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@#BACKGROUND: Xuebijing (XBJ) can alleviate the inflammatory response, improve organ function, and shorten the intensive care unit (ICU) stay in patients with pyogenic liver abscess (PLA) complicated with sepsis, but the molecular mechanisms have not been elucidated. This study aimed to explore the molecular mechanism of XBJ in treating PLA complicated with sepsis using a network pharmacology approach. METHODS: The active ingredients and targets of XBJ were retrieved from the ETCM database. Potential targets related to PLA and sepsis were retrieved from the GeneCards, PharmGKB, DisGeNet, Online Mendelian Inheritance in Man (OMIM), Therapeutic Targets Database (TTD), and DrugBank databases. The targets of PLA complicated with sepsis were mapped to the targets of XBJ to identify potential treatment targets. Protein-protein interaction networks were analyzed using the STRING database. Potential treatment targets were imported into the Metascape platform for Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Molecular docking was performed to validate the interactions between active ingredients and core targets. RESULTS: XBJ was found to have 54 potential treatment targets for PLA complicated with sepsis. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF) were identified as core targets. KEGG enrichment analysis revealed important pathways, including the interleukin-17 (IL-17) signaling pathway, the TNF signaling pathway, the nuclear factor-kappa B (NF-κB) signaling pathway, and the Toll-like receptor (TLR) signaling pathway. Molecular docking experiments indicated stable binding between XBJ active ingredients and core targets. CONCLUSION: XBJ may exert therapeutic effects on PLA complicated with sepsis by modulating signaling pathways, such as the IL-17, TNF, NF-κB, and TLR pathways, and targeting IL-1β, IL-6, and TNF.
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Objective:To investigate the effect of bedside high-flow continuous blood purification (CBP) combined with Xuebijing in the treatment of severe sepsis (SS) and the influence on the patient′s coagulation-fibrinolysis index, immunity index and expression of peripheral blood Toll-like receptor 4 (TLR4).Methods:Ninety-three patients with SS who were admitted and treated in the Lianyungang First People′s Hospitalfrom January 2017 to October 2019 were selected. They were divided into the combined group (51 cases, treatment with bedside high-flow CBP and Xuebijing injection based on bundle therapy) and the control group (42 cases, treatment with Xuebijing injection based on bundle therapy). The changes in coagulation and fibrinolysis index, immunity index, biochemical index such as TLR4 before treatment and after 1 week of treatment were compared between the two groups. The incidences of complications in both groups were statistically analyzed, and the discharge time from ICU, mechanical ventilation time and 28-day mortality were recorded.Results:After 1 week of treatment, the levels of prothrombin time (PT) and activated partial thromboplastin time (APTT) in the two groups were shortened, D-dimer (D-D) and fibrinogen (FIB) were decreased ( P<0.05); and the levels of PT and APTT in the combined group were shorter than those in the control group, the levels of DD and FIB were lower than those in the control group, there were statistical differences ( P<0.05). After 1 week of treatment, the levels of CD 4+ and CD 4+/CD 8+ ratio in both groups were increased ( P<0.05), and the levels of CD 4+ and CD 4+/CD 8+ ratio in the combined group were higher than those in the control group ( P<0.05). After 1 week of treatment, the levels of TLR4, C-reactive protein (CRP), procalcitonin (PCT), white blood cell count (WBC), blood lactate (Lac), blood urea nitrogen (BUN) and serum creatinine (Scr) in both groups were decreased ( P<0.05), meanwhile, the above indexes in the combined group were lower than those in the control group ( P<0.05). The incidence of multiple organ failure and the 28-day mortality rate in the combined group were lower than those in the control group: 3.92%(2/51) vs. 19.05%(8/42), 13.73%(7/51) vs. 30.95%(13/42), there were statistical differences ( P<0.05). The discharge time from ICU and mechanical ventilation time in the combined group were shorter than those in the control group: (12.35 ± 2.14) d vs. (14.17 ± 3.36) d, (7.12 ± 2.23) d vs. (8.51 ± 2.39) d, there were statistical differences ( P<0.05). Conclusions:Bedside high-flow CBP combined with Xuebijing injection in the treatment of SS can improve the patient′s condition, regulate the balance of coagulation and fibrinolysis, avoide the activation of coagulation, inhibite inflammatory response, reduce the expression of TLR4 in peripheral blood, improve immune function, protecte kidney function and promotethe patient′s recovery.
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ObjectiveTo evaluate the effect of the therapy of dispelling stasis， removing toxin， and promoting urination （modified Linggui Zhugantang combined with Xuebijing injection） on the prognosis of sepsis-induced cardiomyopathy （SICM）. MethodA total of 96 patients were randomly assigned into an observation group and a control group， with 48 patients in each group. The patients in the control group received sepsis bundle， and those in the observation group additionally received the therapy of dispelling stasis， removing toxin， and promoting urination （intravenous drip of Xuebijing injection and oral administration of modified Linggui Zhugantang）. The course of treatment in both groups was 7 days. The disease and prognosis indicators ［28-day mortality， intensive care unit （ICU） length of stay， major adverse cardiac events （MACE）， acute physiology and chronic health evaluation Ⅱ （APACHE Ⅱ）， sequential organ failure assessment （SOFA） score， and mortality in emergency department sepsis （MEDS） score］， cardiac function indicators ［left ventricular ejection fraction （LVEF）， E/A ratio of peak velocity blood flow from left ventricular relaxation in early diastole （the E wave） to peak velocity flow in late diastole caused by atrial contraction （the A wave）， E/e′ ratio of mitral peak velocity of early filling （E） to early diastolic mitral annular velocity （e′）， and afterload-corrected cardiac performance （ACP）］， myocardial injury markers ［high-sensitivity cardiac troponin T （hs-cTnT）， N-terminal pro-brain natriuretic peptide （NT-proBNP）， heart-type fatty acid-binding protein （H-FABP）， and high mobility group box-1 （HMGB-1）］， hemodynamic indicators ［extravascular lung water index （EVLWI）， global end-diastolic volume index （GEDVI）， cardiac index （CI）， and systemic vascular resistance index （SVRI）］， and TCM syndrome scores were assessed and compared between the two groups. ResultThe 28-day mortality and the incidence of MACE in the observation group were slightly lower than those in the control group. The ICU length of stay in the observation group was shorter than that in the control group （P<0.05）. After treatment， APACHE Ⅱ， SOFA， MEDS， syndrome score of stasis-caused internal obstruction， E/e′ ratio， hs-cTnT， NT-proBNP， H-FABP， and HMGB1 decreased compared with those before treatment （P<0.05）， while LVEF， E/A ratio， and ACP increased （P<0.05）. Moreover， the changes were more significant in the observation group （P<0.05）. On days 3， 5， and 7 after treatment， the EVLWI and SVRI in the observation group were lower than those in the control group （P<0.05）， while CI showed an opposite trend （P<0.05）. The observation group had higher GEDVI than the control group on days 3 and 5 after treatment （P<0.05）. ConclusionOn the basis of conventional bundle therapy， modified Linggui Zhugantang combined with Xuebijing injection with the effect of dispelling stasis， removing toxin， and promoting urination can inhibit the generation of myocardial injury markers and improve hemodynamics to shorten the length of ICU stay， mitigate the TCM syndrome， and reduce the risk of death， thereby improving the prognosis of SICM.
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The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with high pathogenicity and infectiousness has become a sudden and lethal pandemic worldwide. Currently, there is no accepted specific drug for COVID-19 treatment. Therefore, it is extremely urgent to clarify the pathogenic mechanism and develop effective therapies for patients with COVID-19. According to several reliable reports from China, traditional Chinese medicine (TCM), especially for three Chinese patent medicines and three Chinese medicine formulas, has been demonstrated to effectively alleviate the symptoms of COVID-19 either used alone or in combination with Western medicines. In this review, we systematically summarized and analyzed the pathogenesis of COVID-19, the detailed clinical practice, active ingredients investigation, network pharmacology prediction and underlying mechanism verification of three Chinese patent medicines and three Chinese medicine formulas in the COVID-19 combat. Additionally, we summarized some promising and high-frequency drugs of these prescriptions and discussed their regulatory mechanism, which provides guidance for the development of new drugs against COVID-19. Collectively, by addressing critical challenges, for example, unclear targets and complicated active ingredients of these medicines and formulas, we believe that TCM will represent promising and efficient strategies for curing COVID-19 and related pandemics.
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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.
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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
Objective:To compare the protective effect of Xuebijing injection versus Sivelestat sodium on acute lung injury/acute respiratory distress syndrome (ALI/ARDS) rats.Methods:A total of 71 male Sprague-Dawley (SD) rats were randomly divided into the blank control group ( n = 8), ALI/ARDS model group ( n = 21), Xuebijing injection group ( n = 21) and Sivelestat sodium group ( n = 21). Rats in the blank control group were injected with normal saline while the other three groups were intravenously injected 25 mg/kg lipopolysaccharide (LPS) via the tail vein to establish ALI/ARDS model. After induction of ALI/ARDS model, the blank control group and ALI/ARDS model group were given intraperitoneal injection of an equal volume of normal saline twice a day. Rats in the Xuebijing injection group were given tail vein injection of 8 mL/kg Xuebijing injection twice a day, and those in the Sivelestat sodium group were given intraperitoneal injection of 100 mg/kg Sivelestat sodium three times a day. All rats were administered continuously for five days. During the experiment, the general status of rats was observed, and the weight and survival were recorded. At the end of the experiment, bronchoalveolar lavage fluid (BALF) of rats was collected for the detection of inflammatory cells and inflammatory factors. Histopathological changes of rats lung tissue were observed. Results:Compared with the ALI/ARDS model group, the Xuebijing injection group and Sivelestat sodium group had significantly decreased white blood cell (WBC) count and percent of neutrophil (NEU%) [WBC (×10 9/L): 55.86±6.68, 49.96±6.76 vs. 73.13±7.35, NEU%: 0.459±0.077, 0.315±0.047 vs. 0.709±0.067, all P < 0.05], significantly increased percent of lymphocytes (LYM%: 0.412±0.067, 0.517±0.051 vs. 0.232±0.057, both P < 0.05), and reduced interleukin-6 (IL-6) level (ng/L: 295.2±39.7, 281.9±33.1 vs. 469.6±77.0) in BALF. However, there were no significant differences in these parameters between the Xuebijing injection group and Sivelestat sodium injection group (all P > 0.05). Survival rate at the end of experiment was higher in the Xuebijing group than that in the Sivelestat sodium injection group and ALI/ARDS model group [52.4% (11/21) vs. 28.6% (6/21), 14.3% (3/21)], and survival rate at the end of experiment was higher in the Sivelestat sodium injection group than that in the ALI/ARDS model group, but the differences were not statistically significant ( P > 0.05). In addition, weight and weight growth rate in the Xuebijing injection group were higher than the Sivelestat sodium group at the end of the experiment [weight (g): 217.1±6.4 vs. 207.1±7.0, weight growth rate: (-0.9±2.8)% vs. (-4.3±3.5)%], there were no significant difference between the two groups (both P > 0.05). Lung histopathology in the ALI/ARDS model group revealed high level of inflammatory exudate and inflammatory cells infiltrated in the alveoli of rats, along with damage of local alveolar epithelial cell and alveolar structure. However, these histological changes were improved in the Xuebijing injection group and in the Sivelestat sodium group. Conclusions:Xuebijing injection can alleviate ALI/ARDS-induced lung injury and systemic damage and improve the survival of rats by inhibiting inflammation. The protective effect of Xuebijing injection is essentially consistent with that of Sivelestat sodium.
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Objective:To study the signaling pathway of the up-regulation of claudin-5 expression by Xuebijing injection.Methods:Animal and cell models of acute respiratory distress syndrome (ARDS) were induced by lipopolysaccharide (LPS). ① In vivo study, 20 male Sprague-Dawley (SD) rats were randomly divided into 4 groups: control group, LPS group (LPS injection 10 mg/kg for 12 hours), Xuebijing control group (Xuebijing injection 1 mg/kg, twice a day, for 3 days), and Xuebijing intervention group (LPS injection after pretreatment of Xuebijing injection), according to random number method with 5 rats in each group. The lung tissues were taken to detect lung dry/wet weight ratio (W/D) and the morphological changes in each group. Claudin-5, phosphorylated forkhead box transcription factor O1 (p-FOXO1), total FOXO1 (t-FOXO1), phosphorylated Akt (p-Akt) and total Akt (t-Akt) in lung tissues were detected by immunohistochemical staining (IHC) and Western blotting. ② In vitro study, human pulmonary microvascular endothelial cells (HPMECs) were divided into 6 groups (5 holes in each group): control group, Xubijing control group (incubated with 2 g/L Xubijing for 24 hours), phosphoinositide 3-kinases (PI3K) signaling pathway LY294002 control group (incubated with 10 μmol/L LY294002 for 1 hour), LPS group (incubated with 1 mg/L LPS for 12 hours), Xubijing intervention group (incubated with 2 g/L Xuebijing for 24 hours, then with 1 mg/L LPS for 12 hours) and LY294002 intervention group (incubated with 10 μmol/L LY294002 for 1 hour, then with 2 g/L and Xubijing for 24 hours, and then with 1 mg/L LPS for 12 hours). The expression levels of claudin-5, p-FOXO1, t-FOXO1, p-Akt and t-Akt of HPMECs in each group were assessed by Western blotting. Results:In vivo study: ① Compared with the control group, the lung W/D ratio increased significantly in LPS group (6.79±0.42 vs. 4.19±0.13), and decreased significantly after the intervention of Xuebijing (4.92±0.38 vs. 6.79±0.42, P < 0.01). ② Morphological changes of lung tissue: compared with the control group, the injury of lung tissue in LPS group was more serious, which was significantly improved after Xuebijing intervention. ③ Expression levels of claudin-5, p-Akt/t-Akt and p-FOXO1/t-FOXO1: the expression levels of claudin-5, p-Akt/t-Akt and p-FOXO1/t-FOXO1 in LPS group were significantly decreased as compared with the control group (claudin-5/GAPDH: 0.33±0.03 vs. 1.03±0.07, p-Akt/t-Akt: 0.18±0.02 vs. 1.01±0.13, p-FOXO1/t-FOXO1: 0.16±0.06 vs. 1.00±0.19, all P < 0.01). After the intervention of Xuebijing, the expression levels were significantly increased as compared with the LPS group (claudin-5/GAPDH: 0.53±0.05 vs. 0.33±0.03, p-Akt/t-Akt: 0.56±0.12 vs. 0.18±0.02, p-FOXO1/t-FOXO1: 0.68±0.10 vs. 0.16±0.06, all P < 0.01). In vitro study: compared with the control group, the expression level of claudin-5 in the LPS group was significantly decreased (claudin-5/β-actin: 0.45±0.03 vs. 1.01±0.15, P < 0.01), and the expression level of claudin-5 in Xuebijing intervention group was also significantly decreased (claudin-5/β-actin: 0.80±0.08 vs. 1.01±0.15, P < 0.01). After the intervention of LY294002, the expression of claudin-5 was significantly decreased as compared with the Xubijing intervention group (claudin-5/β-actin: 0.41±0.02 vs. 0.80±0.08, P < 0.01). Conclusion:Xuebijing injection improve pulmonary vascular barrier function in rats with ARDS by up-regulating claudin-5 expression through PI3K/Akt/FOXO1 signaling pathway.
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ObjectiveTo investigate the therapeutic effect of Xuebijing injection （XBJ） on sodium taurocholate （Na-Tc）-induced severe acute pancreatitis （SAP） in rats. MethodForty rats were randomly assigned into 5 groups： sham operation group， SAP model group， and low-， medium-， and high-dose （4， 8， 12 mL·kg·d-1， respectively） XBJ groups. SAP model was established by retrograde injection of Na-Tc （1 mL·kg-1） into the biliary and pancreatic ducts. XBJ was injected intraperitoneally 3 days before and 0.5 h after modeling. The ascitic fluid volume and the pancreas weight-to-body weight ratio were measured. The pathological changes of pancreatic tissue were observed via hematoxylin-eosin （HE） staining. The protein levels of formyl peptide receptor 1 （FPR1） and nucleotide-binding oligomerization domain-like receptor 3 （NLRP3） in pancreatic tissue were detected by immunohistochemistry. Western blot was employed to determine the expression levels of NADH-ubiquinone oxidoreductase chains 1-6 （MT-ND1， MT-ND2， MT-ND3， MT-ND4， MT-ND5， and MT-ND6） in rat plasma. ResultCompared with sham operation group， the SAP model group showcased increased ascitic fluid volume and pancreas weight-to-body weight ratio （P<0.05）， serious lesions in pancreatic tissue， increased total pathological score （P<0.05）， and up-regulated protein levels of FPR1 and NLRP3 in pancreatic tissue （P<0.05）. The model group had lower MT-ND2 level （P<0.05） and higher MT-ND1， MT-ND3， and MT-ND6 levels in plasma （P<0.05） than the sham operation group， while MT-ND4 and MT-ND5 had no significant differences between the two groups. Compared with SAP model group， the XBJ treatment decreased ascitic fluid volume and pancreas weight-to-body weight ratio （P<0.01）， ameliorated pancreatic lesions， and down-regulated the protein levels of FPR1 and NLRP3 in pancreatic tissue （P<0.01）. The treatments， especially high-dose XBJ （P<0.01）， down-regulated the expression of MT-ND1 （P<0.01）， MT-ND3 （P<0.01）， MT-ND6 （P<0.01）， and MT-ND4 and did not change that of MT-ND5. ConclusionXBJ may antagonize partial mitochondrial N-formyl peptides and excessive inflammatory response mediated by FPR1/NLRP3 to treat SAP in rats.
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OBJECTIVE@#To investigate the protective effects and underlying mechanisms of Xuebijing Injection (XBJ) on the lung endothelial barrier in hydrogen sulfide (H@*METHODS@#Sprague-Dawley rats were exposed to H@*RESULTS@#The morphological investigation showed that XBJ attenuated H@*CONCLUSIONS@#XBJ ameliorated H
Subject(s)
Animals , Rats , Claudin-5 , Drugs, Chinese Herbal , Endothelial Cells , Hydrogen Sulfide , Phosphatidylinositol 3-Kinases , Rats, Sprague-Dawley , Respiratory Distress Syndrome, Newborn/drug therapyABSTRACT
Objective:To evaluate the effect of Xuebijing injection on the improvement of pneumonia severity index (PSI) and prognosis in patients with severe coronavirus disease 2019 (COVID-19).Methods:A multicenter prospective cohort study was designed. Adult patients with COVID-19 admitted to the intensive care unit (ICU) of 28 designated COVID-19 hospitals in 15 provinces and cities of China from January to March 2020 were enrolled. All patients were treated according to the standard treatment plan of COVID-19 issued by the National Health Commission of the People's Republic of China. They were divided into Xuebijing group and standard treatment group according to whether they received Xuebijing injection or not. In the standard treatment group, routine medical care measures such as antiviral, respiratory support, circulatory support and symptomatic treatment were taken. In the Xuebijing group, on the basis of standard treatment, Xuebijing was used within 12 hours of admission to the ICU, 100 mL each time, twice daily. The minimum duration of Xuebijing administration was 1 day. The improvement rate of PSI risk rating on the 8th day and clinical outcome on the 28th day were recorded.Results:A total of 276 COVID-19 patients were screened continuously, and the data of 144 severe patients who met PSI risk rating Ⅲ-Ⅴ were analyzed. Seventy-two cases were involved each in standard treatment group and Xuebijing group. The average age of the standard treatment group and Xuebijing group were (65.7±7.9) years old and (63.5±10.9) years old, and male accounted for 75.0% (54/72) and 70.8% (51/72), respectively. There were no significant differences in general conditions, comorbidities, PSI risk rating and score, sequential organ failure assessment (SOFA) score, oxygenation index (PaO 2/FiO 2), respiratory support mode and other baseline indicators between the two groups. Compared with the standard treatment group, the improvement rate of PSI risk rating in Xuebijing group on the 8th day after admission was significantly improved [56.9% (41/72) vs. 20.8% (15/72), between-group difference and 95% confidence interval (95% CI) was 36.1% (21.3% to 50.9%), P < 0.01], PSI score, SOFA score and PaO 2/FiO 2 were significantly improved [PSI score: 83.7±34.8 vs. 108.2±25.6, between-group difference (95% CI) was -24.5 (-34.9 to -14.1); SOFA score: 2.0 (1.0, 4.0) vs. 7.0 (4.0, 10.0), between-group difference (95% CI) was -3.5 (-5.0 to -2.0); PaO 2/FiO 2 (mmHg, 1 mmHg = 0.133 kPa): 289.4±111.6 vs. 188.5±98.1, between-group difference (95% CI) was 100.9 (65.3 to 136.5); all P < 0.01]. The 28-day discharge rate of Xuebijing group was 44.5% higher than that of standard treatment group [66.7% (48/72) vs. 22.2% (16/72), P < 0.01], and the 28-day survival rate was 9.8% [91.7% (66/72) vs. 81.9% (59/72), P < 0.01]. There was no significant difference in the combination of antiviral drugs, antibiotics, anticoagulants and vasopressor drugs between the two groups. There was no significant difference in the incidence of adverse events between the Xuebijing group and standard treatment group [41.7% (30/72) vs. 43.1% (31/72), P > 0.05], and no serious adverse events and adverse reactions of Xuebijing were reported. Conclusion:Standard treatment combined with Xuebijing injection can significantly improve the PSI risk score and clinical prognosis of patients with severe COVID-19 without increasing drug safety risk.
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Objective:To clarify the characteristics of renal cortical microcirculation and its relationship with the expression of plasma endothelial microparticle (EMP) in septic rats, and to evaluate the effect of Xuebijing injection as an adjuvant therapy of antibiotics on septic AKI.Methods:The 8-10 weeks old specific pathogen free (SPF) male Sprague-Dawley (SD) rats were divided into sham operation group (Sham group), positive drug control group and Xuebijing group by the random number table method, with 10 rats in each group. The cecal ligation and puncture (CLP) with large ligation (ligated 75% of the cecum) was used to prepare a rat high-grade sepsis model; in the Sham group, the cecum was stretched without ligation or puncture. Due to the high mortality of CLP with large ligation, Xuebijing injection (4 mL/kg, 12 hours per time) and imipenem/cilastatin injection (90 mg/kg, 6 hours per time) were administered to the rats in the Xuebijing group via the tail vein immediately after the model was produced. Normal saline and imipenem/cilastatin were administered to the rats by the same methods in the positive drug control group. The rats in the Sham group were treated with the same volume of normal saline as any of the other two groups at the same frequency. At 48 hours after model reproduction, the mean arterial pressure (MAP) and blood lactic acid (Lac) of the rats were measured. The renal cortical microcirculation was monitored by using side stream dark-field imaging. Renal hypoxia signals were assessed by pimonidazole chloride immunohistochemistry. Plasma EMP levels were determined by using flow cytometry, and then the correlation between EMP and microcirculation parameters of renal cortex was analyzed. At the same time, the serum creatinine (SCr) was measured, and the renal injury score (Paller score) was used to evaluate the severity of renal tissue pathological damage.Results:Compared with the Sham group, perfused vessel density (PVD), microvascular flow index (MFI) and MAP in the positive drug control group and the Xuebijing group decreased significantly, the positive expression of hypoxia probe (pimonidazole) increased, Lac, EMP, Paller score and SCr increased significantly. However, compared with the positive drug control group, the renal cortical microcirculation in the Xuebijing group was improved significantly, PVD and MFI were increased significantly [PVD (mm/mm 2): 16.20±1.20 vs. 9.77±1.12, MFI: 2.46±0.05 vs. 1.85±0.15, both P < 0.05], Lac was reduced significantly (mmol/L: 4.81±1.23 vs. 6.08±1.09, P < 0.05), MAP increased slightly [mmHg (1 mmHg = 0.133 kPa): 84.00±2.00 vs. 80.00±2.00, P > 0.05], suggested that Xuebijing injection improved renal microcirculation perfusion in septic rats, and this effect did not depend on the change of MAP. The positive expression of pemonidazole in renal cortex of the Xuebijing group was significantly lower than that of the positive drug control group [(35.89±1.13)% vs. (44.93±1.37) %, P < 0.05], suggested that Xuebijing injection alleviated renal hypoxia. The plasma EMP levels of rats in the Xuebijing group were significantly lower than those in the positive drug control group (×10 6/L: 3.49±0.17 vs. 5.78±0.22, P < 0.05), and the EMP levels were significantly negatively correlated with PVD and MFI ( r values were -0.94 and -0.95, respectively, both P < 0.05), indicated that the increase of plasma EMP was highly correlated with renal microcirculation disorder, and Xuebijing injection inhibited the increase of plasma EMP levels. The Paller score in the Xuebijing group was significantly lower than that in the positive drug control group (46.90±3.84 vs. 62.70±3.05, P < 0.05), and the level of SCr was also significantly lower than that in the positive drug control group (μmol/L: 121.1±12.4 vs. 192.7±23.9, P < 0.05), which suggested that Xuebijing injection relieved kidney injury and improved renal function in septic rats. Conclusion:As an adjuvant therapy of antibiotics, Xuebijing injection could inhibit the expression of plasma EMP in rats with sepsis, improve renal cortex microcirculation, and reduce kidney injury.
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Objective:To explore the effects of Xuebijing injection and its component hydroxysafflor yellow A on coagulation and survival rates of septic rats.Methods:① Assessment of coagulation: 144 male Sprague-Dawley (SD) rats were divided into four groups by random number table: sham group, cecal ligation and puncture (CLP) induced sepsis model group (CLP group), CLP+Xuebijing group, and CLP+hydroxysafflor yellow A group, with 36 rats in each group. CLP was used for reproducing septic models. The cecum of the rats in the sham group was exposed by laparotomy and then returned to the abdominal cavity without CLP, while the other steps were the same as those in the CLP group. Rats in the CLP+Xuebijing group and CLP+hydroxysafflor yellow A group were injected with Xuebijing (4 mL/kg, twice a day) or hydroxysafflor yellow A solution (0.378 g/L, 298 μg each time, twice a day) through caudal vein after operation. Levels of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fib), and D-dimer in peripheral blood were measured by automatic coagulation analyzer at 6, 12, 24 hours after operation. The enzyme linked immunosorbent assay (ELISA) was applied to determine levels of tissue factor (TF), tissue factor pathway inhibitor (TFPI), and soluble thrombomodulin (sTM) in peripheral blood. ② Analysis of survival rates: 120 rats were divided into four groups by random number table (the same groups with those in the section of assessment of coagulation), with 30 rats in each group. The Kaplan-Meier survival curve was plotted, and the cumulative survival rates were observed and recorded for 7 days after CLP surgery.Results:① Results of coagulation assessment: compared with the sham group, septic rats in the CLP group showed significant dysfunction in coagulation early, as evidenced by prolonged PT at 6 hours after CLP (s: 8.9±0.2 vs. 8.4±0.4, P < 0.01), and significantly increased levels of Fib, D-dimer, TFPI and sTM [Fib (g/L): 2.8±0.3 vs. 2.3±0.1, D-dimer (ng/L): 1.8±0.2 vs. 1.5±0.1, TFPI (ng/L): 131.1±10.9 vs. 102.8±10.5, sTM (μg/L): 27.2±1.2 vs. 19.8±2.9, all P < 0.01]. The coagulation dysfunction became more and more serious at 12 hours after operation, and further deteriorated with time. The use of both Xuebijing and hydroxysafflor yellow A revealed significant improvement in coagulation of septic rats at 6 hours, as shown by shortened PT (s: 8.3±0.2, 8.3±0.1 vs. 8.9±0.2, both P < 0.01), and decreased Fib, D-dimer, TFPI and sTM as compared with those in the CLP group [Fib (g/L): 2.3±0.1, 2.3±0.2 vs. 2.8±0.3; D-dimer (ng/L): 1.5±0.1, 1.5±0.2 vs. 1.8±0.2; TFPI (ng/L): 109.5±10.2, 91.5±5.0 vs. 131.1±10.9; sTM (μg/L): 22.3±1.5, 21.1±1.8 vs. 27.2±1.2; all P < 0.01]. However, there was no significant difference in coagulation function between the two intervention groups. ② Results of survival rates analysis: the rats in the sham group all survived 7 days after operation. The 7-day cumulative survival rate of the CLP group was only 36.67% (11/30). Compared with the CLP group, the cumulative survival rates were significantly increased in rats of the CLP+Xuebijing group and CLP+hydroxysafflor yellow A group [66.67% (20/30), 66.67% (20/30) vs. 36.67% (11/30), both P < 0.05], but no significant difference was found between the CLP+Xuebijing group and CLP+hydroxysafflor yellow A group. Conclusion:Both Xuebijing and its component hydroxysafflor yellow A appear to be capable of alleviating coagulation disorders and improving survival rates of septic rats effectively, and the effects show no significant difference between them.
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To systematically review the efficacy of Xuebijing Injection combined with western medicine in the treatment of systemic inflammatory response syndrome(SIRS). In this study, CBM, CNKI, Wanfang, VIP, PubMed and EMbase databases were retrieved for clinical randomized controlled trials on the effect of Xuebijing Injection combined with western medicine in the treatment of SIRS from the establishment of the database to July 31, 2020. After screening, Meta-analysis was conducted by RevMan 5.3 software, trial sequential analysis was conducted by TSA 0.9.5.10 beta software, and the evidence quality level was evaluated by GRADEprofiler 3.6.1 software. Meta-analysis showed that Xuebijing Injection combined with western medicine could reduce white blood cell count(MD=-2.32, 95%CI[-2.44,-2.21], P<0.000 01), C-reactive protein count(MD=-22.70, 95%CI[-29.61,-15.79], P<0.000 01), APACHE Ⅱ score(MD=-2.15, 95%CI[-2.43,-1.87], P<0.000 01), tumor necrosis factor alpha count(SMD=-1.23, 95%CI[-1.48,-0.99], P<0.000 01) and interleukin-6 count(SMD=-0.92, 95%CI[-1.15,-0.69], P<0.000 01), improve treatment efficiency(RR=1.39, 95%CI[1.23, 1.56], P<0.000 01), reduce incidence of multiple organ dysfunction(RR=0.47, 95%CI[0.35, 0.64], P<0.000 01) and mortality(RR=0.22, 95%CI[0.13, 0.37], P<0.000 01), which were better than western medicine treatment alone. Trial sequential analysis showed that in terms of reducing the incidence of multiple organ dysfunction and C-reactive protein count, the cumulative Z value passed through the traditional threshold, TSA threshold and expected information value, and reached the required number of cases. GRADE evaluation showed that the level of evidence was low or very low. According to the findings, Xuebijing Injection combined with western medicine is effective in treating SIRS. However, as the low quality of the included studies may affect the reliability of the conclusion, more high-quality studies shall be included for further verification in the future, so as to provide better suggestions for clinical medication.
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Humans , Drugs, Chinese Herbal , Injections , Randomized Controlled Trials as Topic , Reproducibility of Results , Systemic Inflammatory Response Syndrome/drug therapyABSTRACT
Objective:To investigate whether the adverse reactions of Xuebijing injection (XBJJ) are mainly pseudoallergic reactions and explore the influencing factors of its pseudoallergic reactions. Method:Mouse model of pseudoallergic reaction was used to study the anaphylactoid reaction of XBJJ which at 0.5, 1 and 2 times of the highest clinical concentration. Next, we compared the differences in pseudoallergic reactions caused by XBJJ for different storage times after preparation. Specifically, XBJJ was prepared into different concentrations, stored for 10 minutes, 2.5 hours, 6 hours and 24 hours, and then injected into the tail vein of mice. Finally, three different injection speeds of 3 seconds, 45 seconds and 90 seconds were selected for XBJJ injection, and then the differences in the paeudoallergic reactions induced by XBJJ in mice under different injection speeds were compared. Result:XBJJ induces pseudoallergic reactions in mice when the drug concentration is higher than the clinically recommended concentration. Compared with storage for 10 minutes after preparation, the degree of pseudoallergic reaction in mice induced by the same concentration of XBJJ increased with the extension of storage time. In addition, when XBJJ was injected in 3 s (the injection rate was 0.083 mL·s<sup>-1</sup>), it produced the strongest pseudoallergic reaction. Conclusion:The adverse reactions induced by XBJJ are mainly pseudoallergic reactions. Excessive storage time after preparation and fast injection speed of XBJJ will lead to aggravation of pseudoallergic reactions in mice. When XBJJ is used clinically, it should strictly follow the usage, dosage, concentration, and drip rate recommended in the drug instruction manual. Rational drug use is of positive significance for improving the safety of XBJJ.
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Objective:To evaluate the effect of Xuebijing injection on inflammatory indexes and immune function in patients with acute exacerbation of chronic obstructive pulmonary disease （AECOPD）. Method:PubMed，Cochrane Library，Embase，Wed of Science，CBM，CNKI，VIP and Wanfang Data Online Knowledge service platform were searched by computer，all of which were up to February 2020. After literature screening and quality evaluation by two researchers independently，relevant data were extracted and Meta-analysis was carried out by RevMan 5.3 software. Result:A total of 21 randomized controlled trials（RCT） were included，involving 1 618 patients. The results of Meta-analysis showed，Xuebijing injection adjuvant therapy was significantly better than the control group in total effective rate ［relative risk（RR）=1.20，95% confidence interval（CI）（1.14，1.27），<italic>P</italic><0.000 01］，C-reactive protein（CRP）［standard mean difference（SMD）=-1.58，95% CI（-1.98， -1.19），<italic>P</italic><0.000 01］，total white blood cell （WBC）［mean difference（MD）=-1.44，95% CI（-1.84，-1.04），<italic>P</italic><0.000 01］，procalcitonin（PCT）［SMD=-0.57，95% CI（-0.74，-0.41），<italic>P</italic><0.000 01］，interleukin-6（IL-6）［SMD=-1.51，95% CI（-2.07，-0.96），<italic>P</italic><0.000 01］，percentage of neutrophils（N%）［MD=-5.35，95% CI（-7.13，-3.58），<italic>P</italic><0.000 01］，and tumor necrosis factor-<italic>α</italic>（TNF-<italic>α</italic>）［SMD=-1.52，95% CI（-2.23，-0.81），<italic>P</italic><0.000 1］， and had positive effects in regulating cellular immune disorders. Conclusion:Xuebijing injection combined with routine treatment can improve the immune function of AECOPD patients，reduce the number of inflammatory markers，neutrophils and CD8<sup>+</sup> T cells， thus modulating the small airway microcirculation to promote inflammatory absorption and inhibit the progression of the disease， with high safety.
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This study aimed to comprehensively analyze and compare the differences of different clinical study types currently published in the safety evaluation of Xuebijing Injection. Six databases, namely the Cochrane Library, PubMed, EMbase, CNKI, VIP and Wanfang database, were electronically retrieved to collect all types of studies on the safety of Xuebijing Injection, including randomized controlled trials, case-controlled studies, cohort studies, systematic reviews, and centralized monitoring studies of clinical safety(hospital), in order to comprehensively and objectively evaluate the safety of Xuebijing Injection, and analyze the differences of different research results. A total of 211 literatures were included, involving a total of 46 384 patients treated with Xuebijing Injection, and 423 adverse reactions(ADRs) occurred. They included 191 randomized controlled trials, 3 cohort studies, 15 systematic reviews, and 2 centralized monitoring studies of clinical safety(hospital), and the incidence of adverse reactions was 2.54%(common), 2.31%(common), 0.95%(occasionally), and 0.50%(occasionally). More than half of the 423 cases of ADRs occurred in skin and adnexal system(151 cases) and gastrointestinal system(65 cases), including such manifestations as rash, skin itching, nausea and vomiting, diarrhea. The degree of ADRs was mild. Randomized controlled trials showed that the incidence of ADR was the highest when Xuebijing Injection was used for malignant tumor and multiple organ failure. And the systematic evaluation showed that the incidence of ADR was the highest when Xuebijing Injection was used for spontaneous peritonitis of liver cirrhosis. In conclusion, different study types could lead to significant differences in the results of drug safety evaluation. Sample size, study type, and quality control are the main factors for biased results. Due to large sample size and high-quality, centralized monitoring studies become the better clinical safety evaluation model of drugs at present, and full life cycle management could more objectively reflect drug safety and guide clinical rational drug use.
Subject(s)
Humans , Case-Control Studies , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drugs, Chinese Herbal/adverse effects , InjectionsABSTRACT
The latest diagnosis and treatment plan (4th edition) of 2019 novel coronavirus pneumonia has been issued. The diagnosis and treatment plan highlights the concept of integrated traditional Chinese and Western medicine, and Xuebijing injection was referred for three times. Xuebijing injection was successfully developed based on the theory of 'three syndromes and three methods'. The theory of 'three syndromes and three methods' is a theoretical system of integrated traditional Chinese and Western medicine on critical diseases proposed by Professor Wang Jinda and his team in the 1970s, and it is one of the main contents of Wang Jinda's academic thought. The theory of 'three syndromes and three methods' has a deep foundation of traditional Chinese medicine theory, and it is still being continuously enriched and improved. It is also supported by multiple evidence-based data. Therefore, 'three syndromes and three methods' has rich theoretical connotation and tenacious vitality.
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As a representative drug for the treatment of severe community-acquired pneumonia and sepsis, Xuebijing (XBJ) injection is also one of the recommended drugs for the prevention and treatment of coronavirus disease 2019 (COVID-19), but its treatment mechanism for COVID-19 is still unclear. Therefore, this study aims to explore the potential mechanism of XBJ injection in the treatment of COVID-19 employing network pharmacology and molecular docking methods. The corresponding target genes of 45 main active ingredients in XBJ injection and COVID-19 were obtained by using multiple database retrieval and literature mining. 102 overlapping targets of them were screened as the core targets for analysis. Then built the PPI network, TCM-compound-target-disease, and disease-target-pathway networks with the help of Cytoscape 3.6.1 software. After that, utilized DAVID to perform gene ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to predict the action mechanism of overlapping targets. Finally, by applying molecular docking technology, all compounds were docked with COVID-19 3 CL protease(3CLpro), spike protein (S protein), and angiotensin-converting enzyme II (ACE2). The results indicated that quercetin, luteolin, apigenin and other compounds in XBJ injection could affect TNF, MAPK1, IL6 and other overlapping targets. Meanwhile, anhydrosafflor yellow B (AHSYB), salvianolic acid B (SAB), and rutin could combine with COVID-19 crucial proteins, and then played the role of anti-inflammatory, antiviral and immune response to treat COVID-19. This study revealed the multiple active components, multiple targets, and multiple pathways of XBJ injection in the treatment of COVID-19, which provided a new perspective for the study of the mechanism of traditional Chinese medicine (TCM) in the treatment of COVID-19.
Subject(s)
Humans , Angiotensin-Converting Enzyme 2/metabolism , Biological Availability , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Drugs, Chinese Herbal/therapeutic use , Medicine, Chinese Traditional/methods , Molecular Docking Simulation/methods , Protein Interaction Mapping/methods , SARS-CoV-2/physiology , Signal Transduction/drug effects , Spike Glycoprotein, Coronavirus/metabolismABSTRACT
OBJECTIVE：To compare cli nical effect and safety of different doses of Xuebijing injection combined with Ulinastatin injection in the treatment of sepsis complicated with acute lung injury （ALI）. METHODS ：Totally 115 patients diagnosed as sepsis complicated with ALI were collected from Jul. 2015 to Nov. 2019 in intensive care unit of our hospital. According to therapy method ，the patients were divided into control group （26 cases），low-dose group （29 cases），medium-dose group（30 cases），high-dose group （30 cases）. The control group received Ulinastatin injection 300 thousands u intravenously ，q8 h， for consecutive 5 days，on the basis of routine treatment. On the basis of control group ，low-dose group additionally received intravenous drip of Xuebijing injection 50 mL，bid，for consecutive 7 days；medium-dose group additionally received intravenous drip of Xuebijing injection 100 mL，bid，for consecutive 7 days；high-dose group additionally received intravenous drip of Xuebijing injection 100 mL，qid，for consecutive 7 days. The serum inflammatory factors （IL-6，TNF-α，CRP），respiratory function indexes （PaO2，PaO2/FiO2，ELWI）and related scores （APACEⅡ score and SOFA score ）were compared among 4 groups before and after treatment ，and mechanical ventilation time ，ICU hospitalization time ，28-day mortality rate and adverse reactions during the treatment were recorded. RESULTS ：Before treatment ，there was no statistical significance in serum inflammatory factors，respiratory function indexes or related scores among 4 groups（P＞0.05）. After treatment ，serum inflammatory factors ， ELWI and related scores of 4 groups were decreased significantly ；the low-dose ，medium-dose and high-dose groups were significantly lower than the control group ；the high-dose group was significantly lower than the low-dose and medium-dose groups （P＜0.05）. PaO 2 and PaO 2/FiO2 of 4 groups were increased significantly ，compared with before treatment ；the low-dose ， medium-dose and high-dose groups were significantly higher than the control group ；the high-dose group was significantly higher than the low-dose and medium-dose groups （P＜0.05）. The mechanical ventilation time and ICU hospitalization time in the low-dose，medium-dose and high-dose groups were significantly shorter than control group （P＜0.05），but there was no statistical significance in above indexes among different doses groups （P＞0.05）. There was no statistical significance in 28-day mortality among 4 groups（P＞0.05），and no serious adverse reactions were found. CONCLUSIONS ：Different doses of Xuebijing injection combined with Ulinastatin injection could effectively decrease the level of serum inflammatory factors in patients with sepsis complicated with ALI ，improve lung function and relieve the degree of organ failure ；after combined with high-dose Xuebijing injection，the therapeutic effect is more obvious and does not affect the treatment safety.
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Objective@#To explore the therapeutic effect of Xuebijing on patients with acute paraquat poisoning (APP) by using systematic evaluation method.@*Methods@#PubMed, Cochrane Library, Embase, Wanfang database, China National Knowledge Infrastructure (CNKI), VIP database (VIP) and China Biology Medicine (CBM) were searched using the computers to find the literatures published about the Xuebijing injection for the treatment of APP. Randomized controlled trials (RCT) were retrieved from the establishment of the database to August 2019. Patients in experimental group were treated with Xuebijing injection combined with conventional treatment, while the patients in control group were only given conventional treatment. The patients' outcome included the 14-day mortality, arterial oxygen saturation (SaO2) and incidence of pulmonary fibrosis. In addition, the 6-month survival rate, alanine aminotransferase (ALT), serum creatinine (SCr), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) between the two groups were compared. The literature data were extracted by two researchers independently, and the quality of the literatures was evaluated according to the Cochrane 5.1 handbook. The Meta-analysis was performed by using RevMan 5.3 software. The results stability of Meta-analysis was tested by sensitivity analysis. The publication bias was analyzed through drawing of funnel diagram.@*Results@#Twenty-seven RCT studies in total were enrolled, of which 26 were in Chinese and 1 was in English. A total of 1 429 patients were enrolled, among whom 726 were in experimental group and another 703 were in control group. Meta-analysis showed that compared with the control group, the 14-day mortality [relative risk (RR) = 0.62, 95% confidence interval (95%CI) was 0.54 to 0.72, P < 0.000 01] and incidence of pulmonary fibrosis (RR = 0.67, 95%CI was 0.53 to 0.85, P = 0.000 9) of patients in the experimental group were significantly lowered, while SaO2 at 7 days and 14 days were significantly increased [7 days: mean difference (MD) = 16.86, 95%CI was 9.89 to 23.83, P < 0.000 01; 14 days: MD = 16.51, 95%CI was 10.22 to 22.80, P < 0.000 01]. Compared with the control group, the survival rate within 6 months (RR = 1.55, 95%CI was 1.41 to 1.71, P < 0.000 01) and SOD (MD = 13.88, 95%CI was 7.43 to 20.33, P < 0.000 1) of patients in the experimental group were significantly increased, ALT at 14 days (MD = -78.35, 95%CI was -127.35 to -29.34, P = 0.000 5), SCr at 7 days and 14 days (7 days: MD = -135.13, 95%CI was -219.09 to -51.17, P = 0.002; 14 days: MD = -206.05, 95%CI = -290.13 to -121.96, P < 0.000 01), CRP (MD = -11.55, 95%CI was -17.77 to -5.33, P = 0.000 3), TNF-α (MD = -9.27, 95%CI was -15.48 to -3.96, P = 0.000 9) and MDA (MD = -1.27, 95%CI was -1.57 to -0.96, P < 0.000 01) were significantly lowered. The overall effect value of the parameters with high heterogeneity was not significantly changed after furtherMeta-analysis excluding any one of the studies, suggesting that the result was relatively stable. Funnel chart analysis was used to analyze the parameters from more than 10 articles enrolled, and it showed that there was publication bias.@*Conclusion@#Xuebijing injection can reduce the mortality of patients with APP, which may because that it can improve liver and kidney function, reduce inflammation and oxidative stress damage, inhibit pulmonary fibrosis and increase oxygenation level.