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The aim of this study was to investigate the effect and molecular mechanism of Xuebijing Injection in the treatment of sepsis-associated acute respiratory distress syndrome(ARDS) based on network pharmacology and in vitro experiment. The active components of Xuebijing Injection were screened and the targets were predicted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). The targets of sepsis-associated ARDS were searched against GeneCards, DisGeNet, OMIM, and TTD. Weishengxin platform was used to map the targets of the main active components in Xuebijing Injection and the targets of sepsis-associated ARDS, and Venn diagram was established to identify the common targets. Cytoscape 3.9.1 was used to build the "drug-active components-common targets-disease" network. The common targets were imported into STRING for the building of the protein-protein interaction(PPI) network, which was then imported into Cytoscape 3.9.1 for visualization. DAVID 6.8 was used for Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment of the common targets, and then Weishe-ngxin platform was used for visualization of the enrichment results. The top 20 KEGG signaling pathways were selected and imported into Cytoscape 3.9.1 to establish the KEGG network. Finally, molecular docking and in vitro cell experiment were performed to verify the prediction results. A total of 115 active components and 217 targets of Xuebijing Injection and 360 targets of sepsis-associated ARDS were obtained, among which 63 common targets were shared by Xuebijing Injection and the disease. The core targets included interleukin-1 beta(IL-1β), IL-6, albumin(ALB), serine/threonine-protein kinase(AKT1), and vascular endothelial growth factor A(VEGFA). A total of 453 GO terms were annotated, including 361 terms of biological processes(BP), 33 terms of cellular components(CC), and 59 terms of molecular functions(MF). The terms mainly involved cellular response to lipopolysaccharide, negative regulation of apoptotic process, lipopolysaccharide-mediated signaling pathway, positive regulation of transcription from RNA polyme-rase Ⅱ promoter, response to hypoxia, and inflammatory response. The KEGG enrichment revealed 85 pathways. After diseases and generalized pathways were eliminated, hypoxia-inducible factor-1(HIF-1), tumor necrosis factor(TNF), nuclear factor-kappa B(NF-κB), Toll-like receptor, and NOD-like receptor signaling pathways were screened out. Molecular docking showed that the main active components of Xuebijing Injection had good binding activity with the core targets. The in vitro experiment confirmed that Xuebijing Injection suppressed the HIF-1, TNF, NF-κB, Toll-like receptor, and NOD-like receptor signaling pathways, inhibited cell apoptosis and reactive oxygen species generation, and down-regulated the expression of TNF-α, IL-1β, and IL-6 in cells. In conclusion, Xuebijing Injection can regulate apoptosis and response to inflammation and oxidative stress by acting on HIF-1, TNF, NF-κB, Toll-like receptor, and NOD-like receptor signaling pathways to treat sepsis-associated ARDS.
Subject(s)
Humans , Network Pharmacology , Vascular Endothelial Growth Factor A , NF-kappa B , Interleukin-6 , Lipopolysaccharides , Molecular Docking Simulation , Respiratory Distress Syndrome, Newborn , Tumor Necrosis Factor-alpha , Sepsis/genetics , NLR ProteinsABSTRACT
Cardiovascular disease (CVD) is a major contributor to patient deaths worldwide, and its pathogenesis is complex and mortality rates are increasing every year. Numerous researches have shown that the gut microbiota and its metabolites were closely associated with the development of CVD, and gut microbiota was expected to be a potential new target for the treatment of CVD. Traditional Chinese medicine (TCM), characterized by its multi-component, multi-target and integrity, can play a therapeutic role in CVD by regulating the gut microbiota, which has obvious advantages in stabilizing the disease, improving heart function and enhancing quality of life, and is an ideal intestinal microecological regulator. Therefore, this review will mainly discuss the intimate association of gut microbiota and its metabolites with CVD, and the therapeutic strategies of TCM targeting gut microbiota to improve CVD, including regulating the composition of gut microbiota, protecting the intestinal mucosal barrier, influencing the intestinal immune function and modulating the metabolites of gut microbiota, in order to provide a reference for the research of TCM targeting gut microbiota for CVD.
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Krüppel-like transcription factor 2 (KLF2) plays a key regulatory role in endothelial inflammation, thrombosis, angiogenesis and macrophage inflammation and polarization, and up-regulation of KLF2 expression has the potential to prevent and treatment atherosclerosis. In this study, trichostatin C (TSC) was obtained from the secondary metabolites of rice fermentation of Streptomyces sp. CPCC 203909 as a KLF2 up-regulator by using a high throughput screening model based on a KLF2 promoter luciferase reporter assay. TSC significantly inhibited the adhesion of tumor necrosis factor-α (TNFα) induced monocytes (THP-1) to human umbilical vein endothelial cells (HUVECs). Western blot results showed that TSC decreased TNFα induced the protein expression increase of vascular cell adhesion molecule-1 (VCAM-1), and thereby inhibited endothelial inflammation. The results of histone deacetylase (HDAC) overexpression and molecular docking experiments showed that TSC upregulated the expression of KLF2 by inhibiting subtypes of HDAC 4/5/7. In conclusion, this study suggests that TSC up-regulates the expression of KLF2 through inhibiting HDAC 4/5/7 and thus inhibits TNFα induced endothelial inflammation, and it has the potential to prevent and treat atherosclerosis.
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Dyslipidemia is a disease of lipid metabolism. At present, the prevalence of dyslipidemia in adults in China is as high as 40.40%. In the United States, there are more than 100 million individuals with abnormal low-density lipoprotein cholesterol (LDL-C), and the incidence rate is increasing year by year and showing a trend of becoming younger. Dyslipidemia is closely related to a variety of diseases such as fatty liver, atherosclerosis , hypertension, coronary heart disease, diabetes, and stroke. It has now developed into a global public health problem that seriously threatens human life and health. Modern medicine believes that its pathogenesis is complicated and is related to abnormal glucose and lipid metabolism, insulin resistance (IR) and other factors. Chinese medicine ascribes it to primary asthenia-secondary sthenia syndrome, which is closely related to the liver, spleen, and kidney. It is believed that excessive fat and grease can cause phlegm and cause many diseases. In terms of its treatment, western medicine mainly uses statin chemical synthesis preparations, with stable therapeutic effect, but many adverse reactions such as myalgia, myositis, rhabdomyolysis and acute renal injury are the main factors restricting its clinical application. Traditional Chinese medicine (TCM) has a long history, and multi-pathway, multi-target, multi-level regulation of dyslipidemia, few adverse reactions and low drug dependence are the principal advantages of TCM in treating dyslipidemia. At present, there are more and more researches on the prevention and treatment of dyslipidemia by TCM, but they are mainly focused on the observation of curative effect and the summary of prescription, and there are relatively few in-depth discussion and summary of the mechanism of TCM. Through comprehensively retrieving and collating the relevant domestic and foreign literatures in the past five years, we reviews from the perspective of effective ingredients, therapeutic pathways, and targets of action, and comprehensively introduces the latest research progress of TCM on the mechanism of regulating dyslipidemia, and put forward some suggestions for the possible research direction in the future, in order to provide new ideas and theoretical basis for TCM in clinical prevention and treatment of this disease.
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Objective:To investigate the effects of electroacupuncture at Baihui (DU20) and Shenting (DU24) on brain function of APP/PS1 mice. Methods:Sixteen 4-month-old APP/PS1 mice in the same litter were randomly divided into model group (n = 8) and electroacupuncture group (n = 8). Eight transgenic negative mice in the same litter were as control group. The electroacupuncture group accepted electroacupuncture at Baihui and Shenting for 16 weeks. They were assessed with Object Recognition Test before and after intervention, and observed under small animal functional magnetic resonance imaging with regional homogeneity (ReHo) analysis. Results:Compared with the control group, the discrimination ratio decreased in the model group after intervention (P < 0.05), while it increased in the electroacupuncture group compared with that in the model group (P < 0.05). Compared with the control group, ReHo of right basal forebrain and left hippocampus decreased in the model group before intervention. Compared with the control group, ReHo decreased in bilateral hippocampus group and increased in retrosplenial cortex in the model group after intervention; while it increased in bilateral hippocampus and motor cortex and decreased in anterior cingulate gyrus in the electroacupuncture group compared with that in the model group. Conclusion:Electroacupuncture at Baihui and Shenting may delay the decline of learning and memory ability in Alzheimer's disease model mice, which may relate to the regulation of functional activities in hippocampus.
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Objective To study the chemical components from aerial part of Tibetan herbal medicines Biebersteinia heterostemon. Methods The chemical constituents were isolated and purified by silica gel, Sephadex LH-20 chromatography and preparative liquid chromatography. Their structures were identified by physicochemical properties and spectral analysis. Results Thirteen compounds were isolated from B. heterostemon and their structures were identified as umbelliferone (1), 5,7,3’-trihydroxy-8,4’,5’- trimethoxyflavone (2), luteolin (3), quercetin (4), protocatechuic acid methyl ester (5), apigenin (6), alternariol (7), luteolin-7-O-β-D- glucoside (8), quercetin-3-O-β-D-glucoside (9), (+)-dehydrovomifoliol (10), β-sitosterol (11), 4’-methoxytricetin (12), and 3’,4’,5,8- tetrahydroxyflavanone-7-O-β-glucopyranoside (13). Conclusion Compounds 3, 5-7, 10, 11-13 are isolated from B. heterostemon for the first time. Compounds 5, 7, 10, 12, 13 are isolated from the genus Biebersteinia for the first time.
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Drug-induced cardiotoxicity is recently a major concern. Cardiotoxicity is the leading cause of drug withdrawal from the market. Long-QT syndrome is one of the most important manifestations of cardiotoxicity. hERG potassium channel is an important target of drug-induced arrhythmia and antiarrhythmia drugs. Traditional Chinese medicine is a traditional medicine in China with a long history and a wide range of clinical use. However, the multi-organ toxicity caused by traditional Chinese medicine is still a problem to be solved. Some traditional Chinese medicines already in clinical use have been withdrawn from the market because of their potential cardiotoxicity or severe arrhythmias. The cardiac toxicity of more than 50 kinds of traditional Chinese medicines causing arrhythmia was reported, while more than 20 of them are induced by affecting on the hERG potassium channels. Therefore, finding out the mechanism of drug-induced long-QT syndrome and the regulatory target of drug intervention is the key research goal in today's medical field. In this paper, we summarized the mechanisms of long-QT syndrome induced by traditional Chinese medicine with Ikr/hERG potassium channel as the main target. It provides a theoretical basis for the rational use of related traditional Chinese medicine in clinical practice, the avoidance of cardiac toxicity and the development of regulatory targets for drug intervention.
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Objective:To investigate whether electroacupuncture (EA) at Quchi (LI11) and Zusanli (ST36) acupoints may regulate microRNA-34a (miR-34a) to promote neural stem cells differentiation in ischemic peripheral areas in rats with cerebral ischemia-reperfusion injury or not. Methods:A total of 108 rats were randomly assigned into sham group, model group and EA group, and each group was divided into three subgroups (three days, seven days and 14 days), with twelve rats in each subgroup. Besides, 16 rats were randomly divided into EA+dimethyl sulfoxide (DMSO) group and EA+miR-34a inhibitor group, with eight rats in each group. The middle cerebral artery occlusion (MCAO) model was induced for focal cerebral ischemia in rats. EA group was electroacupunctured at the ipsilateral Quchi and Zusanli acupoints on the second day. The dilatational wave was 1/20 Hz, 30 minutes every time, once a day for seven days, totally. At the same time, 5-Bromo-2′-Deoxyuridine (BrdU) was intraperitoneally injected twice a day, with an 8-hours interval. The DMSO and miR-34a inhibitor were injected into the lateral ventricle before modeling. The co-location condition was evaluated by immunofluorescence. The expression of miR-34a in ischemic peripheral areas was detected by reverse transcription real-time quantitative polymerase chain reaction. Results:The Longa's score was lower in EA group than in the model group (t > 2.084, P < 0.05). At the same time points, the paw print areas (right forepaw, right hind paw) and maximum pressures (right forepaw, right hind paw) of the affected limbs decreased in the model group than in the sham group (P < 0.05), and the paw print area of right hind paw gradually increased in the model group (P < 0.05); the paw print areas (right forepaw and right hind paw) of the affected limbs improved in EA group, compared with the model group (P < 0.05); and there was no significant difference in the maximum pressure of the affected limbs three days and seven days after electroacupuncture (P > 0.05); however, it was higher in EA group than in the model group 14 days after electroacupuncture (P < 0.05). And the paw print area of the right hind paw and the maximum pressure of the right forepaw gradually increased in EA group three days and seven days after electroacupuncture, which was in time-dependent manner (P < 0.05). The Nestin+/GFAP+ and BrdU+/GFAP+ cells expressed in ischemic peripheral areas both in the model group and EA group. And the Nestin+/GFAP+ and BrdU+/GFAP+ double positive cells increased in EA group compared to the model group three days, seven days and 14 days after electroacupuncture (t > 3.292, P < 0.05), and they reached peak seven days after electroacupuncture. The expression of miR-34a in ischemic peripheral areas was higher in the model group than in the sham group seven days after modeling (P < 0.01), however, the expression of miR-34a further increased in EA+DMSO group after electroacupuncture (P < 0.05). After injection of miR-34a inhibitor, the expression of miR-34a and BrdU+/GFAP+ cells was lower in EA+miR-34a inhibitor group than in EA group (P < 0.05). Conclusion:Electroacupuncture at Quchi and Zusanli acupoints could promote the neural stem cells differentiation in ischemic peripheral areas by regulation of miR-34a expression.
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Alkaloids are a class of secondary metabolites with many structural types and significant biological activities in natural organisms. As one of the most important active ingredients in medicinal plants, they are characterized by containing nitrogen atoms in chemical structures, most of them have complex cyclic structures, possessing antitumor, antibacterial, antiviral activities, and so on. This review summarizes the structural types of hypoglycemic alkaloids and their mechanisms, which will provide new insights and references for the research on alkaloid hypoglycemic agents discovery, pharmacology, and structure-activity relationship.
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Objective To evaluate the reproducibility of three-dimensional high-resolution magnetic resonance imaging (HR-MRI) for vessel wall in demonstration of intracranial atherosclerotic plaque enhancement and to explore the relationship between plaque enhancement and ischemic stroke.Methods Fifty-two patients with ischemic stroke underwent traditional head MRI,three-dimensional time of flight magnetic resonance angiography and HR-MRI on a 3.0 T MRI scanner.Each identified intracranial plaque was classified as either culprit (the only or most stenotic lesion upstream from a stroke) or non-culprit (not the most stenotic lesion upstream from a stroke or not within the vascular territory of a stroke).The degree of plaque enhancement was graded by two independent radiologists.The degree of plaque enhancement and luminal stenosis were compared between the culprit group and the non-culprit group by using Mann-Whitney U test.Binary logistic regression analysis was performed to assess the relation between the degree of plaque enhancement and culprit plaques.Results Total 118 plaques were identified in 52 patients with ischemic stroke (52 culprit plaques and 66 non-culprit plaques).The degree of enhancement was rated as strong,moderate and none in 40,9 and 3 culprit plaques,and in 4,24 and 38 non-culprit plaques.Both intra-observer and inter-observer agreement were high for identification of plaque enhancement (kappa＞ 0.75).For culprit plaques group,the degree of plaque enhancement(Z =-7.787,P＜0.01) and luminal stenosis (Z =-5.327,P＜0.01) were significantly higher than those in the non-culprit group.Binary logistic regression analysis revealed that strong enhancement of plaques was independently associated with culprit plaques (OR:74.3,95％CI:15.0-367.1,P＜0.01).Conclusions Three-dimensional HR-MRI detects enhancement of intracranial plaques with high reproducibility.Enhancement is more common in culprit plaques and is associated with the likelihood of ischemic stroke.
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<p><b>Background</b>Fine particulate matter (PM) exacerbates airway inflammation and hyperreactivity in patients with asthma, but the mechanism remains unclear. The aim of this study was to observe the effects of prolonged exposure to high concentrations of PMon the pathology and airway hyperresponsiveness (AHR) of BALB/c mice undergoing sensitization and challenge with ovalbumin (OVA) and to observe the effects of apoptosis and T-cell immunoglobulin and mucin domain 1 (TIM-1) in this process.</p><p><b>Methods</b>Forty female BALB/c mice were divided into four groups: control group, OVA group, OVA/PM group, and PM group (n = 10 in each group). Mice in the control group were exposed to filtered clean air. Mice in the OVA group were sensitized and challenged with OVA. Mice in the OVA/PM group were sensitized and challenged as in the OVA group and then exposed to PMfor 4 h per day and 5 days per week for a total of 8 weeks using a nose-only "PMonline enrichment system" in The Second Hospital of Hebei Medical University. Mice in the PM group were exposed to the PM online enrichment system only. AHR was detected. Bronchoalveolar lavage fluid (BALF) was collected for cell classification. The levels of interleukin-4 (IL-4), IL-5, and IL-33 in BALF were measured using enzyme-linked immunosorbent assay. Changes in histological structures were examined by light microscopy, and changes in ultramicrostructures were detected by electron microscopy. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay in the lung tissues. Western blotting and immunohistochemistry were utilized to analyze the expression of Bcl-2, Bax, and TIM-1 in the lungs.</p><p><b>Results</b>The results showed that AHR in the OVA/PM group was significantly more severe than that in the OVA and PM groups (P < 0.05). AHR in the PM group was also considerably more severe than that in the control group (P < 0.05). The BALF of OVA/PM group (28.00 ± 6.08 vs. 12.33 ± 4.51, t = 4.631, P = 0.002) and PM group (29.00 ± 3.00 vs. 12.33 ± 4.51, t = 4.927, P = 0.001) had more lymphocytes than the BALF of the control group. The number of neutrophils in the BALF of the OVA/PM group (6.67 ± 1.53 vs. 3.33 ± 1.53, t = 2.886, P = 0.020) and PM group (6.67 ± 1.53 vs. 3.33 ± 1.53, t = 2.886, P = 0.020) was much higher than those in the BALF of OVA group (P < 0.05). TUNEL assays showed that the number of apoptotic cells in the OVA/PM group was significantly higher than that in the OVA group (Tunel immunohistochemical scores [IHS%], 1.20 ± 0.18 vs. 0.51 ± 0.03, t = 8.094, P < 0.001) and PM group (Tunel IHS%, 1.20 ± 0.18 vs. 0.51 ± 0.09, t = 8.094, P < 0.001), and that the number of apoptotic cells in the PM group was significantly higher than that in the control group (Tunel IHS%, 0.51 ± 0.09 vs. 0.26 ± 0.03, t = 2.894, P = 0.020). The concentrations of IL-4 (77.44 ± 11.19 vs. 48.02 ± 10.02 pg/ml, t = 4.595, P = 0.002) and IL-5 (15.65 ± 1.19 vs. 12.35 ± 0.95 pg/ml, t = 3.806, P = 0.005) and the Bax/Bcl-2 ratio (1.51 ± 0.18 vs. 0.48 ± 0.10, t = 9.654, P < 0.001) and TIM-1/β-actin ratio (0.78 ± 0.11 vs. 0.40 ± 0.06, t = 6.818, P < 0.001) in the OVA/PM group were increased compared to those in the OVA group. The concentrations of IL-4 (77.44 ± 11.19 vs. 41.47 ± 3.40 pg/ml, t = 5.617, P = 0.001) and IL-5 (15.65 ± 1.19 vs. 10.99 ± 1.40 pg/ml, t = 5.374, P = 0.001) and the Bax/Bcl-2 ratio (1.51 ± 0.18 vs. 0.97 ± 0.16, t = 5.000, P = 0.001) and TIM-1/β-actin ratio (0.78 ± 0.11 vs. 0.31 ± 0.06, t = 8.545, P < 0.001) in the OVA/PM group were increased compared to those in the PM group. The concentration of IL-4 (41.47 ± 3.40 vs. 25.46 ± 2.98 pg/ml, t = 2.501, P = 0.037) and the Bax/Bcl-2 ratio (0.97 ± 0.16 vs. 0.18 ± 0.03, t = 7.439, P < 0.001) and TIM-1/β-actin ratio (0.31 ± 0.06 vs. 0.02 ± 0.01, t = 5.109, P = 0.001) in the PM group were also higher than those in the control group.</p><p><b>Conclusions</b>Exacerbated AHR associated with allergic asthma caused by PMis related to increased apoptosis and TIM-1 activation. These data might provide insights into therapeutic targets for the treatment of acute exacerbations of asthma induced by PM.</p>
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The influence of 3α-androstanediol (3α-diol) on twitch and electroencephalogram (EEG) of the epileptic rats induced by pentylenetetrazole (PTZ) has been observed in this experiment in order to comprehensively explore the role of 3α-diol on epileptic attack from the aspects of behavior and EEG. Thirty-two male Sprague-Dawley rats were evenly and randomly divided into 4 groups: the normal and supplied with oil epileptic (N+oil+PTZ) group, the normal and supplied with 3α-diol epileptic (N+3α-diol+PTZ) group, the gonadectomized and supplied with oil epileptic (GDX+oil+PTZ) group and the gonadectomized and supplied with 3α-diol epileptic (GDX+3α-diol+PTZ) group. The changes of the behavior and EEG of epileptic rats in every group were recorded and analyzed. The results of behavior observation showed that the latency to clonic seizure and tonic-clonic seizure was shortened and the number of tonic-clonic seizure was increased significantly in the GDX+oil+PTZ group in comparison with N+oil+PTZ group (P < 0.05); comparing GDX+3α-diol+PTZ group with GDX+oil+PTZ group, or N+3α-diol+PTZ group with N+oil+PTZ group, we found that the latency to clonic seizure and tonic-clonic seizure became prolonged significantly, and the number of clonic seizure and tonic-clonic seizure was decreased significantly (P < 0.05). The results of EEG showed that the latency to epileptic waves was cut and the number of epileptic waves was augmented significantly in the GDX+oil+PTZ group in comparison with N+oil+PTZ group (P < 0.05); comparing GDX+3α-diol+PTZ group with GDX+oil+PTZ group, or N+3α-diol+PTZ group with N+oil+PTZ group, we found that the latency to epileptic waves became lengthened significantly, the number of epileptic waves was reduced significantly and the percentage of change of TP (total power of spectrum) was lessened significantly (P < 0.05). These results indicate that 3α-diol has an antiepileptic activity in the gonadectomized and normal epileptic rats.