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Objective:To explore the active components, targets and mechanism of Guizhi Fuling Pills in the treatment of atherosclerosis (AS) based on network pharmacology and molecular docking technology.Methods:The active components and potential target information of Guizhi Fuling Pills in the treatment of AS was obtained using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), SwissTargetPrediction database and Genecards database. The target protein interaction network was constructed by using STRING database. The DAVID database was used to perform the Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment on potential targets. AutoDockVina and PyMOL software were used to verify the molecular docking of the main active components and key targets of Guizhi Fuling Pills.Results:A total of 74 active components, 239 potential targets and 4 710 AS-related disease targets were screened, and 182 intersection targets were obtained. A total of 484 biological process items, 132 molecular function items and 74 cellular component items were obtained by GO functional enrichment analysis, and 116 signal pathways were screened by KEGG enrichment analysis. The results of molecular docking suggested that the active components of Guizhi Fuling Pills have good binding activity to the key intersection targets.Conclusion:The active components of Guizhi Fuling Pills, such as sitosterol and paeoniflorin, mainly treat AS by regulating estrogen signal pathway and inflammatory signal pathway through TNF, VEGFA and other targets.
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Objective To establish a simple ,low cost and stable method to detect right ventricular pressure in mice .Methods A PE-50 duct length 15 cm(outside diameter :0 .9 mm ,inner diameter :0 .5 mm) was bent on one terminal and the other terminal was inserted into a 7# syringe needle to connect to a pressure transducer .This duct was intubated into right ventricle via right external jugular vein to detect right ventricular pressure in 80 SPF grade male C57BL/6 mice .Successful cases and operation time were re-corded .Besides ,40 SPF grade male C57BL/6 mice were randomized into the control group (n=20) and chronic hyperbaric hypoxia group(n= 20) .Mice in chronic hyperbaric group were raised in a hyperbaric chamber of simulated 5 000 m high altitude for 4 weeks .The control group was raised outside the chamber simultaneously .Right ventricular systolic pressure was detected with the PE duct .Left and right ventricles were detached and weighed ,and Hermann-Willson index was calculated .Results With this PE duct ,right ventricular intubation success rate was 90% (72/80) ,the operation cost approximately 3 to 5 min each mouse from the separation of blood vessels to detect the time needed for the right ventricle waveform .right ventricular systolic pressure[(39 .52 ± 4 .34 )mm Hg] and Hermann-Willson index(0 .356 ± 0 .039)of chronic hyperbaric hypoxia group were significantly higher than that of control group [(21 .24 ± 2 .7)mm Hg and (0 .256 ± 0 .020)] ,which has significant positive correlation (P<0 .01) .Conclusion It is simple ,fast ,stable ,costing low and of high success ratio to detect right ventricular pressure with this method .
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Objective: To observe the effect of hypoxia on changes of proliferation ability of cultured human periodontal ligament fibroblasts (HPLFS) in vitro. Methods: HPLFS were randomly divided into two groups (experimental group and control group) by different oxygen concentrations. The oxygen concentration of control group was 21%. The oxygen concentrations of experiment group were 10%, 5% and 2%. The proliferation ability of HPLFS was detected by MTT colorimetric assay. The cell ultrastructure was observed by transmission electron microscope (TEM). Results: MTT assay results showed that compared with the control group, at the 12 h and 24 h, cell proliferation was enhanced with the hypoxia degree. At 24 h, cell proliferation showed significant differences. At 48 h and 72 h, proliferation of the cultured HPLFS in severe hypoxia group reduced significantly. Observed by TEM, at 24 h, not only the number of mitochondria, rough endoplasmic reticulum but also cell process increased in the cultured HPLFS in severe hypoxia group. At 72 h, the number of lysosome increased and the cell structure degenerated. Conclusion: Long-time severe hypoxia may lower the repair and remodeling abilities of periodontium, which might be one of the important etiological factors of periodontal disease under condition of high altitude.
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Aim To observe the improvement of visual-auditory cognitive functions in the human entering high altitude by taking in tea polyphenols.Methods Thirty eight males living at 3 700 m high altitudes for 90 days constantly were randomly divided into two groups: ①group Ⅰ(placebo,40 mg/day); ②group Ⅱ(TP,300 mg/day).Cognitive functions were measured by integrated visual and auditory continuous performance test and the difference between groups was evaluated by the comparisons of post-treatment to pre-treatment.Results Compared with pre-treatment,PruA was significantly higher after taking in TP(P
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Objective To investigate effect of sodium cyanide(NaCN)at different concentrations on the mitochondrial respiratory oxygen consumption,the mitochondrial membrane potential(MMP)and activity of the complex Ⅳ of mitochondrial breath train in in vitro liver mitochondria from the rats exposed to simulated high altitude hypoxia,and to explore the characteristics of energy metabolism in the mitochondria from the rats subjected to cyanide poisoning during acute hypoxia exposure.Methods Adult Sprague-Dawley(SD)rats were set randomly into control and acute hypoxia groups(n=8 in each group).The acute hypoxic rats were exposed to simulate 5 000 m high altitude in a hypobaric chamber 23 h/d for 3 d.Rats in the control group were bred in the normoxia condition at the same time.The liver mitochondria were isolated by centrifugation.Mitochondrial oxidative respiratory consumption and activity of the complex Ⅳ was measured by Clark electrode after the treatment of NaCN at 0,0.01,0.1 and 0.25 mmol/L respectively,so as to calculate mitochondrial state 3 respiration(ST3),state 4 respiration(ST4),respiratory control rate(RCR),the rate of oxidative phosphorylation(OPR),and oxygen consumption rate of the complex Ⅳ.MMP was detected by Rhodamine 123 method at the above-mentioned concentrations of NaCN.Results NaCNat0.01,0.1and0.25mmol/Linhibited the mito-chondrial oxidative respiratory function,and decreased MMP significantly.The inhibitory effects of NaCN onenergy metabolism in mitochondria was in a dose-dependent manner.Compared with the treatment of NaCN atthe corresponding concentration in the control group,mitochondrial function in the acute hypoxia group was in-hibited more seriously.Conclusion Acute hypoxia exacerbates the inhibitory effects of sodium cyanide on en-ergy metabolism in rat liver mitochondria.Its mechanism might be relevant to the decoupling of oxidative phos-phorylation,functional down-regulation of complexⅣin respiratory chain and changes of the mitochondrialmembrane potential in liver mitochondria from rats exposed to acute hypoxia.
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0.05).Conclusion TP may have protective effects on chronical hypoxia induced polycythemia in rats.
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AIM：To investigate the roles of nitric oxide (NO) and endothelin-1(ET-1) in regulation of coronary vascular reserve (CVR) during hypoxia.METHODS： CVR were measured with 99m TC radiolabelled frog RBC, the changes of NO-2，ET-1 contents， nitric oxide synthase(NOS) activity and the myocardial morphometry were observed. RESULTS： (1) Acute hypoxia caused an increase in left and right ventricular myocardial blood flow，myocardial NO-2，ET-1 contents，NOS activity，but CVR in the left and right ventricle were decreased compared with the control group.(2) Intermittent hypobaric hypoxia for 90 days did not lead to significant change in left ventricular CVR，myocardial ET-1/NO-2 ratio. However, right ventricular myocardial ET-1 contents，ET-1/ NO-2 ratio were increased，right ventricular CVR and myocardial NO-2 contents were decreased. We also observed that perivascular collagen，arterial wall thickness in right ventricle， hematocrit，RV weight index were augmented. CONCLUSION： Rest myocardial blood flow was increased，CVR was decreased；The decreased coronary vascular reserve during chronic hypoxia might be resulted from the increased hematocrit，arterial wall thickness，perivascular collagen，ET-1 content, the decreased NO content and right ventricular hypertrophy
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AIM: To study the changes in capillarity of skeletal muscle during acclimation to high altitude, and explore the effects of a certain extent physical activity under hypoxia on capillary formation and the role of vascular endothelial growth factor (VEGF) in this process. METHODS: 48 Wistar rats were divided into 3 groups: Ⅰ normoxic control; Ⅱ hypoxia and Ⅲ hypoxia+exercise. Rats of Ⅱ and Ⅲ groups were subjected to hypobaric hypoxia for 5 weeks (23 h/d). They were first brought to simulated 4 000 m altitude, where rats of the Ⅲgroup were forced to swim for 1 h/d (6 d/week). Then the animals were ascent to 5 000 m. Biomicrosphere method was used to determine blood flow of skeletal muscle. The mean fiber cross-sectional area (FCSA), capillary density (CD) and capillary/fiber ratio (C/F) of red portion of the lateral head of the gastrocneminus were assayed by myofibrillar ATPase histochemistry. VEGF and its receptor KDR were assayed with immunohistochemistry method.RESULTS: By comparison with the normoxic control, 5-week hypoxic exposure resulted in a decrease in cross-sectional area of skeletal muscle fiber and an increase in CD, but the C/F remained unchanged. The blood supply to the gastrocnemius was not changed. After 5-week-exercise at high altitude, the muscle fibers did not undergo atrophy. CD, C/F, and the blood flow at rest increased significantly. VEGF protein was found primarily in the matrix between muscle fibers; KDR were shown mainly in endothelial cells of capillary. VEGF was more strongly stained in the skeletal muscle of hypoxia-exercise rats.CONCLUSION: Hypoxia itself can not induce neovascularization. While exercise during hypoxic exposure can lead to capillary formation. VEGF and KDR may play roles in it. New capillary formation benefits the blood supply, oxygen delivery and working performance at high altitude.
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AIM: To study the changes in myocardial blood flow (MBF), capillarization and cardiac function in the rat during acclimation to hypoxia. METHODS: Myocardial capillary density (CD) and capillary/myocyte ratio (C/M) was assayed by alkaline phosphatase histochemistry. Biomicrosphere method was used to determine MBF in the rat after 5, 15 or 30 days hypobaric hypoxic exposure (5 000 m). RESULTS: In the course of hypoxia, MBF and cardiac function increased in the right ventricle. However, in the left ventricle, acute hypoxia caused an increase in MBF and a decrease in cardiac function. Both returned to the control level on continued hypoxic exposure. Neovascularization occurred after 15 day or 30 day of hypoxic exposure in both ventricles, judged from the significant increment of C/M ratio albeit the CD remained unchanged in the right ventricle. CONCLUSION: Our findings indicate that adaptive changes in rat heart during acclimation to hypoxia include: ① persistent increase in MBF, hypertrophy associated with increase in capillarity and enhanced cardiac function of the right ventricle; ② increase in MBF and depression of cardiac function at first, then followed by recovery of MBF and increase in capillarity accompanied with recovery of left ventricular function.
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AIM:To determine the right ventricular angiotensin converting enzyme2 (ACE2) activity in adult SD rats under normoxia and hypoxia environment,and to detect the relationship between ACE2 and high altitude heart disease initially. METHODS:Adult male Sprague Dawley (SD) rats were raised under hypoxia environment simulated to high altitude (5 000 m,23 h/d),then divided into hypoxia 1 d,15 d and 30 d groups randomly. The control group was set up under normoxia environment. The right ventricular function,ponderal index,pulmonary artery pressure and right ventricular ACE2 activity were determined. The effect of captopril or nitrendpine on cardiac ACE2 activity in hypoxia 30 d group was also observed. RESULTS:The dramatic up-regulation of cardiac ACE2 expression of mRNA and protein and its activity in hypoxia 30 d group was observed,together with obvious increase in right ventricular function,ponderal index and pulmonary artery pressure. Although captopril or nitrendipine depressed pulmonary artery pressure and cardiac function dramatically,no significant alteration of right ventricular ACE2 activity was detected. CONCLUSION:Chronic hypoxic exposure promotes the ACE2 expression and activity in right ventricular,indicating that ACE2 may be correlated to the changes of cardiac architecture and function induced by hypoxia. Up-regulation of ACE2 expression maybe contribute to the increase in right ventricular ACE2 activity,and pulmonary artery hypertension may not be the main reason for the changes of ACE2 activity under hypoxia environment.
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AIM: To explore the pathogenic mechanism of high altitude pulmonary edema(HAPE). METHODS: Haemodynamic changes and effects of 100 percent oxygen breathing were measured by Swan-Ganz thermistor catheters, high altitude healthy volunteers were served as controls. RESULTS: The important features of haemodynamic changes in HAPE: (1)Pulmonary arterial pressure was raised; (2)Pulmonary arterial resistance and cardiac output were raised; (3)Pulmonary artery wedge pressures and right atrial pressure were normal; (4)Pulmonary arterial pressure and resistance were induced by oxygen breathing. CONCLUSIONS: The normal pulmonary artery wedge pressures with a high cardiac output indicated that HAPE was recognized as a form of noncardiogenic pulmonary edema. The pulmonary hypertension may play an important role in the development of HAPE.
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AIM: This study was designed to explore the effect of hypoxia on expression of P450 2C11 mRNA in cultured rat astrocytes. METHODS: Cultured rat astrocytes were randomly divided into 4 groups: glutamate group (G), hypoxic group (H), hypoxia + glutamate group (H+G) and control (C). Cells of control group were exposed to nomorxic (95% air, 5%CO 2) condition,that of G and H+G were incubated with 100 ?mol/L L-glutamate ,then cells of H and H+G exposed to hypoxic conditions (5%CO 2, 95%N 2) at 37℃?Each group had five timepoints which included 0 h, 3 h, 6 h, 12 h, 24 h, respectively. Expression of mRNAs of P450 2C11 were detected with reverse transcription ploymerase chain reaction (RT-PCR). RESULTS: Expression of P450 2C11 mRNA did not change in H and C at all the above mentioned timepoints. While it showed marked and continuous increase from 6 h to 24 h in G and from 3 h to 24 h in G+H. P450 2C11 mRNA expression was significantly higher in G than both in H and C, and it was the highest of all groups in G+H. CONCLUSIONS: Glutamate and hypoxia+glutamate increased the expression of P450 2C11 mRNA in cultured rat astrocytes continuously in 24 hours. Hypoxia alone did not increase the expression of P450 2C11 mRNA but enhanced the effect of glutamate on expression of P450 2C11 mRNA in astrocytes, which is maybe one of the mechanisms of hypoxic-induced cerebral dilation.
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AIM: To evaluate the prophylactic effect of aminophylline on the pulmonary hypertension rebound reaction to exposure to NO in the hypoxic pigs. METHODS: The 10 pigs undergone Swan-Ganz catheter, the mPAP was measured with a Physio-recording instrument and PaO 2 was measured with a blood gas analyzer, when breathing NO for 30 minutes and suddenly stopping breathing NO, administing aminophylline 0.25 g, followed by 30 minutes with room air. The respiratory rate and heart rate were also monitorried with a Hewlett-Packard portable monitor. RESULTS: The mPAP of the acute hypoxic pig was induced significantly after breathing 10 -5 NO. When suddenly stopping breathing NO, the induced mPAP became more and more high, the level of the mPAP in 5 minutes was similar to the values before absorbing NO, the mPAP in 10 minutes was higher than values before absorbing NO, while the level of PaO 2 was lower than the values before absorbing NO; but suddenly stopping breathing NO, administing aminophylline, although the induced mPAP became high, the speed was slower than the controls, the level of the mPAP in 30 minutes still was lower than the values before absorbing NO. CONCLUSION: Aminophylline has preventive effects on the pulmonary hypertension rebound reaction to exposure to NO in the hypoxic pigs.
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AIM:To investigate the roles of nitric oxide (NO) and endothelin-1(ET-1) in regulation of coronary vascular reserve (CVR) during hypoxia.METHODS: CVR were measured with 99m TC radiolabelled frog RBC, the changes of NO - 2,ET-1 contents, nitric oxide synthase(NOS) activity and the myocardial morphometry were observed. RESULTS: (1) Acute hypoxia caused an increase in left and right ventricular myocardial blood flow,myocardial NO - 2,ET-1 contents,NOS activity,but CVR in the left and right ventricle were decreased compared with the control group.(2) Intermittent hypobaric hypoxia for 90 days did not lead to significant change in left ventricular CVR,myocardial ET-1/NO - 2 ratio. However, right ventricular myocardial ET-1 contents,ET-1/ NO - 2 ratio were increased,right ventricular CVR and myocardial NO - 2 contents were decreased. We also observed that perivascular collagen,arterial wall thickness in right ventricle, hematocrit,RV weight index were augmented. CONCLUSION: Rest myocardial blood flow was increased,CVR was decreased;The decreased coronary vascular reserve during chronic hypoxia might be resulted from the increased hematocrit,arterial wall thickness,perivascular collagen,ET-1 content, the decreased NO content and right ventricular hypertrophy.
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AIM: This study was designed to investigate the protective role of hypobaric hypoxic pretreatment (HHPT) on hippocampal neurons in Babl/c inbred mice. METHODS: HHPT was produced by simulating a 7 000 m high altitude 2.5 h/d for 3 d. At 36 h after last time decompression, three subgroups consisted of both the control and pretreatment mice were subjected to the 12 000 m high altitude hypobaric hypoxia for 4 h, the severe ischemia produced by bilateral common carotid artery occlusion for 18 min, and the severe ischemia/hypoxia produced by permanently ligation of right lateral common carotid artery followed by a 8 000 m high altitude hypobaric hypoxia for 4 h, respectively. The extents of protection to hippocampal CA1 neurons by HHPT were evaluated by accounting the number of intact neurons between HHPT and control group. RESULTS: The results indicated that HHPT protected hippocampal neurons against severe hypobaric hypoxia, severe ischemia, and ischemia combined with hypobaric hypoxia. CONCLUSION: Hypobaric hypoxic pretreatment induces a delayed protection to hippocampal neurons against hypoxic and ischemic injuries.
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The left and right cardiac function of 11 patients with chronic mountain sickness was studied before and after oxygen administration. It was found that after pure oxygen was inhaled, the internal diameter of the right ventricle, the ratio between right and left ventrcular diameters, and the heart rate were decreased significantly, while the ?-wave excursion of the pulmonary valve and the EF slope of the mitral valve were increased obviously. However there was no change of the systolic time interval of both the ventricles and of the left ventricular systolic function. The results suggest that oxygen inhalation could relieve hypoxic pulmonary hypertension and improve left ventricular diastolic function.
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Objective To explore the effects of acute or chronic hypoxia on the viscoelastic properties of polymorphonuclear leukocyte (PMN) of rats. Methods Hypobaric chamber was used to simulate high altitude condition. Fifteen adult Wistar rats were randomized into 3 groups: control, acute hypoxia (5 000 m for 3 d) and chronic hypoxia (5 000 m for 30 d). Micropipette aspiration technique was used to evaluate the biomechanical properties of PMNs of rats and the experimental results were fitted with a three-element standard linear solid model. Results The viscoelastic coefficients of PMNs in acute hypoxic condition [K1=(86.66?26.84) Pa, K2=(399.89?22.03)Pa, ?=(4.23?1.82) Pa?s] or those values in chronic hypoxic condition [K1=(179.61?26.31) Pa, K2=(472.12?30.36) Pa, ?=(9.21?2.65) Pa?s] were significantly higher than the corresponding value of PMNs in control(P
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Objective To investigate the effects of hypoxia on the rheologic properties of leukocytes in microcirculation of rats, and its relationship with the expressive changes of CD18 of neutrophils. Methods Hypobaric chamber was used to simulate the plateau condition for the establishment of animal hypoxic model. Adult Wistar rats were randomized in three groups: control group, short-term hypoxia group (Hypobaric chamber simulated 5000m altitude for 3days) and long-term hypoxia group (Hypobaric chamber simulated 5000m altitude for 30 days). Intravital microscopy and computer image analysis system were used to evaluate the rheologic properties of leuckcytes in mesentery microcirculation. Neutrophils of the three experimental groups were purified and the expression of CD18 was determined by flow cytometer. Results Compared with control group, the rheologic properties of leukocytes were changed obviously at both short-term hypoxia and long-term hypoxia groups, including the number of leukocytes rolling and adherenced on endothelium increased, TLECT (total leukocyte-endothelium contact time) obviously extended (P