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Backgrounds A major side effect of statin, a widely used drug to treat hyperlipidemia, is skeletal myopathy through cell apoptosis. The aim of this study is to investigate the roles of microRNA in statin-induced injury. Methods Apolipoprotein E knockout (ApoE-/-) mice were administered with simvastatin (20 mg/kg/day) for 8 weeks. Exercise capacity was evaluated by hanging grid test, forelimb grip strength, and running tolerance test. Results In cultured skeletal muscle cells, statin increased the levels of miR-1a but decreased the levels of mitogen-activated protein kinase kinase kinase 1 (MAP3K1) in a time or dose dependent manner. Both computational target-scan analysis and luciferase gene reporter assay indicated that MAP3K1 is the target gene of miR-1a. Statin induced cell apoptosis of skeletal muscle cells, but abolished by downregulating of miR-1a or upregulation of MAP3K1. Further, the effects of miR-1a inhibition on statin-induced cell apoptosis were ablated by MAP3K1 siRNA. In ApoE-/- mice, statin induced cell apoptosis of skeletal muscle cells and decreased exercise capacity in mice infected with vector, but not in mice with lentivirus-mediated miR-1a gene silence. Conclusion Statin causes skeletal injury through induction of miR-1a excessive expression to decrease MAP3K1 gene expression.

This work aimed to determine tert-Butylhydroquinone (TBHQ)'s effects on insulin resistance (IR) and liver steatosis in diabetic animals and to explore the underpinning mechanisms.Male ApoEThe model animals showed T2DM signs, and TBHQ decreased FBG, ameliorated glucose tolerance and reduced liver steatosis in these animals. In addition, TBHQ markedly upregulated AMPKα2, GLUT4 and GSK3 β, as well as phosphorylated PI3K and AKT in the liver of mice with T2DM. In agreement, TBHQ decreased HClO-and insulin-related IR in cells and suppressed apoptosis through AMPKα2/PI3K/AKT signaling.TBHQ alleviates IR and liver steatosis in a mouse model of T2DM likely through AMPKα2/PI3K/AKT signaling.

Aims We have previously reported that nano-selenium quantum dots (SeQDs) prevented endothelial dysfunction in atherosclerosis. This study is to investigate whether amorphous SeQDs (A-SeQDs) increase endogenous tetrahydrobiopterin biosynthesis to alleviate pulmonary arterial hypertension. Results Both A-SeQDs and C-SeQDs were stable under physiological conditions, while the size of A-SeQDs was smaller than C-SeQDs by high resolution-transmission electron microscopy scanning. In monocrotaline-injected mice, oral administration of A-SeQDs was more effective to decrease pulmonary arterial pressure, compared to C-SeQDs and organic selenium. Further, A-SeQDs increased both nitric oxide productions and intracellular BH4 levels, upregulated dihydrofolate reductase activity in lungs, and improved pulmonary arterial remodeling. Gene deletion of dihydrofolate reductase abolished these effects produced by A-SeQDs in mice. Finally, the blood levels of tetrahydrobiopterin and selenium were decreased in patients with pulmonary arterial hypertension. Conclusion A-SeQDs increase intracellular tetrahydrobiopterin to prevent pulmonary arterial hypertension through recoupling endothelial nitric oxide synthase. Methods Two polymorphs of SeQDs and A-SeQDs, and a crystalline form of SeQDs (C-SeQDs) were prepared through self-redox decomposition of selenosulfate precursor. Mice were injected with monocrotaline to induce pulmonary arterial hypertension in vivo. Pulmonary arterial pressure was measured.

The insulation wall provides suitable heat for winter production of solar greenhouse. A thermal insulation mortar containing paraffin/expanded perlite composite phase change material based on desulfurized gypsum was studied as an inner insulation mortar to improve heat preservation and storage/exothermic capacities in solar greenhouse walls. Results showed that the ideal mass ratio of paraffin and expanded perlite was 60:40. The phase change temperature of the paraffin/expanded perlite composite particles was 25.3 °C, and the latent heat was 122.3 kJ/kg. The ideal mass ratio of this composite phase change material and desulfurized gypsum was 1:3. The ideal mixing amounts of dispersible polymer powder, redispersible latex powder, citric acid, hydroxypropyl methyl cellulose ether, and polypropylene fiber were 2%, 0.15%, 0.5%, and 0.5% of desulfurized gypsum content, respectively. The prepared composite phase change thermal insulation mortar had a dry density of 363 kg/m3, a compressive strength of 0.73 MPa, a softening coefficient of 0.65, a coefficient of thermal conductivity of 0.076 W/m·K-1, a heat capacity of 1.35×103 J/kg·°C-1, a heat storage coefficient of 11.65 W/m2·K-1, a phase change temperature of 25.6 °C, and a phase change latent heat of 89.8 kJ/kg. The phase change temperature and the phase change latent heat were suitable for solar greenhouse production.

Macrophage activation participates in the pathogenesis of pulmonary inflammation. As a coenzyme, vitamin B6 (VitB6) is mainly involved in the metabolism of amino acids, nucleic acids, glycogen and lipids. We have previously reported that activation of AMP‐activated protein kinase (AMPK) produces anti‐inflammatory effects both in vitro and in vivo. Whether VitB6 via AMPK activation prevents pulmonary inflammation remains unknown. The model of acute pneumonia was induced by injecting mice with lipopolysaccharide (LPS). The inflammation was determined by measuring the levels of interleukin‐1 beta (IL‐1β), IL‐6 and tumour necrosis factor alpha (TNF‐α) using real time PCR, ELISA and immunohistochemistry. Exposure of cultured primary macrophages to VitB6 increased AMP‐activated protein kinase (AMPK) Thr172 phosphorylation in a time/dose‐dependent manner, which was inhibited by compound C. VitB6 downregulated the inflammatory gene expressions including IL‐1β, IL‐6 and TNF‐α in macrophages challenged with LPS. These effects of VitB6 were mirrored by AMPK activator 5‐aminoimidazole‐4‐carboxamide ribonucleoside (AICAR). However, VitB6 was unable to inhibit LPS‐induced macrophage activation if AMPK was in deficient through siRNA‐mediated approaches. Further, the anti‐inflammatory effects produced by VitB6 or AICAR in LPS‐treated macrophages were abolished in DOK3 gene knockout (DOK3 −/−) macrophages, but were enhanced in macrophages if DOK3 was overexpressed. In vivo studies indicated that administration of VitB6 remarkably inhibited LPS‐induced both systemic inflammation and acute pneumonia in wild‐type mice, but not in DOK3 −/− mice. VitB6 prevents LPS‐induced acute pulmonary inflammation in mice via the inhibition of macrophage activation.

Cardiac fibrosis is a key factor to determine the prognosis in patient with myocardial infarction (MI). The aim of this study is to investigate whether the transcriptional factor paired‐related homeobox 2 (Prrx2) regulates Wnt5a gene expression and the role in myocardial fibrosis following MI. The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac remodelling was assessed by measuring interstitial fibrosis performed with Masson staining. Cell differentiation was examined by analysis the expression of alpha‐smooth muscle actin (α‐SMA). Both Prrx2 and Wnt5a gene expressions were up‐regulated in mice following MI, accompanied with increased mRNA and protein levels of α‐SMA, collagen I and collagen III, compared to mice with sham surgery. Adenovirus‐mediated gene knock down of Prrx2 increased survival rate, alleviated cardiac fibrosis, decreased infarction sizes and improved cardiac functions in mice with MI. Importantly, inhibition of Prrx2 suppressed ischaemia‐induced Wnt5a gene expression and Wnt5a signalling. In cultured cardiac fibroblasts, TGF‐β increased gene expressions of Prrx2 and Wnt5a, and induced cell differentiations, which were abolished by gene silence of either Prrx2 or Wnt5a. Further, overexpression of Prrx2 or Wnt5a mirrored the effects of TGF‐β on cell differentiations of cardiac fibroblasts. Gene silence of Wnt5a also ablated cell differentiations induced by Prrx2 overexpression in cardiac fibroblasts. Mechanically, Prrx2 was able to bind with Wnt5a gene promoter to up‐regulate Wnt5a gene expression. In conclusions, targeting Prrx2‐Wnt5a signalling should be considered to improve cardiac remodelling in patients with ischaemic heart diseases.

The medical usage of Doxorubicin (DOX) as a chemotherapeutic agent is restricted owing to its cardiotoxic properties. This study was designed to explore the effect and underlying mechanisms of Citronellal (CT) on DOX-related cardiotoxicity in rats. Rats were divided into six groups: control, DOX, CT, Lithium chloride (LiCl) (a Na+/H+exchanger-1 [NHE1] activator), DOX + CT, and DOX + CT + LiCl. To induce cardiotoxicity, a cumulative dose of 15 mg/kg DOX was intraperitoneally injected into rats. CT (150 mg/kg) and LiCl (1 mg/kg) were given daily by oral gavage for 6 weeks. CT improved cardiac functional parameters and attenuated the cardiac pathological changes induced by DOX. Further study indicated that CT administration regulated the levels of oxidative stress and apoptosis-related factors and in myocardial tissues, reducing cell per-oxidative damage and apoptosis. Besides this, CT attenuated DOX-induced NHE1 upregulation, and the preventive effects of CT against DOX-induced cardiotoxicity were abrogated by the concurrent administration of LiCl. These results demonstrate that CT could ameliorate DOX-induced cardiotoxicity by inhibiting the NHE1-mediated oxidative stress, apoptosis in rats.

Epigallocatechin-3-gallate (EGCG) has a good therapeutic effect on type 2 diabetes mellitus (T2DM). This work was designed to explore EGCG's effectiveness in insulin resistance (IR) and pancreas islet β-cell function in a rat model of T2DM.Eight-week-old male Sprague Dawley rats were randomly divided into 6 groups, including the Control (normal diet), Diabetes (high-sucrose high-fat [HSHF] diet combined with tail vein injection of streptozotocin [STZ] for T2DM induction) and Treatment Diabetic rats which were treated with metformin [500 mg/kg/d] or EGCG [25, 50 or 100 mg/kg/d] intragastric administration for 10 weeks. With the exception of control animals, the other groups were fed the HSHF diet. EGCG's effects on IR and insulin secretion were assessed by measuring body weights, and fasting blood glucose (FBG), postprandial blood glucose (PBG) and insulin levels. The morphological and molecular changes of pancreas islet β-cells were examined by hematoxylin-eosin (HE) staining, transmission electron microscopy (TEM) and immunofluorescence.Rats fed the HSHF diet combined with STZ treatment had increased body weights and blood glucose amounts, accompanied by IR and impaired β-cell function, induced T2DM, and EGCG dose-dependently restored the above indicators. Additionally, EGCG upregulated the pancreatic transcription factors pancreatic duodenal homeobox protein-1 (PDX-1) and musculoaponeurotic fibrosarcoma oncogene homolog A (MafA).These results suggest that EGCG reduces blood glucose amounts, and improve IR and islet β-cell disorder in T2DM.

Aims The impaired angiogenesis is the major cause of diabetic delayed wound healing. The molecular insight remains unknown. Previous study has shown that high glucose (HG) activates Na+/H+ exchanger 1 (NHE1) and induces intracellular alkalinization, resulting in endothelial dysfunction. The aim of this study is to investigate whether activation of NHE1 in endothelial cells by HG damages the angiogenesis in vitro and in vivo. Methods and results We used western blot to detect the phosphorylations of both Akt and Girdin, and pH-sensitive BCECF fluorescence to assay NHE1 activity and pHi value, respectively. The angiogenesis was evaluated by measuring the number of tube formation in vitro, and blood perfusion by laser doppler and neovascularization by staining CD31 in vivo. Our results indicated that induction of intracellular acidosis (IA) increased p-Akt and p-Girdin in human umbilical vein endothelial cells (HUVEC). HG activated NHE1 and increased pHi value in a time-dependent manner, associated with the decreased phosphorylations of both Akt and Gridin, while inhibition of NHE1 by amiloride abolished the HG-induced reductions of p-Akt and p-Girdin. However, silence of Akt by siRNA transfection or pharmacological inhibitors (wortmannin and LY294002) bypassed IA-induced Girdin phosphorylation. Overexpression of constitutively active Akt abolished HG-reduced Girdin phosphorylation. In addition, upregulation of Akt or inhibition of NHE1 remarkably attenuated HG-impaired tube formation in HUVEC. In vivo study revealed that amiloride dramatically rescued hyperglycemia-delayed blood perfusion and neovascularization by augmenting ischemia-induced angiogenesis. Conclusion IA promotes ischemia-induced angiogenesis via Akt-dependent Girdin phosphorylation in diabetic mice.

The effects of long‐term nitrate therapy are compromised due to protein S‐Nitrosylation, which is mediated by nitric oxide (NO). This study is to determine the role of Akt S‐Nitrosylation in the recovery of heart functions after ischaemia. In recombinant Akt protein and in HEK293 cells, NO donor decreased Akt activity and induced Akt S‐Nitrosylation, but was abolished if Akt protein was mutated by replacing cysteine 296/344 with alanine (Akt‐C296/344A). In endothelial cells, NO induced Akt S‐Nitrosylation, reduced Akt activity and damaged multiple cellular functions including proliferation, migration and tube formation. These alterations were ablated if cells expressed Akt‐C296/344A mutant. In Apoe−/− mice, nitroglycerine infusion increased both Akt S‐Nitrosylation and infarct size, reduced Akt activity and capillary density, and delayed the recovery of cardiac function in ischaemic hearts, compared with mice infused with vehicle. Importantly, these in vivo effects of nitroglycerine in Apoe−/− mice were remarkably prevented by adenovirus‐mediated enforced expression of Akt‐C296/344A mutant. In conclusion, long‐term usage of organic nitrate may inactivate Akt to delay ischaemia‐induced revascularization and the recovery of cardiac function through NO‐mediated S‐Nitrosylation.

Currently, the ceramic inner container draws great attention in the field of induction heating pot. Based on the traditional roll-forming process for ceramic pot, a new kind process was proposed to fabricate ceramic inner container and synchronously embed stainless steel plate by one-step high temperature sintering. The key technology for this process is to avoid the oxidation of SUS430 stainless steel plate during the high temperature sintering for a longtime by coating a glass-ceramic layer. In this research, the glass-ceramic coating with excellent high temperature oxidation resistance was optimized. The influences of ZrO2 content in the coating slurry on the high temperature oxidation resistance and thermal shock resistance of SUS430 stainless steel plate with glass-ceramic coating were studied. Meanwhile, the coatings were characterized by Scanning Electron Microscopy, X-ray Diffraction and Thermal Expansion Analysis. The experimental results showed that the glass-ceramic coating was smooth and had excellent thermal shock resistance when the addition of ZrO2 reached 15wt%. The mass gain of the SUS430 stainless steel plate with glass-ceramic coating was only 0.453% after sintering at 1300°C for 10h in air atmosphere, which was less one percent than that of SUS430 stainless steel plate under the same sintering condition.

// Hui Ma 1,2 , Wen-Jing Liang 1 , Mei-Rong Shan 1 , Xue-Qing Wang 1 , Sheng-Nan Zhou 1 , Yuan Chen 1 , Tao Guo 1 , Peng Li 3 , Hai-Ya Yu 4 , Chao Liu 5 , Ya-Ling Yin 3 , Yu-Lin Wang 2 , Bo Dong 2 , Xin-Yan Pang 1 and Shuang-Xi Wang 1,3 1 Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China 2 Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China 3 College of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China 4 Department of Neurology, The People’s Hospital of Xishui County, Huangang, Hubei, China 5 Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China Correspondence to: Shuang-Xi Wang, email: // Xin-Yan Pang, email: // Bo Dong, email: // Keywords : abdominal aortic aneurysm, pravastatin, AMP-activated protein kinase, activator protein 2 alpha, matrix metalloproteinase 2, Pathology Section Received : September 09, 2016 Accepted : January 16, 2017 Published : February 04, 2017 Abstract We have previously reported that activation of AMP-activated kinase alpha 2 (AMPKα2) by nicotine or angiotensin II (AngII) instigates formation of abdominal aortic aneurysms (AAA) in Apoe -/- mice. Statins, used to treat hyperlipidemia widely, activate AMPK in vascular cells. We sought to examine the effects of pravastatin on AAA formation and uncover the molecular mechanism. The AAA model was induced by AngII and evaluated by incidence, elastin degradation, and maximal abdominal aortic diameter in Apoe -/- mice. The phosphorylated levels of AMPKα2 and activator protein 2 alpha (AP-2α) were examined in cultured vascular smooth muscle cells (VSMCs) or in mice. We observed that pravastatin (50 mg/kg/day, 8 weeks) remarkably increased the AngII-induced AAA incidence in mice. In VSMCs, pravastatin increased the levels of pAMPK, pAP-2α, and MMP2 in both basal and AngII-stressed conditions, which were abolished by tempol and compound C. Pravastatin-upregulated MMP2 was abrogated by AMPKα2 or AP-2α siRNA. Lentivirus-mediated gene silence of AMPKα2 or AP-2α abolished pravastatin-worsened AAA formations in AngII-infused Apoe -/- mice. Clinical investigations demonstrated that both AMPKα2 and AP-2α phosphorylations were increased in AAA patients or human subjects taking pravastatin. In conclusion, pravastatin promotes AAA formation through AMPKα2-dependent AP-2α activations.

// Fu Wang 1 , Hui Ma 1 , Wen-Jing Liang 1 , Jing-Jing Yang 1 , Xue-Qing Wang 1 , Mei-Rong Shan 1 , Yuan Chen 1 , Min Jia 2 , Ya-Ling Yin 3 , Xue-Ying Sun 4 , Jia-Ning Zhang 5 , Qi-Sheng Peng 6 , Yu-Guo Chen 1 , Li-Ying Liu 4 , Peng Li 3 , Tao Guo 1 and Shuang-Xi Wang 1 1 The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China 2 Department of Rehabilitation Medicine, Jinan Municipal Hospital of Traditional Chinese Medicine, Jinan, China 3 Department of Pharmacology, College of Pharmacy, Xinxiang Medical University, Xinxiang, China 4 Department of Pharmacology, Pharmaceutical College, Central South University, Changsha, China 5 Biology and Chemistry, Denison University, Granville, OH, USA 6 Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, China Correspondence to: Shuang-Xi Wang, email: // Tao Guo, email: // Peng Li, email: // Keywords : lovastatin, microRNA-29b, oxidative stress, PA200, endothelial dysfunction, Pathology Section Received : June 03, 2016 Accepted : September 25, 2016 Published : January 03, 2017 Abstract Aims: Proteasome-linked oxidative stress is believed to cause endothelial dysfunction, an early event in cardiovascular diseases (CVD). Statin, as HMG-CoA reductase inhibitor, prevents endothelial dysfunction in CVD. However, the molecular mechanism of statin-mediated normalization of endothelial function is not completely elucidated. Methods and Results: Lovastatin time/dose-dependently increased miR-29b expression and decreased proteasome activity in cultured human umbilical vein endothelial cells (HUVECs). Anti-miR-29b or overexpression of PA200 abolished lovastatin-induced inhibition of proteasome activity in HUVECs. In contrast, pre-miR-29b or PA200 siRNA mimics these effects of lovastatin on proteasome activity. Lovastatin inhibited oxidative stress induced by multiple oxidants including ox-LDL, H 2 O 2 , TNFα, homocysteine thiolactone (HTL), and high glucose (HG), which were reversed by inhibition of miR-29b in HUVECs. Ex vivo analysis indicated that lovastatin normalized the acetylcholine-induced endothelium-dependent relaxation and the redox status in isolated rat aortic arteries exposure to multiple cardiovascular risk factors. In vivo analysis revealed that administration of lovastatin remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats with hyperglycemia, dyslipidemia, and hyperhomocysteinemia, as well as increased miR-29b expressions, reduced PA200 protein levels, and suppression of proteasome activity in aortic tissues. Conclusion: Upregulation of miR-29b expression is a common mechanism contributing to endothelial dysfunction induced by multiple cardiovascular risk factors through PA200-dependent proteasome-mediated oxidative stress, which is prevented by lovastatin.

Background Dok-3 has been shown to play an important role in immune system. Tim-3 also has been recognized as an important immune regulator which involves in many diseases. The relationship of them is still unclear. Methods We detected the expression of Tim-3 on spleen immune cells from Dok-3 deficient mice and control mice by flow cytometry. Results In this article, we found that Dok-3−/− mice display almost entirely different immune clustering characteristics compared with wild type 129 mice. The CD4 T cells and CD8 T cells decreased and DC cells, macrophages, MDSCs increased when the Dok-3 gene knocked-out. The Tim-3 expression on CD4 T cells, CD8 T cells, NK cells, DC cells increased when the Dok-3 gene knocked-out. The macrophages and MDSCs just display the opposite results. Conclusions Although Dok-3−/− mice display different immune clustering and Tim-3 expression, the mechanism still needs further study. Electronic supplementary material The online version of this article (10.1186/s40001-019-0384-7) contains supplementary material, which is available to authorized users.

Backgrounds: Cardiac fibrosis is a key factor to determine the prognosis in patient with myocardial infarction (MI). Activation of Wnt signaling by transforming growth factor β (TGF-β) contributes to cell differentiation of fibroblasts in cardiac remodeling. However, the molecular mechanisms by how Wnt protein family 5a (Wnt5a) is upregulated in post-ischemic heart are still mostly unclear. The aim of this study is to investigate whether paired-related homeobox 2 (Prrx2), as a transcriptional factor, regulates Wnt5a gene expression in myocardial fibrosis, and, if so, to identify the role of Prrx2 in the recovery of cardiac functions in mice following MI. Methods: The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac remodeling was assessed by measuring interstitial fibrosis using Masson staining. Cell differentiation was examined by immunofluorescence analysis of alpha smooth muscle actin (α-SMA). Results: Both Prrx2 and Wnt5a gene expressions were upregulated in Apoe-/- mice following MI, accompanied with increased mRNA and protein levels of α-SMA, collagen I, and collagen III in hearts, compared to mice with sham surgery. Adenovirus-mediated gene knockdown of Prrx2 increased survival rate, alleviates cardiac fibrosis, decreased infarction sizes in hearts, and improved cardiac functions in mice with MI after 30 post-ischemia days. Importantly, inhibition of Prrx2 suppressed ischemia-induced Wnt5a gene expression and Wnt5a signaling in mice hearts. In cultured cardiac fibroblasts, TGF-β increased gene expressions of Prrx2 and Wnt5a, and induced cell differentiations, which were abolished by gene silence of either Prrx2 or Wnt5a. Further, overexpression of Prrx2 or Wnt5a mirrored the effects of TGF-β on cell differentiations of cardiac fibroblasts. Gene silence of Wnt5a also ablated cell differentiations induced by Prrx2 overexpression in cardiac fibroblasts. Mechanically, Prrx2 was able to bind with Wnt5a gene promoter to upregulate Wnt5a gene expression. Conclusion: Upregulation of Prrx2 increases Wnt5a gene expression to induce cell differentiations, which contributes to ischemia-induced cardiac fibrosis. In perspective, targeting Prrx2-Wnt5a signaling should be considered to improve cardiac remodeling in patients with ischemic heart diseases. Funding: This project was supported by National Natural Science Foundation of China (81874312, 81770576, 81770493, U1704168, 81673423, and 81570723) and the Natural Science Foundation of Shandong Province (ZR2019PH007, ZR2019QH011, ZR2016HM04). S.X.W. is an exceptional young scholar of Shandong University, a distinguished professor of Henan province, a recipient of Zhong-Yuan-Qian-Ren Program of Henan province (194200510005), an adjunct Tai-Hang Professional Scholarship of Xinxiang Medical University (505067), and an adjunct Lan-Yue Professional Scholar of Hubei University of Science and Technology (2016-18XZ07). L.Z. was supported by general program of Department of Health (B20180875) and clinical medical technology innovation guidance project from Department of Science and Technology (2017SK50504) of Hunan Province. W.D.Q. was sponsored by China Postdoctoral Science Foundation (2018M630788). Declaration of Interest: None. Ethical Approval: The animal protocol was reviewed and approved by the University of Shandong, Animal Care and Use Committee. This animal study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

Objective: Vascular dementia is the second leading cause of dementia, which is strongly associated with diabetes. Ectopic expression of miR-133a in endothelial cells is involved in endothelial dysf...

Aims/Introduction Type 2 diabetes is a worldwide disease that is associated with increased rates of obesity and reduced physical activity. Obesity‐associated insulin resistance in type 2 diabetes is a disorder in the balance between pro‐inflammatory and anti‐inflammatory signals. T cell immunoglobulin and mucin domain‐containing molecule 3 (Tim‐3) has been reported as an important regulatory inflammation molecule, and plays a pivotal role in several inflammation‐related diseases. Materials and Methods Peripheral blood mononuclear cells were obtained from type 2 diabetes patients (n = 31) and healthy donors (n = 18), and Tim‐3 expression on peripheral blood mononuclear cells was evaluated by flow cytometry. Results We showed the downregulated expression of Tim‐3 on CD14+ monocytes from type 2 diabetes patients. In addition, the upregulated expression of Tim‐3 on peripheral CD4+ T cells and CD8+ T cells was observed in the present study. The correlation analysis between Tim‐3 expression on CD14+ monocytes and diabetes duration showed the longer diabetes duration time, the lower Tim‐3 expression on CD14 monocytes. Conclusions The present results suggest that Tim‐3 might participate in the progression of type 2 diabetes by its negative regulation on these immune cells, and Tim‐3 on CD14+ monocytes serves as a novel biological marker for diabetes duration in type 2 diabetes patients.

// Jing-Jing Yang 1 , Peng Li 2 , Fu Wang 1 , Wen-Jing Liang 1 , Hui Ma 1 , Yuan Chen 1 , Zhi-Min Ma 3 , Quan-Zhong Li 4 , Qi-Sheng Peng 5 , Yun Zhang 1 and Shuang-Xi Wang 1,2 1 Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, School of Medicine, Shandong University, Jinan, China 2 Department of Pharmacology, College of Pharmacy, Xinxiang Medical University, Xinxiang, China 3 Division of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China 4 Division of Cardiology, The Affiliated Hospital, Guilin Medical University, Guilin, China 5 Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, China Correspondence to: Shuang-Xi Wang, email: // Yun Zhang, email: // Keywords : activator protein 2α, aspirin, IkBα, atherosclerosis, Pathology Section Received : March 24, 2016 Accepted : June 17, 2016 Published : July 04, 2016 Abstract Aims: Aspirin has been used for the secondary prevention and treatment of cardiovascular disease for several decades. We investigated the roles of transcriptional factor activator protein 2α (AP-2α) in the beneficial effects of aspirin in the growth and vulnerability of atherosclerotic plaque. Methods and Results: In mice deficient of apolipoprotein E ( Apoe -/- ), aspirin (20, 50 mg/kg/day) suppressed the progression of atherosclerosis in aortic roots and increased the plaque stability in carotid atherosclerotic plaques induced by collar-placement. In vivo lentivirus-mediated RNA interference of AP-2α reversed the inhibitory effects of aspirin on atherosclerosis in Apoe -/- mice. Mechanically, aspirin increased AP-2α phosphorylation and its activity , upregulated IkBα mRNA and protein levels, and reduced oxidative stress in cultured vascular smooth muscle cells . Furthermore, deficiency of AP-2α completely abolished aspirin-induced upregulation of IkBα levels and inhibition of oxidative stress in Apoe -/- mice. Clinically, conventional doses of aspirin increased AP-2α phosphorylation and IkBα protein expression in humans subjects. Conclusion: Aspirin activates AP-2α to upregulate IkBα gene expression, resulting in attenuations of plaque development and instability in atherosclerosis.

In some industrial application, thermal property of resin plays an important role as same as strength. Many attempts have been made to enhance the thermal conductivity of resin matrix composite. In this paper, the copper fibers were introduced to the polyimide-based composite. The experimental results showed that the thermal conductivity of polyimide-based composite with 15% Cu fibers was as high as 8.62W/mK which is more than three times that with Cu powders. The PI-Cu composites with copper fiber had a much lower wear loss than that with copper powder. The forming of three-dimensional network by Cu fibers makes it possible that the heat can conduct by electrons in the resin-based composite with Cu fibers.

Backgrounds and aims Increased arterial stiffness may increase cardiovascular morbidity and mortality. Angiotensin II type 1 receptor blocker losartan is potentially useful in controlling the central blood pressure and arterial stiffness in mild to moderate essential hypertension, while the effects of losartan in aged patients with essential hypertension are not entirely investigated. Methods The carotid-femoral arterial pulse wave velocity (PWV) was measured in aged patients with essential hypertension. Results In a cross-sectional study, PWV value was significantly higher in these old patients with essential hypertension, compared with patients without essential hypertension. Logistic regression analysis indicated that age, hypertension duration, and losartan treatment are risk factors of arterial stiffness. In a perspective study, long-term administration of losartan (50 mg/d) remarkably reduced PWV in aged patients with essential hypertension. In a longitudinal study, PWV is an independent predictor of the occurrence of acute coronary syndrome (ACS) in elderly patients with essential hypertension by using multivariate analysis. Further, the ACS occurrence was reduced by long-term administration of losartan in aged patients with essential hypertension, compared with the old hypertensive patients without taking losartan. Conclusion Losartan treatment is a negative risk factor of arterial stiffness and reduces the risk of ACS in aged patients with essential hypertension.

Development of nitrate tolerance is a major drawback to nitrate therapy. Prostacyclin (PGI2) is a powerful vasodilator produced from prostaglandin (PGH2) by prostacyclin synthase (PGIS) in endothelial cells. This study aimed to determine the role of PGIS S-nitrosylation in nitrate tolerance induced by nitroglycerin (GTN). In endothelial cells, GTN increased PGIS S-nitrosylation and disturbed PGH2 metabolism, which were normalized by mutants of PGIS cysteine 231/441 to alanine (C231/441A). Clearance of nitric oxide by carboxy-PTIO or inhibition of S-nitrosylation by N-acetyl-cysteine decreased GTN-induced PGIS S-nitrosylation. Enforced expression of mutated PGIS with C231/441A markedly abolished GTN-induced PGIS S-nitrosylation and nitrate cross-tolerance in Apoe-/- mice. Inhibition of cyclooxygenase 1 by aspirin, supplementation of PGI2 by beraprost, and inhibition of PGIS S-nitrosylation by N-acetyl-cysteine improved GTN-induced nitrate cross-tolerance in rats. In patients, increased PGIS S-nitrosylation was associated with nitrate tolerance. In conclusion, GTN induces nitrate cross-tolerance through PGIS S-nitrosylation at cysteine 231/441.

Diabetes mellitus is one of risk factors of cardiovascular diseases including atherosclerosis. Whether and how diabetes promotes the formation of unstable atherosclerotic plaque is not fully understood. Here, we show that streptozotocin-induced type 1 diabetes reduced collagen synthesis, leading to the formation of unstable atherosclerotic plaque induced by collar placement around carotid in apolipoprotein E knockout (Apoe−/−) mice. These detrimental effects of hyperglycemia on plaque stability were reversed by metformin in vivo without altering the levels of blood glucose and lipids. Mechanistically, we found that high glucose reduced the phosphorylated level of AMP-activated protein kinase alpha (AMPKα) and the transcriptional activity of activator protein 2 alpha (AP-2α), increased the expression of miR-124 expression, and downregulated prolyl-4-hydroxylase alpha 1 (P4Hα1) protein expression and collagen biosynthesis in cultured vascular smooth muscle cells. Importantly, these in vitro effects produced by high glucose were abolished by AMPKα pharmacological activation or adenovirus-mediated AMPKα overexpression. Further, adenovirus-mediated AMPKα gain of function remitted the process of diabetes-induced plaque destabilization in Apoe−/− mice injected with streptozotocin. Administration of metformin enhanced pAP-2α level, reduced miR-124 expression, and increased P4Hα1 and collagens in carotid atherosclerotic plaque in diabetic Apoe−/− mice. We conclude that streptozotocin-induced toxic diabetes promotes the formation of unstable atherosclerotic plaques based on the vulnerability index in Apoe−/− mice, which is related to the inactivation of AMPKα/AP-2α/miRNA-124/P4Hα1 axis. Clinically, targeting AMPKα/AP-2α/miRNA-124/P4Hα1 signaling should be considered to increase the plaque stability in patients with atherosclerosis.

Berberine, as an alkaloid found in many Chinese herbs, improves vascular functions in patients with cardiovascular diseases. We determined the effects of berberine in hypertension and vascular ageing, and elucidated the underlying mechanisms. In isolated aortas, berberine dose-dependently elicited aortic relaxation. In cultured cells, berberine induced the relaxation of vascular smooth muscle cells (VSMCs). Overexpression of transient receptor potential vanilloid 4 (TRPV4) channel by genetic approaches abolished the berberine-induced reduction in intracellular Ca(2+) concentration in VSMCs and attenuated berberine-elicited vessel dilation in mice aortas. In deoxycorticosterone acetate (DOCA)-induced hypertensive model, treatment of mice with berberine or RN-1734, a pharmacological inhibitor of TRPV4, significantly decreased systemic blood pressure (BP) in control mice or mice infected with an adenovirus vector. However, berberine-induced effects of lowering BP were reversed by overexpressing TRPV4 in mice by infecting with adenovirus. Furthermore, long-term administration of berberine decreased mean BP and pulse BP, increased artery response to vasodilator and reduced vascular collagen content in aged mice deficient in apolipoprotein E (Apoe-KO), but not in Apoe-KO old mice with lentivirus-mediated overexpression of TRPV4 channel. In conclusion, berberine induces direct vasorelaxation to lower BP and reduces vascular stiffness in aged mice through suppression of TRPV4.

To explore whether rosiglitazone (RSG), a selective peroxisome proliferator-activated receptor γ (PPARγ) agonist, exerts beneficial effects on endothelial dysfunction induced by homocysteine thiolactone (HTL) and to investigate the potential mechanisms. Incubation of cultured human umbilical vein endothelial cells with HTL (1 mM) for 24 hrs significantly reduced cell viabilities assayed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, as well as enhanced productions of reactive oxygen species, activation of nuclear factor kappa B, and increased intercellular cell adhesion molecule-1 secretion. Pre-treatment of cells with RSG (0.001-0.1 mM), pyrollidine dithiocarbamate (PDTC, 0.1 mM) or apocynin (0.1 mM) for 1 hr reversed these effects induced by HTL. Furthermore, co-incubation with GW9662 (0.01 mM) abolished the protective effects of RSG on HTL-treated cells. In ex vivo experiments, exposure of isolated aortic rings from. rats to HTL (1 mM) for 1 hr dramatically impaired acetylcholine-induced endothelium-dependent relaxation, reduced release of nitric oxide and activity of superoxide dismutase, and increased malondialdehyde content in aortic tissues. Preincubation of aortic rings with RSG (0.1, 0.3, 1 mM), PDTC or apocynin normalized the disorders induced by HTL. In vivo analysis indicated that administration of RSG (20 mg/kg/d) remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats fed HTL (50 mg/kg/d) for 8 weeks. RSG improves endothelial functions in rats fed HTL, which is related to PPARγ-dependent suppression of oxidative stress.

Endothelial dysfunction, which is caused by endothelial nitric oxide synthase (eNOS) uncoupling, is an initial step in atherosclerosis. This study was designed to explore whether Chinese medicine xin-mai-jia (XMJ) recouples eNOS to exert anti-atherosclerotic effects. Pretreatment of XMJ (25, 50, 100 μg/ml) for 30 minutes concentration-dependently activated eNOS, improved cell viabilities, increased NO generations, and reduced ROS productions in human umbilical vein endothelial cells incubated with H2O2 for 2 hours, accompanied with restoration of BH4. Importantly, these protective effects produced by XMJ were abolished by eNOS inhibitor L-NAME or specific eNOS siRNA in H2O2-treated cells. In ex vivo experiments, exposure of isolated aortic rings from rats to H2O2 for 6 hours dramatically impaired acetylcholine-induced vasorelaxation, reduced NO levels and increased ROS productions, which were ablated by XMJ in concentration-dependent manner. In vivo analysis indicated that administration of XMJ (0.6, 2.0, 6.0 g/kg/d) for 12 weeks remarkably recoupled eNOS and reduced the size of carotid atherosclerotic plaque in rats feeding with high fat diet plus balloon injury. In conclusion, XMJ recouples eNOS to prevent the growth of atherosclerosis in rats. Clinically, XMJ is potentially considered as a medicine to treat patients with atherosclerosis.

LED is the fourth generation of the illumination light source. The light efficiency, lifetime and reliability will be reduced, if the heat generated in LED chips couldn’t be dissipated rapidly. Thus, thermal conductivity of the substrate material is a very key factor in the LED field. Silicon Carbide with Aluminum metal composites (Al/SiC) has high thermal conductivity and ideal thermal expansion coefficient. In this paper, the main kinds of substrates for high-power LED were introduced. Al/SiC composite substrate with excellent heat conduct performance was fabricated by pressureless infiltration technology. The microstructure of Al/SiC was observed by scanning electron microscope (SEM). The coefficients of thermal expansion and thermal conductivity of Al/SiC composite substrate, AlN ceramic substrate and Al2O3ceramic substrate were compared. The results showed that the coefficient of thermal expansion (CTE) of Al/SiC varied from 7.77×10-6K-1to 10.89×10-6K-1, which is compatible with Silicon. And the thermal conductivity of Al/SiC is as 9 times high as that of Al2O3.

In this paper, a hybrid genetic algorithm is presented for the flexible job-shop scheduling problem with makespan criterion. A new machine assignment strategy is proposed to improve the initial population. A modified coding scheme is presented, and a population improvement strategy is performed when the best solution of the population did not improve during some generations. This hybrid algorithm is tested on a series of benchmarks instances. Experimental results show that this hybrid algorithm is efficient and competitive compared to some existing methods.

The adsorption and diffusion of Pb(II) atom on the hydroxylated (001) surface of kaolinite were investigated using density-functional theory within the generalized gradient approximation and a supercell approach. The coverage dependence of the adsorption structures and energetics was systematically studied for a wide range of coverage Θ [from 0.11 to 1.0 monolayers (ML)] and adsorption sites. The most stable among all possible adsorption sites was the two-fold bridge site followed by the one-fold top site, and the adsorption energy increased with the coverage, thus indicating the higher stability of surface adsorption and a tendency to the formation of Pb(II) islands (clusters) with increasing coverage. Moreover, the energy barrier for diffusion of Pb(II) atom between the one-fold top and the two-fold bridge adsorption sites on kaolinite(001) surface was 0.23 (0.31) eV, implying that the Pb(II) atom is prone to diffusing on kaolinite(001) surface. The other properties of the Pb(II)/kaolinite(001) system including the different charge distribution, the lattice relaxation, and the electronic density of states were also studied and discussed in detail.

The discovery of supersymmetry (SUSY) via action of the cold dark matter candidate is being led on the indirect collider production front by the LHC, and correspondingly by the XENON100 collaboration on the direct detection front. We undertake a dual case study of the specific SUSY signatures which the No-Scale flipped SU(5) x U(1) X grand unified theory with TeV-scale vector-like particles (No-Scale F-SU(5)) would exhibit at each of these experiments. We demonstrate a correlation between the near-term prospects of these two distinct approaches. We feature a dark matter candidate which is over 99% bino due to a comparatively large Higgs bilinear mass mu term around the electroweak scale, and thus automatically satisfy the current constraints from the XENON100 and CDMS/EDELWEISS experiments. We do however expect that the ongoing extension of the XENON100 run may effectively probe our model. Likewise, our model is also currently being probed by the LHC via a search for events with ultra-high multiplicity hadronic jets, which are a characteristic feature of the distinctive No-Scale F-SU(5) mass hierarchy.

Backgrounds.VitB6 deficiency has been associated with a number of adverse health effects. However, the effects of VitB6 in metabolic syndrome are poorly understood.Methods.VitB6 (50 mg/kg/day) was given toApoe-/-mice with hkdigh-fat diet (HFD) for 8 weeks. Endothelial dysfunction, insulin resistance, and hepatic lipid contents were determined.Results.VitB6 administration remarkably increased acetylcholine-induced endothelium-dependent relaxation and decreased random blood glucose level inApoe-/-mice fed with HFD. In addition, VitB6 improved the tolerance of glucose and insulin, normalized the histopathology of liver, and reduced hepatic lipid accumulation but did not affect the liver functions. Clinical and biochemical analysis indicated that the levels of VitB6 were decreased in patients with fatty liver.Conclusions.Vitamin B6 prevents endothelial dysfunction, insulin resistance, and hepatic lipid accumulation inApoe-/-mice fed with HFD. Supplementation of VitB6 should be considered to prevent metabolic syndrome.

In order to better understand the recycled concrete aggregate, it is essential to investigate the different mixture ratio in it. For determining the better mixture ratio of recycled concrete aggregate, the experimental investigation was conducted by making use of recycled concrete aggregate of different ratio instead of small stones in concrete, while maintaining the proportion of other raw materials of concrete unchanged. Its mechanical properties were also investigated. It is found that the better materials proportion of recycled concrete is that sand: recycled aggregate: water= 1: 1.8 : 2.1: 0.55.

The adsorption and dissociation of isolated H 2 O molecule on Zr(0 0 0 1) surface are investigated by using density-functional theory calculations. It is shown that the flat adsorption states on the top site are dominated by the 1 b 1 – d band coupling, insensitive to the azimuthal orientation. The diffusion between adjacent top sites reveals that the water molecule is very mobile on the surface. For the upright adsorption configuration on the bridge site, the surface → water charge transfer occurring across the Fermi level plays an important role. The dissociation of H 2 O on Zr(0 0 0 1) surface is very facile, in good accordance with the attainable experimental results.

It has been recognized that sodium hydrogen exchanger 1 (NHE1) is involved in the development of diabetic nephropathy. The role of NHE1 in kidney dysfunction induced by advanced glycation end products (AGEs) remains unknown. Renal damage was induced by AGEs via tail vein injections in rats. Function and morphology of kidney were determined. Compared to vehicle- or BSA-treated rats, AGEs caused abnormalities of kidney structures and functions in rats, accompanied with higher MDA level and lower GSH content. Gene expressions of NHE1 gene and TGF-β1 in the renal cortex and urine were also increased in AGEs-injected rats. Importantly, all these detrimental effects induced by AGEs were reversed by inhibition of NHE1 or suppression of oxidative stress. These pieces of data demonstrated that AGEs may activate NHE1 to induce renal damage, which is related to TGF-β1.

The adsorption and dissociation of H2 molecules on the Zr(0 0 0 1) surface are systematically investigated by using density functional theory within the generalized gradient approximation and a supercell approach. After geometry optimization, the most stable equilibrium adsorption state is found to be along the top-y entrance. By calculating the adiabatic potential energy surface, the chemisorbed molecular adsorption states are also identified to be along the parallel channel at the top site. The electronic properties of the stable chemisorbed molecular state are analyzed, which show that the interaction between the molecule and substrate is of covalent characteristic with a sizeable charge redistribution. On the other hand, the hcp site is turned out to be the most stable equilibrium adsorption site for hydrogen atom on Zr(0 0 0 1) surface after the dissociation of H2. The dissociation energetics of H2 are studied by calculating the potential energy surface and the minimum energy path of the transition state is determined by using the climb image nudged elastic band method, wherein the fcc-y channel is found to be most stable and favorable for dissociative adsorption of H2 among the five possible dissociative paths. Remarkably, we find that the adiabatic dissociation process of H2 is an activated type but with a small energy barrier, which is well consistent with the macroscopic phenomenon that the zirconium metal is easily hydrogenated.

Using first-principles calculations, we systematically study the adsorption behavior of a single molecular H$_{2}$O on the Be(0001) surface. We find that the favored molecular adsorption site is the top site with an adsorption energy of about 0.3 eV, together with the detailed electronic structure analysis, suggesting a weak binding strength of the H$_{2}$O/Be(0001) surface. The adsorption interaction is mainly contributed by the overlapping between the $s$ and $p_{z}$ states of the top-layer Be atom and the molecular orbitals 1$b_{1}$ and 3$a_{1}$ of H$_{2}$O. The activation energy for H$_{2}$O diffusion on the surface is about 0.3 eV. Meanwhile, our study indicates that no dissociation state exists for the H$_{2}$O/Be(0001) surface., 10 pages, 4 figures

Mn-doped alumina red pigment was prepared with Mn(NO3)2·6H2O and Al(NO3)3·9H2O as main raw materials by Low-temperature Combustion-Calcination process. The Mn-doped alumina red pigment was tested by XRD, SEM and CIE L*a*b* colour parameter measurement. The results showed that the reaction of Mn(NO3)2·6H2O, Al(NO3)3·9H2O and CH3COONH4with the theoretical ratio could be ignited and self-propagating at 500 °C. One kind pigment with excellent chromatic performance had been gained at the ratio about 1:40 between Mn(NO3)2·6H2O and Al(NO3)3·9H2O. The crystallite of the precursor obtained by Low-temperature Combustion synthesis (LCS) is imperfectly developed and the aggregation of particles is serious. The crystallite of the powder grows up more perfectly after calcined at 1000 °C for 4 hour with a corundum-like structure. The average particle size of the pigment is approximately 5 μm.