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Ultrasound-mediated microbubble cavitation (UMMC) induces therapeutic angiogenesis to treat ischemic diseases. This study aimed to investigate whether diagnostic UMMC alleviates diabetic cardiomyopathy (DCM) and, if so, through which mechanisms. DCM model was established by injecting streptozocin into rats to induce hyperglycemia, followed by a high-fat diet. The combined therapy of cation microbubble with low-intensity diagnostic ultrasound (frequency = 4 MHz), with a pulse frequency of 20 Hz and pulse length (PL) of 8, 18, 26, or 36 cycles, was given to rats twice a week for 8 consecutive weeks. Diagnostic UMMC therapy with PL at 8, 18, and 26 cycles, but not 36 cycles, dramatically prevented myocardial fibrosis, improved heart functions, and increased angiogenesis, accompanied by increased levels of PI3K, Akt, and eNOS proteins in the DCM model of rats. In cultured endothelial cells, low-intensity UMMC treatment (PL = 3 cycles, sound pressure level = 50%, mechanical index = 0.82) increased cell viability and activated PI3K-Akt-eNOS signaling. The combination of diagnostic ultrasound with microbubble destruction dose-dependently promoted angiogenesis, thus improving heart function through PI3K-Akt-eNOS signaling in diabetes. Accordingly, diagnostic UMMC therapy should be considered to protect the heart in patients with diabetes.

We have previously reported that the long-term exposure of Isocarbophos, a kind of organophosphorus compounds, induces vascular dementia (VD) in rats. Studies have also shown that organophosphorus compounds have adverse effects on offsprings. Vitamin B6 is a coenzyme mainly involved in the regulation of metabolism and has been demonstrated to ameliorate VD. Sphingosine-1-phosphate (S1P), a biologically active lipid, plays a vital role in the cardiovascular system. However, whether S1P is involved in the therapeutic effects of Vitamin B6 on posterior cerebral artery injury has yet to be further answered. In the present study, we aimed to explore the potential influence of Vitamin B6 on Isocarbophos-induced posterior cerebral artery injury in offspring rats and the role of the S1P receptor in this process. We found that Vitamin B6 significantly improves the vasoconstriction function of the posterior cerebral artery in rats induced by Isocarbophos by the blood gas analysis and endothelium-dependent relaxation function assay. We further demonstrated that Vitamin B6 alleviates the Isocarbophos-induced elevation of ICAM-1, VCAM-1, IL-1, and IL-6 by using the enzyme-linked immunosorbent assay kits. By performing immunofluorescence and the western blot assay, we revealed that Vitamin B6 prevents the down-regulation of S1P in posterior cerebral artery injury. It is worth noting that Fingolimod, the S1P inhibitor, significantly inhibits the Vitamin B6-induced up-regulation of S1P in posterior cerebral artery injury. Collectively, our data indicate that Vitamin B6 may be a novel drug for the treatment of posterior cerebral artery injury and that S1P may be a drug target for its treatment.

Endothelial dysfunction is the pathological basis of atherosclerosis. Incomplete understanding of endothelial dysfunction etiology has impeded drug development for this devastating disease despite the currently available therapies. Floralozone, an aroma flavor, specifically exists in rabbit ear grass. Recently, floralozone has been demonstrated to inhibit atherosclerosis, but the underlying mechanisms are undefined. The present study was undertaken to explore whether floralozone pharmacologically targets endothelial dysfunction and therefore exerts therapeutic effects on atherosclerosis. The Na+/H+ exchanger 1 (NHE1), a channel protein, plays a vital role in atherosclerosis. Whether NHE1 is involved in the therapeutic effects of floralozone on endothelial dysfunction has yet to be further answered. By performing oil red staining and hematoxylin-eosin staining, vascular functional study, and oxidative stress monitoring, we found that floralozone not only reduced the size of carotid atherosclerotic plaque but also prevented endothelial dysfunction in atherosclerotic rats. NHE1 expression was upregulated in the inner membrane of carotid arteries and H2O2-induced primary rat aortic endothelial cells. Inspiringly, floralozone prevented the upregulation of NHE1 in vivo and in vitro. Notably, the administration of NHE1 activator LiCl significantly weakened the protective effect of floralozone on endothelial dysfunction in vivo and in vitro. Our study demonstrated that floralozone exerted its protective effect on endothelial dysfunction in atherosclerosis by ameliorating NHE1. NHE1 maybe a drug target for the treatment of atherosclerosis, and floralozone may be an effective drug to meet the urgent needs of atherosclerosis patients by dampening NHE1.

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.

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.

Diabetic cardiomyopathy (DCM), a cardiovascular complication of patients with diabetes, is a special cardiomyopathy that is independent of coronary heart disease, hypertension, and valvular disease. Citronellal (CT) is a monoterpene compound generated by the secondary metabolism of plants. In this work, the therapeutic effect and mechanism of CT in DCM were investigated. Experimental diabetic rat models were constructed through a high-fat and high-carbohydrate diet combined with low-dosage streptozotocin (STZ) treatment. CT was intragastrically administered at the dosage of 150 mg/kg/day. The cardiac functions of the rats were evaluated via cardiac Doppler ultrasound. Changes in myocardial structure were analyzed through histopathology. Changes in the representative indices of oxidative stress, namely, superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were detected on the basis of a biochemical test. Related protein levels were assayed via immunofluorescence and Western blot analyses. The DCM rats in the nontreatment group experienced diastolic and systolic dysfunctions, associated with myocardial hypertrophy, fibrosis, and cardiomyocyte apoptosis. Moreover, this condition was concurrent with metabolic disorders, the degradation of SOD activity in myocardial tissues, the increase in MDA content, the abnormal activation of sodium–hydrogen exchanger 1 (NHE1), and the aggravation of cell apoptosis (Bax levels were elevated, whereas Bcl-2 levels decreased). Myocardial hypertrophy, fibrosis, oxidative stress, and cell apoptosis were obviously inhibited after treatment with CT (150 mg/kg/day). The abnormal activation of NHE1 was recovered under the action of CT. Our study results showed that CT might play a protective role in the treatment of DCM by repressing the abnormal activation of NHE1.

Vascular dementia (VD) is the second largest type of dementia after Alzheimer's disease. At present, the pathogenesis is complex and there is no effective treatment. Floralozone has been shown to reduce atherosclerosis in rats caused by a high-fat diet. However, whether it plays a role in VD remains elusive. In the present study, the protective activities and relevant mechanisms of Floralozone were evaluated in rats with cognitive impairment, which were induced by bilateral occlusion of the common carotid arteries (BCCAO) in rats. Cognitive function, pathological changes and oxidative stress condition in the brains of VD rats were assessed using Neurobehavioral tests, Morris water maze tests, hematoxylin-eosin staining, Neu N staining, TUNEL staining, Golgi staining, Western blot assay and antioxidant assays (MDA, SOD, GSH), respectively. The results indicated that VD model was established successfully and BCCAO caused a decline in spatial learning and memory and hippocampal histopathological abnormalities of rats. Floralozone (50, 100, 150 mg/kg) dose-dependently alleviated the pathological changes, decreased oxidative stress injury, which eventually reduced cognitive impairment in BCCAO rats. The same results were shown in further experiments with neurobehavioral tests. At the molecular biological level, Floralozone decreased the protein level of transient receptor potential melastatin-related 2 (TRPM2) in VD and normal rats, and increased the protein level of NR2B in hippocampus of N-methyl-D-aspartate receptor (NMDAR). Notably, Floralozone could markedly improved learning and memory function of BCCAO rats in Morris water maze (MWM) and improved neuronal cell loss, synaptic structural plasticity. In conclusion, Floralozone has therapeutic potential for VD, increased synaptic structural plasticity and alleviating neuronal cell apoptosis, which may be related to the TRPM2/NMDAR pathway.

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.

Cisplatin-induced acute kidney injury (AKI) is associated with high morbidity and mortality worldwide, but the underlying mechanisms are not fully understood. Downstream-of-kinase 3 (Dok3), a member of the Dok family of adaptor proteins plays a critical role in inflammatory response and immune regulation; however, the role of Dok3 in cisplatin-induced AKI remains unclear. This study explored the effect and potential molecular mechanisms of Dok3 in cisplatin-induced AKI using Dok3 knockout (Dok3−/−) and control mice (129S) with or without administration of a single intraperitoneal injection of cisplatin. Apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, lactate dehydrogenase (LDH) release, and Hoechst staining. Inflammatory factors were measured using ELISA kits. Protein and gene expression levels were measured by western blot analysis and real-time PCR, respectively. The results showed that Dok3 was expressed in renal tubular epithelial cells. Dok3 expression was decreased in kidneys of mice treated with cisplatin and cisplatin-treated HK2 cells. Dok3−/− mice showed lower creatinine levels and NGAL expression, and increased survival rates compared to 129S mice. Cisplatin-induced production of TNF-α and IL-6, and renal tubular cell apoptosis was attenuated in Dok3−/− mice. In vitro experiments demonstrated that HK2 cells overexpressing Dok3 exhibited exacerbated cisplatin-induced apoptosis and production of TNF-α and IL-6. These findings demonstrate that Dok3 regulates cisplatin-induced AKI by regulating apoptosis and inflammation.

Experiments on falling film flow with a 60 wt% [EMIm]Ac (1-ethyl-3-methylimidazolium acetate) aqueous solution on cooled/heated horizontal tubes were conducted using an infrared thermal imaging camera to investigate the effect of Marangoni flow on the flow pattern and film width. The thermal stability of the [EMIm]Ac ionic liquid and the dependence of viscosity and surface tension on the temperature were presented. The physics of film flows with the Marangoni effect on horizontal tubes was analyzed. It is evidenced that the Marangoni effect exists on horizontal tubes and has significant influence on the falling film flow pattern and film width. When the film was heated, the film contracted and exhibited a sheet flow pattern, whereas a columnar pattern was observed under isothermal conditions. When the film was cooled, the film expanded and the columnar flow pattern was retained but with an increase in number of columns. Compared to the pure water, the average spreading film width with the 60 wt% [EMIm]Ac aqueous solution was narrower by approximately 20.1% and 9.8% at a liquid flow rate of 0.2473 kg m−1 s−1 as the film was cooled and heated, respectively.

Citronellal (CT) is an acyclic monoterpene aldehyde isolated from lemon citronella, which could ameliorate vascular endothelial dysfunction in atherosclerosis in our previous study, however, whether CT can alleviate vascular endothelial dysfunction related with type 2 diabetes (T2DM) is still unknown. So, we investigated the role of CT in vascular dysfunction related to T2DM and the mechanism involved. T2DM rat model was induced by a single intraperitoneal injection of low-dose streptozotocin (STZ) (60 mg/kg) to rats fed with high-fat diet (HFD) (4 weeks). After treated with CT (150 mg/kg/d), both the thoracic aorta injury and micro-vascular pathological injury in T2DM rats ex vivo were alleviated, and the oxidative stress in T2DM rats treated with CT were attenuated, manifested as increased content of endothelial nitric oxide synthase (eNOS) and superoxide dismutase (SOD), and decreased content of malondialdehyde (MDA). Furthermore, CT (15 μg/L) increased the migration capacity of human umbilical vein endothelial cells (HUVECs) under high glucose circumstance (30 mM), and increased the endothelial-dependent relaxation in thoracic aorta isolated from T2DM rats in vitro. Finally, all of these effects of CT were blocked by fingolimod (FTY720), a sphingosine-1-phosphate receptor agonist, and the expression of sphingosine-1-phosphate receptor 1 (S1P1) was increased by CT. In conclusion, CT improved vascular function through S1P/S1P1 signaling pathway.

Aims: This study aimed to evaluate the effects and mechanisms of tertiary butylhydroquinone (TBHQ) on insulin resistance (IR) and diabetic liver steatosis. Methods: Male ApoE-/- mice were received streptozocin (STZ) injection and a high-sugar-high-fat diet to form type 2 diabetes mellitus (T2DM). Then, the mice were given TBHQ for six weeks. Body weight, fasting blood-glucose (FBG), postprandial blood glucose (PBG), insulin and oral glucose tolerance test (OGTT) were detected on all the mice. Hematoxylin-eosin staining and western-blot were performed to detect the morphological structure and the target proteins expression in liver tissues. In vitro, HepG2 cells were induced by HClO and insulin to develop IR. Western-blot was used to evaluate the related proteins expression. Hoechst staining was conducted to measure cell apoptosis. Results: Mice that received STZ injection and a high-sugar-high-fat diet developed T2DM. TBHQ reduced blood glucose level, improved glucose tolerance, alleviated liver steatosis in diabetic mice. Moreover, TBHQ significantly increased AMPKα2, GLUT4 and GSK3β expression, up-regulated PI3K and AKT phosphorylation level in diabetic mice liver. Notably, TBHQ down-regulated HClO and insulin-induced cell IR and inhibited cell apoptosis via AMPKα2/PI3K/AKT pathway. Conclusion: TBHQ alleviated IR and liver steatosis in T2DM mice and the mechanism may relate to AMPKα2/PI3K/AKT pathway.

Previous studies demonstrated that HIn this study, GYY4137 (a HOur results showed that GYY4137 normalized the SBP (P 0.0001), increased EDR (P 0.01), reduced oxidative stress (increased the content of SOD and reduced the content of MDA) of SHR. Meanwhile, GYY4137 could promote the proliferation (P 0.01) and migration (P 0.01) of HUVECs, increase the expression of endothelial NO synthase (eNOS) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) both in SHR and HUVECs treated with GYY4137. In addition to the above results, the PIP3/Akt signaling pathway was activated and the expression of caspase 3 was increased by GYY4137. However, all the above effects of GYY4137 were blocked by ZD6474 (a VEGFR2 inhibitor).GYY4137 had a hypotensive and vascular protect effect on PH. This effect might be mediated through upregulating the expression of VEGFR2, which subsequently alleviating oxidant-provoked vascular endothelial dysfunction, and promoting the proliferation and migration of endothelial cells in SHR.

Doxorubicin (DOX) is a very effective broad-spectrum anticancer drug, yet its clinical application is badly restricted due to its serious side effects. Citronellal (CT), a specialized metabolite of plants found in Cymbopogon spp., is proved to exhibit many beneficial properties. In the current study, we intended to investigate the effect of CT on DOX-induced hepatotoxicity in rats. Rats were treated with CT (200 mg/kg b.w./day orally), and given DOX (2.5 mg/kg b.w./week, intraperitoneally) to induce hepatotoxicity for six consecutive weeks. The results showed that CT administration could attenuate the DOX-induced pathological changes of liver tissues and ameliorated the inappropriate alteration of liver function biomarkers (serum glutamic aspartate aminotransferase, glutamic pyruvic transaminase, and albumin) in serum and oxidative stress parameters (malondialdehyde, superoxide dismutase, and reduced glutathione) in the liver. Moreover, CT mitigated the Bax/Bcl-2 ratio and caspase-3 expression to inhibit cell apoptosis. Further study indicated that CT therapy could enhance the protein levels of p-PI3K, p-Akt, and CD31 in the liver. These results demonstrate that CT can ameliorate DOX-induced hepatotoxicity in rats mediated by antioxidative stress, antiapoptosis, and proangiogenesis.

Background Pulmonary arterial hypertension (PAH) is characterized by the apoptosis resistance and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Its pathogenesis has not been revealed. Here, we carried out experiments to investigate the functions of miR-140-5p and tumor necrosis factor-α (TNF-α). Methods We selected GSE703 from Gene Expression Omnibus (GEO) Database to conduct microarray analysis using R software and Gene Set Enrichment Analysis (GSEA). Combing bioinformatics results, the upregulation of miR-140-5p inhibited PAH progression through targeting TNF-α. RNA expression was measured by quantitative real-time polymerase chain reaction (RT-qPCR) and protein level was measured by western blot analysis and enzyme-linked immunosorbent assays (ELISA). We conducted monocrotaline (MCT) injection to rats to form PAH animal models. The lung tissues were observed by hematoxylin-eosin (HE) staining and Sirius red-picric acid staining. Right ventricular systolic pressure (RVSP) and the ratio of right ventricle (RV)-to-left ventricle (LV) plus septum (S) weight (RV/[LV + S]) were measured in MCT-induced animal models. Overexpression of miR-140-5p and TNF-α were utilized to research the proliferation, migration, and phenotypic variation of hypoxia-mediated PASMCs. The binding between miR-140-5p and TNF-α 3'-untranslated region (3'-UTR) was confirmed via luciferase reporter assay. Results Downregulation of miR-140-5p and upregulation of TNF-α were observed in PAH rat model and hypoxia-mediated PASMCs. And we proved that overexpression of miR-140-5p could suppress the proliferation, migration, and phenotypic variation of PASMCs, therefore inhibiting PAH pathogenesis. Luciferase assay verified that miR-140-5p targeted TNF-α directly. A converse correlation was also shown between miR-140-5p and TNF-α in PASMCs. Conclusions miR-140-5p and TNF-α are important regulators in PAH pathology and may serve as a therapeutic target for PAH.

Our study explored the effects of lncRNA UCA1 on the proliferation and apoptosis in hypoxic human pulmonary artery smooth muscle cells (HPASMCs) and highlighted the endogenous relationship between UCA1, ING5, and hnRNP I in cell proliferation. Hypoxia-induced HPASMCs were used to simulate pulmonary arterial hypertension in vitro. Microarray assay was adopted to screen the dysregulated expressed lncRNAs in HPASMCs to find out the target gene of our study. And RT-qPCR was performed to detect the expression of lncRNA UCA1 under hypoxia and normoxia. After transfection, the relationship between UCA1 and cell proliferation in HPASMCs under hypoxia were determined by cell proliferation assay and relative expression of PCNA. Next, ELISA assays were conducted to measure the protein levels of PCNA and ING5. What's more, flow cytometry was employed to measure the apoptosis rate in differentially UCA1-expressed HPASMCs. RIP assays were conducted to further clarify the endogenous relationship between UCA1 and ING5 in hypoxic HPASMCs. Finally, the effects of ING5 to HPASMCs were detected after transfection of ING5 and UCA1 to figure out the role of ING5 in HPASMCs. Hypoxia was revealed to induce proliferation and inhibited apoptosis in HPASMCs. Besides, UCA1 was confirmed to be highly expressed under hypoxia compared with normoxia. UCA1 boosted cell proliferation under hypoxia in HPASMCs. However, the apoptosis was suppressed in the hypoxic HPASMCs transfected with pcDNA3.1-UCA1. Further, mechanism studies found that UCA1 competed with ING5 for hnRNP I, so that upregulating UCA1 inhibited the protein levels of ING5. And finally we found that ING5 restrained cell viability, but promoted cell apoptosis in hypoxic HPASMCs, which was reversed by UCA1 over-expression. In summary, our findings manifested that UCA1 promoted proliferation and restrained apoptosis by competing with ING5 for hnRNP I in HPASMCs induced by hypoxia, indicating their potential roles for the cure of hypoxic pulmonary hypertension.

// 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.

The ionic liquid (IL) 1-ethyl-3-methylimidazolium acetate ([EMIm]Ac) was investigated as a promising absorbent for absorption refrigeration. To improve the thermal conductivity of pure [EMIm]Ac, IL-based nanofluids (ionanofluids, INFs) were prepared by adding graphene nanoplatelets (GNPs). The thermal stability of the IL and INFs was analysed. The variations of the thermal conductivity, viscosity and specific heat capacity resulting from the addition of the GNPs were then measured over a wide range of temperatures and mass fractions. The measured data were fitted with appropriate equations and compared with the corresponding classical models. The results revealed that the IL and INFs were thermally stable over the measurement range. The thermal conductivity greatly increased with increasing mass fraction, while only slightly changed with increasing temperature. A maximum enhancement in thermal conductivity of 43.2% was observed at a temperature of 373.15 K for the INF with a mass fraction of 5%. The numerical results revealed that the dispersion of the GNPs in the pure IL effectively improved the local heat transfer coefficient by up to 28.6%.

Aim The aim of this study was to evaluate the antihypertensive effect of Xin Mai Jia (XMJ) and to explore the mechanism of its hypotensive effect. Methods A total of 50 spontaneously hypertensive rats (SHR) were randomised into five groups. A total of 30 Wistar-Kyoto rats were randomised into three groups, comprising the control group. All of the rats were administered medicine through a gastrogavage once a day for 8 weeks. The tail-cuff method was applied to their monitor blood pressure. After 8 weeks of treatment, serum NO, SOD activity, MDA level, ET, ALD, AngII, RE, and CGRP in the serum were detected in all of the rats. Pathological changes in the aorta were observed via haematoxylin-eosin (HE) and immunohistochemical staining. Vasodilation function was assessed by measuring acetylcholine-induced vessel relaxation in the rats’ organ chambers. The function of the mesenteric arteries was measured using DMT wire myography. Human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs) injury models were induced by hydrogen peroxide (H2O2). HASMCs and HUVECs were injured by H2O2 and then exposed to various drugs. HASMC and HUVEC migration was evaluated using the cell scratch test. The expression of the AT1 receptors (AT1R) in the HASMCs was detected via immunofluorescence (IFC) assay. Results After 8 weeks of treatment, XMJ reduced the systolic blood pressure of the SHR. XMJ significantly reduced the serum RE, AngII, ALD, and ET-1 levels and increased the content of CGRP and NO in the SHR, upregulated the SOD content, and downregulated MDA level of the SHR. XMJ improved pathological damage of the aorta to varying degrees, decreased the expression of AT1R in the SHR aortic vessels, and improved the mesenteric microvascular relaxation of the SHR. Cell experiments confirmed that XMJ inhibited the migration of the HUVECs and HASMCs induced by H2O2 and the expression of AT1R in the HASMCs. Conclusion XMJ had satisfactory hypotensive action on the SHR in this study. Its mechanism may be associated with inhibiting RAAS activity and improving RAAS function, inhibiting hypertensive-induced vascular diastolic dysfunction, and improving vascular endothelial function.

Atherosclerosis (AS) is a chronical pathological process of the arterial narrows due to the AS plaque formation. The aim of this study was to explore the therapeutic effect and the underlying mechanism of Floralozone on experimental atherosclerotic model rats. Experimental atherosclerotic model rats were induced by the right carotid artery balloon injury and intraperitoneal injection of vitamin D3 in rats after 4 weeks high-fat diet. The results exhibited that Floralozone could ameliorate vascular injury and vasorelaxation of descending aortas and increase the superoxide dismutase activity and the expression of sphingosine 1-phosphate (S1P) 1 and reduce the intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, interleukin (IL)-1, IL-6 level, and the malondialdehyde activity in experimental atherosclerotic rats. However, Fingolimod, an S1P1 inhibitor, could reverse these Floralozone effects in experimental atherosclerotic rats. Our results indicated that Floralozone could inhibit the atherosclerotic plaque formation and improves arterial stenosis and reduces endothelial dysfunction in experimental atherosclerotic rats, which might be involved with S1P1 enhancement.

Aims Previous studies demonstrated that H2S has an antihypertension effect on hypertension, but the mechanism involved is unclear until now. The aim of the study is to elucidate the effect of H2S on PH and the mechanism involved. Main methods In this study, GYY4137 (a H2S donor) were administered to spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) by intraperitoneally injection daily for consecutive 14 days. Systolic blood pressure (SBP), endothelial-dependent relaxation (EDR), plasma malondialdehyde (MDA), superoxide dismutase (SOD), and H2S levels were measured. Human umbilical vein endothelial cells (HUVECs) were also used to elucidate the mechanism involved in the protect effect of H2S on the injured vessels. Key findings Our results showed that GYY4137 normalized the SBP (P Significance GYY4137 had a hypotensive and vascular protect effect on PH. This effect might be mediated through upregulating the expression of VEGFR2, which subsequently alleviating oxidant-provoked vascular endothelial dysfunction, and promoting the proliferation and migration of endothelial cells in SHR.

Supplemental Digital Content is available in the text., Background: GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase uncoupling in endothelial dysfunction. MicroRNAs (miRs) are a class of regulatory RNAs that negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation. Methods: Endothelial function was assessed by measuring acetylcholine-induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by quantitative reverse transcription polymerase chain reaction and fluorescence in situ hybridization. Results: We first demonstrated that GCH1 mRNA is a target of miR-133a. In endothelial cells, miR-133a was robustly induced by cytokines/oxidants and inhibited by lovastatin. Furthermore, lovastatin upregulated GCH1 and tetrahydrobiopterin, and recoupled endothelial nitric oxide synthase in stressed endothelial cells. These actions of lovastatin were abolished by enforced miR-133a expression and were mirrored by a miR-133a antagomir. In mice, hyperlipidemia- or hyperglycemia-induced ectopic miR-133a expression in the vascular endothelium, reduced GCH1 protein and tetrahydrobiopterin levels, and impaired endothelial function, which were reversed by lovastatin or miR-133a antagomir. These beneficial effects of lovastatin in mice were abrogated by in vivo miR-133a overexpression or GCH1 knockdown. In rats, multiple cardiovascular risk factors including hyperglycemia, dyslipidemia, and hyperhomocysteinemia resulted in increased miR-133a vascular expression, reduced GCH1 expression, uncoupled endothelial nitric oxide synthase function, and induced endothelial dysfunction, which were prevented by lovastatin. Conclusions: Statin inhibits aberrant miR-133a expression in the vascular endothelium to prevent endothelial dysfunction by targeting GCH1. Therefore, miR-133a represents an important therapeutic target for preventing cardiovascular diseases.

Backgrounds and aims: Increased arterial stiffness may increase cardiovascular morbidity and mortality. Angiotensin II type 1 receptor blockers (ARBs) are potentially useful in controlling ...

Berberine has several preventive effects on cardiovascular diseases. Increased expression of miR-29b has been reported to attenuate cardiac remodeling after myocardial infarction (MI). We hypothesized that berberine via an miR-29b-dependent mechanism promotes angiogenesis and improves heart functions in mice after MI.The MI model was established in mice by ligation of left anterior descending coronary artery. The expression of miR-29b was examined by RT-qPCR. Angiogenesis was assessed by immunohistochemistry.Berberine increased miR-29b expression and promoted cell proliferations and migrations in cultured endothelial cells, which were abolished by miR-29b antagomir or AMP-activated protein kinase inhibitor compound C. In mice following MI, administration of berberine significantly increased miR-29b expressional level, promoted angiogenesis, reduced infarct size, and improved heart functions after 14 postoperative days. Importantly, these in vivo effects of berberine were ablated by antagonism of miR-29b.Berberine via upregulation of miR-29b promotes ischemia-induced angiogenesis and improves heart functions.

Astragalus polysaccharides (APS) have been shown to possess a variety of biological activities including anti-oxidant and anti-inflammation functions in a number of diseases. However, their function in pulmonary arterial hypertension (PAH) is still unknown. Rats received APS (200[Formula: see text]mg/kg once two days) for 2 weeks after being injected with monocrotaline (MCT; 60[Formula: see text]mg/kg). The pulmonary hemodynamic index, right ventricular hypertrophy, and lung morphological features of the rat models were examined, as well as the NO/eNOS ratio of wet lung and dry lung weight and MPO. A qRT-PCR and p-I[Formula: see text]B was used to assess IL-1[Formula: see text], IL-6 and TNF-[Formula: see text] and WB was used to detect the total I[Formula: see text]B. Based on these measurements, it was found that APS reversed the MCT-induced increase in mean pulmonary arterial pressure (mPAP) (from 32.731[Formula: see text]mmHg to 26.707[Formula: see text]mmHg), decreased pulmonary vascular resistance (PVR) (from 289.021[Formula: see text]mmHg[Formula: see text][Formula: see text] min/L to 246.351[Formula: see text]mmHg[Formula: see text][Formula: see text][Formula: see text]min/L), and reduced right ventricular hypertrophy (from 289.021[Formula: see text]mmHg[Formula: see text][Formula: see text][Formula: see text]min/L to 246.351 mmHg[Formula: see text][Formula: see text][Formula: see text]min/L) ([Formula: see text]0.05). In terms of pulmonary artery remodeling, the WT% and WA% decreased with the addition of APS. In addition, it was found that APS promoted the synthesis of eNOS and the secretion of NO, promoting vasodilation and APS decreased the MCT-induced elevation of MPO, IL-1[Formula: see text], IL-6 and TNF-[Formula: see text], reducing inflammation. Furthermore, APS was able to inhibit the activation of pho-I[Formula: see text]B[Formula: see text]. In couclusion, APS ameliorates MCT-induced pulmonary artery hypertension by inhibiting pulmonary arterial remodeling partially via eNOS/NO and NF-[Formula: see text]B signaling pathways.

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.

The aim of the present study was to evaluate the protective effect of the ultrafiltration extract of Xin Mai Jia (XMJ) on a human umbilical vein endothelial cell (HUVEC) injury model induced by hydrogen peroxide (H2O2), by providing experimental data to investigate the mechanism and efficacy underlying the therapeutic effects on atherosclerosis. HUVECs were first injured by H2O2 and then varying final concentrations of the Chinese herb extract were added. Effects of the XMJ extract on morphology, activity, monolayer permeability, biochemical indicators, cytokines, endothelial nitric oxide synthase (eNOS) protein content and eNOS gene expression in the HUVECs were analyzed. H2O2 significantly promoted HUVEC injury. The XMJ ultrafiltration extract significantly improved the morphological changes in the injured HUVECs. In addition, XMJ treatment increased cell activity and decreased monolayer permeability. The expression levels of intracellular adhesion molecule-1, vascular adhesion molecule-1, interleukin-1 and -6 and nuclear factor-κB decreased, while the expression levels of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 increased with XMJ administration. Increased levels of nitric oxide (NO), eNOS protein and eNOS gene expression were also observed. Therefore, the XMJ ultrafiltration extract exhibits marked anti-inflammatory effects and antioxidant abilities. These properties significantly inhibited the H2O2-induced injury of HUVECs, which may be associated with the NO-cyclic guanosine monophosphate signaling pathway.

We examined the protective effects of ultrafiltered XinMaiJia (XMJ) extract in a hydrogen peroxide (H2O2)-induced injury model in human umbilical vein endothelial cells (HUVECs) and determined the corresponding changes in the Na(+)-H(+) exchanger (NHE1) protein content and NHE1 gene expression. H2O2-induced HUVECs were treated with different concentrations of XMJ extract and the corresponding changes in morphology, activity, membrane permeability, biochemical indicators, cytokine concentration, NHE1 protein content, and NHE1 gene expression were determined. H2O2 significantly promoted HUVEC injury, whereas ultrafiltered XMJ extract significantly improved the morphological changes in injured HUVECs, increased their activity, and decreased NHE1 gene and protein expression, as well as limited the decrease in membrane permeability and expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, interleukin (IL)-1, IL-6, and nuclear factor-kB. Ultrafiltered XMJ extract inhibited H2O2-induced HUVEC injury by inhibiting NHE1 activity.

The ionic liquid of 1-Ethyl-3-methylimidazolium acetate ([EMIm]Ac) was investigated as a promising absorbent for absorption refrigeration. Water and graphene nanoplatelets (GNP) were added to the pure [EMIm]Ac ionic liquid to lower its viscosity and improve its thermal conductivity, respectively. The thermophysical properties (density, viscosity, specific heat capacity, thermal conductivity and surface tension) of [EMIm]Ac-water binary and GNP-[EMIm]Ac/water ternary mixtures were investigated. The measured data were fitted with appropriate equations. Comparisons of the thermophysical properties between the ternary/binary mixtures and pure ionic liquid were conducted. Compared to the pure [EMIm]Ac ionic liquid, the viscosity of the GNP-[EMIm]Ac/water ternary system was reduced by up to 94.99% for the 0.05% mass fraction of GNP and a temperature of 282.15 K, and the maximum increment in thermal conductivity was 114.61% for the 1% mass fraction of GNP and a temperature of 353.15 K.

An efficient parallel-flow evaporator has been applied to cryogenic equipment in recent years. The experiment studied the four different construction forms of parallel-flow evaporator in different conditions, the distribution of liquid flux in tubes, and observed the flow patterns. The following results are obtained: the uniformity of the liquid flux was improved a little and sometimes worsened through increasing the inner diameter to regulate the liquid distribution in the branch pipe; the inlet tube should be arranged in the middle of the header tube rather than sides of it, which is more beneficial to the even distribution of the liquid flux in the branch pipe.

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.

Vascular dementia, being the most severe form of vascular cognitive impairment (VCI), is caused by cerebrovascular disease. Whether organophosphorus causes VCI remains unknown. Isocarbophos (0.5 mg/kg per 2 days) was intragastrically administrated to rats for 16 weeks. The structure and function of cerebral arteries were assayed. The learning and memory were evaluated by serial tests of step‐down, step‐through and morris water maze. Long‐term administration of isocarbophos reduced the hippocampal acetylcholinesterase (AChE) activity and acetylcholine (ACh) content but did not alter the plasma AChE activity, and significantly damaged the functions of learning and memory. Moreover, isocarbophos remarkably induced endothelial dysfunction in the middle cerebral artery and the expressions of ICAM‐1 and VCAM‐1 in the posterior cerebral artery. Morphological analysis by light microscopy and electron microscopy indicated disruptions of the hippocampus and vascular wall in the cerebral arteries from isocarbophos‐treated rats. Treatment of isocarbophos injured primary neuronal and astroglial cells isolated from rats. Correlation analysis demonstrated that there was a high correlation between vascular function of cerebral artery and hippocampal AChE activity or ACh content in rats. In conclusion, chronic administration of isocarbophos induces impairments of memory and learning, which is possibly related to cerebral vascular dysfunction.

The aim of this study was to investigate the protective effects of Xin Mai Jia (XMJ) on atherosclerosis (AS) in rabbits and to explore the underlying mechanisms in order to provide experimental evidence for the clinical application of XMJ. An intraperitoneal injection of vitamin D3, combined with a high-fat diet and sacculus injury, was utilized to establish the AS rabbit model. Following the oral administration of lovastatin, Zhibituo and different dosages of XMJ, respectively, blood was drawn from each rabbit for the detection of blood rheological indicators, such as serum lipids. The pathological changes in the right common carotid artery were observed. Vascular function experiments and the expression detection of common carotid artery-related proteins by immunohistochemistry were conducted. XMJ was observed to decrease the blood lipid levels of the AS rabbits; increase the concentration of high-density lipoprotein and apolipoprotein A; decrease blood viscosity, erythrocyte sedimentation rate and hematocrit; elevate the levels of endothelial nitric oxide synthase (eNOS) and Na+/H+ exchanger 1 in vascular tissues and decrease the levels of angiotensin II receptor, type 1 (AT-1) and endothelin-1 (ET-1). In conclusion, XMJ was shown to lower the blood lipid levels of the experimental AS rabbits, improve the abnormal changes in hemorheology, increase the eNOS content in the vascular tissue, decrease the AT-1 and ET-1 levels and increase the endothelium-dependent vasodilation reaction. XMJ therefore has an anti-AS effect.

The aim of the present study was to explore whether an ultra-filtration extract from Xin Mai Jia (XMJ), a Chinese medicinal formulation, has a protective effect on human aortic smooth muscle cell (HASMC) injury models induced by hydrogen peroxide (H2O2), and to consider the mechanism and efficacy of the therapeutic action of XMJ on atherosclerosis. HASMCs were injured by H2O2 and then exposed to various concentrations of XMJ. The morphological changes, growth, proliferation, migration and cytokine release of HASMCs were detected using 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT), an enzyme-linked immunosorbent assay and a scratch adhesion test. H2O2 significantly promoted the proliferation of HASMCs. The ultra-filtration extract from XMJ was observed to significantly attenuate the morphological changes of injured HASMCs, reduce the expression levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), interleukin (IL)-1, IL-6 and nuclear factor (NF)-κB, and increase the expression levels of matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP). XMJ has clear anti-inflammatory and antioxidant effects, and significantly inhibits the proliferation and migration of HASMCs.

To explore the proliferation and differentiation-inducing effects of aminosteroid H42648 on K562 leukemia cells.The effects of H42648 on K562 cell proliferation were determined by cell count, colony count and MTT assay, and the differentiation by morphology, benzidine stain and flow cytometry.The growth of K562 cells was inhibited after the treatment with H42648 for 5 days. The inhibition rates for K562 cells in MTT assay were (26.90+/-3.18)% and (43.26+/-2.54)% after the treatment by 10(-8)mol/L and 10(-6)mol/L H42648. The inhibitions for K562 cells in colony culture assay were (22.21+/-9.20)% and (48.71+/-8.24)% at 10(-8)mol/L and 10(-6)mol/L H42648, respectively. H42648 also induced K562 cells toward erythroid differentiation. It was verified by benzidine stain that the OD value at 10(-8)mol/L H42648 was increased by (153+/-17.65)% compared with the control, and at 10(-6)mol/L H42648 the OD value was increased by (250+/-4.60)% compared with the control. The morphology showed the differentiation tendency of K562 cells after the treatment. Data from flow cytometry showed that after the treatment with 10(-6)mol/L H42648 for 4 days, positive CD71 expression in differentiated K562 cells was 89.91%.H42648 can inhibit the proliferation of K562 cell lines and induce toward erythroid differentiation. H42648 may become a new lead for the differentiation-inducing therapy for leukemia.