Yan Wang

Xiamen University, Amoy, Fujian, China

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Publications (59)166.33 Total impact

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    ABSTRACT: SKF-96365 is a TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in different systems, which was recently reported to induce QTc prolongation on ECG by inhibiting TRPC channels. The present study investigates whether the blockade of cardiac repolarization currents would be involved in the increase of QTc interval. Cardiac repolarization currents were recorded in HEK 293 cells stably expressing human ether-à-go-go-related gene potassium (hERG or hKv11.1) channels, hKCNQ1/hKCNE1 channels (IKs) or hKir2.1 channels and cardiac action potentials were recorded in guinea pig ventricular myocytes using a whole-cell patch voltage-clamp technique. The potential effect of SKF-96365 on QT interval was evaluated in ex vivo guinea pig hearts. It was found that SKF-96365 inhibited hERG current in a concentration-dependent manner (IC50, 3.4μM). The hERG mutants S631A in the pore helix and F656V of the S6 region reduced the inhibitory sensitivity with IC50s of 27.4μM and 11.0μM, suggesting a channel pore blocker. In addition, this compound inhibited IKs and hKir2.1currents with IC50s of 10.8 and 8.7μM. SKF-96365 (10μM) significantly prolonged ventricular APD90 in guinea pig ventricular myocytes and QTc interval in ex vivo guinea pig hearts. These results indicate that the TRPC channel antagonist SKF-96365 exerts blocking effects on hERG, IKs, and hKir2.1 channels. Prolongation of ventricular APD and QT interval is related to the inhibition of multiple repolarization potassium currents, especially hERG channels.
    Full-text · Article · Dec 2015 · Pharmacological Research
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    ABSTRACT: Background: Several mammalian species display distinct biophysical properties between atrial and ventricular voltage-gated sodium current (INa); however, the potential mechanism behind this phenomenon is unknown. Objective: The present study was designed to investigate the potential molecular identities of the different INa in atrial and ventricular myocytes of rat hearts. Methods: Whole-cell patch voltage-clamp and molecular biology techniques were employed in the present study. Results: It was found that ventricular INa exhibited a slower inactivation, more positive potential of inactivation, and quicker recovery from inactivation compared to atrial INa. Real-time PCR and Western blot analysis revealed that mRNA and protein levels of NaVβ2 and NaVβ4 subunits, but not NaV1.5, were greater in ventricular myocytes than in atrial myocytes. INa in heterologous HEK 293 cell expression system with co-expressing hNaV1.5 and hNaVβ2/hNaVβ4 showed the similar biophysical properties to ventricular INa. Greater protein expression of NaVβ2 and NaVβ4 subunits was also observed in human ventricles. Interestingly, pharmacological study revealed that the anti-arrhythmic drug dronedarone (10 μM) inhibited atrial INa more (by 73%) than ventricular INa (by 42%), and shifted its inactivation to more negative voltages (-4.6 mV) compared to ventricular INa. CONCLUSION: Our results demonstrate the novel information that the distinctive biophysical properties of INa in atrial and ventricular myocytes can be attributed to inhomogeneous expression of NaVβ2 and NaVβ4 subunits, and that atrial INa is more sensitive to inhibition by dronedarone.
    No preview · Article · Nov 2015 · Heart rhythm: the official journal of the Heart Rhythm Society
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    ABSTRACT: Cardiac c-kit(+) progenitor cells are important for maintaining cardiac homeostasis and can potentially contribute to myocardial repair. However, cellular physiology of human cardiac c-kit(+) progenitor cells is not well understood. The present study investigates the functional store-operated Ca(2+) entry (SOCE) channels and the potential role in regulating cell cycling and migration using confocal microscopy, RT-PCR, Western blot, co-immunoprecipitation, cell proliferation and migration assays. We found that SOCE channels mediated Ca(2+) influx, and TRPC1, STIM1 and Orai1 were involved in formation of SOCE channels in human cardiac c-kit(+) progenitor cells. Silencing TRPC1, STIM1, or Orai1 with the corresponding siRNA significantly reduced the Ca(2+) signaling through SOCE channels, decreased cell proliferation and migration, and reduced expression of cyclin D1, cyclin E, and/or p-Akt. Our results demonstrate the novel information that Ca(2+) signaling through SOCE channels regulates cell cycling and migration via activating cyclin D1, cyclin E and/or p-Akt in human cardiac c-kit(+) cells.
    Full-text · Article · Oct 2015 · AJP Heart and Circulatory Physiology
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    ABSTRACT: Our previous study demonstrated that a large-conductance Ca2+-activated K+ current (BKCa), a voltage-gated TTX-sensitive sodium current (INa.TTX), and an inward rectifier K+ current (IKir) were heterogeneously present in most of human cardiac c-kit+ progenitor cells. The present study was designed to investigate the effects of these ion channels on cell cycling progression and migration of human cardiac c-kit+ progenitor cells with approaches of cell proliferation and mobility assays, siRNA, RT-PCR, Western blots, flow cytometry analysis, etc. It was found that inhibition of BKCa with paxilline, but not INa.TTX with tetrodotoxin, decreased both cell proliferation and migration. Inhibition of IKir with Ba2+ had no effect on cell proliferation, while enhanced cell mobility. Silencing KCa.1.1 reduced cell proliferation by accumulating the cells at G0/G1 phase and decreased cell mobility. Interestingly, silencing Kir2.1 increased the cell migration without affecting cell cycling progression. These results demonstrate the novel information that blockade or silence of BKCa channels, but not INa.TTX channels, decreases cell cycling progression and mobility, whereas inhibition of Kir2.1 channels increases cell mobility without affecting cell cycling progression in human cardiac c-kit+ progenitor cells.
    Full-text · Article · Sep 2015 · PLoS ONE
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    ABSTRACT: Several previous studies have indicated that diabetic have higher risk of suffering from Alzheimer's disease, which severely induced cognitive dysfunction. However, the underlying molecular mechanism and more details on the cognitive deficits induced by hyperglycemia have not been elucidated. Here in our present study, on the basis of Goto-Kakizaki (GK) rats and streptozotocin (STZ)-induced diabetic model, we detected the variation of dendritic spine density in hippocampus as well as the differential expression of some important signal transduction molecules that were of relevance in learning and memory function. We found that the magnitude of escape latency time was significantly increased in such diabetic animals; the phosphorylated Akt/CREB; SYP and BDNF as well as other downstream molecules in hippocampus neurons were also downregulated in both diabetic groups compared to the normal groups. Thus, all of these data indicate the obstacle of neuronal pathology and the Akt/CREB signaling pathway caused by hyperglycemia that may suppress cognitive behavior, which may provide a novel way for the prevention of diabetic encephalopathy and the cognitive deficits of Alzheimer's disease.
    No preview · Article · Sep 2015 · Neuropeptides
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    ABSTRACT: Both of gp91(phox) (an isoform of nicotinamide adenine dinucleotide phosphate reduced oxidases) and Src (a non-receptor protein tyrosine kinase) are abundantly expressed in the brain and play a prominent role in mediating ischemic alteration in neurons. The inhibitory strategy of them is believed to be the promising treatment of stroke. The present study was designed to investigate the effect of equol (0.625-2.5 mg•kg(-1), i.g. for 3 days), a predominant active metabolite of daidzein, on neuroprotection against cerebral ischemia/reperfusion injury in rats and the underlying mechanisms. We found that equol decreased the mortality, neurological deficit, brain histological damage, infarct volume, serum lactate dehydrogenase activity and malondialdehyde content in a dose-dependent manner in rats with 2-h middle cerebral artery occlusion, followed by 22-h reperfusion. Western blot analysis revealed that protein levels of gp91(phox) and phosphorylated Src-Tyr416 (p-Src) in ischemic cerebral cortex were increased in rats treated with vehicle, which was reversed in animals treated with equol. In rat pheochromocytoma cell line (PC12) with hypoxia/reoxygenation injury, silencing of gp91(phox) with specific siRNA did not affect the increase of p-Src level by hypoxia/reoxygenation injury and the inhibition of p-Src level by equol, while silencing of Src suppressed the upregulation of gp91(phox) by hypoxia/reoxygenation injury and enhanced the inhibitory effect of equol on gp91(phox) expression. These results demonstrate that equol confers a neuroprotection in rats via inhibiting the activation of Src and upregulation of gp91(phox) induced by focal cerebral ischemia/reperfusion, and Src may play a partial role in regulating gp91(phox) expression of neurons.
    Full-text · Article · Sep 2014 · Current Neurovascular Research
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    ABSTRACT: The present study was designed to investigate the effect of metformin on the impairment of intermediate-conductance and small-conductance Ca(2+)-activated potassium channels (IKCa and SKCa)-mediated relaxation in diabetes and the underlying mechanism. The endothelial vasodilatation function of mesenteric arteries was assessed with the use of wire myography. Expression levels of IKCa and SKCa and phosphorylated Thr(172) of AMP-activated protein kinase (AMPK) were measured by using Western blot technology. The channel activity was observed by using whole-cell patch voltage-clamp. Reactive oxygen species (ROS) were measured by using dihydroethidium and 2', 7'-dichlorofluorescein diacetate. Metformin restored the impairment of IKCa and SKCa-mediated vasodilatation in mesenteric arteries from streptozotocin-induced type 2 diabetic rats and that from normal rats incubated with advanced glycation end products (AGEs) for 3 h. In cultured human umbilical vein endothelial cells (HUVECs), 1 μM metformin reversed AGEs-induced increase of ROS and attenuated AGEs- and H2O2- induced downregulation of IKCa and SKCa after long term incubation (>24 h). While short-term treatment (3 h) with 1 μM metformin reversed the decrease of IKCa and SKCa currents induced by AGEs-incubation for 3 h without changing the channel expression and the AMPK activation in HUVECs. These results demonstrate for the first time that metformin restored IKCa and SKCa-mediated vasodilatation impaired by AGEs in rat mesenteric artery, in which the upregulation of channel activity and protein expression is likely involved.
    Full-text · Article · Aug 2014 · Molecular Pharmacology
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    ABSTRACT: The interpenetrating morphology formed by the electron donor and acceptor materials is critical for the performance of polymer:fullerene bulk heterojunction (BHJ) photovoltaic (PV) cells. In this work we carried out a systematic investigation on a high PV efficiency (>6%) BHJ system consisting of a newly developed 5,6-difluorobenzo[c] thiadiazole-based copolymer, PFBT-T20TT, and a fullerene derivative. Grazing incidence X-ray scattering measurements reveal the lower-ordered nature of the BHJ system as well as an intermixing morphology with intercalation of fullerene molecules between the PFBT-T20TT lamella. Steady-state and transient photo-induced absorption spectroscopy reveal ultrafast charge transfer (CT) at the PFBT-T20TT/fullerene interface, indicating that the CT process is no longer limited by exciton diffusion. Furthermore, we extracted the hole mobility based on the space limited current (SCLC) model and found that more efficient hole transport is achieved in the PFBT-T20TT:fullerene BHJ as compared to pure PFBT-T20TT, showing a different trend as compared to the previously reported highly crystalline polymer:fullerene blend with a similar intercalation manner. Our study correlates the fullerene intercalated polymer lamella morphology with device performance and provides a coherent model to interpret the high photovoltaic performance of some of the recently developed weakly-ordered BHJ systems based on conjugated polymers with branched side-chain.
    Full-text · Article · Jun 2014 · Scientific Reports
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    ABSTRACT: Cardiac progenitor cells play an important role in cardiac repair and regeneration; however, their cellular biology and electrophysiology are not understood. The present study characterizes the functional ion channels in human cardiac c-kit(+) progenitor cells using whole-cell patch voltage-clamp, RT-PCR, and Western blots. We found that several ionic currents were present in human cardiac c-kit(+) progenitor cells, including a large-conductance Ca(2+)-activated K(+) current (BKCa) in 86 % of cells, an inwardly rectifying K(+) current (I Kir) in 84 % of cells, a transient outward K(+) current (I to) in 47 % of cells, a voltage-gated tetrodotoxin-sensitive Na(+) current (I Na,TTX) in 61 % of cells. Molecular identities of these ionic currents were determined with RT-PCR and Western-blot analysis. KCa.1.1 (for BKCa), Kir2.1 (for I Kir), Kv4.2 and Kv4.3 (for I to), Nav1.3 and Nav1.6 (for I Na.TTX) were abundantly expressed in human cardiac c-kit(+) progenitor cells, which do not resemble cardiomyocytes at all. These results demonstrate for the first time that four types of ionic currents including BKCa, I to, I Kir, and I Na.TTX, are heterogeneously present in human cardiac c-kit(+) cells, which may be involved in regulating cellular physiology.
    Full-text · Article · May 2014 · Archiv für Kreislaufforschung
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    ABSTRACT: Cellular excitability is an important physiological factor in maintaining normal cardiac activity. The present study was designed to investigate the ionic mechanism underlying different excitability in atrial and ventricular myocytes of guinea pig heart using a whole-cell patch configuration. We found that excitability is lower in ventricular myocytes than that in atrial myocytes. Although the density of voltage-gated fast Na(+) current (INa) was lower in ventricular myocytes, it would not correlate to the lower excitability since its availability was greater than that in atrial myocytes around threshold potential. Classical inward rectifier K(+) current (IK1) was greater in ventricular myocytes than that in atrial myocytes, which might contribute in part to the lower excitability. In addition, the transient outward K(+) current with inward rectification (Itoir) elicited by depolarization was greater in ventricular myocytes than that in atrial myocytes and might contribute to the lower excitability. In ventricular myocytes, Ba(2+) at 5 µmol/L significantly inhibited Itoir, enhanced excitability, and shifted the threshold potential of INa activation to more negative, and the effect was independent of affecting INa. Our results demonstrate the novel information that in addition to classical IK1, Itoir plays a major role in determining the distinctive excitability in guinea pig atrial and ventricular myocytes and maintaining cardiac excitability. More effort is required to investigate whether increase of Itoir would be protective via reducing excitability.
    Full-text · Article · Feb 2014 · Sheng li xue bao: [Acta physiologica Sinica]
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    ABSTRACT: To investigate the changes in aorta morphology and Ca(2+)-activated K(+) (KCa) channel expression in the diabetic rats. A diabetic rat model was established by a single intraperitoneal injection of streptozotocin (30 mg/kg) after a modified high fat and glucose diet for 8 weeks. Pathological changes in the aorta were observed with HE staining, elastic fiber staining, Masson's trichrome staining and immunohistochemistry. Both the mRNA and protein levels of KCa channels in the aorta were measured by RT-PCR and Western blotting. Early atherosclerotic changes were observed in the aorta wall of the diabetic rats. The mRNA and protein levels of KCa1.1 channel α- and β-subunits were significantly decreased, while the expression of KCa3.1 channels was obviously enhanced in the middle layer of the aorta in the diabetic rats. KCa channel switching in smooth muscles may play a role in the development of atherosclerosis in diabetic rats.
    No preview · Article · Feb 2014 · Nan fang yi ke da xue xue bao = Journal of Southern Medical University
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    ABSTRACT: 5,6-Difluorobenzo[c][1,2,5]thiadiazole (FBT)-based conjugated donor–acceptor (D-A) polymers with straight and branched side chains were synthesized via Stille-coupling copolymerization to study their physical, optoelectronic and photovoltaic properties. The results show that both the nature of pendant side chains and the electron acceptor strength of the acceptor moiety of D–A polymers have critical impacts on material and photovoltaic properties. Better π–π stacking of polymer backbones enabled by appropriate substituents such as fluorine atoms and branched alkyl chains leads to a reasonably high power conversion efficiency of over 6% when the polymer is utilized as a donor material with PC71BM as an active layer in bulk heterojunction solar cells.
    No preview · Article · Dec 2013 · Macromolecules
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    ABSTRACT: Cholesterol is one of the major lipid components of the plasma membrane in mammalian cells and is involved in the regulation of a number of ion channels. The present study investigates how large conductance Ca(2+)-activated K(+) (BK) channels are regulated by membrane cholesterol in BK-HEK 293 cells expressing both the α-subunit hKCa1.1 and the auxiliary β1-subunit or in hKCa1.1-HEK 293 cells expressing only the α-subunit hKCa1.1 using approaches of electrophysiology, molecular biology, and immunocytochemistry. Membrane cholesterol was depleted in these cells with methyl-β-cyclodextrin (MβCD), and enriched with cholesterol-saturated MβCD (MβCD-cholesterol) or low-density lipoprotein (LDL). We found that BK current density was decreased by cholesterol enrichment in BK-HEK 293 cells, with a reduced expression of KCa1.1 protein, but not the β1-subunit protein. This effect was fully countered by the proteasome inhibitor lactacystin or the lysosome function inhibitor bafilomycin A1. Interestingly, in hKCa1.1-HEK 293 cells, the current density was not affected by cholesterol enrichment, but directly decreased by MβCD, suggesting that the down-regulation of BK channels by cholesterol depends on the auxiliary β1-subunit. The reduced KCa1.1 channel protein expression was also observed in cultured human coronary artery smooth muscle cells with cholesterol enrichment using MβCD-cholesterol or LDL. These results demonstrate the novel information that cholesterol down-regulates BK channels by reducing KCa1.1 protein expression via increasing the channel protein degradation, and the effect is dependent on the auxiliary β1-subunit.
    Full-text · Article · Nov 2013 · PLoS ONE
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    ABSTRACT: To investigate the role of oxidative stress in impaired intermediate-conductance Ca(2+)-activated potassium channels (IKCa)- and small-conductance Ca(2+)-activated potassium channels (SKCa)-mediated relaxation in diabetic resistance arteries. Rat diabetic model was induced by a high fat and high glucose diet and streptozotocin (STZ) injection. Endothelial function of mesenteric arteries was assessed with the use of wire myography. The expression levels of IKCa and SKCa in cultured human umbilical vein endothelial cells (HUVECs) treated with H2O2 and/or antioxidant alpha lipoic acid (ALA) were measured using Western blotting. IKCa- and SKCa-mediated vasodilatation in response to acetylcholine was impaired in the third-order mesenteric arterioles of diabetic rats. In cultured HUVECs, H2O2 significantly decreased the protein expression of IKCa and SKCa. ALA alleviated the impairment of both vasodilatation function of the mesenteric arterioles ex vivo and enhanced the expression of IKCa and SKCa challenged with H2O2 in cultured HUVECs. Our data demonstrated for the first time that impaired IKCa- and SKCa-mediated vasodilatation in diabetes was induced, at least in part, by oxidative stress via down-regulation of IKCa and SKCa channels.
    Full-text · Article · Jul 2013 · Nan fang yi ke da xue xue bao = Journal of Southern Medical University
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    ABSTRACT: The present study was designed to investigate the role of advanced glycation end products (AGEs) in intermediate-conductance and small-conductance Ca2+-activated potassium channels (KCa3.1 and KCa2.3)-mediated relaxation in rat resistance arteries and the underlying mechanism. The endothelial function of mesenteric arteries was assessed with the use of wire myography. Expression levels of KCa3.1 and KCa2.3 were measured by using Western blot. Reactive oxygen species (ROS) were measured by using dihydroethidium and 2′, 7′-dichlorofluorescein diacetate. KCa3.1 and KCa2.3-mediated vasodilatation responses to acetylcholine and NS309 (opener of KCa3.1 and KCa2.3) were impaired by incubation of the third-order mesenteric arteries from normal rats with AGEs (200 μg ml−1 for 3 h). In cultured human umbilical vein endothelial cells (HUVECs), AGEs increased ROS level and decreased the protein expression of KCa3.1 and KCa2.3. Antioxidant alpha lipoic acid restored the impairment in both vasodilatation function and expression of KCa3.1 and KCa2.3. H2O2 could mimic the effect of AGEs on the protein expression of KCa3.1 and KCa2.3 in cultured HUVECs. These results demonstrate for the first time that AGEs impaired KCa3.1 and KCa2.3-mediated vasodilatation in rat mesenteric arteries via downregulation of both KCa3.1 and KCa2.3, in which the enhanced oxidative stress was involved.
    Full-text · Article · Jul 2013 · Pflügers Archiv - European Journal of Physiology
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    ABSTRACT: Dinoflagellate cysts are useful for reconstructing upper water conditions. For adequate reconstructions detailed information is required about the relationship between modern day environmental conditions and the geographic distribution of cysts in sediments. This Atlas summarises the modern global distribution of 71 organic-walled dinoflagellate cyst species. The synthesis is based on the integration of literature sources together with data of 2405 globally distributed surface sediment samples that have been prepared with a comparable methodology and taxonomy. The distribution patterns of individual cyst species are being compared with environmental factors that are known to influence dinoflagellate growth, gamete production, encystment, excystment and preservation of their organic-walled cysts: surface water temperature, salinity, nitrate, phosphate, chlorophyll-a concentrations and bottom water oxygen concentrations. Graphs are provided for every species depicting the relationship between seasonal and annual variations of these parameters and the relative abundance of the species. Results have been compared with previously published records; an overview of the ecological significance as well as information about the seasonal production of each individual species is presented.The relationship between the cyst distribution and variation in the aforementioned environmental parameters was analysed by performing a canonical correspondence analysis. All tested variables showed a positive relationship on the 99% confidence level. Sea-surface temperature represents the parameter corresponding to the largest amount of variance within the dataset (40%) followed by nitrate, salinity, phosphate and bottom-water oxygen concentration, which correspond to 34%, 33%, 25% and 24% of the variance, respectively. Characterisations of selected environments as well as a discussion about how these factors could have influenced the final cyst yield in sediments are included.
    Full-text · Article · Apr 2013 · Review of Palaeobotany and Palynology
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    ABSTRACT: The proliferation of cardiac fibroblasts is implicated in the pathogenesis of myocardial remodeling and fibrosis. Intermediate-conductance calcium-activated K(+) channels (KCa3.1 channels) have important roles in cell proliferation. However, it is unknown whether angiotensin II (Ang II), a potent profibrotic molecule, would regulate KCa3.1 channels in cardiac fibroblasts and participate in cell proliferation. In the present study, we investigated whether KCa3.1 channels were regulated by Ang II, and how the channel activity mediated cell proliferation in cultured adult rat cardiac fibroblasts using electrophysiology and biochemical approaches. It was found that mRNA, protein, and current density of KCa3.1 channels were greatly enhanced in cultured cardiac fibroblasts treated with 1μM Ang II, and the effects were countered by the angiotensin type 1 receptor (AT1R) blocker losartan, the p38-MAPK inhibitor SB203580, the ERK1/2 inhibitor PD98059, and the PI3K/Akt inhibitor LY294002. Ang II stimulated cell proliferation and the effect was antagonized by the KCa3.1 blocker TRAM-34 and siRNA targeting KCa3.1. In addition, Ang II-induced increase of KCa3.1 expression was attenuated by transfection of activator protein-1 (AP-1) decoy oligodeoxynucleotides. These results demonstrate for the first time that Ang II stimulates cell proliferation mediated by upregulating KCa3.1 channels via interacting with the AT1R and activating AP-1 complex through ERK1/2, p38-MAPK and PI3K/Akt signaling pathways in cultured adult rat cardiac fibroblasts.
    Full-text · Article · Mar 2013 · Biochemical pharmacology
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    ABSTRACT: BiOBr photocatalyst was prepared by a facile hydrolysis method, and then characterized by X-ray diffraction, scanning electron microscopy, N2 sorption isotherms, and diffuse reflectance spectroscopy. The as-prepared BiOBr photocatalyst was found to be a tetragonal crystal structure, homogeneous particles of fine ferrite plates, surface area of 32.19 m2/g, and band gap of 2.92 eV. The photocatalytic property and mechanism of BiOBr were investigated by the degradation of methylene orange (MO) in aqueous solution under xenon lamp irradiation. The results indicated that the optimum amount of BiOBr powder was 0.8 g/L for MO degradation under xenon lamp irradiation, and its catalytic performance was as good as that of P25-TiO2. The mechanism study showed that photogenerated holes and •OH played important roles in photocatalytic degradation. The photocatalytic degradation results of humic acids, methylene blue, and MO in aqueous solution further verified the high catalytic activity and non-selectivity of BiOBr.
    No preview · Article · Mar 2013 · Journal of Solid State Chemistry
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    ABSTRACT: Diabetic patients have a signifiantly higher risk of developing all forms of dementia. Pentamethylquercetin (PMQ) has been proven to have potential as an anti-diabetic agent. Nevertheless, whether PMQ can improve diabetes-induced cognitive dysfunction has not been investigated. To address this, we evaluated the effectiveness and underlying mechanisms of PMQ for ameliorating diabetes-related cognitive dysfunction in vivo and in vitro. Our results showed that Goto-Kakizaki (GK) rats displayed impairment in their learning abilities and memory capabilities. Furthermore, GK rats reflected cognitive dysfunction in proportion to the intensity of insulin resistance index. In addition, dendritic spine density and the % cell viability significantly decreased in hippocampus neurons. High glucose conditions induced hippocampal neurons damage, inflcted dendritic spine dysontogenesis, and reduced Akt/cAMP response element-binding protein activation. Treatment with PMQ in GK rats significantly ameliorated cognitive deficits and neuronal damage and increased dendritic spine density, at least in part, by improving insulin resistance and metabolic disorders. Furthermore, PMQ significantly activated the Akt/cAMP response element-binding protein pathway and increased the expression of memory-related proteins in the downstream part of the Akt/cAMP response element-binding protein pathway, such as synaptophysin and glutamate receptor 1. In addition, PMQ inhibited high glucose-induced cellular toxicity. LY294002 appeared to partly inhibit PMQ-mediated protective effects in hippocampal neurons. The results suggest that insulin resistance could predominantly reduce Akt/cAMP response element-binding protein activation in the brain, which is associated with a higher risk of cognitive dysfunction. PMQ could provide a new potential option for the prevention of cognitive dysfunction in diabetes.
    No preview · Article · Dec 2012 · Journal of Alzheimer's disease: JAD
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    ABSTRACT: The mechanisms underlying the involvement of advanced glycation endproducts (AGEs) in diabetic atherosclerosis are not fully understood. The present study was designed to investigate whether intermediate-conductance Ca(2+)-activated K(+) channels (K(Ca)3.1 channels) are involved in migration and proliferation induced by AGEs in cultured rat vascular smooth muscle cells (VSMCs) using approaches of whole-cell patch voltage-clamp, cell proliferation and migration assay, and western blot analysis. It was found that the current density and protein level of K(Ca)3.1 channels were enhanced in cells incubated with AGE-BSA (bovine serum albumin), and the effects were reversed by co-incubation of AGE-BSA with anti-RAGE (anti-receptors of AGEs) antibody. The ERK1/2 inhibitors PD98059 and U0126, the P38-MAPK inhibitors SB203580 and SB202190, or the PI3K inhibitors LY294002 and wortmannin countered the K(Ca)3.1 channel expression by AGE-BSA. In addition, AGE-BAS increased cell migration and proliferation, and the effects were fully reversed with anti-RAGE antibody, the K(Ca)3.1 channel blocker TRAM-34, or K(Ca)3.1 small interfering RNA. These results demonstrate for the first time that AGEs-induced increase of migration and proliferation is related to the upregulation of K(Ca)3.1 channels in rat VMSCs, and the intracellular signals ERK1/2, P38-MAPK and PI3K are involved in the regulation of K(Ca)3.1 channel expression.Laboratory Investigation advance online publication, 19 November 2012; doi:10.1038/labinvest.2012.163.
    Full-text · Article · Nov 2012 · Laboratory Investigation

Publication Stats

660 Citations
166.33 Total Impact Points

Institutions

  • 2014-2015
    • Xiamen University
      Amoy, Fujian, China
  • 2013-2014
    • Nanyang Technological University
      • School of Chemical and Biomedical Engineering
      Tumasik, Singapore
  • 2008-2014
    • The University of Hong Kong
      • Department of Medicine
      Hong Kong, Hong Kong
    • Beijing Medical University
      • Department of Gastroenterology
      Peping, Beijing, China
  • 2007-2014
    • Xi'an Jiaotong University
      • • School of Medicine
      • • Department of Pharmacology
      Ch’ang-an, Shaanxi, China
  • 2010-2013
    • Shanghai Jiao Tong University
      Shanghai, Shanghai Shi, China
  • 2009-2013
    • Taiyuan University of Technology
      Yangkü, Shanxi Sheng, China
  • 2003-2013
    • Jinan University (Guangzhou, China)
      Shengcheng, Guangdong, China
  • 2011-2012
    • Huazhong University of Science and Technology
      • School of Basic Medicine
      Wu-han-shih, Hubei, China
    • Tongji Medical University
      • Department of Pharmacology
      Wu-han-shih, Hubei, China
  • 2009-2010
    • Jilin University
      • Department of Chemistry
      Yung-chi, Jilin Sheng, China
  • 2006-2008
    • Northeast Normal University
      • Department of Chemistry
      Hsin-ching, Jilin Sheng, China
  • 2003-2005
    • Fourth Military Medical University
      • Department of Pharmacology
      Xi’an, Liaoning, China