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Coronary microcirculation disorder after myocardial ischemia reperfusion （MIR） is a prominent problem in the treatment of coronary heart disease. According to the physiological commonality between “collaterals-sweat pore qi and fluid” and coronary microcirculation， and the evolution of the course of MIR， it is believed that “heart collateral stasis obstruction， sweat pore constraint and block” is the cause of coronary microcirculation disorder. The evolution of the pathogenesis can be divided into three periods. During the myocardial ischemia period， the pathogenesis is heart collaterals obstruction and sweat pores empty， while during the ischemia reperfusion period， it is internal formulation of deficiency wind， spasms of collaterals or slight heart collaterals obstruction； in the coronary microcirculation disorder period， sweat pores constraint and block， constraint transforming into heat， qi and fluid failing to diffuse are the pathogenesis. The corresponding treatment principle is assisting dredge with supplementation， and supplementing deficiency to dispel stasis； treating wind and blood simultaneously， and extinguishing wind to arrest convulsion； clearing heat and cooling blood， and diffusing qi and unblocking qi and fluid. Moreover， it is recommended to treat the heart and lungs simultaneously， and regulate the heart and liver at the same time.
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This study is to explore the mechanism of Xueshuantong improving cerebral microcirculation disorder through the combination of network pharmacology and experimental validation in vivo. Structural formulas of main Panax notoginseng saponins, including notoginsenoside R1, and ginsenoside Rg1, Re, Rb1 and Rd were obtained from Pubchem website and their potential targets were predicted by Swiss Target Prediction database. Potential molecular targets of brain microcirculation disorder were acquired from OMIM and GeneCards database. The overlapped molecular targets between the drug and disease were analyzed. Protein interaction analysis and topology maps were constructed through the STRING online analysis platform and Cytoscape software. Core action targets were selected. GO function and KEGG pathway were analyzed by DAVID database. Immunohistochemical method was used to examine the expression of platelet endothelial cell adhesion molecule-1 (CD31) in the ischemic cortex of middle cerebral artery occlusion and reperfusion (MCAO/R) rats. The levels of mRNA and protein expressions of core action targets in MCAO/R model rats′ brain microvessels were verified by RT-qPCR and Western blot. Based on network pharmacology, 242 targets of Xueshuantong, 425 targets of brain microcirculation disorder, and 35 overlapped targets were obtained. The potential key targets of Xueshuantong, protein kinase B (AKT1), vascular endothelial growth factor A (VEGFA), caspase 3 (CASP3), matrix metallopeptidase 9 (MMP-9), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), signal transducer and activator of transcription 3 (STAT3) involved in the alleviation of cerebral microcirculation disorder were obtained by setting degree and betweenness centrality as screening parameters. Xueshuantong at the dose of 48 mg·kg-1 was shown to significantly improve the injury of neurological behaviors, as well as the density and morphology of microvessels of MCAO/R model rats. Xueshuantong could down-regulate the mRNA levels of AKT1, MMP-9, and STAT3, increase the protein expression levels of CD31, phosphorylated AKT and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and the ratio of B-cell lymphoma 2/Bcl-2-associated X (Bcl-2/Bax), but decrease the protein expression levels of MMP-9, cleaved caspase-3 and phosphorylated STAT3. In summary, Xueshuantong could improve ischemic cerebral microcirculation disorder and thereby reduce nerve damage in ischemia-reperfusion rats by regulating signaling pathways related with PI3K, AKT, MMP-9, STAT3 and caspase-3 in microvessels. The study strictly adhered to all ethical protocols that experimental animals should follow in the course of medical research.
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Objective:To observe the effects of adjuvant therapy of Huayu pills on neurological recovery of patients with acute cerebral infarction (ACI) and syndrome of Qi deficiency and blood stasis, and to investigate its mechanism of action for antioxidation, anti-inflammation and improvement of microcirculation. Method:One hundred and forty patients were randomly divided into control group (70 cases) and observation group (70 cases) by random number table. During the study period, there were 3 drop-out cases, 2 excluded cases, and 65 completed cases in the control group. There were 1 drop-out cases, 4 excluded case, and 65 completed cases in the observation group. Western medicine was given in both groups. Patients in control group additionally got oral administration of Xiaoshuang Tongluo tablets, 6 tablets/time, 3 times/day. The patients in observation group got oral administration of Huayu pills, 5 g/time, 2 times/days. The treatment course was 4 weeks in both groups. Before the treatment, and at the second and fourth week after treatment, scores of national institute of health stroke scale (NIHSS) were graded. Before and after treatment, scores of functional independent measures (FIM) scale, fugl-meyer assessment of motor function (FMA), Qi deficiency and blood stasis syndrome were graded. Disability/mortality and safety were discussed after treatment. Levels of the whole blood viscosity (BV), plasma viscosity (PV), platelet aggregation rate (PAG), fibrinogen (FIB), P-selectin (CD62p), D-dimer (D-D), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), lipid peroxide (PLO), homocysteine (Hcy), tumor necrosis factor -α (TNF-α), serum cystatin C (Cys-C) and hypersensitive C-reactive protein (hs-CRP) were detected both before and after treatment. Result:In the analysis of rank sum test, clinical efficacy in observation group was better than that in control group (Z=2.131, P<0.05). At the second and fourth week after treatment, scores of NIHSS, Qi deficiency and blood stasis, as well as levels of NO, PLO, MDA, Hcy, Cys-C, hs-CRP, TNF-α, BV, PV, PAG, FIB, CD62 p and D-D in observation group were lower than those in control group (P<0.01), while levels of FIM, FMA and SOD were all higher than those in control group (P<0.01). Conclusion:Based on the comprehensive treatment of Western medicine, adjuvant therapy of Huayu pills can improve the degree of nerve function defect, improve the ability of exercise and daily life, reduce the degree of disability, improve the microcirculation and hemorheology, reduce the inflammatory reaction, eliminate oxygen free radicals, and relieve the oxidative stress injury in patients with ACI and Qi deficiency and blood stasis syndrome, and the clinical efficacy is better than that of Western medicine alone.
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Objective: To explore the mechanism of Shenqi Jiangtang Granules (SJG) in the treatment of diabetic microcirculation disorder based on network pharmacology. Methods: The targets of diabetic kidney disease, diabetic retinopathy, diabetic peripheral neuropathy, diabetic foot disease and small cerebral vascular disease were searched through Genecards database to be integrated as the targets of diabetic microcirculation disorder disease. The targets of SJG' active components for treatment of diabetic microcirculation disorder were screened and predicted by utilizing PubChem Search and Swiss target prediction online tool. Cytoscape 3.3.0 software was adopted to construct an active component-diabetic microcirculation disorder target network. The protein-protein interaction (PPI) network was established by using STRING database. Gene ontology (GO) biological process and Kyoto Encyclopedia of Genes and Gnomes (KEGG) pathway enrichment analysis were performed using Clue GO. Results: A total of 85 active components of SJG and 10 targets (ACE, VEGFA, TNF, IL6, STAT3, ALB, PON1, PTPN22, PPARG and NOS3) related to diabetic microcirculation disorder were screened. Through GO and KEGG pathway enrichment analysis, it was found that the active components of SJG in the treatment of diabetic microcirculation disorder may participate in multiple signaling pathways, such as AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, insulin resistance, hypertrophic cardiomyopathy, inflammatory bowel disease, rheumatoid arthritis, etc. Conclusion: This study reflects the characteristics of multi-components, multi-targets and multi-pathways of SJG, which provides new ideas and clues for further research on the mechanism of SJG in the treatment of diabetic microcirculation disorder.
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OBJECTIVE@#To investigate the mechanism by which dripping pills (STDP) improves coronary microcirculation disorder (CMD) and cardiac dysfunction in a porcine model of myocardial ischemia-reperfusion injury.@*METHODS@#Fourteen minipigs were randomly selected for interventional balloon occlusion of the middle left anterior descending branch to induce CMD, and another 7 pigs received sham operation. The pig models of CMD were randomized equally into the model group and STDP-treated group. All the animals were fed with common feed for 8 weeks, and in STDP-treated group, the pigs were given STDP at the daily dose of 3 mg/kg (mixed with feed) for 8 weeks. Before and at the 8th week after the operation, the pigs underwent coronary angiography and echocardiography to determine the vessel lumen diameter and TIMI frame count (CTFC). The pathologies of the myocardium and the microvessels were examined with HE staining at the 8th week. Western blotting was used to detect the expression of silencing information regulator (Sirt1), peroxidase proliferator-activated receptor-γ coactivator-1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), extracellular signal-regulated kinase1/2 (ERKI/2), Toll-like receptor 4 (TLR4), and uncoupling protein 2 (UCP2) in myocardial tissue.@*RESULTS@#Before and at the 8th week after the operation, the diameter of the anterior descending vessel in the 3 groups did not differ significantly ( > 0.05). At the 8th week, the number of CTFC frames in the model group increased significantly compared with that in the sham-operated group, but was obviously lowered by treatment with STDP ( < 0.05). Myocardial ischemia-reperfusion injury significantly increased the interventricular septal thickness at end-diastole, left ventricular end-diastole dimension, end-diastole volume, interventricular septal thickness at end-systole and left ventricular mass at 8 weeks after the modeling ( < 0.05), but such changes were significantly alleviated by treatment with STDP (P < 0.05). STDP treatment markedly alleviated myocardial microvascular congestion, thrombosis and peripheral inflammatory cell infiltration induced by myocardial ischemia-reperfusion, but atrophy of the myocardial muscle fiber remained distinct. STDP obviously suppressed the down-regulation of Sirt1, PGC-1α, and PPARα and the up-regulation of ERK1/ 2, TLR4, and UCP2 in the myocardial tissues induced by myocardial ischemia-reperfusion injury.@*CONCLUSIONS@#STDP has anti-inflammatory effects and regulates energy metabolism in the myocardium through modulating Sirt1, PGC-1α, PPARα, ERKI/2, TLR4, and UCP2 to improve CMD and cardiac dysfunction after myocardial ischemia-reperfusion.
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Animals , Rats , Drugs, Chinese Herbal , Microcirculation , Myocardial Reperfusion Injury , Myocardium , Rats, Sprague-Dawley , SwineABSTRACT
OBJECTIVE@#To observe the effect of bloodletting acupuncture at twelve -well points of hand on microcirculatory disturbance in mice with traumatic brain injury (TBI), and to explore the protective effect of bloodletting therapy on TBI.@*METHODS@#Sixty clean adult male C57BL/6J mice were randomly divided into a sham-operation group, a model group and a treatment group, 20 mice in each group. The TBI model was established by using electronic controlled cerebral cortex impact instrument in the model group and the treatment group. The mice in the treatment group were treated with bloodletting acupuncture at bilateral "Shaoshang" (LU 11), "Shangyang" (LI 1), "Zhongchong" (PC 9), "Guanchong" (TE 1), "Shaochong" (HT 9) and "Shaoze" (SI 1) immediately after trauma. The mice in the sham-operation group only opened the bone window but did not receive the strike. The regional cerebral blood flow (rCBF) was monitored by laser speckle contrast analysis (LASCA) using a PeriCam PSI System before trauma, immediately after trauma and 1, 2, 12, 24, 48, 72 h after trauma. The brain water content was measured by wet-dry weight method 24 h after trauma. The severity of functional impairment at 2, 12, 24, 48 and 72 h after trauma was evaluated by modified neurological scale scores (mNSS).@*RESULTS@#① 2 h after trauma, the mNSS in the model group and treatment group were >7 points, suggesting the successful establishment of model; compared with the sham-operation group, the mNSS was increased significantly from 12 to 72 h after trauma in the model group ( all <0.01), but the mNSS in the treatment group was significantly lower than that in the model group from 2 to 24 h after trauma (<0.01, <0.05). ② Compared with the sham-operation group, rCBF in the model group was decreased significantly immediately after trauma (<0.01), and the rCBF in the model group was lower than that in the sham-operation group from 1 to 72 h after trauma ( all <0.01); rCBF in the treatment group began to rise and was significantly higher than that in the model group 1-2 h after trauma (<0.01); 12-48 h after trauma, the increasing of rCBF in the two groups tended to be gentle until 72 h after injury, and rCBF in the model group was decreased while that in the treatment group continued to rise and was higher than that in the model group (<0.01). ③ 24 h after trauma, the brain water content in the model group was significantly higher than that in the sham-operation group (<0.01), and brain water content in the treatment group was significantly lower than that in the model group (<0.01).@*CONCLUSION@#The bloodletting acupuncture at twelve -well points of hand could improve microcirculation disturbance, increase microcirculation perfusion, alleviate secondary brain edema and promote the recovery of nerve function in mice with TBI.
Subject(s)
Animals , Male , Mice , Acupuncture Points , Acupuncture Therapy , Bloodletting , Brain Injuries, Traumatic , Therapeutics , Mice, Inbred C57BL , Microcirculation , Random AllocationABSTRACT
Objective To study the effect and mechanism of capillary microcirculation disturbance on intracerebral hemorrhage. Methods The loading effect of capillaries was replaced by the introduction of porous media. A microcirculation model from the capillaries to the veins was established. The appropriate mechanical boundary conditions were set up for the model by referring to various physiological conditions of human body, and the changes in blood pressure and stress of vascular wall under various conditions were simulated. Results Under normal circumstances, the whole blood pressure of the LSA was relatively low, and the pressure difference between the beginning and the end of the LSA was more obvious, and the stress of all parts of the vascular wall was at the same level. In the case of microcirculation disorder, the whole blood pressure of the LSA increased and the pressure difference between the beginning and the end of the LSA significantly decreased. The stress for each part of the vessel increased and the stress at the end of the LSA increased most significantly. Conclusions The influence of microcirculation disturbance on hemodynamics of the LSA was particularly significant. It was an important factor leading to hemorrhage of the LSA rupture. The research findings are of important theoretical and practical significance for understanding the mechanism of cerebral vascular rupture and preventing the occurrence of cerebral hemorrhage in the case of microcirculation disturbance.
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Objective To observe the clinical therapeutic effect of Xuebijing injection on vascular endothelial cell ( VEC) injury,microcirculation disorder and organ dysfunction in patients with sepsis. Methods Seventy?three patients with sepsis were randomly divided into two groups:Xuebijing injection?treated group (40 cases) and control group (33 cases). Routine medicine therapy was applied in both groups. Additionally, the Xuebijing injection?treated group was treated with Xuebijing injection 100 ml and saline 100 ml by intravenous drip every 12 hours for consecutive 5 days. Vascular endothelial injury index, including soluble thrombomodulin( sTM) ,vascular endothelial growth factor 2 ( VEGF?2) ,endothelial specific molecule 1 ( ESM?1),microcirculation index of arterial blood lactic acid (Lac),central venous oxygen saturation (ScvO2),total microvessel density (TVD),the perfusion vascular density (PVD),proportion of perfused vessels (PPV) and microvessel flow index ( MFI) of the two groups before and after therapy were observed and the sequential organ failure score ( SOFA) was recorded before and after treatment. Results Senventy?three patients with sepsis had different degrees of increase in vascular endothelial damage markers,lactate and sequential organ failure scores in arterial blood, while the central venous blood oxygen saturation ( ScvO2 ) , the total vascular density of the sublingual microvasculature ( TVD) ,perfused vessel density ( PVD) ,proportion of perfused vessels ( PPV) and microcirculatory flow index ( MFI) decreased before treatment. After 5?day treatment,the above indicators of all patients were improved,the indexes in the Xuebijing injection group decreased significantly,compared with the control group ,sTM ( (16. 91±4. 55) μg/L,(19. 51±4. 09) μg/L,t=-6. 021,P<0. 05),VEGF?2 (50. 8 (17. 8,127. 7) ng/L vs. 74. 9(22. 7,155. 1) ng/L,t=4. 227,P<0. 05),ESM?1 ( (10. 20 ±2. 43) μg/L vs. (14. 80±3. 52) μg/L,t=-4. 113,P<0. 05),Lac( (2. 1±0. 7) mmol/L vs. (3. 7±1. 1) mmol/L,t=2. 366,P<0. 05) and SOFA ( (5. 9±2. 1) vs. (8. 7±2. 6),t=-7. 990,P<0. 05). ScvO2( (0. 771±0. 153) % vs. (0. 641±0. 113) %,t=5. 061,P<0. 05),PVD ( (16. 8±6. 1) mm/mm2 vs. (12. 1±5. 1) mm/mm2,t=4. 002, P<0. 05),PPV ( (66. 2±21. 3) % vs. (50. 4±19. 3) %,t=-2. 550,P<0. 05) and MFI (6. 2 ±2. 4) vs. (3. 8 ±2. 2),t=-5. 001,P<0. 05) were significantly higher than those in the control group in the same period. sTM and PPV had a significant negative correlation (r=-0. 755,P=0. 000),PVD,PPV,ESM?1 and MFI were negatively correlated (r=-0. 665,P=0. 000; r=-0. 600,P=0. 000; r=-0. 469,P=0. 000),PPV,MFI and SOFA were negatively correlated ( r=-0. 798,P=0. 000;r=-0. 995,P=0. 000);sTM,ESM?1 and SOFA were significantly positively correlated ( r = 0. 883, P = 0. 000;r = 0. 881, P = 0. 000 ) . Conclusion Vascular endothelial cell dysfunction probably plays an important role in the pathophysiology of sepsis and Xuebijing injection has therapeutic effect on sepsis by protecting vascular endothelial cell function.
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Objective To explorethe relationship between serum uric acid (SUA ) and transcutaneousoxygenpressure(TcPO2)inpatientswithT2DM.Methods 622hospitalizedpatients with T2DM were recruited and divided into high SUA (HUA) group and normal SUA (T2DM) group.The differences in TcPO2 (initial value ,stable value ,initial value‐stable value ,leg‐raising initial value and leg‐raising maximum value)were compared between two groups.The correlations between SUA and TcPO2 were evaluated. Results The levels of TcPO2 were lower in HUA group than in T2DM group [initial value:left (34.05 ± 13.17) vs (39.26 ± 15.82) ,right (34.71 ± 14.90) vs (40.15 ± 16.23);stable value:left (38.93 ± 12.23) vs(45.19 ± 13.40) ,right (39.98 ± 12.34) vs (45.90 ± 16.77) ,P<0.05]. Pearson correlation analysis showed that the SUA levels negatively related with the stable TcPO2 value of leftor right side ,and with the change between the initial value and the stable value of TcPO2 (P<0.05 or P<0.01). The multiple linear regression analysis showed that SUA level was the impact factorof the left TcPO2 stable value. Conclusion HUA may be one of the risk factors microcirculation disorder in T2DM patients.