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We designed and synthesized eighteen lycorine derivatives with five different structural types, and evaluated their antiviral activities on a HCoV-OC43-infected H460 cell model. Structure-activity relationships suggested that the introduction of appropriate substituents on the 6N atom of lycorine was beneficial to activity. Compound 6a gave a good activity with the half effective concentration (EC50) and selectivity index (SI) values of 2.36 μmol·L-1 and 16.52, respectively. Surface plasmon resonance (SPR) result indicated that 6a might target the non-structural protein 12 (NSP12) subunit in RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with the dissociation constant (KD) value of 1.36 μmol·L-1. Molecular docking indicated that 6a might act on nidovirus RdRp-associated nucleotidyltransferase (NiRAN) catalytic center of NSP12, distinct from the mechanism of nucleoside-like drugs such as remdesivir. This study provides scientific data for the development of lycorine derivatives into a new class of anti-SARS-CoV-2 small molecule inhibitors.
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ObjectiveTo observe the preventive and control effects of Danggui Niantongtang against adjuvant arthritis differentiated into wind-damp-heat impediment in rats and its influences on the expression of autophagy-related proteins microtubule-associated protein 1 light chain 3 (LC3), homolog of yeast Atg6 (Beclin1) and p62. MethodThe six-week-old male SD rats were randomly divided into the normal group, wind-damp-heat impediment model group, low-, medium-, and high-dose Danggui Niantongtang (5.67, 11.34, 22.68 g·kg-1) groups, and methotrexate (MTX, 1.35 mg·kg-1) group, with 10 rats in each group. A rat model of adjuvant arthritis was established by subcutaneous injection of inactivated Mycobacterium tuberculosis into the tail root, followed by exposure to the manual climatic box for 16 d for inducing the wind-damp-heat impediment. The drugs were administered intragastrically on the day of immunization for 28 d. The general conditions of rats were observed and the swelling degree of toes and arthritis index (AI) were detected. The pathological changes in the synovial tissues of the knee joints were observed by hematoxylin-eosin (HE) staining. The mRNA expression levels of LC3, Beclin1, and p62 in the synovial tissues were measured by real-time fluorescence quantitative polymerase chain reaction (Real-time PCR), followed by the assay of their protein expression by Western blot and immunohistochemistry. ResultCompared with the normal group, the wind-damp-heat impediment model group exhibited significantly increased swelling degree of toes (P<0.01), increased AI (P<0.01), proliferated synovial cells (P<0.01), up-regulated LC3 and Beclin1 protein and mRNA expression (P<0.01), and down-regulated p62 protein and mRNA expression (P<0.01) after 16, 20, 24, 28-d medication. Compared with the wind-damp-heat impediment model group, each medication group displayed alleviated toe swelling and synovial hyperplasia to different degrees, decreased mRNA and protein expression levels of LC3 and Beclin1 (P<0.01), and increased p62 mRNA and protein expression (P<0.05,P<0.01), with the best outcomes observed in the medium-dose Danggui Niantongtang group. ConclusionDanggui Niantongtang effectively relieves adjuvant arthritis due to wind-damp-heat impediment in rats, which may be related to its regulation of the expression of autophagy-related proteins LC3, Beclin1, and p62 and the inhibition of autophagy.
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ObjectiveTo explore the effect of Danggui Niantongtang (DGNTT) on cell apoptosis and autophagy in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). MethodRA-FLS were isolated and cultured from the synovial tissue of RA patients. The cells were treated with 10% blank serum (blank control group), 10% sera containing low, medium and high doses of DGNTT. Wound healing assa and cell invasion test were applied to observe the effect of RA-FLS invasion technique. The apoptosis and autophagy level of RA-FLS cells was detected by Hoechst33342 method and monodansylcadaverine (MDC) staining. The mRNA and protein expression levels of B cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), microtubule-associated protein 1 light chain 3 (LC3), autophagy key molecular yeast Atg6 homolog 1 (Beclin1) were detected by Real-time fluorescence quantitative polymerase chain reaction(Real-time PCR)and Western blot. ResultCompared with the blank control group,each dose of serum could slow down the wound healing and significantly Reduce the number of RA-FLS cells invading the lower chamber(P<0.01),the mRNA and protein expression levels of Bcl-2,LC3,Beclin1 were significantly decreased(P<0.01), and Bax were significantly increased(P<0.01). Hoechst33342 results showed that low, medium and high doses DGNTT could promote RA-FLS cell apoptosis. After MDC staining,autophagosome in low, medium and high doses DGNTT decreased significantly(P<0.01). ConclusionDanggui Niantongtang can effectively inhibit the proliferation of fibroblast-like synoviocytes. Its mechanism may be related to promote apoptosis and inhibit autophagy of fibroblast-like synoviocytes.
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OBJECTIVES: The purpose of this study was to evaluate the diagnostic value of multimodal ultrasonography, including SWE and CEUS, for the differentiation of benign and malignant cervical lymphadenopathy. METHODS: A total of 103 patients with 109 enlarged neck lymph nodes underwent SWE and CEUS. There were 25 hyperplastic lymph nodes, 66 metastatic lymph nodes, and 18 cases of lymphoma. RESULTS: Using 31.6 kPa as the Emax cutoff, the sensitivity, specificity and accuracy of measurements on both benign and malignant cervical lymph nodes were 55.95%, 96%, and 65.2%, respectively. CEUS showed that lymph nodes with reactive hyperplasia mainly exhibited uniform perfusion via the lymphatic hilum (18/25; 72%; P < 0.01). The main manifestation of lymphoma was uniform perfusion through the lymphatic hila (10/18; 55.6%; P < 0.01). Metastatic lymph nodes mainly exhibited uneven perfusion (57/66; 86.4%; P < 0.01). The sensitivity, specificity, and accuracy of multimodal ultrasonography for the diagnosis of benign and malignant cervical lymphadenopathies were 90.5%, 72%, and 86.2%, respectively. CONCLUSIONS: Our findings suggest that multimodal ultrasonography can detect the stiffness (elasticity), perfusion pattern, and characteristics of lymph nodes and is a valuable tool for differentiating between benign and malignant lymphadenopathies.
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Diagnóstico por Imagen de Elasticidad , Linfadenopatía , Diagnóstico Diferencial , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Linfadenopatía/diagnóstico por imagen , Cuello/diagnóstico por imagen , Sensibilidad y Especificidad , UltrasonografíaRESUMEN
Objective:To observe the effect of Danggui Niantongtang on the protein and mRNA expression of key regulatory factors of the extrinsic and intrinsic apoptotic pathway in synovial tissue of adjuvant arthritis (AA) rats, and to further explore the mechanism of Danggui Niantongtang in the prevention and treatment of rheumatoid arthritis. Method:The general condition of AA rats, including its body weight, were observed. The changes of toe volume were detected by toe volume meter. Histopathological changes of synovium of knee joint were observed by hematoxylin-eosin (HE) staining. The mRNA and protein expression levels of tumor necrosis factor receptor super family 6 (Fas), Fas-associating protein with a novel death domain(FADD), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax) and cysteinyl aspartate specific proteinase Caspase-3 (Caspase-3) were detected by Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) and Western blot. Result:Compared with the normal group, the toe volume of the model group increased significantly (<italic>P</italic><0.01), with significantly proliferated synovial cells, significantly reduced mRNA and protein expression levels of Fas, FADD, Bax and Caspase-3 in synovial tissues(<italic>P</italic><0.05,<italic> P</italic><0.01), and significantly increased Bcl-2 level (<italic>P</italic><0.01). Compared with the model group, the swelling degree of toes in Danggui Niantongtang group and Tripterygium group was significantly alleviated (<italic>P</italic><0.01), with significantly improved synovial hyperplasia, significantly increased mRNA and protein expression levels of Fas, FADD, Bax and Caspase-3 (<italic>P</italic><0.05, <italic>P</italic><0.01), and significantly decreased expression levels of bcl-2 mRNA and protein (<italic>P</italic><0.05, <italic>P</italic><0.01). Conclusion:Danggui Niantongtang can effectively reduce joint swelling and abnormal proliferation of synovial tissue in AA rats. Its mechanism may be related to regulating the expression of Fas, FADD, Bax, Bcl-2 and Caspase-3, and promoting the apoptosis of synovial cells.
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Nonspecific low back pain is a major contributor to disease burden worldwide and may affect people of all ages. As a key strategy in the management of low back pain, exercise rehabilitation has been unanimously recommended by several clinical practice guidelines. However, the guidelines didn't make it clear that the most optimum types, intensity, frequency and duration of exercise rehabilitation for patients with nonspecific low back pain. In the future, researchers should highlight the design of the exercise program, identify the patient subsets benefiting from specific exercise programs, exploit and popularize more effective and cost-effective exercise programs and promote active exercise in the patients with nonspecific low back pain to achieve complete rehabilitation.
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Objective To analyze the application status and problems of PACS so as to facilitate its future development.Methods The application of PACS in some hospital from June 2015 to May 2016was reviewed,and considerations were taken on the hospital conditions to explore the application status and problems of PACS in China.Results There were a number of problems found in Department of International Diagnosis and Treatment,including 13-a active time of image acquisition devices,6.8% of the workstations and 14.2% of the image acquisition devices having no interface with PACS,and 2.9% of the images non-uploaded to PACS.Conclusion PACS in China has to emphasize on stability,high efficiency,safety and reliability to facilitate its future application to medicine,scientific research and teaching.
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Objective To analyze the application status and problems of PACS so as to facilitate its future development.Methods The application of PACS in some hospital from June 2015 to May 2016was reviewed,and considerations were taken on the hospital conditions to explore the application status and problems of PACS in China.Results There were a number of problems found in Department of International Diagnosis and Treatment,including 13-a active time of image acquisition devices,6.8% of the workstations and 14.2% of the image acquisition devices having no interface with PACS,and 2.9% of the images non-uploaded to PACS.Conclusion PACS in China has to emphasize on stability,high efficiency,safety and reliability to facilitate its future application to medicine,scientific research and teaching.
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Aberrant autophagic processes have been found to have fundamental roles in the pathogenesis of different kinds of tumors, including hepatocellular carcinoma (HCC). P300/CBP-associated factor (PCAF), a histone acetyltransferase (HAT), performs its function by acetylating both histone and non-histone proteins. Our previous studies showed that PCAF was downregulated in HCC tissues and its high expression was significantly associated with patient survival after surgery, serving as a prognostic marker. In this study we found that overexpression of PCAF induced autophagy of HCC cells and its knockdown depressed autophagy. As type II programmed cell death, autophagy induced by PCAF-elicited cell death in HCC cells. In vivo experiments confirmed that PCAF-induced autophagy inhibited tumor growth. Subsequent in vitro experiments showed that PCAF promoted autophagy by inhibiting Akt/mTOR signaling pathway. Our findings show that PCAF is a novel modulator of autophagy in HCC, and can serve as an attractive therapeutic strategy of HCC treatment.
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Autofagia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Factores de Transcripción p300-CBP/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Macrólidos/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Oligopéptidos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIM: To investigate whether prophylactic abdominal drainage is necessary after pancreatic resection. METHODS: PubMed, Web of Science, and the Cochrane Library were systematically searched to obtain relevant articles published before January 2014. Publications were retrieved if they met the selection criteria. The outcomes of interest included: mortality, morbidity, postoperative pancreatic fistula (POPF), clinically relevant pancreatic fistula (CR-PF), abdominal abscess, reoperation rate, the rate of interventional radiology drainage, and the length of hospital stay. Subgroup analyses were also performed for pancreaticoduodenectomy (PD) and for distal pancreatectomy. Begg's funnel plot and the Egger regression test were employed to assess potential publication bias. RESULTS: Nine eligible studies involving a total of 2794 patients were identified and included in this meta-analysis. Of the included patients, 1373 received prophylactic abdominal drainage. A fixed-effects model meta-analysis showed that placement of prophylactic drainage did not have beneficial effects on clinical outcomes, including morbidity, POPF, CR-PF, reoperation, interventional radiology drainage, and length of hospital stay (Ps > 0.05). In addition, prophylactic drainage did not significantly increase the risk of abdominal abscess. Overall analysis showed that omitting prophylactic abdominal drainage resulted in higher mortality after pancreatectomy (OR = 1.56; 95%CI: 0.93-2.92). Subgroup analysis of PD showed similar results to those in the overall analysis. Elimination of prophylactic abdominal drainage after PD led to a significant increase in mortality (OR = 2.39; 95%CI: 1.22-4.69; P = 0.01). CONCLUSION: Prophylactic abdominal drainage after pancreatic resection is still necessary, though more evidence from randomized controlled trials assessing prophylactic drainage after PD and distal pancreatectomy are needed.
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Absceso Abdominal/prevención & control , Drenaje , Pancreatectomía , Fístula Pancreática/prevención & control , Pancreaticoduodenectomía , Absceso Abdominal/diagnóstico , Absceso Abdominal/etiología , Adulto , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Drenaje/efectos adversos , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pancreatectomía/efectos adversos , Fístula Pancreática/diagnóstico , Fístula Pancreática/etiología , Pancreaticoduodenectomía/efectos adversos , Reoperación , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
<p><b>OBJECTIVE</b>To detect the inhibitory effect of a p38MAPK inhibitor SB203580 in combination with gefitinib on lung adenocarcinoma cell line PC-9 cells and A549 cells, and its cellular and molecular mechanisms of action.</p><p><b>METHODS</b>MTT test was used to detect the growth inhibition of PC-9 and A549 cells by SB203580 alone and in combination with gefitinib. Cell apoptosis and cell cycles were determined by flow cytometry. The expressions of p38 and phosphorylated -p38 proteins in the two cell lines were analyzed by immunofluorescence microscopy. The associated protein expression was determined by Western-blot.</p><p><b>RESULTS</b>Compared with the SB203580 group and gefitinib group, the growth inhibition and cell apoptosis of PC-9 cells in the SB203580 + gefitinib group were significantly increased (P < 0.05). The inhibition rate of PC-9 cells of 2 µmol/L SB203580 + 0.01 µmol/L gefitinib group was (46.6 ± 2.4)%, significantly higher than that induced by 0.01 µmol/L gefitinib (12.7 ± 1.5%) (P < 0.05). Immunofluorescence microscopy showed a low expression of phosphorylated-p38 protein in A549 cells and high expression in PC-9 cells. Flow cytometry showed that PC-9 cells in the SB203580 + gefitinib group were (77.35 ± 2.83)% at G0/G1 phase, (3.38 ± 0.84)% at S phase, and (19.56 ± 1.99)% at G2/M phase. Western-blotting showed that compared with the control group, the expression of phosphorylated Akt and phospho-p38 proteins in PC-9 cells of the SB203580 + gefitinib group was almost completely suppressed.</p><p><b>CONCLUSIONS</b>The results indicate that the small molecular inhibitor SB203580 can effectively enhance the inhibitory effect of gefitinib on lung adenocarcinoma PC-9 cells. The enhanced inhibitory effect of SB203580 may be correlated with the blockage of p38MAPK signal transduction pathway.</p>
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Humanos , Adenocarcinoma , Metabolismo , Patología , Antineoplásicos , Farmacología , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Sinergismo Farmacológico , Inhibidores Enzimáticos , Farmacología , Imidazoles , Farmacología , Neoplasias Pulmonares , Metabolismo , Patología , Fosforilación , Proteínas Proto-Oncogénicas c-akt , Metabolismo , Piridinas , Farmacología , Quinazolinas , Farmacología , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos , MetabolismoRESUMEN
<p><b>AIM</b>To prepare the microemulsion of vinpocetine in order to increase solubility and its in vitro transdermal delivery by using appropriate proportion of oil, surfactant (S), cosurfactant (CoS) and water. The formulation of proportion was optimized. The physicochemical properties and the skin irritation of the microemulsion was studied.</p><p><b>METHODS</b>Pseudo-tertiary phase diagrams were prepared to obtain the concentration ratio of components of the microemulsion. Using simplex lattice method, the formulation of microemulsion was optimized and the physicochemical properties including pH, viscosity, refractive index, conductivity and particle size distribution were examined. The MTT method was applied to test the skin irritation of the microemulsion on the Hacat cell.</p><p><b>RESULTS</b>The diagrams showed that the areas of O/W microemulsion increased with the increasing ratio of surfactant to cosurfactant (S/CoS). The predicted values from simplex lattice system were close to that of the experiment. The property of optimized microemulsion showed to be stable behavior and not irritant to Hacat cell.</p><p><b>CONCLUSION</b>The drug solubility and in vitro perscutaneous permeation flux of the optimized microemulsion was improved significantly and the irritation study showed that optimized microemulsion was safe as an ideal transdermal delivery system.</p>