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Objective:To explore the mechanism of Tripterygium wilfordii in treating renal cell carcinoma using network pharmacology and experimental validation. Methods:The traditional Chinese medicine systems pharmacology (TCMSP) database and analysis platform was utilized to screen the active ingredients of T. wilfordii and predict the targets using the Swiss database. Renal cell carcinoma related targets were collected from DisGeNET, GeneCards, and OMIM databases, and intersecting targets were obtained through Venny 2.1.0. Protein-protein interaction (PPI) networks were mapped using the STRING database and Cytoscape software, and gene ontology (GO) and kyoto encyclopedia of genes and genomics (KEGG) enrichment analyses were performed. Component-target-pathway networks were constructed using Cytoscape software. To induce the subcutaneous transplantation tumor model of renal cell carcinoma, nude mice were randomly divided into a control group and a treatment group, with 5 mice in each group. In the treatment group, mice were gastrically instilled with 615 mg/ml of T. wilfordii solution (1 845 mg T. wilfordii granules dissolved into 3 ml water) 2.46 g/kg, 10 μl/time, once daily for 21 d. In the control group, mice were gastrically instilled with an equal amount of saline. Tumor volume was measured once every 5 days, and the expression of serine/threonine protein kinase 1 (AKT1), signal transduction and transcription activator 3 (STAT3), tumor necrosis factor (TNF), tumor protein p53 (TP53), JUN, mitogen-activated protein kinase 8 (MAPK8), and MAPK14 was detected by enzyme-linked immunoassay. Results:Twenty-eight active pharmaceutical ingredients and 117 potential targets of T. wilfordii were screened; 13 425 related disease targets were identified; and finally, 113 drug-disease intersecting targets were obtained. In the PPI network, AKT1, STAT3, TNF, TP53, JUN, MAPK8, and MAPK14 were the core targets. GO analysis showed that BP mainly included nuclear receptor activity, ligand-activated transcription factor activity, RNA polymerase-specific DNA-binding transcription factor binding, nuclear steroid receptor activity, and adrenergic receptor activity, etc. CC mainly included the response to hormones, the cellular response to lipids, the positive regulation of cell migration, the response to TNF, the inflammatory response, the cellular response to hormonal stimulation, the response to hypoxia, the response to metal ions, etc. MF involves membrane rafts, membrane microregions, the outer side of the plasma membrane, the lateral side of the membrane, plasma membrane rafts, presynaptic membranes, vesicles, transcriptional regulatory complexes, post-synaptic membranes, synaptic membranes, etc. KEGG analysis showed that T. wilfordii treatment of RCC involves signaling pathways such as lipid and atherosclerosis, advanced glycosylation end product-receptor for advanced glycosylation end products (AGE-RAGE), TNF, Toll-like receptor, phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt), and MAPK. The experimental validation results showed that the tumor volume was reduced after treatment with tretinoin ( P < 0.05), the expression of TP53 protein was increased ( P < 0.001), and the expression of AKT1, STAT3, TNF, JUN, MAPK8, and MAPK14 proteins were all reduced (all P < 0.001). Conclusions:In this study, the target and signaling pathways of T. wilfordii treatment of renal cell carcinoma were initially predicted, providing a reference basis for further research on its protective mechanism and clinical application.
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Objective:To investigate the correlation between mild cognitive impairment(MCI)and abnormal glucose metabolism and thus to provide a basis for MCI prevention.Methods:A total of 1 074 elderly outpatients with normal cognitive function and without confirmed diabetes mellitus, hyperlipoidemia or gout were enrolled.During a five-year follow-up period, 121 subjects were diagnosed with MCI based on the mini mental state examination(MMSE)and the Montreal cognitive assessment(MoCA). Furthermore, annual blood glucose and glycated hemoglobin monitoring was carried out to examine the long-term effects of abnormal glucose metabolism on MCI risk.Results:According to cognitive function, 1 074 subjects were divided into the MCI group and the non-MCI group.Compared with the non-MCI group, the mean values of fasting blood glucose(FBG), glycosylated hemoglobin(HbA1c), triglycerides(TG)and total cholesterol(TC)in the MCI group were elevated( P<0.05). The receiver operating characteristic(ROC)curve showed that the cut-off value of FBG was 6.2 mmol/L for the hyperglycemia group(sensitivity: 84.1%, specificity: 90.9%, area under curve: 0.875, P<0.001)and 4.5mmol/L for the hypoglycemic group(sensitivity: 77.4%, specificity: 87.3%, area under curve: 0.823, P<0.001); the cut-off value of HbA1c was 5.5%(sensitivity: 76.0%, specificity: 87.0%, area under curve: 0.815, P<0.001). Multiple Logistic regression analysis showed that increased risk of MCI was associated with the mean values of fasting blood glucose <4.5 mmol/L( RR: 1.69, 95% CI: 1.11-2.59)or ≥6.2 mmol/L( RR: 1.81, 95% CI: 1.15-2.86)and of glycosylated hemoglobin ≥ 5.5%( RR: 2.13, 95% CI: 1.51-2.99). Conclusions:Impaired fasting glucose tolerance and low fasting blood glucose are independent risk factors for MCI in the elderly.
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Objective:To determine the relationship between uric acid (UA) and mild cognitive impairment (MCI), and its potential effect on inflammation.Methods:450 patients with MCI diagnosed by neuropsychological scale and 450 controls with normal cognitive function were included. All subjects were≥60 years old. There were 184 obese subjects in MCI group and 199 obese subjects in control group.Results:A correlation between increased serum UA level and decreased risk of MCI was found in all MCI patients and non-obese MCI patients ( OR: 0.60, 95% CI 0.45-0.78; OR: 0.42, 95% CI 0.29-0.62), but not in obese MCI patients ( OR: 0.86, 95% CI: 0.54-1.35). The levels of UA and hypersensitive C reactive protein (hs-CRP) in obese patients with MCI were higher than those in non-obese patients ( P<0.01). There was a linear positive correlation between serum UA and hs-CRP levels in obese patients with MCI ( r=0.505, P<0.01), but not in non-obese MCI patients ( r=0.053, P=0.385). Conclusion:A significant correlation between lower serum uric acid levels and higher risk of MCI in non-obese subjects was found. Inflammation caused by obesity may weaken this relationship.
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Objective@#To observe the species distribution, clinical features, efficacy and safety of anti-fungus therapy in advanced elderly patients with fungemia.@*Methods@#Clinical data of patients aged 70 years and over with fungemia admitted into geriatric intensive care unit (GICU) of our hospital from Nov. 2012 to Nov. 2017 were retrospectively analyzed. The specie distribution, liver toxicity, differences in biochemical liver and renal functions before and after 28 days of treatment between the caspofungin group and the azole group (fluconazole plus voriconazole), and 28-d survival rate and its risk factors for death were analyzed.@*Results@#A total of 72 patients were enrolled, with a median age of 85.5 years (83, 90), a median score of Acute Physiology and Chronic Health Enquiry (APACHE-Ⅱ) of 25.5 (20.3, 31.5), a median score of Sequential Organ Failure Assessment (SOFA) 7 (4.0, 9.8). There were 33 patients (45.8%) with diabetes, 2 patients (2.8%) with hematological diseases, 44 patients (61.1%) with solid tumors and 18 patients (25.0%) with renal insufficiency. Thirty patients (41.7%) needed mechanical ventilation. The detection rate of Candida parapsilosis was 73.6% (53 cases), Candida famata 9.7% (7 cases), Candida tropicalis 5.6% (4 cases), Candida albicans 2.8% (2 cases), Candida glabrata 2.8% (2 cases) and others 5.6% (4 cases). The incidence rate of total liver toxicity was 23.6% after anti-fungus treatment. After 28 days of treatment, 29 patients survived in the caspofungin group (n=42) and 16 patients survived in the azole group (n=30). There were no significant differences in liver and renal function between the two groups before and after treatment. Logistic regression analysis showed that solid tumors (OR: 19.904, 95%CI: 1.944-203.808) and the median APACHE Ⅱ score were the independent risk factors for 28-day death in advanced patients with fungemia.@*Conclusions@#Fungemia is becoming more and more prominent in the GICU, which requires clinician’s constant attention in order to provide more basis for the treatment of fungemia in elderly patients.
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Objective To observe the species distribution,clinical features,efficacy and safety of anti-fungus therapy in advanced elderly patients with fungemia.Methods Clinical data of patients aged 70 years and over with fungemia admitted into geriatric intensive care unit (GICU) of our hospital from Nov.2012 to Nov.2017 were retrospectively analyzed.The specie distribution,liver toxicity,differences in biochemical liver and renal functions before and after 28 days of treatment between the easpofungin group and the azole group (fluconazole plus voriconazole),and 28-d survival rate and its risk factors for death were analyzed.Results A total of 72 patients were enrolled,with a median age of 85.5 years (83,90),a median score of Acute Physiology and Chronic Health Enquiry (APACHE-Ⅱ) of 25.5 (20.3,31.5),a median score of Sequential Organ Failure Assessment (SOFA) 7 (4.0,9.8).There were 33 patients (45.8％) with diabetes,2 patients (2.8％) with hematological diseases,44 patients (61.1％) with solid tumors and 18 patients (25.0％) with renal insufficiency.Thirty patients (41.7％) needed mechanical ventilation.The detection rate of Candida para psilosis was 73.6％ (53 cases),Candida famata 9.7％ (7 cases),Candida tropicalis 5.6％ (4 cases),Candida albicans 2.8％ (2 cases),Candida glabrata 2.8％ (2 cases) and others 5.6％ (4 cases).The incidence rate of total liver toxicity was 23.6％ after anti-fungus treatment.After 28 days of treatment,29 patients survived in the caspofungin group (n=42) and 16 patients survived in the azole group (n=30).There were no significant differences in liver and renal function between the two groups before and after treatment.Logistic regression analysis showed that solid tumors (OR:19.904,95％CI:1.944-203.808) and the median APACHE Ⅱ score were the independent risk factors for 28-day death in advanced patients with fungemia.Conclusions Fungemia is becoming more and more prominent in the GICU,which requires clinician's constant attention in order to provide more basis for the treatment of fungemia in elderly patients.
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Objective To observe the clinical features of senile patients suffering from fungemia of Candida parapsilosis, and the effect and safety of antifungal therapy in treatment of this disease in geriatric intensive care unit (GICU). Methods The clinical data of patients with fungi positive either in peripheral blood culture or catheter culture admitted to the GICU of Tianjin Medical University General Hospital from November 2012 to June 2015 were retrospectively analyzed, of them 45 cases were of infection of Candida parapsilosis (parapsilosis group) and 15 cases infection of non-Candida parapsilosis (non-parapsilosis group). The clinical features of the two groups were collected, such as sex, age, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score, sequential organ failure assessment (SOFA) score, timing of antifungal therapy, number of patients mechanical ventilation, concomitant disease, catheter-related infection, method of catheter-indwelling, levels of creatinine (Cr), hemoglobin (Hb), platelet count (PLT), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), etc.; the differences in above indicators were compared between the two groups; multifactor Cox-regression-analysis was used to analyze the risk factors that could affect the patients' prognosis; the patients' survival rates on 7, 14 and 28-day were calculated and compared between the two groups, and the therapeutic effects of different anti-fungal drugs on patients' survival rates and liver function damage were recorded and compared. Results The non-parapsilosis group had a higher rate in mechanical ventilation than parapsilosis group [73.3% (11/15) vs. 33.3% (15/45), P < 0.05], and in the comparisons of other clinical features, there were no statistical significant differences between the two groups (all P > 0.05). There were no statistical significant differences in survival rates in the duration of 7, 14 and 28 days between the two groups[7 days: 82.2% (37/45) vs. 66.7% (10/15), 14 days: 75.6% (34/45) vs. 60.0% (9/15), 28 days: 66.7% (30/45) vs. 46.7% (7/15), all P > 0.05]. When the patients in parapsilosis group treated with echinocinomycin were compared with those treated with azolol, no statistical significant differences were found between the 2 types of therapy in the survival rates in the duration of 7, 14, and 28 days after treatment [7 days: 100.0% (23/23) vs. 82.4% (14/17), 14 days: 91.3% (21/23) vs. 76.5% (13/17), 28 days: 78.3% (18/23) vs. 70.6% (12/17), all P > 0.05]. Multifactor Cox-regression-analyses showed:diabetes [odds ratio (OR) = 0.268, 95% confidence interval (95%CI) = 0.077 - 0.928, P = 0.038), infection of Candida parapsilosis (OR = 0.260, 95%CI = 0.072 - 0.946, P = 0.041), APACHE Ⅱ score (OR = 1.241, 95%CI = 1.051 - 1.466, P = 0.011) and SOFA score (OR = 1.405, 95%CI = 1.005 - 1.966, P = 0.047) were the risk factors affecting the prognosis of the patients. When the patients in parapsilosis group treated with echinocinomycin were compared with those treated with azolol, there were no statistical significant differences in incidences of aggravation of liver damage and newly developed liver damage (aggravation of liver damage: 18.8% vs. 21.0%, newly developed liver damage: 6.2% vs. 10.5%, both P > 0.05). Conclusion The patients with fungemia in GICU are mainly the infection of Candida parapsilosis, and diabetes, infection of parapsilosis, APACHE Ⅱ score and SOFA score are the risk factors affecting the prognosis of the patients.
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Objective To explore the correlation and role of E2F3 gene,miR-17-5p and miR-20a in the cell lines of transitional cell carcinoma of bladder. Methods The plasmids of pcDNA3.1-HA-E2F3 and pAAV-siRNA-E2F3 were used to overexpress and knockdown E2F3.The mimics of miR-17-5p,miR-20a and their anti-miRNA oligonucleotides were used to overexpress and screen miR-17-5p and miR-20a.The expression levels of E2F3 gene,miR-17-5p and miR-20a were detected by quantitative real-time PCR,and E2F3 protein were detected by Western blot. Results When E2F3 was overexpressed,the 2- △△Ct of miR-17-5p and miR-20a were 2.26 ± 0.30 and 4.04 ± 0.51,it was statistically significant to compared with control (P ＜ 0.05) ; when E2F3 was knockdown,the 2 △△Ct of miR-17-5p and miR-20a were 0.49 ± 0.02and 0.65 ± 0.04 (P ＜ 0.05) ; when miR-17-5p and miR-20a were overexpressed simultaneously,the level of E2F3 mRNA was significantly decreased,the average E2F3 protein gray scale was 55.31 ± 7.89,the control was 103.67 ± 13.61 (P ＜ 0.05 ) ; when miR-17-5p and miR-20a were knockdown simultaneously,the E2F3 mRNA was significantly increased,the E2F3 protein gray scale was 295.68 ± 19.25,the control was 103.67 ± 13.61 ( P ＜ 0.05 ). Conclusions miR-17-5p and miR-20a could be up-regulated by E2F3 gene,and the E2F3 gene could be down-regulated by miR-17-5p and miR-20a.The regulatory feedback loop of E2F3 gene,miR-17-5p and miR-20a exists in transitional cell carcinoma of bladder. The loop maybe plays a key role in the development of bladder cancer.