Key Laboratory of Stasis and Phlegm

Isle of Islay, United Kingdom

Key Laboratory of Stasis and Phlegm

Isle of Islay, United Kingdom

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He K.,Peking University | He K.,Key Laboratory of Microcirculation | He K.,Key Laboratory of Stasis and Phlegm | Yan L.,Peking University | And 30 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2014

Cardiac ischemia-reperfusion (I/R) injury remains a challenge for clinicians, which initiates with energy metabolism disorder. The present study was designed to investigate the protective effect of notoginsenoside R1 (NR1) on I/R-induced cardiac injury and underlying mechanism. Male Sprague-Dawley rats were subjected to 30-min occlusion of the left coronary anterior descending artery followed by reperfusion with or without NR1 pretreatment (5 mg•kg−1•h−1). In vitro, H9c2 cells were cultured under oxygen and glucose deprivation/reoxygenation conditions after NR1 (0.1 mM), Rho kinase (ROCK) inhibitor Y-27632 (10 μM), or RhoA/ROCK activator U-46619 (10 nM) administration. Myocardial infarct size, myocardial histology, and cardiac function were evaluated. Myofibril and mitochondria morphology were observed by transmission electron microscopy. F-actin and apoptosis were determined by immunofluorescence and TUNEL staining. ATP and AMP content were assessed by ELISA. Phosphorylated-AMP-activated protein kinase, ATP synthase subunits, apoptosis-related molecules, and the level and activity of ROCK were determined by Western blot analysis. We found that NR1 pretreatment ameliorated myocardial infarction, histological injury, and cardiac function induced by I/R. Furthermore, similar to the effect of Y-27632, NR1 improved H9c2 cell viability, maintained actin skeleton and mitochondria morphology, and attenuated apoptosis induced by oxygen and glucose deprivation/reoxygenation. Importantly, NR1 prevented energy abnormity, inhibited the expression and activation of ROCK, and restored the expression of the mitochondrial ATP synthase δ-subunit both in vivo and in vitro, whereas U-46619 suppressed the effect of NR1. These results prove NR1 as an agent able to prevent I/R-induced energy metabolism disorder via inhibiting ROCK and enhancing mitochondrial ATP synthase δ-subunits, which at least partially contributes to its protection against cardiac I/R injury. © 2014 the American Physiological Society.


Yan B.-Y.,Peking University | Pan C.-S.,Peking University | Pan C.-S.,Key Laboratory of Microcirculation | Pan C.-S.,Key Laboratory of Stasis and Phlegm | And 29 more authors.
Brain Research | Year: 2014

Objective: the purpose of the present study was to examine the protective effect of Icariside II (IS) on cerebral microcirculatory disturbance and neuronal injury in hippocampal CA1 region induced by global cerebral I/R and the underlying mechanism. Methods: male Mongolian gerbils (50-70 g) were subjected to bilateral common carotid arteries occlusion for 30 min and followed by reperfusion for 72 h. IS (20 mg/kg) was administered orally 2 h before ischemia and 6, 24, 48, 70 h after reperfusion. After 72 h of reperfusion, the leukocyte adhesion, albumin leakage, and velocity of RBC in the venules were determined with an upright microscope. Neuronal injury in hippocampal CA1 region was assessed by Nissl staining and the in situ TUNEL assay. Bax, Bcl-2, and cleaved caspase-3 proteins were detected by Western blot, and MDA content and complex I activity by ELISA assay in hippocampus. Results: IS inhibited I/R-elicited leukocyte adhesion, albumin leakage and increased the velocity of RBC in cerebral venules. IS down-regulated Bax and cleaved caspase-3 expression, up-regulated Bcl-2 expression of hippocampus and decreased the number of TUNEL positive neurons and the neuronal loss induced by I/R in hippocampal CA1 region. In addition, IS could increase the activity of complex I and decrease the production of MDA after I/R. Conclusions: IS could alleviate the microcirculatory disturbance and neuronal injury in hippocampal CA1 region induced by global cerebral I/R, which might involve regulating complex I activity. © 2014 Elsevier B.V. All rights reserved.


Ma L.-Q.,Peking University | Ma L.-Q.,Key Laboratory of Microcirculation | Ma L.-Q.,Key Laboratory of Stasis and Phlegm | Pan C.-S.,Peking University | And 29 more authors.
Microcirculation | Year: 2014

Objective: The aim of present study was to investigate the efficacy of MXSGT, a traditional Chinese medicine formula used for treatment of respiratory system diseases, in the LPS-induced rat ALI particularly with a focus on its effect on lung microvascular hyperpermeability and inflammatory reaction. Methods: Male Sprague-Dawley rats were injected with LPS (7.5 mg/kg, 1.5 mg/mL) intraperitoneally. MXSGT (0.52 g or 2.61 g/kg) was given by gavage six hours after LPS injection. Results: LPS stimulation resulted in a reduced survival rate, deteriorated vital signs, an increase in the number of leukocytes adhering to lung venules, the albumin leakage, the activity of MPO in lung tissues, the production of pro-inflammatory cytokines and lung perivascular edema. After LPS stimulation, western blot analysis revealed an increase in the expression of ICAM-1 and toll-like receptor 4, a decrease in tight junction proteins and an activation of cav-1, Src, and NF-κB. All the LPS-induced alterations were significantly attenuated by posttreatment with MXSGT. Conclusions: This study demonstrated MXSGT as a potential strategy for lung microvascular hyperpermeability and inflammatory reaction in ALI, and suggested that the beneficial role of MXSGT was correlated with toll-like receptor 4, Src, and NF-κB. © 2014 John Wiley & Sons Ltd.


Tang H.,Harbin Medical University | Pan C.-S.,Peking University | Pan C.-S.,Key Laboratory of Microcirculation | Pan C.-S.,Key Laboratory of Stasis and Phlegm | And 17 more authors.
Microcirculation | Year: 2014

Objective: TSI is a new drug derived from Chinese medicine for treatment of ischemic stroke in China. The aim of this study was to verify the therapeutic effect of TSI in a rat model of MCAO, and further explore the mechanism for its effect. Methods: Male Sprague-Dawley rats were subjected to right MCAO for 60 minutes followed by reperfusion. TSI (1.67 mg/kg) was administrated before reperfusion via femoral vein injection. Twenty-four hours after reperfusion, the fluorescence intensity of DHR 123 in, leukocyte adhesion to and albumin leakage from the cerebral venules were observed. Neurological scores, TTC staining, brain water content, Nissl staining, TUNEL staining, and MDA content were assessed. Bcl-2/Bax, cleaved caspase-3, NADPH oxidase subunits p47phox/p67phox/gp91phox, and AMPK/Akt/PKC were analyzed by Western blot. Results: TSI attenuated I/R-induced microcirculatory disturbance and neuron damage, activated AMPK, inhibited NADPH oxidase subunits membrane translocation, suppressed Akt phosphorylation, and PKC translocation. Conclusions: TSI attenuates I/R-induced brain injury in rats, supporting its clinic use for treatment of acute ischemic stroke. The role of TSI may benefit from its antioxidant activity, which is most likely implemented via inactivation of NADPH oxidase through a signaling pathway implicating AMPK/Akt/PKC. © 2014 John Wiley & Sons Ltd.


Yang X.-Y.,Peking University | He K.,Peking University | Pan C.-S.,Peking University | Li Q.,Peking University | And 16 more authors.
Scientific Reports | Year: 2015

The present study aimed to detect the role of 3, 4-dihydroxyl-phenyl lactic acid (DLA) during ischemia/reperfusion (I/R) induced myocardial injury with emphasis on the underlying mechanism of DLA antioxidant. Male Spragu-Dawley (SD) rats were subjected to left descending artery occlusion followed by reperfusion. Treatment with DLA ameliorated myocardial structure and function disorder, blunted the impairment of Complex I activity and mitochondrial function after I/R. The results of 2-D fluorescence difference gel electrophoresis revealed that DLA prevented the decrease in NDUFA10 expression, one of the subunits of Complex I. To find the target of DLA, the binding affinity of Sirtuin 1 (SIRT1) to DLA and DLA derivatives with replaced two phenolic hydroxyls was detected using surface plasmon resonance and bilayer interferometry. The results showed that DLA could activate SIRT1 after I/R probably by binding to this protein, depending on phenolic hydroxyl. Moreover, the importance of SIRT1 to DLA effectiveness was confirmed through siRNA transfection in vitro. These results demonstrated that DLA was able to prevent I/R induced decrease in NDUFA10 expression, improve Complex I activity and mitochondrial function, eventually attenuate cardiac structure and function injury after I/R, which was possibly related to its ability of binding to and activating SIRT1.


Pan C.-S.,Peking University | Pan C.-S.,Key Laboratory of Microcirculation | Pan C.-S.,Key Laboratory of Stasis and Phlegm | Liu Y.-H.,Peking University | And 27 more authors.
PLoS ONE | Year: 2015

Lipopolysaccharide (LPS) causes microvascular barrier disruption, leading to albumin leakage from microvessels resulting in a range of disastrous sequels. Salvianolic acid B (SalB) is a major water-soluble component derived from Salvia miltiorrhiza. Previous studies showed its potential to attenuate microvascular barrier dysfunction, but the underlying mechanism is not fully understood. The present study was intended to investigate the impact of SalB on endothelial cell barrier in vivo in rat mesenteric venules as well as in vitro in human umbilical vein endothelial cells (HUVECs), aiming at disclosing the mechanism thereof, particularly the role of Src in its action. Male Wistar rats were challenged by infusion of LPS (2 mg/kg/h) through left femoral vein for 90 min. SalB (5 mg/kg/h) was administrated either simultaneously with LPS or 30 min after LPS infusion through the left jugular vein. Vesicles in venular walls were observed by electron microscopy. HUVECs were incubated with LPS with or without SalB. The expression of Zonula occluden-1 (ZO-1), VE-cadherin, caveolin-1 and Src in HUVECs was assessed by Western blot and confocal microscopy, binding of SalB to Src was measured using Surface Plasmon Resonance and BioLayer Interferometry. Treatment with SalB inhibited albumin leakage from rat mesenteric venules and inhibited the increase of vesicle number in venular endothelial cells induced by LPS. In addition, SalB inhibited the degradation of ZO-1, the phosphorylation and redistribution of VE-cadherin, the expression and phosphorylation of caveolin-1, and phosphoirylation of Src in HUVECs exposed to LPS. Furthermore, SalB was found able to bind to Src. This study demonstrates that protection of SalB against microvascular barrier disruption is a process involving both para- and trans-endothelial cell pathway, and highly suggests Src as the key enzyme for SalB to work. © 2015 Pan et al.


Mu H.-N.,Peking University | Mu H.-N.,Key Laboratory of Stasis and Phlegm | Li Q.,Peking University | Li Q.,Key Laboratory of Stasis and Phlegm | And 18 more authors.
Free Radical Biology and Medicine | Year: 2015

Abstract Sirtuin 3 (Sirt3) plays critical roles in regulating mitochondrial oxidative metabolism. However, whether Sirt3 is involved in liver ischemia and reperfusion (I/R) injury remains elusive. Caffeic acid (CA) is a natural antioxidant derived from Salvia miltiorrhiza. Whether CA protects against liver I/R injury through regulating Sirt3 and the mitochondrial respiratory chain (MRC) is unclear. This study investigated the effect of CA on liver I/R injury, microcirculatory disturbance, and potential mechanisms, particularly focusing on Sirt3-dependent MRC. Liver I/R of male Sprague-Dawley rats was established by occlusion of portal area vessels for 30 min followed by 120 min of reperfusion. CA (15 mg/kg/h) was continuously infused via the femoral vein starting 30 min before ischemia. After I/R, Sirt3 expression, and MRC activity decreased, acetylation of NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 and succinate dehydrogenase complex, subunit A, flavoprotein variant provoked, and the liver microcirculatory disturbance and injury were observed. Treatment with CA attenuated liver injury, inhibited Sirt3 down-expression, and up-regulated MRC activity. CA attenuated rat liver microcirculatory disturbance and oxidative injury through regulation of Sirt3 and the mitochondrial respiratory chain. © 2015 Elsevier Inc.

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