs. 5.2% (11/213), P=0.030) and had higher systolic blood pressure ((157±35) mmHg vs. (136±22)mmHg, 1 mmHg=0.133 kPa, P=0.007). However, patients developing postoperative delirium had lower preoperative average heart rate ( (47±18)bpm vs. (58±15)bpm, P=0.007). Multiple regression analysis showed that advanced age (OR= 2.984, 95% CI: 1.226-7.624, P=0.016) and blood pressure fluctuations (OR=27.393, 95% CI: 6.735-111.417, P<0.001) are the independent risk factors for pacemaker patients with postoperative delirium., Conclusion: Advanced age and blood pressure fluctuations are independent risk factors of postoperative delirium in patients post permanent pacemaker implantation.

Background: Previous studies have demonstrated that patients with obstructive sleep apnea (OSA) may develop left ventricular (LV) diastolic dysfunction. We aimed to study whether OSA patients have LV regional systolic dysfunction with myocardial deformation changes, despite a normal LV ejection fraction, using real-time 3D speckle-tracking echocardiography (Rt3D-STE)., Methods: Seventy-eight patients with OSA and no comorbidities were studied. They were divided into the following three groups according to the apnea-hypopnea index (AHI): 5~15/h as group I (mild OSA, 26 cases), 15~30/h as group II (moderate OSA, 29 cases), and ≥30/h as group III (severe OSA, 23 cases). Thirty gender-age-matched normal subjects were included as controls. The parameters of LV diastolic function were acquired with traditional echocardiography. The LV myocardial deformation parameters were obtained, including the longitudinal (LS), circumferential (CS), radial (RS), and area (AS) strains, with Rt3D-STE., Results: LV global systolic function was normal in all patients, but diastolic function was impaired in groups II and III (E/E' was 9.6 ± 2.8 and 10.4 ± 2.5, respectively, p < 0.0001). The global LS and AS were significantly reduced in groups II and III compared with the controls and group I (LS 15.9 ± 1.4 % and 14.8 ± 1.5 % vs 18.2 ± 1.7 % and 17.8 ± 1.5 %; AS 27.4 ± 1.8 % and 24.9 ± 2.3 % vs 33.4 ± 2.2 % and 32.7 ± 2.9 %, respectively, p < 0.0001), but the global CS and RS were significantly reduced only in group III (17.3 ± 1.4 % and 43.1 ± 6.5 % vs 19.6 ± 1.6 % and 55.4 ± 4.0 %, respectively, <0.0001). The severity of OSA was significantly associated with the LV global AS value (r = -0.80, p < 0.0001), LS (r = -0.64, p < 0.0001), CS (r = -0.51, p < 0.0001), and RS (r = -0.62, p < 0.0001)., Conclusions: Patients with moderate and severe OSA tended to have both LV diastolic dysfunction and abnormalities in regional systolic function with myocardial deformation changes, in spite of the normal LV ejection fraction. Myocardial strains of the LV were negatively correlated with the AHI. Rt-3DST had important clinical significance in the early evaluation of cardiac dysfunction in OSA patients.

Insulin resistance (IR) is a metabolic disorder characterized by impaired glucose uptake in response to insulin. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the chief conduit for post-receptor signaling. We recently demonstrated that GIV, a Guanidine Exchange Factor (GEF) for the trimeric G protein, Gαi, is a major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind the InsR, IRS1 and PI3K, GIV enhances the InsR-IRS1-Akt-AS160 (RabGAP) signaling cascade and cellular glucose uptake via its GEF function. Phosphoinhibition of GIV-GEF by the fatty-acid/PKCθ pathway inhibits the cascade and impairs glucose uptake. Here we show that GIV directly and constitutively binds the exocyst complex subunit Exo-70 and also associates with GLUT4-storage vesicles (GSVs) exclusively upon insulin stimulation. Without GIV or its GEF function, membrane association of Exo-70 as well as exocytosis of GSVs in response to insulin are impaired. Thus, GIV is an essential component within the insulin signaling cascade that couples upstream signal transducers within the InsR and G-Protein signaling cascade to downstream vesicular trafficking events within the exocytic pathway. These findings suggest a role of GIV in coordinating key signaling and trafficking events of metabolic insulin response., (Published by Elsevier Inc.)

Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles., (© 2015 Ma et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)