Search

BACKGROUND AND PURPOSE Endothelium-derived hyperpolarizing factor (EDHF) has been suggested as a therapeutic target for vascular protection against ischaemic brain injury. However, the molecular entity of EDHF and its action on neurons remains unclear. This study was undertaken to demonstrate whether the hydrogen sulfide (H2 S) acts as EDHF and exerts neuroprotective effect via large-conductance Ca2+ -activated K+ (BKCa /KCa 1.1) channels. EXPERIMENTAL APPROACH The whole-cell patch-clamp technology was used to record the changes of BKCa currents in rat neurons induced by EDHF. The cerebral ischaemia/reperfusion model of mice and oxygen-glucose deprivation/reoxygenation (OGD/R) model of neurons were used to explore the neuroprotection of EDHF by activating BKCa channels in these neurons. KEY RESULTS Increases of BKCa currents and membrane hyperpolarization in hippocampal neurons induced by EDHF could be markedly inhibited by BKCa channel inhibitor iberiotoxin or endothelial H2 S synthase inhibitor propargylglycine. The H2 S donor, NaHS-induced BKCa current and membrane hyperpolarization in neurons were also inhibited by iberiotoxin, suggesting that H2 S acts as EDHF and activates the neuronal BKCa channels. Besides, we found that the protective effect of endothelium-derived H2 S against mice cerebral ischaemia/reperfusion injury was disrupted by iberiotoxin. Importantly, the inhibitory effect of NaHS or BKCa channel opener on OGD/R-induced neuron injury and the increment of intracellular Ca2+ level could be inhibited by iberiotoxin but enhanced by co-application with L-type but not T-type calcium channel inhibitor. CONCLUSION AND IMPLICATIONS Endothelium-derived H2 S acts as EDHF and exerts neuroprotective effects via activating the BKCa channels and then inhibiting the T-type calcium channels in hippocampal neurons.

The effect of cystathionine-γ-lyase (CSE)-derived hydrogen sulfide (H2S) on the reactive proliferation of astrocytes and neural functional recovery over 30 d after acute cerebral ischemia and reperfusion (I/R) was determined by applying wild-type (WT) and CSE knockout (KO) mice. The changes of glial fibrillary acidic protein (GFAP) expression in hippocampal tissues was tested. Besides, we assessed the changes of mice spatial learning memory ability, neuronal damage, RhoA, Rho kinase 2 (ROCK2), and myelin basic protein (MBP) expressions in hippocampal tissues. The results revealed that cerebral I/R resulted in obvious increase of GFAP expression in hippocampal tissues. Besides, we found the neuronal damage, learning, and memory deficits of mice induced by cerebral I/R as well as revealed the upregulation of RhoA and ROCK2 expressions and reduced MBP expression in hipppcampal tissues of mice following cerebral I/R. Not surprisingly, the GFAP expression and cerebral injury as well as the upregulation of the RhoA/ROCK2 pathway were more remarkable in CSE KO mice, compared with those in WT mice over 30 d following acute cerebral I/R, which could be blocked by NaHS treatment, a donor of exogenous H2S. In addition, the ROCK inhibitor Fasudil also inhibited the reactive proliferation of astrocytes and ameliorated the recovery of neuronal function over 30 d after cerebral I/R. For the purpose of further confirmation of the role of H2S on the astrocytes proliferation following cerebral I/R, the immunofluorescence double staining: bromodeoxyuridine (BrdU) and GFAP was evaluated. There was a marked upregulation of BrdU-labeled cells coexpressed with GFAP in hippocampal tissues at 30 d after acute cerebral I/R; however, the increment of astrocytes proliferation could be ameliorated by both NaHS and Fasudil. These findings indicated that CSE-derived H2S could inhibit the reactive proliferation of astrocytes and promote the recovery of mice neural functional deficits induced by a cerebral I/R injury via inhibition of the RhoA/ROCK2 signal pathway.

SB-706375 is a selective receptor antagonist of human urotensin-II (hU-II), which can block the aorta contraction induced by hU-II in rats. The effect of SB-706375 on myocardial ischaemia–reperfusion (I/R) injury is unclear. The major objective of this study was to investigate whether SB-706375 has a protective effect on myocardial I/R injury in rats and explore its possible mechanisms. Isolated hearts of Adult Sprague–Dawley were perfused in a Langendorff apparatus, and haemodynamic parameters, lactate dehydrogenase (LDH), creatine phosphokinase-MB (CK-MB), cardiac troponin I (cTnI), RhoA, and the protein expressions of U-II receptor (UTR), receptor-interacting protein 3 (RIP3), Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) and Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) were assessed. We found that SB-706375 (1 × 10−6 and 1 × 10−5 mol/L) significantly inhibited the changes of haemodynamic parameters and reduced LDH and CK-MB activities and also cTnI level in the coronary effluents in the heart subjected to myocardial I/R injury. Further experiments studies showed that SB-706375 obviously prevented myocardial I/R increased RhoA activity and UTR, RIP3, ROCK1, and ROCK2 protein expressions. ROCK inhibition abolished the improving effect of SB-706375 on myocardial I/R-induced haemodynamic change in the isolated perfused rat heart. These findings suggested that SB-706375 provides cardio-protection against I/R injury in isolated rats by blocking UTR-RhoA/ROCK-RIP3 pathway.

A 23-month-old female child accidentally fell while inside a factory, and 2–5 fingers (Tamai IV area) of her right dominant hand were completely cut off by a high-speed cutting machine gear (Fig. 3.1a, b). The amputated fingers were refrigerated immediately after the injury.

3-Mercaptopyruvate sulfurtransferase (3-MST) is the major source of hydrogen sulfide (H2S) production in the brain and participates in many physiological and pathological processes. The present study was designed to investigate the role of 3-MST-derived H2S (3-MST/H2S) on oxygen-glucose deprivation/reoxygenation (OGD/R) injury in cerebrovascular endothelial cells (ECs). Using cerebrovascular specimens from patients with acute massive cerebral infarction (MCI), we found abnormal morphology of the endothelium and mitochondria, as well as decreases in H2S and 3-MST levels. In an OGD/R model of ECs, 3-mercaptopyruvate (3-MP) and l-aspartic acid (l-Asp) were used to stimulate or inhibit the production of 3-MST/H2S. The results showed that OGD/R induced significant decreases in H2S and 3-MST levels in both ECs and mitochondria, as well as increases in oxidative stress and mitochondrial energy imbalance. Cellular oxidative stress, destruction of mitochondrial ultrastructure, accumulation of mitochondrial reactive oxygen species (ROS), reduction of mitochondrial adenosine triphosphate (ATP) synthase activity and ATP production, and decreased mitochondrial membrane potential were all significantly ameliorated by 3-MP, whereas they were exacerbated by l-Asp pretreatment. Contrary to the effects of l-Asp, the increase in RhoA activity and expression of ROCK1 and ROCK2 induced by OGD/R were markedly inhibited by 3-MP pretreatment in subcellular fractions without mitochondria and mitochondrial fractions. In addition, 3-MST−/− rat ECs displayed greater oxidative stress than 3-MST+/+ rat ECs after OGD/R injury. These findings suggest that 3-MST/H2S protects ECs against OGD/R-induced injury, which may be related to preservation of mitochondrial function and inhibition of the RhoA/ROCK pathway.

The role of CSE-produced H2S on cerebrovascular relaxation and cerebral ischemia-reperfusion (I/R) injury was investigated using CSE knockout (CSE-/-) and wild-type (CSE+/+) mice. The relaxation of the cerebral basilar artery (BA) to CSE-produced H2S and its mechanism were detected. The results revealed that both NaHS, a donor of exogenous H2S, and ROCK inhibitor Y27632 could induce significant relaxation of the BA, but the relaxation of the BA to NaHS was significantly attenuated by Y27632. In addition, removal of endothelium could reduce the relaxation of the BA to Y27632; CSE knockout also significantly attenuated Y27632-induced BA relaxation with endothelium rather than without endothelium. By contrast, the contraction of the BA from CSE-/- mice to RhoA agonist LPA or U46619 was stronger than that from CSE+/+ mice. Furthermore, RhoA activity and ROCK protein expression remarkably increased in the BA vascular smooth muscle cells (VSMCs) from CSE-/- mouse, which were inhibited by NaHS pretreatment. These findings revealed that the CSE-produced H2S induced cerebrovascular relaxation is generated from endothelial cells and the mechanism of vascular relaxation may relate to inhibition of RhoA-ROCK pathway. We next sought to confirm the protective effect of CSE-produced H2S on cerebral I/R injury produced by middle cerebral artery occlusion and bilateral common carotid artery occlusion in mice. We investigated the changes of neurological deficit, cerebral infarct, brain water content, LDH decrease, MDA increase as well as impairment of learning and memory function. The results showed that the cerebral injury became more grievous in CSE-/-mice than that in CSE+/+mice, which could be remarkably alleviated by NaHS pretreatment.

Anfibatide (ANF) is a GPIb antagonist derived from the protein complex agglucetin. Previous studies have showed that it has protective effect on cerebral ischemia/reperfusion injury, the mechanism of which is still unclear, however. The present study was designed to investigate the protective effect of ANF on cerebral I/R injury in rats and the possible mechanisms. Focal cerebral ischemia was induced by 90 min of transient middle cerebral artery occlusion (MCAO). ANF (1, 2, 4 μg/kg) was achieved by intravenous injection after 120 min of MCAO followed by 1 h, 24 h ,48 h and 72 h reperfusion. Neurological deficit, infarct volume, histopathology, neuronal apoptosis, NeuN and the expression of TLR4, total and phosphorylated c-Jun NH2-terminal kinase (JNK/p-JNK), Bcl-2, Bax, caspase-3, NF-κB protein in rat brain, the levels of IL-1β, IL-6 and TNF-α in serum were evaluated 72 h after reperfusion. ANF could significantly decrease neurological score, reduce the infarct volumes, ameliorate the histopathological alteration, attenuate the neuronal apoptosis and increase the fluorescence density of NeuN in the rat brain. Furthermore, ANF could obviously decrease the expression of TLR4, p-JNK, caspase-3, NF-κB , relative ratio of Bax/Bcl-2 in brain and the levels of IL-1β, IL-6 and TNF-α in serum. The results indicate that ANF has protective effect against cerebral I/R injury in rats and the underlying mechanism may be associated with the suppression of apoptosis through inhibiting TLR4/JNK/caspase-3 signaling pathway.

Our previous studies have indicated that pretreatment with total flavones of Rhododendra flower (TFR) may protect against myocardial ischemic injuries in rats and mice. The cystathionine γ-lyase/hydrogen sulfide (CSE/H2S) pathway have been associated with several cardiovascular diseases, but the effect of TFR on the Rho-associated protein kinase (ROCK) and CSE/H2S signaling pathways remains unknown. In the present study, the protective effects of TFR as a ROCK inhibitor in a mice model of myocardial infarction induced by isoproterenol (ISO) were investigated, and the hearts from the wild type and CSE knockout (KO) mice were examined. It was identified that the CSE KO mice exhibited decreased levels of ST segment elevation following anoxia/reoxygenation damage, increased LDH and CK-MB levels, aggravated pathological damage, and increased ROCK1, ROCK2 and MLC1 protein levels. In the CSE KO mice, there were no marked changes of the above experimental results between the TFR group and the model group. These results suggested that TFR-based inhibition of the RhoA/ROCK signal pathway may be mediated by the CSE-H2S signalling pathway and may be a novel therapeutic target for myocardial ischemia injury.

Tanshinone IIA (Tan IIA) is a pharmacologically active substance extracted from the rhizome of Salvia miltiorrhiza Bunge (also known as the Chinese herb Danshen), and is widely used to treat atherosclerosis. The pregnane X receptor (PXR) is a nuclear receptor that is a key regulator of xenobiotic and endobiotic detoxification. Tan IIA is an efficacious PXR agonist that has a potential protective effect on endothelial injuries induced by xenobiotics and endobiotics via PXR activation. Previously numerous studies have demonstrated the possible effects of Tan IIA on human umbilical vein endothelial cells, but the further mechanism for its exerts the protective effect is not well established. To study the protective effects of Tan IIA against hydrogen peroxide (H₂O₂) in human umbilical vein endothelial cells (HUVECs), we pretreated cells with or without different concentrations of Tan IIA for 24 h, then exposed the cells to 400 μM H₂O₂ for another 3 h. Therefore, our data strongly suggests that Tan IIA may lead to increased regeneration of glutathione (GSH) from the glutathione disulfide (GSSG) produced during the GSH peroxidase-catalyzed decomposition of H₂O₂ in HUVECs, and the PXR plays a significant role in this process. Tan IIA may also exert protective effects against H₂O₂-induced apoptosis through the mitochondrial apoptosis pathway associated with the participation of PXR. Tan IIA protected HUVECs from inflammatory mediators triggered by H₂O₂ via PXR activation. In conclusion, Tan IIA protected HUVECs against H₂O₂-induced cell injury through PXR-dependent mechanisms.

Sufentanil has been used broadly in cardiac surgery, but the mechanisms by which it modulates coronary vascular tone after ischemia–reperfusion injury are largely unknown. Effects of sufentanil on coronary tone and on the relaxation of rat coronary arteries (CAs) in response to endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) relaxing agents in the presence of hypoxia–reoxygenation (H/R) was studied in an in vitro organ chamber setup. Sufentanil (10−7–10−4 mol/L) relaxed rat CA rings in endothelium-dependent and endothelium-independent manners. In endothelium-intact rings, preincubation of H/R-treated CAs with sufentanil (10−5 mol/L) significantly increased the acetylcholine response, but did not augment sodium nitroprusside-induced relaxation. Sufentanil-mediated potentiation of acetylcholine-induced relaxation was not affected by a nitric oxide synthase inhibitor or by intermediate- or small-conductance Ca2+-activated K+ channel blockers. However, potentiation was abolished by iberiotoxin (100 nmol/L), a selective inhibitor of large-conductance Ca2+-activated K+ channels, as well as Rp-cAMPS (30 μmol/L), a cyclic AMP-dependent protein kinase (PKA) inhibitor. Sufentanil induced endothelium-dependent and endothelium-independent relaxation and attenuated H/R-induced impairment of endothelium-dependent vasodilation in the rat CAs. The potentiating effect of sufentanil may involve activation of large-conductance Ca2+-activated K+ channels via cAMP-dependent mechanisms.

To degrade the adverse effects of biases in the direct inertial navigation system/global navigation satellite system integration, a novel robust partly strong tracking consider state-dependent Riccati equation filter (PSTCSDREF) algorithm is proposed. A nonlinear "consider" approach is utilized to incorporate statistics of biases into state estimation error covariance of the state-dependent Riccati equation filter (SDREF), and a new consider SDREF(CSDREF) is proposed. Then, the prediction covariance of the state is partly multiplied by a strong tracking factor, which does not include the bias covariance, to mitigate the adverse effects navigation performance of model uncertainties. Numerical simulation demonstrates that the proposed PSTCSDREF has a better navigation accuracy comparing with extended Kalman filter, SDREF, and CSDREF.

The role of CSE-produced H

Evidences from previous studies confirmed that intrathecal morphine preconditioning (ITMP) reduces the cardiac injury of ischemia-reperfusion (IR) via the central nervous system. However, the molecular mechanism is not fully understood. The breath of central nerve growth factor (NGF) during nociceptive transmission has been well documented, and little is known about the significance of NGF in myocardial injury of IR and intrathecal morphine-induced cardioprotection. To address these questions, we over-expressed or silenced NGF in the spinal cord by using intrathecal injection of lentivirus-NGF or shRNA respectively, accompanied by ITMP in the IR rat model. The levels of NGF and tropomyosin receptor kinase A (Trka) as well as transient receptor potential vanilloid 1 (TRPV1) in the T2-6 spinal cord were evaluated. The results showed that cardiac damage indicators induced by IR, including the increased infarct size, arrhythmia score and serum troponin levels were attenuated after ITMP. However, overexpression of spinal NGF significantly reversed these decreases, as well as reduced the expression and phosphorylation of TRPV1 that was elicited by ITMP. Conversely, silencing of spinal NGF enhanced ITMP-induced cardioprotective effects. Phosphorylation and expression of TRPV1 in the spinal cord were significantly decreased after regional NGF silencing. These findings suggested that the cardioprotective effects of ITMP may implement by mediating through spinal NGF expression, wherein it involves the nociceptor TRPV1. NGF may act as a potential therapeutic target in the development of new agents for the treatment of cardiac injury induced by IR.

Total flavones ofRhododendron simsiiPlanch flower (TFR) have a significant protective effect against cerebral ischemia-reperfusion injury. However, its mechanism is unclear. This study investigated the protection of TFR against cerebral ischemia-reperfusion injury via cystathionine-γ-lyase- (CSE-) produced H2S mechanism. CSE-/-mice and CSE-siRNA-transfected rat were used. Relaxation of cerebral basilar artery (CBA), H2S, and CSE mRNA were measured. TFR significantly inhibited cerebral ischemia-reperfusion-induced abnormal neurological symptom and cerebral infarct in the normal rats and the CSE+/+mice, but not in the CSE-/-mice, and the inhibition was markedly attenuated in CSE-siRNA-transfected rat; TFR elicited a significant vasorelaxation in rat CBA, and the relaxation was markedly attenuated by removal of endothelium or CSE-siRNA transfection or coapplication of NO synthase inhibitor L-NAME and PGI2synthase inhibitor Indo. CSE inhibitor PPG drastically inhibited TFR-evoked vasodilatation resistant to L-NAME and Indo in endothelium-intact rat CBA. TFR significantly increased CSE mRNA expression in rat CBA endothelial cells and H2S production in rat endothelium-intact CBA. The increase of H2S production resistant to L-NAME and Indo was abolished by PPG. Our data indicate that TFR has a protective effect against the cerebral ischemia-reperfusion injury via CSE-produced H2S and endothelial NO and/or PGI2to relax the cerebral artery.

Objectives Total flavones of Rhododendron simsii Planch flower (TFR) are an effective part extracted from the flower. The present study was designed to investigate the protective effect of TFR in isolated rat heart following global ischaemia-reperfusion and the possible underlying mechanisms. Methods Langendorff perfusion apparatus was used to perfuse isolated rat heart which was subjected to global ischaemia-reperfusion. The hemodynamic parameters were continuously monitored. Coronary flow as well as lactate dehydrogenase (LDH), creatine phosphokinase-MB (CK-MB) and cardiac troponin I (cTnI) in coronary effluents was measured. RhoA activity and urotensin receptor (UTR) and Rho-related coiled-coil-forming protein kinase (ROCK) protein expressions in rat myocardium were examined, respectively. Cardiac dysfunction was indicated by the alterations of hemodynamic parameters and the reduced coronary flow. Key findings Total flavones of Rhododendron simsii Planch flower significantly improved ischaemia-reperfusion–induced cardiac dysfunction and leakages of LDH, CK-MB and cTnI, and inhibited myocardial ischaemia-reperfusion–increased RhoA activity and UTR, ROCK1 and ROCK2 protein expressions. The improvement of TFR in the cardiac dysfunction and the leakage of LDH, CK-MB and cTnI were markedly attenuated under the UTR blockade and ROCK inhibition. TFR-inhibited RhoA activity was decreased under the UTR blockade. Conclusions Total flavones of Rhododendron simsii Planch flower had a protective effect on ischaemia-reperfusion injury in isolated rat heart, which may be attributed to the blocking of UTR and subsequent inhibition of the RhoA-ROCK pathway.

Ethnopharmacological relevance Inflammatory bowel disease (IBD) is associated with chronic inflammation of the intestinal tract. Piperine (1-peperoylpiperidine), the primary lipophilic component in black pepper (Piper nigrum) and long pepper (Piper longum), has been reported to be effective for anti-inflammatory. Rencently, several ethnopharmacological purity compounds, such as baicalin and artemisinin, are reported to have potentially therapeutic role in treating IBD. In the present study, the effects of piperine on pregnane X receptor (PXR)-mediated CYP3A expression and its therapeutic role in IBD were investigated. Materials and methods LS174T cells and C57BL/6J mice were treated by the piperine. Gene expressions were analyzed by real-time PCR, Western blot analysis, transient transfections assay and histological analysis. Results Data indicated that treatment of LS174T cells with piperine markedly increased both CYP3A4 and PXR mRNA and protein. Transient transfection experiments indicated that transcriptional activation of the CYP3A4 gene via piperine was PXR-dependent. Data show that pre-administration of piperine decreased clinical hallmarks of colitis in DSS-treated PXR mice as measured by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. Inflammatory mediators (CCR2, ICAM-1, IL-1β, IL-6, IL-10, iNOS, MCP-1, and TNFα) after DSS treatment were significantly decreased in mice pretreated with piperine but corresponding conditions did not occur in mice with down-regulation of PXR by small interfering RNA (siRNA). Conclusion Piperine is a potential agonist of PXR and an inducer of PXR, which may induce CYP3A4 gene expression at the mRNA and protein levels. These results establish that piperine may contribute to prevention or reduction of colonic inflammation.

Objectives. Total flavones from Rhododendron simsii Planch. (TFR) are the effective part extracted from the flowers of Rhododendron simsii Planch. and have obvious protective effects against cerebral ischemic or myocardial injuries in rabbits and rats. However, their mechanism of cardioprotection is still unrevealed. Therefore, the present study was designed to investigate the effect of TFR on myocardial I/R injury and the underlying mechanism. Methods. TFR groups were treated by gavage once a day for 3 days at a dose of 20, 40, and 80 mg/kg, respectively, and then the model of myocardial I/R injury was established. Myocardial infarction, ST-segment elevation, and the expression of UTR, ROCK1, ROCK2, and p-MLC protein in rat myocardium were determined at 90 min after reperfusion. UTR siRNA in vivo transfection and competition binding assay method were used to study the relationship between the protective effect of TFR and UTR. Results. The expression of UTR protein markedly decreased in myocardium of UTR siRNA transfection group rats. TFR could significantly reduce the infarct size and inhibit the increase of RhoA activity and ROCK1, ROCK2, and p-MLC protein expressions both in WT and UTR knockdown rats. The reducing rate of TFR in myocardial infarction area, RhoA activity, and ROCK1, ROCK2, and p-MLC protein expressions in UTR knockdown rats decreased markedly compared with that in WT rats. In addition, TFR had no obvious effect on the increase of ΣST in UTR knockdown rats in comparison with that in model group. In particular, TFR could significantly inhibit the combination of [I125]-hu-II and UTR, and IC50 was 0.854 mg/l. Conclusions. The results indicate that the protective effect of TFR on I/R injury may be correlated with its blocking UTR and the subsequent inhibition of RhoA/ROCK signaling pathway.

Background. Total flavonoids of Rhododendron (TFR) is extracted from Rhododendron, a herbal medicine widely used in China. The main components are flavone compounds such as warfarin, rutin, quercetin, and hyperoside. We investigated the role of TRPV4 channel in the TFR induced endothelium-dependent hyperpolarizing factor- (EDHF-) mediated responses against ischemia/reperfusion injury (IR) in cerebral IR (CIR) rats. Methods. The morphological changes of cerebral cortex, the relaxation of cerebral basal artery (CBA), and cell membrane potential recording were studied in CIR rats. The outward potassium current in smooth muscle cell was recorded by whole-cell patch clamp recording. The protein expression of TRPV4, SKca, and IKca was determined. Confocal laser was used to measure the Ca2+ fluorescence intensity. Results. After treatment with TFR, the number of pyramidal cells in brain tissue increased and the number of empty or lightly stained cells decreased and these effects were eliminated by using HC-067047, Apamin, or TRAM-34. TFR induced and EDHF-mediated dilatation and hyperpolarization in CBA were also attenuated by using these inhibitors. The increased outward current density elicited by TFR in acutely isolated CBA smooth muscle cells was abolished by using TRAM-34 and Apamin. TFR upregulated the protein expression of TRPV4, SKca, and IKca that was also eliminated by these inhibitors. Laser scanning showed that the increased mean fluorescence intensity of Ca2+ by CIR was decreased by using TFR and that this effect was again eliminated by the above inhibitors. Conclusions. We conclude that in the CBA of the CIR rats the protective effect of TFR on ischemic cerebrovascular injury may be related to the activation of the TRPV4 in both endothelium and smooth muscle by increasing its expression and activity. The activation of TRPV4 channel in the endothelium may be linked to the opening of endothelial IKca/SKca channels that induces EDHF-mediated relaxation and hyperpolarization in the smooth muscle cell. In addition, the activation of TRPV4 in the smooth muscle cell in CBA may be linked with the activation of BKCa channel through a TRPV4-dependent pathway, reduce Ca2+ concentration in the cell, and relaxes the vessel. These findings may form a new therapeutic target for protection of ischemic brain injury and facilitate the use of Chinese medicine in brain protection.

Many flavonoids have cardioprotection against myocardial ischemia/reperfusion (I/R) injury. Total flavones fromRhododendron simsiiPlanch flower (TFR) can protect myocardial ischemic injuries. However, its protective mechanism is still unknown. The present study was designed to investigate the mechanism of TFR on myocardial I/R and anoxia/reoxygenation (A/R) injuries. Rat model of myocardial I/R injury was made, and myocardial infarction was determined. A/R injury was induced in cultured rat cardiomyocytes; cellular damage was evaluated by measuring cell viability, LDH and cTnT releases, and MDA content. Expressions of ROCK1and ROCK2protein were examined by Western blot analysis, and K+currents were recorded by using whole-cell patch clamp technique. TFR 20~80 mg/kg markedly reduced I/R-induced myocardial infarction. TFR 3.7~300 mg/L significantly inhibited A/R-induced reduction of cell viability, LDH and cTnT releases, and MDA production. Exposure to A/R significantly increased ROCK1and ROCK2expressions in rat cardiomyocytes, but TFR 33.3~300 mg/L obviously inhibited this increase. 300 mg/L TFR significantly augmented inward rectifier K+current and other K+currents in rat cardiomyocytes. These results indicate that TFR has a protective effect on rat cardiomyocytes A/R damage, and the protective mechanism may be engaged with the inhibition of ROCK1and ROCK2and activation of K+channels.

The results of a toxicity analysis showed differences from those of the existing experimental data. Therefore, HPLC-ICP-MS was used to analyze the soluble arsenic content at different valences in realgar prepared with water grind processing, which were collected from 3 companies. The results showed that the free arsenic of the 3 companies did not exceed the limit of Chinese Pharmacopoeia. However, if the free arsenic was calculated based on the total value of As(Ⅲ) + As(Ⅴ), free arsenic of 1 company exceeded the limit of Chinese Pharmacopoeia. The method of determining free arsenic in Chinese Pharmacopoeia. was ancient Cai's arsenic detection method, which had a certain limitation and failed to effectively avoid the toxicity of remaining arsenics except for trivalent arsenic. Then, we examined the effects of water and temperature on the content and form of soluble arsenic in realgar. The results showed that the content of soluble arsenic increased with the rise of water content, and the form of soluble arsenic did not change, there were only As (Ⅲ) and As (Ⅴ); With the simple temperature factor, there was an increasing trend in the content of soluble arsenic in the samples, the maximum increment was As (Ⅲ) 2.489 mg•g⁻¹ and As (Ⅴ) 0.546 mg•g⁻¹; When water and temperature played an synergistic effect, the increase of soluble arsenic in the samples significantly changed, the maximum increment was As (Ⅲ) 23.690 mg•g⁻¹, As (Ⅴ) 0.468 mg•g⁻¹, respectively. Through comprehensive analysis, we believed that the quality of realgar was susceptible to water content and temperature. Both of the single effect of water content and the synergistic effect of water and temperature can significantly change the content of soluble arsenic in realgar, and the water content was a high-risk factor. In the current Chinese Pharmacopoeia 2015 version, the free arsenic detection method had limitations, hence new techniques shall be introduced; At the same time, realgar does not have a water content inspection item in the current pharmacopoeia, which shall be added. However, due to the limit of water content, more in-depth studies are required.

Ethnopharmacological relevance Bufo gargarizans (Cantor, 1842) (BGC), a traditional medicinal animal distributed in many provinces of China, is well known for the pharmaceutical value of Chansu and Chanpi. As traditional Chinese medicines (TCMs), Chansu and Chanpi, with their broad-spectrum of therapeutic applications, have long been applied to detoxification, anti-inflammation, analgesia, etc. Overarching objective We critically analyzed the current evidence for the traditional uses, chemical profiles, pharmacological activity, toxicity and quality control of BGC (Bufonidae family) to provide a scientific basis for future in-depth studies and perspectives for the discovery of potential drug candidates. Methodology All of the available information on active constituents and TCMs derived from BGC was obtained using the keywords “Bufo gargarizans”, “Chansu”, “Chanpi”, “Huachansu”, or “Cinobufacini” through different electronic databases, including PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), the Wanfang Database, and Pharmacopoeia of China. In addition, Chinese medicine books from different times were used to elucidate the traditional uses of BGC. Electronic databases, including the “IUCN Red List of Threatened Species”, “American Museum of Natural History” and “AmphibiaWeb Species Lists”, were used to validate the scientific name of BGC. Results To date, about 118 bufadienolide monomers and 11 indole alkaloids have been identified from BGC in total. The extracts and isolated compounds exhibit a wide range of in vitro and in vivo pharmacological effects. The literature search demonstrated that the ethnomedicinal uses of BGC, such as detoxification, anti-inflammation and the ability to reduce swelling and pain associated with infections, are correlated with its modern pharmacological activities, including antitumor, immunomodulation and attenuation of cancer-derived pain. Bufadienolides and indole alkaloids have been regarded as the main active substances in BGC, among which bufadienolides have significant antitumor activity. Furthermore, the cardiotoxicity of bufadienolides was discussed, and the main molecular mechanism involves in the inhibition of Na+/K+-ATPase. Besides, with the development of modern analytical techniques, the quality control methods of BGC-derived TCMs are being improved constantly. Conclusions An increasing number of reports suggest that BGC can be regarded as an excellent source for exploring the potential antitumor constituents. However, the future antitumor research of BGC needs to follow the standard pharmacology guidelines, so as to provide comprehensive pharmacological information and aid the reproducibility of the data. Besides, to ensure the efficacy and safety of BGC-derived TCMs, it is vital to construct a comprehensive quality evaluation model on the basis of clarifying pharmacodynamic-related and toxicity-related compositions.

This study investigated the effect of total flavone fromRhododendron simsiiPlanch. flower (TFR) on postischemic cardiac dysfunction and ventricular remodeling and was to test the hypothesis that TFR has an antiventricular remodeling effect through inhibition of urotensin-II receptor- (UTR-) mediated activation of RhoA-ROCK pathways. Twenty-four hours after ligation of the left anterior descending coronary artery, male Sprague-Dawley rats were randomized to receive 4-week treatment with saline (model group) or TFR. Compared to the model group, TFR treatment restored cardiac function, attenuated cardiomyocyte hypertrophy, and reduced interstitial fibrosis. Expression levels of several fibrosis-related factors, including alpha-smooth muscle actin, transforming growth factor-beta 1, matrix metalloproteinase-2, and collagen type I, were increased after MI. TFR treatment attenuated the upregulation of these factors, downregulated UTR expression, and markedly diminished the expression of RhoA and ROCK1/2. These results suggested that TFR could improve cardiac function and ameliorate ventricular remodeling through blocking UTR-mediated activation of RhoA-ROCK pathways in myocardial infarction rats.

We investigated the effects of endothelium-derived hyperpolarizing factor (EDHF) and the role of hydrogen sulphide (H2S) in the cerebral vasorelaxation induced by acetylcholine (ACh) in global cerebral ischemia–reperfusion (CIR) rats. CIR was induced by occlusion of bilateral carotid and vertebral arteries. Isolated arterial segments from the cerebral basilar (CBA) and middle artery (MCA) of CIR rats were studied in a pressurized chamber. Transmembrane potential was recorded using glass microelectrodes to evaluate hyperpolarization. In the CIR CBAs and MCAs preconstricted by 30 mM KCl, ACh induced concentration-dependent vasorelaxation and hyperpolarization that were partially attenuated by NG-nitro-l-arginine methyl ester (l-NAME, 30 μM) and l-NAME plus indomethacin (10 μM). The residual responses were abolished by the H2S inhibitor dl-propargylglycine (PPG, 100 μM). The H2S donor NaHS and l-Cys, the substrate of endogenous H2S synthase, elicited similar responses to ACh and was inhibited by tetraethylamonine (1 mM) or PPG. ACh induces EDHF-mediated vasorelaxation and hyperpolarization in rat cerebral arteries. These responses are up-regulated by ischemia–reperfusion while NO-mediated responses are down-regulated. Further, the ACh-induced, EDHF-mediated relaxation, and hyperpolarization and the inhibition of these responses are similar to the H2S-induced responses, suggesting that H2S is a possible candidate for EDHF in rat cerebral vessels. Keywords:: endothelium, nitric oxide, endothelium-derived hyperpolarizing factor (EDHF), hydrogen sulphide, cerebral artery

Urantide is the most potent UT receptor antagonist compound found to date. Our previous studies have shown that it has cardioprotective effect against ischemia–reperfusion injury. However, it is unclear which signal transduction pathways are involved in the urantide-induced cardioprotective effect. This study was designed to investigate whether the effect of urantide on myocardial ischemia–reperfusion injury in rats via the protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K)–Akt signaling pathway. The results showed that urantide at 10 and 30 µg/kg markedly inhibited the increases in serum creatine kinase fraction and lactate dehydrogenase activities and the level of cardiac troponin I, reduced the ratio of myocardial infarct size to area at risk. Urantide significantly decreased the histological damage to the myocardium and modified the ultrastructural damage in cardiac myocytes. In the presence of chelerythrine (an inhibitor of PKC, 1 mg/kg) or LY294002 (an inhibitor of PI3K–Akt, 0.3 mg/kg), the protective effect of urantide was almost completely abolished. Urantide (30 µg/kg) markedly enhanced the expression of p-Akt protein during myocardial ischemia–reperfusion injury, and this enhancement was significantly attenuated by LY294002. Therefore, our results demonstrate that urantide has a potent protective effect against myocardial ischemia–reperfusion injury in rats that may be involved with the PKC and PI3K–Akt signaling pathways.

The aim of the present study is to investigate the effects and its possible underlying mechanisms of vitexin on myocardial ischemia/reperfusion (I/R) injury in isolated rat hearts. Isolated rat hearts were perfused with Langendorff apparatus, which subjected to 30 min ischemia and then followed by 60 min reperfusion. In the isolated rat heart subjected to I/R injury, treatment of vitexin (50, 100, 200 μmol/L) significantly enhanced coronary flow, and decreased the pathological scores of myocardium. 50, 100, 200 μmol/L vitexin significantly attenuated I/R-induced increases of myocardial TNF-α and IL-1β, and 25, 50, 100, 200 μmol/L vitexin significantly reduced apoptosis index of cardiac muscle cell of rat isolated heart subjected to I/R injury. Vitexin significantly inhibited I/R-induced increase of myocardial Bax protein expression; however, 100, 200 μmol/L vitexin markedly increased myocardial Bcl-2 protein expression. Furthermore, vitexin at concentrations of 50, 100, 200 μmol/L significantly reduced expression of myocardial NF-κBp65 protein. Therefore, these results demonstrate that vitexin exhibits significant protective effect against myocardial I/R injury in isolated rat heart, which is related to inhibition of the release of inflammatory cytokines and the apoptosis of cardiac muscle cell via up-regulating protein expression of Bcl-2 as well as down-regulating Bax and NF-κBp65.

Background and aim Hyperin, a flavonol compound extracted from the Chinese herb Abelmoschus manihot L. Medic, is reported to exert protective actions in cerebral ischemic injury. The specific aim of the present study was to study the relaxation of Hyperin in rat isolated basilar artery and identify the underlying cellular mechanisms. Methods Rat isolated basilar artery segments were cannulated and perfused while being superfused with PSS solution. Vessel images were recorded by video microscopy and diameters measured. Membrane potential was recorded using glass microelectrodes to evaluate the basilar artery smooth muscle cell hyperpolarization. Results Perfusion of Hyperin (1 ~ 100 μM) elicited a concentration-dependent relaxation of basilar artery segments preconstricted with 0.1 μM U46619. The response was significantly inhibited by the removal of the endothelium. Hyperin also elicited marked and concentration-dependent hyperpolarization of smooth muscle cells. 30 μM nitro-L-arginine (an inhibitor of nitric oxide synthase) and indomethacin (an inhibitor of cyclooxygenase), partially inhibited Hyperin-induced relaxation and hyperpolarization leaving an attenuated, but significant, endothelium-dependent relaxation and hyperpolarization. This remaining effect was almost completely blocked by 1 mM tetraethylammonium (an inhibitor of Ca2+-activated K+ channels), or by 100 μM DL-propargylglycine, an inhibitor of cystathionine-γ-lyase (a synthase of the endogenous H2S). Conclusion These findings show that Hyperin produces significant hyperpolarization in rat basilar artery smooth muscle cells and relaxation through both endothelium-dependent and endothelium-independent mechanisms. The underlying mechanisms appeared to be multi-factorial involving nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Our data further suggest that endogenous H2S is a component of the EDHF-mediated hyperpolarization and relaxation to Hyperin.

Objective Cilnidipine is a novel, long-action L/N-type dihydropyridine calcium channel blocker that has recently been used for antihypertensive therapy. We investigated the vasorelaxation effect of cilnidipine with regard to its calcium channel blockage and nitric oxide-cyclic guanosine monophosphate-dependent mechanism in human internal thoracic artery. Methods Fresh human internal thoracic arteries taken from discarded tissues of patients undergoing coronary artery bypass surgery were studied. Concentration-relaxation curves for cilnidipine in comparison with nifedipine were studied. The expression level of endothelial nitric oxide synthase mRNA was assayed by quantitative real-time polymerase chain reaction, and the phosphorylation of endothelial nitric oxide synthase at Ser 1177 was determined by Western blotting analysis. Results Cilnidipine and nifedipine caused nearly full relaxation in potassium-precontracted internal thoracic artery. Pretreatment with cilnidipine at the clinical plasma concentration significantly depressed the maximal contraction. Endothelium denudation (47.7% ± 7.0%, P 05) and inhibition of endothelial nitric oxide synthase (48.6% ± 6.1%, P 05) or guanylate cyclase (41.6% ± 3.8%, P 01) significantly reduced the cilnidipine-induced endothelium-dependent relaxation (73.9% ± 6.4%). Cilnidipine increased the expression of endothelial nitric oxide synthase mRNA by 42.4% ( P 05) and enhanced phosphorylation level of endothelial nitric oxide synthase at Ser 1177 by 37.0% ( P 05). Conclusions The new generation of calcium channel antagonist cilnidipine relaxes human arteries through calcium channel antagonism and increases production of nitric oxide by enhancement of endothelial nitric oxide synthase. The dual mechanisms of cilnidipine in human arteries demonstrated in this study may prove particularly important in vasorelaxing therapy in cardiovascular diseases.

Internal mammary (IMA) and radial artery (RA) have different incidence of vasospasm and long-term patency rates in arterial grafting. We compared the vasoreactivity of human urotensin II (hU-II) and its receptor with mechanism investigations in IMA and RA.IMA and RA taken from patients undergoing coronary bypass surgery were studied in organ baths. Urotensin receptor expression was determined by RT-PCR.hU-II contracted IMA with pD(2) of 8.57+/-0.41 and 45.4+/-9.1% E(max) of contraction to 100 mM KCl, whereas caused less contractile responses in RA (pD(2):8.30+/-0.79, E(max):20.4+/-4.8%, p0.05). Nifedipine inhibited hU-II-contraction in IMA. In U(46619)-precontraction, hU-II elicited comparable relaxation in IMA (pD(2):8.39+/-0.43, E(max):56.1+/-4.0%) and RA (pD(2):9.03+/-0.46, E(max):65.2+/-7.1%). The relaxation was abolished by endothelium denudation and by indomethacin, oxadiazoloquinoxalinone or N(omega)-nitro-L-arginine, oxyhemoglobin, and Ca2+-activated K+ channel (K(Ca)) blockers. Urotensin receptor mRNA was detected in both arteries.hU-II is an important spasmogen in arterial grafts with receptors expressed in IMA and RA. hU-II elicits stronger contraction in IMA than in RA and a moderate endothelium-dependent relaxation attributable to nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor with involvement of K(Ca) activation. The relaxant response of endothelium-intact IMA and RA to hU-II demonstrates the importance of preservation of endothelium in these grafts.

The purpose of this research was to demonstrate the protective effects and possible mechanisms of total flavones of rhododendra (TFR) against global cerebral ischemia reperfusion injury in rats. Global cerebral ischemia/reperfusion injury was caused by four vessel occlusion (bilateral vertebral arteries and bilateral carotid arteries, 4-VO). The electroencephalographic (EEG) changes were recorded. The EEG, brain water content, levels of malondialdehyde (MDA) and lactate dehydrogenase (LDH) activity in plasma, aggregation of platelets induced by ADP, and the resting and CaCl2-induced increase of free intracellular calcium concentration ([ Ca2+]i), were also evaluated. TFR dramatically elevated EEG amplitude, reduced the brain water content and the resting cytoplasmic free calcium concentration, inhibited the increase of [ Ca2+]iinduced by CaCl2and had an inhibitory effect on platelet aggregation. The LDH activity and the MDA content in plasma were also decreased. These results indicate that TFR has protective effects against cerebral injury in rats, which might be associated with its antioxidant properties, antiplatelet effects and possible inhibition of Cal2+influx to reduce [ Ca2+]i.

Bidens bipinnata L. is well known in China as a traditional Chinese medicine and has been used to treat hepatitis in clinics for many years. In a previous study we found that total flavonoids of Bidens bipinnata L. (TFB) had a protective effect against carbon tetrachloride (CCl4)-induced acute liver injury in mice. Now this study was designed to investigate its therapeutic effect against CCl4-induced liver fibrosis in rats and to determine, in part, its mechanism of action. The liver fibrosis model was established by subcutaneous injection of 50% CCl4 twice a week for 18 weeks. TFB (40, 80 and 160 mg kg−1) was administered by gastrogavage daily from the 9th week. The results showed that TFB (80 and 160 mg kg−1) treatment for 10 weeks significantly reduced the elevated liver index (liver weight/body weight) and spleen index (spleen weight/body weight), elevated levels of serum transaminases (alanine aminotransferase and aspartate aminotransferase), hyaluronic acid, type III procollagen and hepatic hydroxyproline. In addition, TFB markedly inhibited CCl4-induced lipid peroxidation and enhanced the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase. Moreover, TFB (80 and 160 mg kg−1) treatment improved the morphologic changes of hepatic fibrosis induced by CCl4 and suppressed nuclear factor (NF)-kB, α-smooth muscle actin (SMA) protein expression and transforming growth factor (TGF)-β1 gene expression in the liver of liver fibrosis of rats. In conclusion, TFB was able to ameliorate liver injury and protect rats from CCl4-induced liver fibrosis by suppressing oxidative stress. This process may be related to inhibiting the induction of NF-kB on hepatic stellate cell activation and the expression of TGF-β1.

Lead-free piezoelectric ceramics Lix(K0.46Na0.54)1-xNb0.86Ta0.1Sb0.04O3 (with x ranging from 0 to 0.1) were synthesized by conventional solid state sintering method. The effect of cationic substitution of Li for K and Na in the A sites of perovskite lattice on the structure, phase transition behavior and electrical properties were investigated. Morphotropic phase boundaries(MPB) between orthorhombic and tetragonal phase are found in the composition range of 0.06≤x≤0.08. Analogous to Pb(Zr,Ti)O3, the dielectric and piezoelectric properties are enhanced for the composition near the morphotropic phase boundary. The Li0.06(K0.46Na0.54)0.94- Nb0.86Ta0.1Sb0.04O3 ceramics show excellent electrical properties, that is, piezoelectric constant d33=215 pC/N, planar electromechanical coupling factor kp=41%, dielectric constant ɛ 33 T / ɛ 0 = 1 303 , and dielectric loss tan δ=2.45%. The results indicate that Lix(K0.46Na0.54)1-x Nb0.86 Ta0.1Sb0.04O3 ceramic is a promising lead-free piezoelectric material.

Bi2O3 doped (Bi0.5Na0.5)0.94Ba0.06TiO3 (BNBT6) lead-free piezoelectric ceramics were fabricated by a conventional sintering technique. The effects of Bi2O3 on the piezoelectric properties and microstructures of the doped BNBT6 were investigated. X-ray diffraction analysis showed that a solid solution was formed when Bi2O3 diffused into BNBT6 lattice and the crystal structure of the sintered hybrid changed from rhombohedral to tetragonal symmetry with increasing Bi2O3 amount. Piezoelectric and dielectric properties measurements revealed that doping Bi2O3 within a certain range enhanced the piezoelectric coefficient (d33), electromechanical coupling factor (kp), relative dielectric constant (ε33 T/ε0), and dielectric loss (tanδ). When 3mol% Bi2O3 was doped, both d33 and kp of the ceramics reached their maxima, 165pC/N and 24%, respectively.

Lead-free piezoelectric ceramics (Bi0.5Na0.5)0.94(Ba1-xSrx)0.06TiO3 (abbreviated as BNBST-100x, with x ranges from 0.02 to 0.1) have been investigated. Effects of amount of Sr-substitution on the electrical properties and crystal structure of the ceramics were studied. The BNBST-100x ceramics sintered at 1200°C for 2h in air have high density around 5.69~5.75g/cm3. X-ray diffraction (XRD) analysis shows that all of the BNBST-100x ceramics have pure perovskite structure. At high amount level of Sr-substitution, the crystal structure of the samples changes from rhombohedral to tetragonal symmetry. Piezoelectric and dielectric measurements reveal that Sr-substitution amount within a certain range will lead to the increase of piezoelectric coefficient (d33), electromechanical coupling factor (kp), and relative dielectric constant (ε33 T/ε0). At 6 mol% Sr-substitution level, the d33 and kp of the ceramics reach maximum, with values of 168 pC/N and 34%, respectively.

Vanillin is a naturally occurring compound and food-flavoring agent with antioxidant and antimutagenic activities. In present study, we explored the radioprotective effect of a novel vanillin derivative VND3207 (4-hydroxy-3,5-dimethoxybenzaldehyde). VND3207 has a much higher potential in scavenging hydroxyl radical and superoxide radical than vanillin as indicated in the ESR spin-trapping measurement, and it can effectively protect plasmid DNA against 10-50 Gy gamma-ray induced breaks in vitro at the concentrations as low as 10-20 microM. Using human lymphoblastoid AHH-1 cells and human fibroblastoid HFS cells, we demonstrated that VND3207 at 5-40 microM concentrations significantly attenuated the inhibition of proliferation and occurrence of apoptosis produced by 1-8 Gy gamma-irradiation. In the cultured cells, VND3207 significantly decreased the initial production and residual level of DNA double-strand breaks (DSBs) induced by 2 or 8 Gy irradiation. Treatment of VND3207 enhanced the level of DNA-PKcs protein, a critical component of DNA DSB repair pathway in the cells with or without gamma-irradiation. Consistently, the phosphorylation of Akt protein, a mediator of survival signal, as well as its substrate GSK3beta was concurrently increased by VND3207. Our results suggest that VND3207 has radioprotection effect through its capabilities as a powerful antioxidant, in minimizing DNA damage, and activating survival signal Akt pathway, and it may be of value in the development of radioprotective compounds.

p38 mitogen-activated protein kinases (MAPK) in ischemic preconditioning (IPC) may be essential to cardioprotection. We assessed whether protective effect of morphine-induced preconditioning (MPC) on myocardial ischemia and reperfusion injury in rat hearts involved p38 MAPK activation.Male Spargue-Dawley rats (weighing 300-350 g) were randomly assigned to 1 of the following 8 groups: control (CON, saline vehicle, n=9), SB 203580 (SB, a p38 MAPK inhibitor, n=6), MPC (n=6), IPC (n=9), SB+MPC, SB+IPC, MPC+SB, and IPC+SB (n=6). Infarct sizes (IS), a percentage of the area at risk (AAR), were determined by triphenyltetrazolium (TTC) staining. Tissue samples were processed from the entire AAR of left ventricle for the determination of p38 MAPK protein expression (5 hearts/group). The bands representing the proteins were visualized using an enhanced chemiluminescence detection system.The IS/AAR was significantly reduced by IPC (12.9+/-1.6)% or MPC (25.3+/-2.9)% compared to the control (52.7+/-5.5)%. SB 203580 administered prior to preconditioning abolished the effect of IPC (SB+IPC: (43.8+/-2.6)%, P0.05 vs CON, P0.01 vs IPC), but not MPC (SB+MPC: (30.7+/-0.9)%, P0.01 vs CON, P0.05 vs MPC). Treatment with SB 203580 prior to sustained ischemia diminished the protective effect of both MPC (MPC+SB: (42.4+/-2.9)%, P0.05 vs CON) and IPC (IPC+SB: (52.0+/-2.5)%, P0.05 vs CON) on IS/AAR. In the IPC group, phospho-p38 MAPK protein increased significantly within 5 minutes into ischemia and remained elevated at 30 minutes into reperfusion, while phospho-p38 MAPK protein in the MPC group only increased significantly at 30 minutes into reperfusion.The activation of p38 MAPK just acts as a mediator of MPC, whereas it acts as both a trigger and a mediator in IPC.

The anti-reducing sintering of (Ca,Sr,Ba)TiO3-based dielectrics was achieved by the cooperating effect of Mn2+, Ca2+, Mg2+, Dy3+ and Yb3+. A small quantity of Zr4+ partly substitution for Ti4+ can improve the temperature dependence of dielectric constant. But ZrO2 will also reduce the solid solubility of BaTiO3-SrTiO3-CaTiO3 ternary system, and may cause phase separation. The separated ferroelectric phase increases the capacitance change under DC bias. Non-reducible (Ca,Sr,Ba)(Ti,Zr)O3-based dielectrics with single orthorhombic phase of perovskite structure was obtained. The dielectric and DC bias properties are: .C/C (DC bias: 1.5kV/mm)

Objectives Due to potential therapeutic value of vascular endothelial growth factor (VEGF) in coronary artery disease, the effect and mechanism of VEGF in human arteries used as coronary bypass grafts become important but not fully understood. VEGF-mediated endothelial regulation in vasorelaxation was studied in internal mammary artery (IMA) and radial artery (RA), compared with that of the classical agent-acetylcholine (ACh). The role of nitric oxide (NO), prostacyclin (PGI 2 ), and endothelium-derived hyperpolarizing factor (EDHF) was investigated. Methods VEGF- and ACh-induced responses were measured in RA and IMA with or without endothelium and in the absence or presence of inhibitors of nitric oxide synthase or prostacyclin. In addition, the VEGF-induced PGI 2 was measured by enzyme immunoassay. Results VEGF induced similar relaxation in RA (59.2 ± 9.3%) and IMA (56.1 ± 6.4%) that was significantly inhibited by N ω -nitro- l -arginine ( l -NNA) plus oxyhemoglobin (HbO) (IMA: 24.9 ± 4.3%, P = 0.03 vs. RA: 25.0 ± 8.6%, P = 0.01) or by indomethacin (INDO) (IMA: 21.8 ± 2.5%, P = 0.000 vs. RA: 30.0 ± 6.6%, P = 0.04) with more inhibition in IMA than RA ( P 2 was significantly higher in IMA than RA (11.5 ± 2.1 vs. 4.9 ± 1.1 pg/ml/mg, P = 0.002). INDO + l -NNA + HbO reduced the VEGF-induced relaxation to 20.8 ± 4.6% in RA vs. 4.8 ± 1.6% in IMA ( P = 0.01). In contrast, the maximal relaxation induced by ACh in RA (55.9 ± 6.0%) and IMA (48.5 ± 5.3%) was largely inhibited by l -NNA in IMA and RA (14.7 ± 3.0%, P = 0.000 vs. 15.2 ± 3.2%, P = 0.004) but little affected by INDO. Conclusions VEGF induces similar relaxation in IMA and RA with significantly more PGI 2 -mediated relaxation and higher stimulated PGI 2 level in IMA but more EDHF-mediated relaxation in RA. In comparison, ACh-induced relaxation mainly depends on NO. Thus, our study reveals a significant difference in the mechanism of the endothelium-dependent relaxation induced by VEGF and ACh.

A lead-free piezoelectric ceramic ternary system based on (Bi0.5Na0.5)TiO3 (BNT)-(Bi0.5 K0.5)TiO3(BKT)-BaTiO3(BT) near the morphotropic phase boundary (MPB) between the tetragonal and rhombohedral phases has been investigated. The samples were prepared by a conventional sintering technique. Piezoelectric properties, dielectric properties and microstructures of BNT-BKT-BT lead-free piezoelectric ceramic were studied. The X-ray diffraction (XRD) patterns show that the ceramics possess a single-phase perovskite structure. The measurements of piezoelectric properties reveal that this system has a relatively high piezoelectric performance: the piezoelectric constant d33 reached to 178pC/N and planar electromechanical coupling factor kp enhanced to 0.325. The BNT-BKT-BT ternary system ceramics could be well sintered at 11500C with a high-density ratio of more than 95% of the theoretical density.