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Intervertebral disc degeneration is one of the common causes of chronic low back pain. As a common spinal disease， its clinical symptoms are mainly low back pain and limited function， which seriously affects physical and psychological health. Because of its complex and unclear pathogenesis， the treatment of intervertebral disc degeneration has been the focus of scientific researchers and clinical workers. At present， the treatment of intervertebral disc degeneration mainly includes non-surgical therapy and surgical therapy， which can alleviate the clinical symptoms of patients to a certain extent， but easily induce new complications， and it is difficult to restore the normal physiological function of the intervertebral disc. In recent years， along with the advanced research on matrix metalloproteinases （MMPs） in the tissues of intervertebral disc degeneration， it has been found that MMPs can be used as molecular therapeutic targets. The expression of MMPs in the intervertebral disc tissues can be regulated by reducing the content and composition of the extracellular matrix of the intervertebral disc， so as to slow down intervertebral disc degeneration and even reverse the occurrence of intervertebral disc degeneration. This treatment is expected to delay intervertebral disc degeneration caused by changes in extracellular matrix composition or content. In recent years， with the continuous development of network pharmacology and bioinformatics research， a large number of researchers have explored the treatment of intervertebral disc degeneration by traditional Chinese medicine （TCM） and found that TCM can reduce the degradation of extracellular matrix by inhibiting the expression of MMPs， thus alleviating the symptoms of intervertebral disc degeneration and slowing down the progression of intervertebral disc degeneration. This paper reviewed the research progress of TCM intervention in MMP expression in the treatment of intervertebral disc degeneration， aiming at providing references for the application of TCM in the prevention and treatment of intervertebral disc degeneration.
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Objective:To evaluate the clinical efficacy of modified Qiwei Baizhu Powder combined with conventional therapy in the treatment of type 2 diabetes mellitus (T2DM) with abnormal lipid metabolism.Methods:A total of 96 patients with T2DM and abnormal lipid metabolism from March 2018 to March 2021 in Anhui Integrated Traditional Chinese and Western Medicine Hospital who met the inclusion criteria were divided into 2 groups according to the random number table method, with 48 in each group. The control group was treated with conventional western medicine, while the observation group was treated with modified Qiwei Baizhu Powder and treatment of the control group. Both groups were treated for 3 months. TCM syndrome scores were performed before and after treatment. Fasting blood glucose (FPG) and 2 hPG were detected by glucose oxidase method, HbA1c was detected by HPLC, TC, TG, HDL-C and LDL-C were detected by cholesterol peroxidase method, glycerophosphate oxidase method, direct inhibition method and direct surfactant clearance method. Adverse events during treatment were recorded and clinical efficacy was evaluated.Results:The total effective rate was 93.8% (45/48) in the observation group and 79.2% (38/48) in the control group, with a statistically significant difference between the two groups ( χ2=4.36, P=0.037). After treatment, the scores of dry mouth, fatigue, anorexia, dizziness, tongue, pulse and total scores in the observation group were significantly lower than those in the control group ( t values were 3.58, 3.17, 3.24, 3.59, 3.58, 2.76 and 8.44, respectively, all Ps<0.05); the levels of FPG, 2 hPG and HbA1c in the observation group were significantly lower than those in the control group ( t values were 3.37, 2.05 and 3.73 respectively, all Ps<0.05). After treatment, the levels of TC [(4.30±0.85) mmol/L vs. (4.78±0.94) mmol/L, t=2.62], TG [(3.00±0.37) mmol/L vs. (3.19±0.54) mmol/L, t=2.01], LDL-C [(2.60±0.71) mmol/L vs. (2.95±0.44) mmol/L, t=2.90] were significantly lower than those in the control group ( P<0.05). After treatment, the HDL-C [(2.07±0.63) mmol/L vs. (1.82±0.55) mmol/L, t=2.01] level was significantly higher than that of the control group ( P<0.05). Conclusion:Modified Qiwei Baizhu Powder combined with conventional therapy can improve blood glucose and blood lipid levels in T2DM patients with abnormal lipid metabolism, relieve clinical symptoms and improve curative effect.
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External treatment of Traditional Chinese Medicine (TCM) is a common treatment for lumbar disc herniation, which mainly includes fumigation and washing of TCM, and hot ironing therapy. It can cooperate with oral administration of TCM, Tuina, acupuncture and other therapies to play a synergistic effect and enhance the efficacy. External application of TCM in the treatment of lumbar intervertebral disc herniation is effective with long duration, easy-operated and safe It has showed curative effect in alleviating clinical symptoms and improving lumbar function. Its mechanism mainly includes regulating nerve inflammatory reaction, improving hemorheology and exerting analgesic effect.
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Osteoporosis is a chronic skeletal disease characterized by low bone mass， destruction of bone tissue microarchitecture， and imbalance of bone homeostasis， leading to increased bone fragility and increased risk of fractures. Oxidative stress caused by the disruption of the balance between excess reactive oxygen species （ROS） and the anti-oxidative system is an important factor in the occurrence and progression of osteoporosis. Nuclear factor E2-related factor 2 （Nrf2）/heme oxygenase-1 （HO-1） is an important anti-oxidative stress pathway. Nrf2 is a primary factor in regulating cellular oxidative stress. Activating Nrf2 can stimulate the expression of HO-1. HO-1 is a key enzyme whose metabolites are bile green Oxygen， carbon monoxide， and free iron. The metabolites can scavenge ROS， thereby exerting an antioxidant effect in cells. At present， domestic and foreign scholars have reported that the Nrf2/HO-1 signaling pathway is closely related to the occurrence and development of osteoporosis and the mechanism of drugs. Chinese medicine can effectively solve the insufficiency of western medicine with multi-target， multi-channel， and multi-level advantages. Chinese medicine can resist oxidative stress， inflammatory response， and apoptosis by regulating the Nrf2/HO-1 signaling pathway， thus treating osteoporosis. This article reviewed the relationship between Nrf2/HO-1 signaling pathway and its key target protein factors and osteoporosis， to clarify the important role of the Nrf2/HO-1 signaling pathway in osteoporosis. At the same time， a systematic summary of Chinese medicines targeting and regulating the Nrf2/HO-1 signaling pathway for the treatment of osteoporosis was conducted， to provide a theoretical basis for further precise treatment of osteoporosis.
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Objective:To evaluate the effectiveness of antimicrobial stewardship based on self-developed antibiotic clinical decision support system (aCDSS) in the inpatients at a tertiary hospital for consecutive 6 years, and to provide reference for rational use and antimicrobial stewardship.Methods:aCDSS was self-designed based on information technology and applied in clinical use in our hospital from 2015. Data of inpatient information and antibacterial use from January 2015 to December 2020 were collected from HIS and aCDSS. A retrospective study was conducted in all inpatients on the utilization rate and antibiotic use density.Results:Since 2015, with the comprehensive implementation of antimicrobial stewardship based on the aCDSS,there was a significant decline on the annual rate of antibiotic usage from 44.18% in 2015 to 38.70% in 2020, as well as on the usage rate of extended-spectrum antimicrobial agents including carbapenems, broad-spectrum β-lactam/β-lactamase inhibitors, tigecycline, broad-spectrum cephalosporins, fluoroquinolones, as well as glycopeptide and antifungal drugs. Compared with 2015, the usage of carbapenems, tigecycline and broad-spectrum β-lactam/β-lactamase inhibitors was declined nearly 50% in 2020, and the density of carbapenems and tigecycline were decreased by 29.6% and 7.1%, respectively in 2020. On the other side, the utilization rate and use density of narrow-spectrum cephalosporins continued to increase by year, the use density of narrow-spectrum cephalosporins accounting for 28.2% of all antibiotics in 2020.Conclusions:With the comprehensive implementation of aCDSS, the utilization rate and density of broad-spectrum and high-priced antibacterial drugs in our hospital have decreased continuously to decline in the past 6 years, while the proportion of narrow-spectrum antimicrobials has increased year by year, indicating that the structure of antimicrobial use has been continuously optimized and that antimicrobial stewardship based on the information technology have achieved remarkable results.
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ObjectiveTo develop a quantitative analysis of multi-components by single marker （QAMS） for determination of bufalin， cinobufagin and resibufogenin in Shexiang Baoxin pills， and to provide a method for improving the national standard of the pills. MethodHigh performance liquid chromatography （HPLC） was developed for simultaneous determination of bufalin， cinobufagin and resibufogenin in Shexiang Baoxin pills and the methodology validation was carried out. The chromatographic separation was performed on a Nucleosil 100-5 C18 column （4.6 mm×250 mm， 5 μm） with the mobile phase of acetonitrile -0.1% potassium dihydrogen phosphate aqueous solution （pH adjusted to 3.2 with phosphoric acid） （48∶52）， and the flow rate was 0.6 mL·min-1， the detection wavelength was set at 296 nm and the column temperature was 35 ℃. Taking cinobufagin as the internal standard， the relative correction factors （RCFs） of bufalin and resibufogenin were calculated， and the key influencing factors of RCFs were investigated. Relative retention time was used for the chromatographic peak location of the analyte， combining with the on-line ultraviolet spectroscopy and accurate relative molecular weight obtained by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry （UPLC-QTOF/MS）. The external standard method was used to verify the contents of three components obtained by QAMS. ResultQAMS was established for the determination of bufalin， cinobufagin and resibufogenin in the samples， and RCFs of cinobufagin to bufalin and resibufogenin were 0.922 and 1.01， respectively. The total content of the three marker compounds in 11 batches of Shexiang Baoxin pills was 33.7-36.0 µg per pill. There was no significant difference between the quantitative results of QAMS and external standard method. ConclusionThe established method can be used for the quality control of bufalin， cinobufagin and resibufogenin in Shexiang Baoxin pills. It is suggested that bufalin should be considered as one of three marker compounds， and the sum of bufalin， cinobufagin and resibufogenin should be used for the content limit of this preparation.
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Objective To investigate the effect of compound Fufangteng mixture-containing serum on the proliferation of bone marrow mesenchymal stem cell (BMSC) and its mechanism. Methods Rat BMSC were isolated, cultured and purified in vitro by direct adherence method. Cell morphology was observed. Surface markers were identified by flow cytometry. The rats were treated with compound Fufangteng mixture at a dose of 3 mL/(kg·d) by gavage for 14 d, and then the drug-containing serum was collected. BMSC were divided into the blank control group, drug-containing serum group, Notch1 small interfering ribonucleic acid (siRNA) group and Notch1 siRNA+drug-containing serum group. The proliferation rate of BMSC was detected and the relative expression levels of Notch1 signaling pathway-associated messenger ribonucleic acid (mRNA) and proteins were measured in each group. Results Microscopic observation showed that the first generation BMSC were seen in the long spindle shape, and grown in the parallel or spiral pattern. The third generation BMSC positively expressed CD90 and CD44, whereas were negative for CD45. Compared with the blank control group, the proliferation rate of BMSC in the drug-containing serum group and Notch1 siRNA+ drug-containing serum group was significantly increased, whereas that of BMSC was significantly decreased in the Notch1 siRNA group (all P < 0.05). Compared with the Notch1 siRNA group, the proliferation rate of BMSC was significantly increased in the Notch1 siRNA+drug-containing serum group (P < 0.05). Compared with the blank control group, the relative expression levels of Hey1 and Delta-like ligand (DLL)1 mRNA and proteins were significantly up-regulated in the drug-containing serum group, whereas those were significantly down-regulated in the Notch1 siRNA group and Notch1 siRNA+drug-containing serum group (all P < 0.05). Compared with the Notch1 siRNA group, the relative expression levels of Hey1 and DLL1 mRNA and proteins were significantly up-regulated in the Notch1 siRNA+drug-containing serum group (all P < 0.05). Conclusions Compound Fufangteng mixture-containing serum may promote the proliferation of rat BMSC, and its mechanism is probably associated with the activation of Notch1 signaling pathway.
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Islet transplantation is one of the effective therapies for diabetes mellitus. Nevertheless, multiple issues still exist, such as shortage of donors and adverse reactions caused by long-term use of immunosuppressants, which limit the islet survival post-transplantation. Microencapsulated islet transplantation may overcome these difficulties to certain extent, whereas many factors, such as the destruction of immune isolation microenvironment within the microcapsules and insufficient supply of oxygen and nutrients, constrain the application of microencapsulated islet transplantation in clinical practice. In recent years, how to enhance the effect of microencapsulated islet transplantation has been gradually studied. The application of stem cells in microencapsulated islet transplantation has steadily become a research hot spot. Therefore, the optimizing strategies for microencapsulated islet transplantation and the application of stem cells in microencapsulated islet transplantation were reviewed, and the potential improvement techniques of microencapsulated islet transplantation were investigated in this article, aiming to provide reference for further clinical application of microencapsulated islet transplantation.
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【Objective】 To explore the feasibility of tirofiban, a platelet surface glycoprotein (GP)Ⅱb/Ⅲa receptor antagonist intervene in transfusion-related acute lung injury (TRALI), by inhibiting platelet activation and by preventing platelet and neutrophil binding to form aggregates. 【Methods】 1) Fifty wild-type male Balb/c mice, aged 8 to 10 weeks, were randomly divided into TRALI, normal, tirofiban TRALI intervention, isotype control and tirofiban normal intervention groups. In the TRALI model, tirofiban TRALI intervention and isotype control groups, each mouse was injected intraperitoneally with lipopolysaccharide (LPS) 0.1 mg/kg, and after 18 h with 4.5 mg/kg anti-MHC-I or IgG2a isotype control antibody, in which 0.5 μg/g tirofiban was injected 30 min before anti-MHC-I injection, and was labeled as tirofiban TRALI intervention. The group without any treatment was set as normal group. The tirofiban normal intervention group was injected with only 0.5 μg/g tirofiban into the tail vein, 30 min before the injection of anti-MHC-I. 2) After antibody injection, the mice were observed for 2 h, then executed with their lungs removed, and the extent of lung injury and the intervention effect of tirofiban were analyzed by comparing the differences in lung dry to wet ratio, total protein, myeloperoxidase (MPO), inflammatory factors and quantitative results of HE staining. The platelet activation level in whole blood and immunofluorescence (IF) quantification of platelet and neutrophil fluorescence were detected by flow cytometry to analyze the mechanism of tirofiban on TRALI. 【Results】 1) The indexes of lung injury in the tirofiban TRALI intervention group and TRALI model group for HE staining were 0.663 3±0.141 9 vs. 0.173 3±0.120 4 (P<0.05), respectively; 2) Platelet activation levels(%)in whole blood in the TRALI group, normal group and tirofiban TRALI intervention group were 22.87±9.943 vs 5.070±2.234 vs 5.767±3.224(P<0.05), respectively. 3) The mean fluorescence density of platelet neutrophil aggregates for IF detection in the tirofiban intervention group and TRALI model group was 21.89±3.536 vs. 32.77±0.9624 (P<0.05). 【Conclusion】 The platelet GP Ⅱ b/Ⅲa-specific inhibitor tirofiban inhibited platelet-neutrophil binding in mice, thus could possibly intervene in TRALI.
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Objective:To evaluate the effectiveness of the information management system on the clinical application of special-grade antimicrobial.Methods:Using the established knowledge database, a computer program was designed and developed, which was embedded in the electronic medical record to intervene the clinical use of the special-grade antimicrobial since 2015. The basic information of all discharged patients from the Second Affiliated Hospital of Zhejiang University School of Medicine from January 2013 to December 2020 were extracted from the HIS system, including the medical orders for antibiotics and the drug storehouse dispensing data.The trend analysis was carried out on the changes of the use rates and antibiotic use density (AUD) of the special-grade antimicrobials in the whole hospital and intensive care units (ICU). The data were processed and analyzed using SPSS 24.0.Results:From 2013 to 2015, except for meropenem and amphotericin B, the usage rate of all special-grade antimicrobials in the whole hospital showed an upward trend ( P<0.05). The proportion of special-grade antimicrobials used in the hospital increased year by year ( χ2=7 804.081, P<0.01). The total usage rate of special-grade antimicrobials in ICU showed an upward trend year by year ( χ2=67.028, P<0.01). Since the implementation of the special-grade antimicrobial information management system in 2015, the total use rate of special-grade antimicrobials in the hospital, the use rate of various antibiotics except linezolid, amphotericin B and posaconazole, and the proportion of special-grade antimicrobials used in the hospital have all shown a downward trend year by year ( P<0.01). The total usage rate and total AUD of special-grade antimicrobials in ICU showed a decreasing trend year by year ( χ2=343.514, P<0.01, β=-0.963, P=0.002). Conclusion:The information management system for special-grade antimicrobial can effectively reduce the utilization rate and AUD of most special-grade antibiotics in hospitalized patients including ICU, and has a good clinical application value in antimicrobial stewardship.
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Objective: To investigate the mechanisms of andrographolide against non-alcoholic steatohepatitis (NASH) based on network pharmacology, so as to provide a reference for further study of andrographolide in the treatment of NASH and other metabolic diseases. Methods: The methionine- and choline-deficient (MCD) diet-induced NASH mice were treated by administration of andrographolide, and serum transaminase and pathological changes were analyzed. The network pharmacology-based bioinformatic strategy was then used to search the potential targets, construct protein–protein interaction (PPI) network, analyze gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment, and conduct molecular docking to explore the molecular mechanisms. Results: The predicted core targets TNF, MAPK8, IL6, IL1B and AKT1 were enriched in non-alcoholic fatty liver disease (NAFLD) signaling pathway and against NASH by regulation of de novo fatty acids synthesis, anti-inflammation and anti-oxidation. Conclusion: This work provides a scientific basis for further demonstration of the anti-NASH mechanisms of andrographolide.
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Objective:To explore the prognostic factors that may affect the postoperative survival of gastric cancer by analyzing patients with radical gastrectomy.Methods:The data of 525 patients with radical gastrectomy, including 387 male and 138 female with average age (62.5±10.7) years old (ranged from 16 to 89 years), were analyzed retrospectively in Anqing Municipal Hospital between October 2010 to July 2015. The relationship between 33 variables and prognosis was analyzed by a Cox proportionalhazards regression model, meanwhile ROC curve was established in order to explore the risk factor of postopertive survival.Results:The over survival(OS) rate of all patients was 89.3% at 1 year, 68.4% at 3 years and 59.6% at 5 years. The 5-year OS rate was 81.9% at stage Ⅰ, 71.4% at stage Ⅱ and 44.1% at stage Ⅲ. In the multivariate analysis that included these factors, preoperative comorbidity ( HR=1.595, P=0.001), hemoglobin( HR=1.377, P=0.017), CA199( HR=1.618, P=0.004), tumor distribution( HR=1.943, P=0.032), pT stage( HR=1.731, P=0.012), pN stage( HR=2.118, P=0.000), signet ring cell( HR=1.642, P=0.038)and intravascular tumor thrombus( HR=1.391, P=0.039) were independent risk factors associating with postopertive survival.According to ROC curve, the following area (AUC value) could predict survival after radical gastrectomy, including CA199 (AUC=0.568), hemoglobin(AUC=0.586), preoperative comorbidity(AUC=0.554), pT stage(AUC=0.636), pN stage(AUC=0.670)and intravascular tumor thrombus(AUC=0.626)( P<0.05). Conclusion:According to ROC curve analysis, preoperative comorbidity, anemia, CA199, pN stage, pT stage and intravascular tumor thrombus played an role in predicting long-term survival after radical resection of gastric cancer.
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Objective:To evaluate the effects of neuregulin-1 (NRG-1) pretreatment on diaphragmatic function in septic rats.Methods:Twenty-six clean-grade healthy adult male Sprague-Dawley rats, weighing 220-260 g, were divided into 3 groups using a random number table method: sham operation group (group S, n=6), sepsis group (group Sep, n=10) and NRG-1 group (group N, n=10). Sepsis was induced by cecal ligation and puncture in anesthetized rats.Group S underwent simple laparotomy.At 30 min before operation, recombinant human NRG-1β 10 μg/kg was injected through tail vein in group N, while the equal volume of normal saline was given in S and Sep groups.At 24 h after operation, the survived rats were sacrificed, and the diaphragm was removed for determination of the contractile function and contents of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) (by enzyme-linked immunosorbent assay) and for examination of the pathological changes (by hematoxylin and eosin staining). Results:Compared with group S, the force-frequency curve was shifted downward, and the levels of TNF-α and IL-6 were increased ( P<0.01), inflammatory cell infiltration was observed in Sep and N groups.Compared with group Sep, the force-frequency curve was shifted upward , and the levels of TNF-α and IL-6 were decreased ( P<0.01), inflammatory cell infiltration was alleviated in group N. Conclusion:NRG-1 pretreatment can improve diaphragmatic contractile function in septic rats, and the mechanism is related to reducing diaphragmatic inflammatory responses.
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Objective: To investigate the efficacy and safety of percutaneous closure of ventricular septal rupture (VSR) after acute myocardial infarction (AMI) and the risk factors of all-cause mortality at 30 days after operation. Methods: This is a retrospective case series study. A total of 69 patients with post-AMI VSR, underwent percutaneous closure of VSR from October 2013 to May 2020 in Department of Cardiology of Henan Provincial People's Hospital and Department of Cardiology of Central China Fuwai Hospital, were included. Patients were divided into survival group (53 cases) and non-survival group (16 cases) according to the status at 30 days after operation. Clinical data were collected and analyzed during hospitalization. Telephone follow-up was performed 30 days after operation. The primary safety endpoint was occlusion failure and all-cause mortality at 30 days post operation. The secondary safety endpoint was the operation related or non-operation related complications. Efficacy endpoint included NYHA classification of cardiac function, index measured by right heart catheterization and echocardiography. Multivariate logistic regression was performed to analyze the risk factors of all-cause mortality at 30 days after operation. Results: A total of 69 patients, aged 67 (64, 71) years, including 42 women (60.9%), were enrolled in this study. All-cause death occurred in 16 patients (23.2%), including 13 in-hospital death and 3 death during follow-up. There were 4 cases of closure failure (5.8%). Among the 65 patients with successful closure, 12 (18.5%) experienced operation-related complications, among which 8 (12.3%) experienced valve injury. The mortality was significantly higher in patients with operation-related complications than that in patients without operation-related complications (41.7% (5/12) vs. 13.2% (7/53), P = 0.022). One case received percutaneous closure of VSR and PCI, this patient experienced new-onset AMI immediately post procedure and died thereafter (1.5%). One case (1.5%) developed multiple organ failure and 2 cases (3.1%) developed gastrointestinal bleeding post operation. All of the 65 patients with successful occlusion completed postoperative echocardiography, 56 patients completed cardiac function assessment at discharge, and 53 patients who survived up to 30 days post discharge completed clinical follow up by telephone. The NYHA cardiac function at discharge and 30 days after operation were significantly improved as compared to that before operation (P<0.001), the ratio of NYHA Ⅰ and Ⅱ patients was significantly higher post operation at these two time points as compared to baseline level (76.8% (43/56) vs. 23.1% (15/65), P<0.001, 77.4% (41/53) vs. 23.1% (15/65), P<0.001). The pulmonary circulation/systemic circulation blood flow ratio (Qp/Qs), pulmonary artery systolic pressure (PASP) and left ventricular end-diastolic diameter (LVDd) were decreased, aortic systolic pressure (ASP) and left ventricular ejection fraction (LVEF) were increased post operation (P<0.05). Multivariate logistic regression analysis showed that WBC>9.8×109/L (OR=20.94, 95%CI 1.21-362.93, P=0.037) and NT-ProBNP>6 000 ng/L (OR=869.11, 95%CI 2.93-258 058.34, P=0.020) were the independent risk factors of mortality at 30 days. Conclusions: Percutaneous closure in VSR after AMI is safe and effective. The increase of WBC and NT-ProBNP are the independent risk factors of all-cause mortality at 30 days after operation.
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Female , Humans , Aftercare , Hospital Mortality , Myocardial Infarction , Patient Discharge , Percutaneous Coronary Intervention , Retrospective Studies , Stroke Volume , Ventricular Function, Left , Ventricular Septal Rupture/surgeryABSTRACT
Organoids are tissue structures, generated from pluripotent stem cells and cultured in vitro, which form self-organize and recapitulate tissues with similar structure and function to the original organs. Organoids have similar appearance and function to the original tissues, and have been widely applied in basic research and clinical trial. At present, the organoids of liver, kidney, islet, brain, intestine and other organs have been successfully cultivated. The use of islet organoid is a hotspot in the field of organoid research. However, islet organoid is currently applied in basic research because rejection after organ transplantation and other issues remain unresolved. In this article, the origin, development and basic application of islet organoid were reviewed, aiming to provide reference for the transformation from basic research of islet organoid into clinical application as well as the treatment of diabetes mellitus.
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@#Objective To investigate the prognostic survival status and influence factors for surgical treatment of esophageal squamous cell carcinoma (ESCC) in pathological stage T1b (pT1b). Methods The patients with ESCC in pT1b undergoing Ivor-Lewis or McKeown esophagectomy in Lanzhou University Second Hospital from 2012 to 2015 were collected, including 78 males (78.3%) and 17 females (21.7%) with an average age of 61.4±7.4 years. Results The most common postoperative complications were pneumonia (15.8%), anastomotic leakage (12.6%) and arrhythmia (8.4%). Ninety-three (97.9%) patients underwent R0 resection, with an average number of lymph node dissections of 14.4±5.6. The rate of lymph node metastasis was 22.1%, and the incidence of lymph vessel invasion was 13.7%. The median follow-up time was 60.4 months, during which 25 patients died and 27 patients relapsed. The overall survival rate at 3 years was 86.3%, and at 5 years was 72.7%. Multivariate Cox regression analysis showed that lymph node metastasis (P=0.012, HR=2.60, 95%CI 1.23-5.50) and lympovascular invasion (P=0.014, HR=2.73, 95%CI 1.22-6.09) were independent risk factors for overall survival of pT1b ESCC. Conclusion Esophagectomy via right chest approach combined with two-fields lymphadenectomy is safe and feasible for patients with pT1b ESCC. The progress of pT1b ESCC with lymph node metastasis or lymphovascular invasion is relatively poor.
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Network pharmacology, molecular docking and in vivo experiments were used to explore the pharmacodynamic basis and potential mechanism of Danggui Sini Decoction in the treatment of primary dysmenorrhea(PD). The chemical constituents of Danggui(Angelicae Sinensis Radix), Guizhi(Cinnamomi Ramulus), Tongcao(Tetrapanacis Medulla), Baishao(Paeoniae Radix Alba), Xixin(Asari Radix et Rhizoma), Gancao(Glycyrrhizae Radix et Rhizoma), and Dazao(Jujubae Fructus) from Danggui Sini Decoction were retrieved through TCMSP(Traditional Chinese Medicine Systems Pharmacology Database), and the action targets of Danggui Sini Decoction were collected through DrugBank. "Primary dysmenorrhea" and "dysmenorrhea" were used as the key words to search the corresponding targets in the GeneCards, OMIM and TTD databases, and then the intersection targets of Danggui Sini Decoction and the primary dysmenorrhea targets were taken for reverse screening to obtain the corresponding active ingredients. Cytoscape 3.6.1 software was used to construct a traditional Chinese medicine-compound-target-disease network; STRING database was used to build a protein-protein interaction(PPI) network; Gene ontology(GO) function enrichment analysis and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis were conducted by using DAVID database. The action mechanism of the intersection targets were then predicted, and a histogram chart and bubble chart were drawn for visualization. Then the top five targets in the PPI network were used for docking with the most compounds. In animal experiments, Sprague Dawley(SD) female rats were used to establish a primary dysmenorrhea model by intraperitoneal injection of diethylstilbestrol once a day. A total of 60 SD female rats were randomly divided into 6 groups, namely control group, model group, Danggui Sini Decoction low(1.5 g·kg~(-1)), medium(3.0 g·kg~(-1)), high(6.0 g·kg~(-1)) dose groups, and ibuprofen(20 mg·kg~(-1)) positive control group, with 10 rats in each group. From day 4, except for the control group, rats in the other groups were given intragastric administration of corresponding drugs, and the control group received intragastric administration of normal saline for 7 consecutive days. The number of writhing before and after the administration, the ute-rine contraction inhibition rate and the uterine index after administration were observed, and ELISA assay was used to detect the levels of prostaglandin-endoperoxide synthase 2(PTGS2) and vascular endothelial growth factor A(VEGFA) in the tissues of each group as well as the levels of serum inflammatory factors interleukin 1(IL-1), interleukin 6(IL-6), and tumor necrosis factor-alpha(TNF-α). According to network analysis, 7 Chinese medicines contained 114 active ingredients, 149 targets, and 30 common target genes with PD were obtained. The key targets included VEGFA, IL6, PTGS2, TNF, etc.; GO function enrichment analysis showed a total of 399 terms(P<0.05) were obtained, 353 of which were biological process(BP) terms, 21 were cell composition(CC) terms, and 25 were molecular function(MF) terms. In KEGG pathway enrichment analysis, 14 signaling pathways were obtained, 3 of which were related to inflammation, namely arachidonic acid metabolism, MAPK signaling pathway and NOD-like receptor signaling pathway. The compounds in Danggui Sini Decoction can play a therapeutic role in the treatment of PD by acting on VEGFA, IL-6, PTGS2, TNF and other targets to regulate arachidonic acid and inflammatory signaling pathways.
Subject(s)
Animals , Female , Humans , Rats , Drugs, Chinese Herbal , Dysmenorrhea/drug therapy , Molecular Docking Simulation , Rats, Sprague-Dawley , Vascular Endothelial Growth Factor AABSTRACT
【Objective】 To explore the efficacy and possible mechanisms of activation of Death receptor 3 (DR3) signaling pathway in the prevention of antibody-mediated transfusion-related acute lung injury (TRALI) via DR3 agonistic (αDR3) antibody. 【Methods】 8-10-week-old male wild-type Balb/c mice (40) were randomly divided into Naïve group, isotype control group, TRALI model group, and intervention group. Mice without any treatment served as Naïve group. Isotype and TRALI model were established by intraperitoneally priming 8-10-week Balb/c mice with LPS 18 h prior to injection of an IgG2a isotype antibody and anti-MHC-Ⅰ antibody via tail vein, respectively. Intervention group: mice were intraperitoneally injected with a single dose of αDR3 antibody (1 mg/kg) on day 1; after 3 days, the mice were challenged with LPS 18 h prior to injection of an anti-MHC-I antibody. The lung tissues and spleens of mice in each group were collected at the mice died or 2 hours after TRALI modeling for the lung injury severity. Spleens were collected to measure the proportion of Treg by flow cytometry. Foxp3, iNOS, and CD206 immunohistochemical staining combining with optical density analysis of lung tissues were used to represent Treg, M1 macrophages and M2 macrophages, respectively. The concentration of IL-6, IL-1β, TNF-α, and IL-10 cytokines in lung tissues was detected via Cytometric Beads Array. 【Results】 Compared with TRALI group, 1) the lung injury of mice were significantly alleviated in intervention group; 2) the proportion of Treg(%) in the spleens (9.295±1.349 vs 2.257±0.610, P<0.05), Foxp3 expression of Treg in the lungs (0.302 6±0.052 6 vs 0.230 2±0.016 3, P<0.05), and the concentration of Treg derived cytokines IL-10 in the lungs (29.52±8.885 vs 8.045±1.911, P<0.05) increased significantly in intervention group; 3) the iNOS expression of M1 macrophages (0.209 6±0.013 9 vs 0.279 6±0.045 2) and the concentration of M1 macrophage derived cytokines IL-6 (23.22±19.35 vs 301.1±157.7), IL-1β (46.76±25.34 vs 307.6±183.8), and TNF-α (45.99±14.16 vs 143.9±44.43) in the lungs was significantly reduced(P<0.05), while CD206 expression of M2 macrophages (0.291 2±0.032 1 vs 0.221 5±0.012 7) and the concentration of M2 macrophage derived IL-10 cytokines (29.52±8.885 vs 8.045±1.911) in the lungs increased significantly in intervention group(P<0.05). 【Conclusion】 Activation of DR3 signaling pathway by αDR3 antibody prevents antibody-mediated TRALI via expanding Treg, which regulates macrophage polarization by IL-10 derived from Treg.
ABSTRACT
Transfusion-related acute lung injury (TRALI), with clinical manifestation, diagnosis and pathological mechanism consistent with acute lung injury(ALI), belongs to a sub-category of ALI. Excessive deposition of fibrin in lung is one of the characteristic of ALI, and reversing fibrin formation is of great significance to intervene ALI. The decrease of fibrinolytic activity is one of the important causes of excessive deposition of fibrin in lung, and also the important pathological feature of TRALI. This article discusses the potential of modulating fibrinolytic activity to intervene TRALI from the perspective of regulating the effectiveness of fibrinolytic activity to intervene ALI.
ABSTRACT
BRAF is a serine/threonine kinase that harbors activating mutations in ∼7% of human malignancies and ∼60% of melanomas. Despite initial clinical responses to BRAF inhibitors, patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAF inhibitor resistant melanoma, we conduct CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAF inhibitors. To investigate the mechanisms and pathways enabling resistance to BRAF inhibitors in melanomas, we integrate expression, ATAC-seq, and CRISPR screen data. We identify the JUN family transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6, which together enable resistance to BRAF inhibitors in melanoma cells. Our findings reveal genes contributing to resistance to a selective BRAF inhibitor PLX4720, providing new insights into gene regulation in BRAF inhibitor resistant melanoma cells.