Reference Standards of Cardiorespiratory Fitness Measured With the Cardiopulmonary Exercise Test Using the Treadmill in Chinese Adults Younger Than 60 Years.

PURPOSE: Cardiorespiratory fitness (CRF) is a strong predictor of cardiorespiratory diseases and varies by race. The purpose of this study was to provide CRF reference standards and a prediction equation for peak oxygen uptake (V˙O 2peak ) from treadmill-based cardiopulmonary exercise testing (CPX) in Chinese individuals. METHODS: Healthy participants (n = 4199) who completed a CPX using a treadmill were studied. The percentiles of V˙O 2peak were determined for four age groups (decades). A regression prediction model was developed from the derivation cohort (n = 3361), validated in the independent validation cohort (n = 838), and compared with the widely used Wasserman equation and the Fitness Registry and the Importance of Exercise National Database (FRIEND) equation. RESULTS: The mean V˙O 2peak values of four age groups (20-29, 30-39, 40-49, and 50-59 yr) were 42.6, 41.2, 38.7, and 35.9 mL/kg/min, respectively, for men, and 37.1, 34.7, 32.0, and 30.3 mL/kg/min, respectively, for women. The 50th percentiles of relative V˙O 2peak decreased with age for both sexes. The prediction equation was: Absolute V˙O 2peak (mL/min) = 236.68 - (504.64 × sex [male = 0; female = 1]) + (21.23× weight [kg]) - (14.31 × age [yr]) + (9.46 × height [cm]) (standard error of the estimate = 379.59 mL/min, R2 = 0.66, P < .001).Percentage predicted V˙O 2peak for the validation sample was 100.2%. The novel equation performed better than the other two equations. CONCLUSION: This study reports the first CRF reference standards and prediction equation generated from treadmill CPX in China. These reference standards provide a framework for interpreting the CRF of the Chinese population and could be useful information for a global CRF database.

Influence of age on static postural control in adults with type 2 diabetes mellitus: a cross-sectional study.

Aim: It was the aim of this study to assess static postural control characteristics in people with type 2 diabetes mellitus (T2D) of different ages using a force platform. A relationship was also established between static postural control parameters and age in this study. Methods: A total of 706 participants with T2D were included in this study. The participants were stratified into three age groups: Group 1 (<60 years old), Group 2 (60-70 years old), and Group 3 (>70 years old). Static postural control assessment during two-leg stance was performed on a force platform by all participants. The center of pressure (CoP)-related parameters were measured under two stance conditions (eyes open and closed). Kruskal-Wallis tests were applied to explore the difference among the different age groups. Multivariate regression analysis was performed to determine the relation between age and static postural control parameters. Results: Group 1 (<60 years old) had significantly less CoP total tracking length (TTL), sway area (SA), and CoP velocity along the Y direction (V-Y) under both eyes-open and eyes-closed conditions compared with Group 2 (60-70 years old) and Group 3 (>70 years old). Group 1 (<60 years old) had significantly less CoP maximum sway length along the X direction (MSL_X) and longer tracking length each area unit (TTL/SA) under the eyes-open condition compared with Group 2 (60-70 years old) and Group 3 (>70 years old). There was a significantly positive correlation between age and the most static postural parameters such as CoP TTL, SA, MSL-X, MSL-Y, and V-Y. There was a significantly negative correlation between age and TTL/SA. Conclusion: This study suggested that older T2D participants had worse static postural control ability than younger ones. Most static postural parameters presented a significant correlation with age; the higher the age, the worse the static postural control.

Evaluation of microcirculation in asymptomatic cerebral infarction with multi-parameter imaging of spectral CT.

OBJECTIVE: To investigate the role of spectral CT multiparametric imaging in the evaluation of cerebral microcirculatory perfusion. METHODS: The imaging data of 145 patients with asymptomatic cerebral infarction confirmed by MR were retrospectively analyzed, and all cases underwent head CTA and cranial CT perfusion imaging (CTP) on double-layer detector spectral CT. Single energy level images (MonoE45 keV), iodine density maps, and effective atomic number maps were reconstructed based on spectral CTA data, and CT values, iodine density values, and effective atomic number values were measured in the infarcted area, healthy control area, centrum semiovale and posterior limb of the internal capsule, respectively; perfusion values, such as cerebral blood volume (CBV) values, cerebral blood flow (CBF) values, time to peak (TTP) values, and mean passage time, were measured in the above-mentioned areas on CTP images. (TTP) values, and mean time to passage (MTT) values. CT values, iodine density values, effective atomic number values, and perfused CBV, CBF, TTP, and MTT values were compared between the infarcted area and the healthy side, the center of the hemianopia, and the posterior limb of the internal capsule. The role of spectral CT parameters and perfusion parameters in the evaluation of asymptomatic cerebral infarction was analyzed. RESULTS: CT values, iodine density values, and effective atomic number values were statistically different between the infarcted area and the healthy side; CT values, iodine density values, and effective atomic number values were not statistically different between the infarcted side and the healthy side of the hemispheric centrum and the posterior limb of the internal capsule; CBV and CBF were statistically different between the infarcted side and the healthy side, and MTT and TTP were not statistically different. There were statistically significant differences in TTP between the infarcted area and the healthy side of the hemiaxial center, and no statistically significant differences in CBV, CBF, and MTT. There were no statistical differences in CBV, CBF, TTP, and MTT in the inner capsule area. ROC curve analysis of spectral CT-related parameters and CT perfusion parameters for the diagnosis of asymptomatic cerebral infarction: area under the curve of MonoE 45Kv 0.71, area under the curve of iodine density values 0.76, area under the curve of effective atomic number values 0.74; area under the curve of CBV value 0.64, area under the curve of CBF value 0.61, area under the curve of MTT value 0.50, The area under the TTP curve was 0.52. The area under the ROC curve of the multivariate logistic regression model based on spectral parameters is 0.76, which is higher than that of the logistic regression model with perfusion parameters (P < 0.05). CONCLUSION: Spectral CT can better demonstrate small intracranial ischemic lesions, and iodine density values have a better evaluation of microcirculation in asymptomatic cerebral infarcts.

Functional Connectivity of Ipsilateral Striatum in Rats with Ischemic Stroke Increased by Electroacupuncture.

BACKGROUND: This study aimed to investigate the effects of electroacupuncture (EA) treatment at Zusanli (ST36) and Quchi (LI11) on cortico-striatal network connectivity after ischemia stroke by resting-state functional magnetic resonance imaging (fMRI). METHODS: A rat model of middle cerebral artery occlusion (MCAO) was established. Rats were randomly assigned into a sham-operated control group (SC group, n = 8), untreated MCAO model group (MCAO group, n = 8), and MCAO group receiving EA treatment at ST36 and LI11 (MCAO + EA group, n = 8). Rats in the SC and the MCAO groups received no treatment. The MCAO + EA group was treated with EA from the 1st day to the 7th day after surgery. The behavioral tests including Zea Longa test and modified neurologic severity score (mNSS) for all rats were performed before and after treatment for MCAO + EA group. fMRI scans were performed after behavioral tests on the 7th day after surgery. RESULTS: The neurologic severity scores estimated by Zea Longa and mNSS were significantly improved in the rat ischemic stroke model of MCAO within 1 week after EA treatment at acupoints ST36 and LI11. Besides, voxel-wise analysis showed that EA could increase the functional connectivity of the left striatum with the bilateral sensory cortex, bilateral motor cortex, left retrosplenial cortex, right cerebellum, bilateral hippocampus, bilateral auditory cortex, bilateral visual cortex, left parietal cortex, left cingulate gyrus, and left superior colliculus. Further graph theory analysis showed that EA significantly decreased the characteristic path length and increased the global efficiency of the cortico-striatal network. CONCLUSIONS: EA at ST36 and LI11 could improve the cortico-striatal network to impact the brain's protective in MCAO, which is a potential treatment for ischemia stroke.

Automated assessment of balance: A neural network approach based on large-scale balance function data.

Balance impairment (BI) is an important cause of falls in the elderly. However, the existing balance estimation system needs to measure a large number of items to obtain the balance score and balance level, which is less efficient and redundant. In this context, we aim at building a model to automatically predict the balance ability, so that the early screening of large-scale physical examination data can be carried out quickly and accurately. We collected and sorted out 17,541 samples, each with 61-dimensional features and two labels. Moreover, using this data a lightweight artificial neural network model was trained to accurately predict the balance score and balance level. On the premise of ensuring high prediction accuracy, we reduced the input feature dimension of the model from 61 to 13 dimensions through the recursive feature elimination (RFE) algorithm, which makes the evaluation process more streamlined with fewer measurement items. The proposed balance prediction method was evaluated on the test set, in which the determination coefficient (R2) of balance score reaches 92.2%. In the classification task of balance level, the metrics of accuracy, area under the curve (AUC), and F1 score reached 90.5, 97.0, and 90.6%, respectively. Compared with other competitive machine learning models, our method performed best in predicting balance capabilities, which is especially suitable for large-scale physical examination.

Correlation between impaired hemodynamic response and cardiopulmonary fitness in middle-aged type 2 diabetes mellitus patients: a case-control study.

PURPOSE: Impaired cardiorespiratory fitness (CRF) is a predictor of mortality in patients with type 2 diabetes mellitus (T2DM). It is still not known how the exercise hemodynamic response correlates with CRF. The purpose was to assess the correlation between hemodynamic changes and CRF in middle-aged patients with T2DM. METHODS: After 1:1 matching by age and sex, 139 T2DM patients and 139 non-T2DM controls who completed the exercise treadmill test were included. Maximal aerobic capacity (VO2max), exercise-induced changes in heart rate (ΔHR), systolic blood pressure (ΔSBP), diastolic blood pressure (ΔDBP), and rate-pressure product (ΔRPP) were measured. HRR1 was calculated as the maximum heart rate minus the heart rate after 1 min of rest. RESULTS: Compared to the control population, T2DM patients had decreased ΔHR (87 (77, 97) v 93 (84, 104) bpm, p < 0.05), ΔRPP (3833.64 ± 1670.34 v 4381.16 ± 1587.78 bpm∙mmHg, p < 0.05), HRR1 (21 (14, 27) v 21 (17, 27) bpm, p < 0.05), and VO2max (32.76 ± 5.63 v 34.68 ± 5.70 ml/kg/min, p < 0.05). Multiple linear regression analysis showed that ΔHR and HRR1, yielded a positive correlation with VO2max in T2DM patients (ß = 0.325, P < 0.001; ß = 0.173, P = 0.01). CONCLUSION: The presence of impaired hemodynamic response and VO2max in middle-aged T2DM patients and the association of impaired ΔHR, HRR1, and VO2max may indicate a physiological pathway of impaired CRF, and our results support the need for cardiorespiratory screening and individualized treatment of middle-aged T2DM patients.

Strong and thermostable hydrothermal carbon coated 3D needled carbon fiber reinforced silicon-boron carbonitride composites with broadband and tunable high-performance microwave absorption.

Excellent electromagnetic wave (EMW) absorbing materials with high-temperature stable and superior mechanical properties are among the most promising candidates for practical application. Here, novel hydrothermal carbon coated three-dimensional (3D) needled carbon fiber reinforced silicon-boron carbonitride (HC-CF/SiBCN) composites with a hierarchical A (CF)/B (HC)/C (SiBCN) structure were constructed and prepared for the first time by combining hydrothermal transformation and precursor infiltration and pyrolysis (PIP) process. The thickness of the HC coating controlled by the glucose concentration played a crucial role in tailoring the EMW capacity of the composite. The incorporation of SiBCN could not only effectively improve the oxidation resistance but also actively enhance the mechanical properties of the HC coated CF structure. Compared to the weak high-temperature oxidation resistance and mechanical properties of pristine 3D needled CF felt, the composites after the introduction of HC and SiBCN were thermostable in air atmosphere beyond 1000 °C to about above 70% weight retention, and the maximum flexural and compression strength of the composites could reach to 23.51 ± 1.37 and 12.22 ± 1.12 MPa, respectively. A substantial enhancement of EMW absorption ability was achieved through incorporation of HC and SiBCN, which could be attributed to the matched characteristic impedance and enhanced loss ability, whose optimization EMW absorption performance was the minimum reflection loss (RLmin) of -52.08 dB and effective absorption bandwidth (EAB) of 7.64 GHz for the composite obtained by two PIP cycles with 24 wt% glucose solution, demonstrating that the HC-CF/SiBCN composites with high-temperature stable, excellent mechanical and superior EMW absorption properties could be considered as a promising candidate for the applications in harsh environments.

Impact of Body Mass Index on Static Postural Control in Adults With and Without Diabetes: A Cross-Sectional Study.

Aim: The objective of this research was to determine the static postural control differences measured from a force platform in Type 2 diabetes mellitus (T2DM) and healthy control groups with different levels of body mass index (BMI), and detect the static postural control difference between T2DM and healthy control groups stratified by different BMI category. This research also explored the relationship of BMI and static postural performance. Methods: We recruited 706 participants with T2DM and 692 healthy controls who were sufficiently matched for age, gender, and BMI in this cross-sectional study. The participants were stratified into three groups by BMI: normal weight, overweight, and obesity. All participants performed two-legged static stance postural control assessment on a firm force platform. The Center of Pressure (CoP) parameters were collected under eyes-open and eyes-closed conditions. Mann-Whitney U test was used to compare the static postural control parameters within each BMI category in both groups. The static postural control parameters among different weight groups were compared by Kruskal-Wallis test, post hoc pair-wise comparison were conducted. Generalized linear model was conducted to examine the association between BMI and static postural control parameters while controlling for confounding factors. Results: Healthy control group had statistical difference in most CoP parameters compared to T2DM group based on all BMI categories. Normal weight participants presented significant difference compared with overweight and/or obesity for total track length (TTL) and velocity of CoP displacements in Y direction (V-Y) under eyes-open condition, and for most CoP parameters under eyes-closed condition in both groups. There were statistically significant correlations between BMI and most static postural control parameters under only eyes-closed condition according to the result of generalized linear model. Conclusion: T2DM patients had impaired static postural control performance compared to healthy controls at all BMI categories. The findings also indicated the association between BMI and static postural control, where higher BMI individuals showed more static postural instability in both T2DM and healthy controls.

Effects of a traditional Chinese mind-body exercise, Baduanjin, on the physical and cognitive functions in the community of older adults with cognitive frailty: study protocol for a randomised controlled trial.

INTRODUCTION: Cognitive frailty (CF) is a clinical manifestation characterised by the simultaneous presence of both physical frailty and cognitive impairment among older adults without dementia and has become a new target for healthy ageing. Increasing evidence shows that regular Baduanjin (a traditional Chinese mind-body exercise) training is beneficial in improving physical function and cognitive ability in the older adults. The primary aim of this trial is to observe the effect of Baduanjin on physical and cognitive functions in older adults with CF. METHODS AND ANALYSIS: In this prospective, outcome assessor-blind, two-arm randomised controlled trial, a total of 102 participants with CF will be recruited and randomly allocated (1:1) into the Baduanjin training or usual physical activity control group. The control group will receive health education for 30 min at least once a month. Based on health education, participants in the Baduanjin exercise group will receive a 24-week Baduanjin training with 60 min per session and 3 sessions per week, while those in the usual physical activity control group will maintain their original lifestyle. Primary outcomes (frailty index and global cognitive ability), body composition, grip force, balance, fatigue, specific cognitive domain, including memory, execution and visual spatial abilities, and life quality of secondary outcomes will be measured at baseline, and at 13 and 25 weeks after randomisation, while the structural and functional MRI will be measured at baseline and 25 weeks after randomisation. The mixed linear model will be conducted to observe the intervention effects. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee of the second people's hospital of Fujian province (Approval no. 2018-KL015). Results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR1800020341; Pre-results.

PAR2 promotes M1 macrophage polarization and inflammation via FOXO1 pathway.

Macrophages polarization plays essential but different roles in most diseases such as atherosclerosis, adipose tissue inflammation, and insulin resistance. Our previous study revealed that protease-activated receptor 2 (PAR2), a G-protein coupled receptor influenced macrophage function, but little is known regarding the regulation of macrophage polarization process and its potential mechanisms. In the present study, bone marrow-derived macrophages (BMDM) isolated from C57/BL6 mice and cultured with L929-conditional medium and murine macrophage cell line RAW264.7 were used to study the function of PAR2 activation in vitro. BMDM was stimulated by the small molecular PAR2 agonist, 2-furoyl-LIGRLO-amide trifluoroacetate salt, followed by transcription factor microarray to screen the significantly activated signaling pathways under PAR2 activation. Western blot analysis, quantitative real-time polymerase chain reaction (qRT-PCR) was used to evaluate the expression of targeted genes and transcription factors. Immunofluorescence was used to observe the subcellular distribution of transcription factors. Our results demonstrated that M1-like polarization was presented by PAR2 agonist treatment with significant upregulation of interleukin-1ß, interleukin-6, monocyte chemotactic protein-1, and tumor necrosis factor-α in BMDM and RAW264.7. Microarray identified forkhead box protein O1 (FOXO1) was significantly increased under PAR2 agonist stimulation, which was confirmed by qPCR and Western blot analysis. Immunofluorescence demonstrated that increased FOXO1 accumulated in the nucleus, which is necessary to promote transcription for targeted genes. We further knocked down FOXO1 expression using small interfering RNA, which alleviated PAR2-induced proinflammatory gene expression. The PAR2/FOXO1 pathway mediated stimulation of proinflammatory genes was further confirmed by tryptase, an endogenous ligand of PAR2. In conclusion, this study demonstrated that PAR2 activation-induced M1 polarization and inflammation through the FOXO1-dependent pathway.

Tryptase promotes breast cancer angiogenesis through PAR-2 mediated endothelial progenitor cell activation.

Mast cells have been demonstrated to accumulate around and within solid tumors of numerous types, and express a number of pro-angiogenic compounds, including tryptase. They may serve an early role in angiogenesis within developing tumors. In the present study, the role and mechanism of tryptase in the activation of endothelial progenitor cells (EPCs) in breast cancer angiogenesis were evaluated. Human umbilical cord blood EPCs were isolated and cultured. MB-MDA-231 breast cancer cells were then pretreated with tryptase, and the conditioned medium was collected. The effects of tryptase on the migratory and angiogenesis abilities of EPCs were determined using wound-healing and tube formation assays, respectively. The effect of tryptase on the proliferation of EPCs was detected using a Cell Counting Kit-8 assay. Alterations in proteinase activated receptor (PAR)-2, phosphorylated (p)-protein kinase B (AKT), p-extracellular signal-regulated kinase (p-ERK) and vascular endothelial growth factor receptor (VEGFR)-2 expression were analyzed, in tryptase or conditioned medium-treated EPCs, by western blot analysis and reverse transcription-quantitative polymerase chain reaction. It was confirmed that the EPCs expressed PAR-2; and that tryptase treatment promoted the migration and tube formation of EPCs. Treatment with a PAR-2 agonist had a similar effect to tryptase, whereas treatment with a tryptase inhibitor, APC366, or a PAR-2 inhibitor, SAM 11, inhibited the effect of tryptase treatment. Tryptase and PAR-2 agonists did not affect the rate of EPC proliferation. MB-MDA-231 cells also expressed PAR-2. Treatment with tryptase or conditioned medium increased the expression of PAR-2, p-AKT, p-ERK and VEGFR-2 in EPCs. In conclusion, tryptase activated EPCs via PAR-2-mediated AKT and ERK signaling pathway activation, thereby enhancing angiogenesis in breast cancer.

Establishment of a PRKAG2 cardiac syndrome disease model and mechanism study using human induced pluripotent stem cells.

PRKAG2 cardiac syndrome is a distinct form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular pre-excitation and progressive cardiac conduction disorder. However, it remains unclear how mutations in the PRKAG2 gene give rise to such a complicated disease. To investigate the underlying molecular mechanisms, we generated disease-specific hiPSC-derived cardiomyocytes from two brothers both carrying a heterozygous missense mutation c.905G>A (R302Q) in the PRKAG2 gene and further corrected the R302Q mutation with CRISPR-Cas9 mediated genome editing. Disease-specific hiPSC-cardiomyocytes recapitulated many phenotypes of PRKAG2 cardiac syndrome including cellular enlargement, electrophysiological irregularities and glycogen storage. In addition, we found that the PRKAG2-R302Q mutation led to increased AMPK activities, resulting in extensive glycogen deposition and cardiomyocyte hypertrophy. Finally we confirmed that disrupted phenotypes of PRKAG2 cardiac syndrome caused by the specific PRKAG2-R302Q mutation can be alleviated by small molecules inhibiting AMPK activity and be rescued with CRISPR-Cas9 mediated genome correction. Our results showed that disease-specific hiPSC-CMs and genetically-corrected hiPSC-cardiomyocytes would be a very useful platform for understanding the pathogenesis of, and testing autologous cell-based therapies for, PRKAG2 cardiac syndrome.

Interactions between ACYP2 genetic polymorphisms and environment factors with susceptibility to ischemic stroke in a Han Chinese Population.

AIMS: To investigate the association of several single nucleotide polymorphisms (SNPs) within ACYP2 gene and additional gene- environment interaction with ischemic stroke (IS) risk in a Chinese population. RESULTS: IS risk was significantly higher in carriers with the G allele of rs11896604 than those with CC genotype (CG or GG versus CC), adjusted OR (95%CI) =1.60 (1.18-2.20), and higher in carriers with the A allele of rs12615793 than those with GG genotype (GA or AA versus GG), adjusted OR (95%CI) = 1.66 (1.24-2.15). GMDR model shown a significant two-locus model (p = 0.0010) involving rs11896604 and alcohol drinking, and a significant two-locus model (p = 0.0010) involving rs12615793 and smoking. Current smokers with rs12615793- GA or AA genotype have the highest IS risk, compared to never- smokers with rs12615793-GG genotype, OR (95%CI) = 2.72 (1.64-3.86); current drinkers with rs11896604-CG or GG genotype have the highest IS risk, compared to never- drinkers with rs11896604-CC genotype, OR (95%CI) = 2.51 (1.70-3.40). MATERIALS AND METHODS: A total of 1202 participants (660 males, 542 females) were selected, including 600 IS patients and 602 control participants. The mean age of all participants was 68.2 ± 15.8 years. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination. Logistic regression was performed to investigate the impact of 4 SNPs within ACYP2 gene, additional gene-smoking or drinking interaction on IS risk. CONCLUSIONS: We found that the G allele of rs11896604 and the A allele of rs12615793 within ACYP2 gene, rs12615793- smoking interaction, and rs11896604-alcohol drinking interaction were all associated with increased IS risk.

Resveratrol inhibits Extranodal NK/T cell lymphoma through activation of DNA damage response pathway.

BACKGROUND: Extranodal NK/T cell lymphoma (NKTCL) is a highly aggressive non-Hodgkin lymphoma with poor prognosis. Resveratrol (RSV, 3,5,4'-trihydroxystilbene), a natural nontoxic phenolic compound found in the skin of grapes and some other spermatophytes, performs multiple bioactivities, such as antioxidant activity, anti-aging activity, reduction of cardiovascular disease risk and anticarcinogenic effect. Here we report the anti-tumor effect of RSV in NKTCL cell lines SNT-8, SNK-10 and SNT-16. RESULTS: RSV inhibited NKTCL cell proliferation in a dose- and time-dependent manner and arrested cell cycle at S phase. It induced NKTCL cells apoptosis through mitochondrial pathway, shown as down-regulation of MCl-1 and survivin, up-regulation of Bax and Bad, and activation of caspase-9 and caspase-3. In addition, we found that RSV suppressed the phosphorylation level of AKT and Stat3, and activated DNA damage response (DDR) pathway directly or through up-regulation of Zta of Epstein-Barr virus (EBV). Furthermore, using KU55933 as the inhibitor of pATM, we verified that DDR played an important role in RSV inducing NKTCL apoptosis. RSV also showed synergistic effect on activating DDR pathway in combination with etoposide or ionizing radiation, which resulted in cell proliferation inhibition and apoptosis. CONCLUSIONS: Our results provide in vitro evidence that RSV produces anti-tumor effect by activating DDR pathway in an ATM/Chk2/p53 dependent manner. So we suggest that RSV may be worthy for further study as an anti-tumor drug for NKTCL treatment.

Steroidogenic Acute Regulatory Protein (StAR) Overexpression Reduces Inflammation and Insulin Resistance in Obese Mice.

Steroidogenic acute regulatory protein (StAR), a mitochondrial cholesterol delivery protein, plays a beneficial role in hyperlipidemia, NAFLD, and endothelial inflammation. Elevated circulating fatty acids and low grade inflammation are known as key risk factors of insulin resistance and type 2 diabetes. In the present study, C57BL/6J mice were fed with HFD and infected with recombinant adenovirus expressing StAR by tail-vein injection. Intraperitoneal glucose/insulin tolerance test was performed to assess the insulin sensitivity. Morphological analysis and intramuscular lipid determination were used to illustrate the adipose hypertrophy and ectopic fat accumulation in skeletal muscle. The levels of inflammatory factor and nitric oxide were determined by ELISA and classic Griess reagent methods, respectively. The fatty acids composition was analysis using gas chromatography-mass spectrometry (GC-MS). The expression of genes associated with inflammation and insulin resistance were determined by Western blotting and qPCR to elucidate the underlying mechanism. We demonstrated that StAR overexpression ameliorated insulin resistance and systemic inflammatory response with the reduction of adipose hypertrophy and intramuscular lipid in HFD-fed mice. In addition, StAR overexpression increased serum unsaturated fatty acids (UFAs) and PPARγ expression in muscle and adipose tissue of obese mice. In conclusion, StAR may activate PPARγ by increasing UFAs, which leads to a protective role in systemic inflammation and insulin resistance in obese mice. J. Cell. Biochem. 118: 3932-3942, 2017. © 2017 Wiley Periodicals, Inc.

Steroidogenic acute regulatory protein (StAR) overexpression attenuates HFD-induced hepatic steatosis and insulin resistance.

Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology. Intracellular lipid accumulation is the first step in the development and progression of NAFLD. Steroidogenic acute regulatory protein (StAR) plays an important role in the synthesis of bile acid and intracellular lipid homeostasis and cholesterol metabolism. We hypothesize that StAR is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. The hypothesis was identified using free fatty acid (FFA)-overloaded NAFLD in vitro model and high-fat diet (HFD)-induced NAFLD mouse model transfected by recombinant adenovirus encoding StAR (StAR). StAR expression was also examined in pathology samples of patients with fatty liver by immunohistochemical staining. We found that the expression level of StAR was reduced in the livers obtained from fatty liver patients and NAFLD mice. Additionally, StAR overexpression decreased the levels of hepatic lipids and maintained the hepatic glucose homeostasis due to the activation of farnesoid x receptor (FXR). StAR overexpression attenuated the impairment of insulin signaling in fatty liver. This protective role of StAR was owing to a reduction of intracellular diacylglycerol levels and the phosphorylation of PKCε. Furthermore, FXR inactivation reversed the observed beneficial effects of StAR. The present study revealed that StAR overexpression can reduce hepatic lipid accumulation, regulate glucose metabolism and attenuate insulin resistance through a mechanism involving the activation of FXR. Our study suggests that StAR may be a potential therapeutic target for NAFLD.

Upregulation of hydroxysteroid sulfotransferase 2B1b promotes hepatic oval cell proliferation by modulating oxysterol-induced LXR activation in a mouse model of liver injury.

Hydroxysteroid sulfotransferase 2B1b (SULT2B1b) sulfates cholesterol and oxysterols. Hepatic oval cells (HOCs), thought to be progenitor cells, can be triggered in chemically injured livers. The present study focused on the role of SULT2B1b in HOC proliferation after liver injury. Our experiments revealed that the expression of SULT2B1b was increased dramatically in a chemical-induced liver injury model, mainly in HOCs. Upon challenge with a hepatotoxic diet containing 0.1 % 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), SULT2B1-/- mice presented alleviated liver injury and less HOC proliferation compared with wild-type (WT) mice, and these findings were verified by serum analysis, histopathology, immunofluorescence staining, RNA-seq, and Western blotting. HOCs derived from SULT2B1-/- mice showed lower proliferative capability than those from WT mice. SULT2B1b overexpression promoted growth of the WB-F344 hepatic oval cell line, whereas SULT2B1b knockdown inhibited growth of these cells. The IL-6/STAT3 signaling pathway also was promoted by SULT2B1b. Liquid chromatography and mass spectrometry indicated that the levels of 22-hydroxycholesterol, 25-hydroxycholesterol, and 24,25-epoxycholesterol were higher in the DDC-injured livers of SULT2B1-/- mice than in livers of WT mice. The above oxysterols are physiological ligands of liver X receptors (LXRs), and SULT2B1b suppressed oxysterol-induced LXR activation. Additional in vivo and in vitro experiments demonstrated that LXR activation could inhibit HOC proliferation and the IL-6/STAT3 signaling pathway, and these effects could be reversed by SULT2B1b. Our data indicate that upregulation of SULT2B1b might promote HOC proliferation and aggravate liver injury via the suppression of oxysterol-induced LXR activation in chemically induced mouse liver injury.

The homocysteine associated variant rs548987 of SLC17A3 confers susceptibility to ischemic stroke in Chinese population.

Ischemic stroke is a common cause of death due to obstructed blood supply of the brain. Despite growing numbers of research, etiology underlying ischemic stroke remains complex and elusive. Elevated plasma homocysteine has been known as a risk factor for ischemic stroke. Recently, a genome-wide association study reported association between rs548987 of SLC17A3 and homocysteine. Given existing relation between homocysteine and ischemic stroke, SLC17A3 was believed to be a promising candidate gene of ischemic stroke. Indeed, its association with ischemic stroke was previously reported in a western population. Herein, we used rs548987 as a candidate genetic variant of ischemic stroke and performed association analysis in a Chinese population with 918 ischemic stroke cases and 979 controls. Although rs548987 failed to show significant association with total ischemic stroke and large vessel disease subtype, the C allele of rs548987 showed significant association with small vessel disease subtype of ischemic stroke (OR=0.68, p=0.004). Our preliminary results suggested different genetic etiology underlying the two most common subtypes of ischemic stroke and provided additional evidence to understand contribution of homocysteine to the disease.

Effect of serum from postmenopausal women with osteoporosis exhibiting the Kidney-Yang deficiency pattern on bone formation in an hFOB 1.19 human osteoblastic cell line.

The aim of the present study was to investigate the underlying mechanism of the Kidney-Yang deficiency (KYD) pattern of osteoporosis in postmenopausal women of a certain age range by comparing the effect of serum from postmenopausal women with osteoporosis exhibiting the KYD pattern with that of serum from postmenopausal women without osteoporosis on bone formation in an hFOB 1.19 human osteoblastic cell line. A random selection of 30 female, postmenopausal volunteers aged 60-70 years, including 15 cases without osteoporosis and 15 cases with the KYD pattern of osteoporosis, were enrolled at the Physical Examination Center of the Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine. Venous blood was extracted and the serum was separated. The hFOB 1.19 cells were treated with 10% KYD pattern-serum or control serum from postmenopausal women of the same age range without osteoporosis. It was found that the KYD pattern-serum significantly decreased the cell viability, activity of alkaline phosphatase and number of calcified nodules, as well as downregulated the expression of osteocalcin and osteoprotegerin (OPG) and upregulated that of receptor activator of nuclear factor κB ligand (RANKL) in the hFOB 1.19 cells. In addition, the present results showed that the concentrations of estradiol (E2), OPG and insulin-like factor-1 (IGF-1) in the KYD pattern-serum were lower than those in the control serum. In combination, these findings suggest that the downregulation of E2, OPG and IGF-1 in the KYD pattern-serum inhibits the OPG/RANKL system, leading to a decrease in bone formation in the hFOB 1.19 cells. This indicates that the alterations in E2, OPG and IGF-1 may account for the susceptibility of certain postmenopausal women to the KYD pattern of osteoporosis.

Activation of protease­activated receptor­2 is associated with increased expression of inflammatory factors in the adipose tissues of obese mice.

Previous studies have indicated that mast cells are critical for the pathogenesis of inflammatory diseases. Proteases released from mast cells have been reported to stimulate protease­activated receptors (PAR), which induces microleakage and widespread inflammation. In order to investigate the pro­inflammatory effect of PAR­2 activation on adipose inflammation in obese mice, the varying distributions of macrophages and PAR­2 in adipose tissue samples were compared between C57BL/6J (C57) and obese mice [B6(D)­Leprdb/J, BKS(D)­Leprdb/J and B6.V­Lepob/J (ob/ob)] using immunohistochemical staining. Murine primary adipocytes and bone marrow­derived macrophages (BMDMs) were used and the alterations in expression levels of inflammatory factors, induced by PAR­2 activation, were detected by reverse transcription­quantitative polymerase chain reaction and ELISA. In addition, the migratory capacity of primary BMDMs and the macrophage cell line, RAW264.7 were evaluated by co­culture with primary adipocytes. The current study demonstrated a larger number of macrophages in the adipose tissues of obese mice compared with C57 mice. Furthermore, PAR­2 expression was detected in various adipose tissues of mice and the protein expression levels of PAR­2 were observed to be significantly higher in the total adipose tissues of ob/ob mice when compared with the C57 mice. The expression levels of inflammatory factors were increased in adipocytes and macrophages, and enhanced migratory ability was observed in macrophages pretreated with PAR­2 agonists. The data of the current study suggests that PAR­2 is involved in the process of obesity­associated chronic low­grade systemic inflammation, which indicates that the PAR­2 signaling pathway may be a potential target for the treatment of obesity and its associated diseases.