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ObjectiveTo develop traditional Chinese medicine （TCM） formulae for the treatment of nonsevere coronavirus disease 2019 （COVID-19） and to explore its anti-inflammatory mechanism. MethodsThe dysregulated signaling pathways were determined in macrophages from bronchoalveolar lavage fluid of COVID-19 patients and in lung epithelial cells infected with SARS-CoV-2 in vitro based on transcriptome analysis. A total of 102 TCM formulae for the clinical treatment of nonsevere COVID-19 were collected through literature. The pathway-reversing rates of these formulae in macrophages and lung epithelial cells were evaluated based on signature signaling pathways， and the basic formula was determined in conjunction with TCM theory. The commonly used Chinese materia medica for nonsevere COVID-19 were summarized from the 102 TCM formulae as abovementioned. And together with the screening results from the Pharmacopoeia of the People's Republic of China， a “Chinese materia medica pool” was esta-blished for the development of TCM formulae for COVID-19. The regulatory effects of each herb on signaling pathways were obtained based on targeted transcriptome analysis. Oriented at reversing dysregulated signaling pathways of COVID-19， the calculation was carried out， and the artificial intelligent methods for compositing formulae， that are exhaustive method and parallel computing， were used to obtain candidate compound formulas. Finally， with reference to professional experience， an innovative formula for the treatment of nonsevere COVID-19 was developed. The ethanol extract of the formula was evaluated for its anti-inflammatory effects by detecting the mRNA expression of interleukin 1b （Il1b）， C-X-C motif chemokine ligand 2 （Cxcl2）， C-X-C motif chemokine ligand 10 （Cxcl10）， C-C motif chemokine ligand 2 （Ccl2）， nitric oxide synthase 2 （Nos2）， and prostaglandin-endoperoxide synthase 2 （Ptgs2） using reverse transcription-quantitative polymerase chain reaction （RT-qPCR） in RAW264.7 cells treated with lipopolysaccharide （LPS）. ResultsIn macrophages and lung epithelial cells， 34 dysregulated signaling pathways associated with COVID-19 were identified respectively. The effects of the 102 formulae for clinical treatment of nonsevere COVID-19 were evaluated based on the dysregulated signaling pathways and targeted transcriptome， and the result showed that Yinqiao Powder and Pingwei Powder （银翘散合平胃散， YQPWP） ranked first， reversing 91.18% of the dysregulated signaling pathways in macrophages and 100% of the dysregulated signaling pathways in lung epithelial cells. Additionally， YQPWP had the function of scattering wind and clearing heat， resolving toxins and removing dampness in accordance with the pathogenesis of wind-heat with dampness in COVID-19. It was selected as the basic formula， and was further modified and optimized to develop an innovative fomula Qiaobang Zhupi Yin （翘蒡术皮饮， QBZPY） based on expert experience and artificial intelligence in composing formulae. QBZPY can reverse all the dysregulated signaling pathways associated with COVID-19 in macrophages and lung epithelial cells， with the reversing rates of 100%. The chief medicinal of QBZPY， including Lianqiao （Fructus Forsythiae）， Xixiancao （Herba Siegesbeckiae） and Niubangzi （Fructus Arctii）， can down-regulate multiple signaling pathways related with virus infection， immune response， and epithelial damage. RT-qPCR results indicated that compared with the model group， the QBZPY group down-regulated the mRNA expression of Il1b， tumor necrosis factor （Tnf）， Cxcl2， Cxcl10， Ccl2， Nos2 and Ptgs2 induced by LPS in RAW264.7 cells （P＜0.05 or P＜0.01）. ConclusionBased on targeted transcriptome analysis， expert experience in TCM and artificial intelligence， QBZPY has been developed for the treatment of nonsevere COVID-19. The ethanol extract of QBZPY has been found to inhibit mRNA expression of several pro-inflammatory genes in a cellular inflammation model.
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Objective: To explore the relationship between low density lipoprotein cholesterol (LDL-C)/high density lipoprotein cholesterol (HDL-C) ratio with the severity of coronary artery disease and 2-yeat outcome in patients with premature coronary heart disease. Methods: This prospective, multicenter, observational cohort study is originated from the PROMISE study. Eighteen thousand seven hundred and one patients with coronary heart disease (CHD) were screened from January 2015 to May 2019. Three thousand eight hundred and sixty-one patients with premature CHD were enrolled in the current study. According to the median LDL-C/HDL-C ratio (2.4), the patients were divided into two groups: low LDL-C/HDL-C group (LDL-C/HDL-C≤2.4, n=1 867) and high LDL-C/HDL-C group (LDL-C/HDL-C>2.4, n=1 994). Baseline data and 2-year major adverse cardiovascular and cerebrovascular events (MACCE) were collected and analyzed in order to find the differences between premature CHD patients at different LDL-C/HDL-C levels, and explore the correlation between LDL-C/HDL-C ratio with the severity of coronary artery disease and MACCE. Results: The average age of the low LDL-C/HDL-C ratio group was (48.5±6.5) years, 1 154 patients were males (61.8%); the average age of high LDL-C/HDL-C ratio group was (46.5±6.8) years, 1 523 were males (76.4%). The number of target lesions, the number of coronary artery lesions, the preoperative SNYTAX score and the proportion of three-vessel coronary artery disease in the high LDL-C/HDL-C group were significantly higher than those in the low LDL-C/HDL-C group (1.04±0.74 vs. 0.97±0.80, P=0.002; 2.04±0.84 vs. 1.85±0.84, P<0.001; 13.81±8.87 vs. 11.70±8.05, P<0.001; 36.2% vs. 27.4%, respectively, P<0.001). Correlation analysis showed that there was a significant positive correlation between LDL-C/HDL-C ratio and preoperative SYNTAX score, the number of coronary artery lesions, the number of target lesions and whether it was a three-vessel coronary artery disease (all P<0.05). The 2-year follow-up results showed that the incidence of MACCE was significantly higher in the high LDL-C/HDL-C group than that in the low LDL-C/HDL-C group (6.9% vs. 9.1%, P=0.011). There was no significant difference in the incidence of all-cause death, cardiac death, myocardial infarction, stroke, revascularization and bleeding between the two groups. Cox multivariate regression analysis showed that the LDL-C/HDL-C ratio has no correlation with 2-year MACCE, death, myocardial infarction, revascularization, stroke and bleeding events above BARC2 in patients with premature CHD. Conclusion: High LDL-C/HDL-C ratio is positively correlated with the severity of coronary artery disease in patients with premature CHD. The incidence of MACCE of patients with high LDL-C/HDL-C ratio is significantly higher during 2 years follow-up; LDL-C/HDL-C ratio may be an indicator for evaluating the severity of coronary artery disease and long-term prognosis in patients with premature CHD.
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Male , Humans , Adult , Middle Aged , Female , Coronary Artery Disease/complications , Cholesterol, HDL , Cholesterol, LDL , Prospective Studies , Myocardial Infarction/etiology , Stroke , Risk FactorsABSTRACT
Objective:To construct Doctor-Nurse-Patient shared decision-making framwork for breast cancer surgery patients, so as to provide a foundation for clinical practice.Methods:The content of the shared decision-making framwork were initially constructed through systematic literature search and group discussion. From March to May 2021, 24 experts were consulted by the Delphi method, and the weight of each element would be determined by the analytic hierarchy process.Results:A total of 2 rounds of expert letter questionnaires were implemented. The authority coefficient of the experts in this study was 0.832, the Kendall coefficient of the experts in the first round was 0.130-0.261 ( P<0.01), and the Kendall coefficient of the experts in the second round was 0.130-0.272 ( P<0.01). The final shared decision-making framwork includes 5 first-level indicators, 15 second-level indicators and 52 third-level indicators. Conclusions:The Doctor-Nurse-Patient shared decision-making framwork of breast cancer surgery patients constructed in this study is scientific and practical, and provides a reference for clinical practice of shared decision-making in the future.
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The potential medicinal value of Ma bamboo (Dendrocalamus latiflorus), one of the most popular and economically important bamboo species in China, has been underestimated. In the present study, we found that D. latiflorus leaf extract (DLE) reduced fasting blood glucose levels, body weight, and low-density lipoprotein cholesterol with low liver toxicity in db/db mice. In addition, gene expression profiling was performed and pathway enrichment analysis showed that DLE affected metabolic pathways. Importantly, DLE activated the AKT signaling pathway and reduced glucose production by downregulating glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1) expression. Moreover, network pharmacology analysis identified rutin as an active component in DLE through targeting insulin growth factor 1 receptor (IGF1R), an upstream signaling transducer of AKT. Due to its hypoglycemic effects and low toxicity, DLE may be considered an adjuvant treatment option for type 2 diabetes patients.
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Objective To investigate the effects of microRNA( miR)-29a-3p on the proliferation and invasion of gastric cancer cells and analyze its related molecular mechanism. Methods The expression level of miR-29a-3p in gastric cancer cells was detected, and the role of miR-29a-3p in the proliferation, migration, and invasion of gastric cancer cells was evaluated. Western blotting and luciferase analysis showed that miR-29a-3p was directly bound to Serpinhl 3 ' -untranslated region(3' UTR). In addition, the effects of the miR-29a-3p/Serpinhl axis on the proliferation, migration, and invasion of gastric cancer cells were detected by MTT assay, colony formation assay, and Transwell assay in vitro. Results After transfection, the expression of miR-29a-3p in the miR-29a-3p mimic group was significantly higher than that in the miR-29a-3p negative control and blank group. After transfection, the proliferation of BGC823 cells decreased significantly. Luciferase analysis showed that miR-29a-3p inhibited the expression of Serpinhl by targeting the 3 ' UTR of Serpinhl. In addition, overexpression of miR-29a-3p significantly inhibited the proliferation, invasion, and migration of gastric cancer cells by targeting Serpinhl. Conclusion MiR-29a-3p can target Serpinhl and regulate the proliferation and invasion of gastric cancer cells.
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Aim To investigate the molecular mecha-nism of mTORC1/2 inhibitor PP242, which inhibiting cholangiocyte cell preliferation and cystic diliatation via inducing apoptosis and autophagy in the polycystic kid-ney ( PCK ) rats. Methods The expression of p-mTOR and p-Akt in the bile duct epithelial cells was examined by immunohistochemistry. The inhibiting effect of rapamycin and PP242 on cell proliferation ac-tivity on bile duct epithelial cells, the effect of gene si-lence on LC3, Beclin-1 and the effect of the authoph-agy-specific inhibitor 3-methyladenine (3-MA) on cell proliferation were respectively analyzed by WST-1 as-say. The expression of PI3K/Akt signaling pathway re-lated proteins, autophagy-related proteins LC3, Bec-lin-1 and clevead caspase-3, which were treated by PP242 were determined by Western blot. The effect of PP242 on apoptosis was detected by Annexin V/PI double staining and ELISA. The expression of LC3 in cytoplasm was detected by immunofluorescence. The a-bility of rat bile duct epithelial cells spheroid formation was detected by 3D cell culture method, and the cells were treated by single applied with rapamycin and ap- plied rapamycin combined with Rictor gene silencing respectively. Results The protein levels of p-Akt and p-mTOR markedly increased in the bile duct epitheli-um of PCK rats. PP242 inhibited the proliferation of bile duct epithelial cells more effectively than rapamy-cin and showed a dose-and time-dependent manner ( P<0.05 ) . PP242 significantly reduced the levels of PI3K/Akt signaling pathway-related proteins in PCK rat cholangiocytes. PP242 induced apoptosis and auto-phagy, up-regulated the levels of cleaved caspase-3, Beclin-1 and increased the ratio of LC3-II/LC3-I. The combination of Rictor gene silencing and rapamycin was more effective than rapamycin alone in inhibiting cholangiocytes in PCK rats. The inhibitory effect of PP242 on the cell viability was significantly weakened by treatment with 3-MA and knockdown of LC3 and Beclin-1 ( P <0.05 ) . Conclusions PP242 inhibits the proliferation of PCK rat cholangiocytes through PI3K/Akt/mTOR signaling pathway, and the mecha-nism is closely related with autophagy and apoptosis.
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AIM:To explore the effects of mammalian target of rapamycin (mTOR) double inhibitor AZD8055 on autophagy and apoptosis of human cholangiocarcinoma cell line HuCCT1. METHODS:The effect of AZD8055 on the viability of HuCCT1 cells was detected by MTT assay. Autophagosome was detected by acridine orange (AO) staining. Af-ter treated with AZD8055, the expression levels of apoptosis-related proteins Bcl-2, Bax and cleaved caspase-3 and auto-phagy marker proteins beclin 1, LC3 and p62 were determined by Western blot. Apoptotic rate was analyzed by flow cyto-metry with Annexin V-FITC/PI double staining. RESULTS:AZD8055 significantly inhibited the viability of HuCCT1 cells (P<0.05). AO staining showed that AZD8055 significantly increased orange granules in the cytoplasm. After treated with AZD8055, compared with the control group, the protein level of beclin 1 and the ratio of LC3-Ⅱ/LC3-Ⅰ were enhanced, while p62 was attenuated (P<0.05). The protein expression level of pro-apoptotic regulator Bax was down-regulated and anti-apoptotic regulator Bcl-2 was increased. The protein level of cleaved caspase-3 was reduced (P<0.05). The results of flow cytometry showed that AZD8055 inhibited cell apoptosis. CONCLUSION:AZD8055 inhibits the viability of cholangiocarcinoma cells, and the mechanism is closely related with autophagy induced by AZD8055.
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Objective To clarify the impairment mechanisms of acute hyperglycemia in the first-phase insulin se-cretion in mice. Methods The mouse model of acute glucose toxicity was established by glucose infusion through jugular vein catheterization. The glucose and insulin levels were assessed by IPGTT and OGTT in the mice of acute hyperglycemia and control groups. The histology of pancreatic islets was observed using HE staining and the insulin granules and other cy-toplasmic organelles were observed by electron microscopy. Results The mouse model of acute hyperglycemia was suc-cessfully established. The IPGTT showed that the blood glucose level was decreased by 87% ( 10. 3 ± 0. 33 mmol/L vs. 19. 3 ± 1. 66 mmol/L) at 15 min in the acute hyperglycemia group compared with the control group. The OGTT showed that the blood glucose level was decreased by 85% (9. 8 ± 0. 31 mmol/L vs. 18. 16 ± 1. 01 mmol/L) at 30 min in the acute hy-perglycemia group compared with the control group. However, the peak values of insulin secretion were delayed in both IPGTT and OGTT. Insulin levels at 2. 8 and 16. 7 mmol/L glucose stimulation in the acute hyperglycemia group was de-clined by 46% and 67% than the control group, respectively (P<0. 05). Residual insulin content in isletβcells was de-clined by 49% at 2. 8 mmol/L and 94% at 16. 7 mmol/L glucose infusion than the control group (P<0. 05). The histolo-gy showed irregular structure of pancreatic islets in the acute hyperglycemia group. The electron microscopy revealed that the amount of insulin granules was decreased, and more cytoplasmic vacuoles and swollen mitochondria were observed. Conclusions Acute intravenous glucose load decreases insulin content of isletβcells, leading to decrease and delay of the first-phase insulin secretion.
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Objective To clarify the impairment mechanisms of acute hyperglycemia in the first-phase insulin se-cretion in mice. Methods The mouse model of acute glucose toxicity was established by glucose infusion through jugular vein catheterization. The glucose and insulin levels were assessed by IPGTT and OGTT in the mice of acute hyperglycemia and control groups. The histology of pancreatic islets was observed using HE staining and the insulin granules and other cy-toplasmic organelles were observed by electron microscopy. Results The mouse model of acute hyperglycemia was suc-cessfully established. The IPGTT showed that the blood glucose level was decreased by 87% ( 10. 3 ± 0. 33 mmol/L vs. 19. 3 ± 1. 66 mmol/L) at 15 min in the acute hyperglycemia group compared with the control group. The OGTT showed that the blood glucose level was decreased by 85% (9. 8 ± 0. 31 mmol/L vs. 18. 16 ± 1. 01 mmol/L) at 30 min in the acute hy-perglycemia group compared with the control group. However, the peak values of insulin secretion were delayed in both IPGTT and OGTT. Insulin levels at 2. 8 and 16. 7 mmol/L glucose stimulation in the acute hyperglycemia group was de-clined by 46% and 67% than the control group, respectively (P<0. 05). Residual insulin content in isletβcells was de-clined by 49% at 2. 8 mmol/L and 94% at 16. 7 mmol/L glucose infusion than the control group (P<0. 05). The histolo-gy showed irregular structure of pancreatic islets in the acute hyperglycemia group. The electron microscopy revealed that the amount of insulin granules was decreased, and more cytoplasmic vacuoles and swollen mitochondria were observed. Conclusions Acute intravenous glucose load decreases insulin content of isletβcells, leading to decrease and delay of the first-phase insulin secretion.
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Objective:To describe the current situation in the nursing practice and their turnover intention in township health centers, and to analyze the changing potential influence in the nursing practice scope and workloads on their intention to leave those health centers. Methods:By means of a questionnaire, we conducted a survey on 167 nurses and interviewed 44 of them, all from 45 township hospitals within three provinces in China. Results:Since the healthcare system reform, the nursing workload in the township health centers significantly increased. 62% of the re-spondents considered their workload as heavy. Typically, the nursing work accounted for about 60% and the public health service work accounted for only 21% of the working hours. About 30% of the respondents were intended to leave their current job. The participating public health service was associated with intention to leave the job after con-trolling the province, workload, marital status, formal position, educational level and length of nursing service (P<0. 05). Conclusions:Since the healthcare system reform, the nursing practice scope in township health centers has been expanded and the workload increased considerably. But so far, expanding the scope of the nursing work may have potentials in reducing the intention of nurses to leave their current positions.
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Objective:To analyze the job preference of doctors at township health center ( THC) and provide references for formulating effective policy. Methods:238 cases of doctors were sampled from Shandong, Anhui and Shaanxi provinces. Using a discrete choice experiment, we analyzed the data with a conditional logit model. Results:The most important job attribution was salary, followed by education for children, permanent post, work location, training opportunity, and years before promotion. The OR value of the monthly income of 8 000 yuan is 7. 0 compared to 2 000 yuan. Doctors will pay 3 857 yuan and 3 294 yuan respectively for better education for children and perma-nent posts. Monthly income increasing to 8 000 yuan will reduce the quitting rate from 35% to 8%, and providing better education for children and permanent posts will reduce 5%. The permanent posts at township health center and non-permanent posts in county hospital have the same appeal to the doctor. Conclusion:When choosing a job, doc-tors at THCs valued salary the most. Improving the education level for children can be beneficial for attracting and re-taining doctors at THCs. A permanent post is more attractive to doctors than non-permanent posts at THCs.
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<p><b>OBJECTIVE</b>To investigate the therapeutic value of inhibiting the expression of insulin-like growth factor-I receptor (IGF-IR) using picropodophyllin (PPP) by studying the effects on proliferative and metastatic potentials of human hepatocellular carcinoma (HCC) using an in vitro cultured cell system.</p><p><b>METHODS</b>IGF-IR expression in human HCC cell lines (Bel-7404, Bel-7402, HepG2, and Huh-7) and human hepatocytes (L02) was assessed at baseline (pre-treatment) and after PPP treatment by western blotting. Changes in cell cycle were analyzed by flow cytometry and in cell viability by sulforhodamine B staining. Early apoptosis was detected by annexin-V/FITC and propidium iodide double-staining assay. Caspase-3/7 activity was suppressed by z-VAD-FMK and analyzed by homogeneous luminescence assay. Effects on cell motility were tested by wound-scratch test. Between-group differences were assessed by t-test or one-way analysis of variance.</p><p><b>RESULTS</b>IGF-IR was markedly up-regulated in all HCC cell lines (vs. non-hepatoma hepatocytes). HCC cells with PPP-inhibited IGF-IR showed time-dependent decreases in cell motility and viability. After treatment with PPP for 24 hours, the proportion of HCC cells in G1 phase was 2.1% +/- 0.4%, in S phase was 11.0% +/- 0.7%, and in G2/M phase was 87.1% +/- 0.6%, and no healing was observed in the wound-scratch assay. The PPP treatment induced cell apoptosis, as evidenced by enhanced caspase-3/7 activity; the proportion of annexin-V+/PI- cells was significantly higher in the HepG2 cells than in the non-hepatoma hepatocytes (16.4% +/- 0.4% vs. 5.8% +/- 0.2%, t = 14.05, P less than 0.01). After z-VAD-FMK treatment, the apoptosis rate was significantly higher in the HepG2 cells than in the non-hepatoma hepatocytes (11.3% +/- 0.7% vs. 5.8% +/- 0.2%, t = 11.83, P less than 0.01).</p><p><b>CONCLUSION</b>IGF-IR is associated with proliferation, cell motility, and apoptosis of HCC cells, and may be a promising molecular target for HCC.</p>
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Humans , Apoptosis , Carcinoma, Hepatocellular , Metabolism , Pathology , Cell Line, Tumor , Cell Proliferation , Liver Neoplasms , Metabolism , Pathology , Podophyllotoxin , Pharmacology , Receptor, IGF Type 1 , MetabolismABSTRACT
To investigate whether epigenetic alterations in the insulin-like growth factor-II (IGF-II) gene that cause differential transcription or expression are correlated with onset and severity of hepatocellular carcinoma (HCC). Patient-matched specimens of HCC, paracancerous, and non-cancerous tissues were collected from 40 primary liver cancer patients. Epigenetic alterations in the promoter (P3) sequence of the IGF-II gene were analyzed by methylation-specific PCR (MSP) and IGF-II transcription was measured by RT-PCR. IGF-II protein expression and clinicopathological features were assessed by immunohistochemistry and microscopic observation. The rate of IGF-II P3 methylation was significantly lower in HCC tissues (0%) than in paracancerous tissues (vs. 47.5%; x2 = 24.918, P less than 0.001) and non-cancerous tissues (vs. 100%; x2 = 80.000, P less than 0.001). IGF-II mRNA expression was significantly higher in HCC tissues (100%) than in paracancerous tissues (vs. 52.5%; x2 = 24.918, P less than 0.001) and non-cancerous tissues (vs. 0%; x2 = 80.000, P less than 0.001). IGF-II protein expression was significantly higher in HCC tissues (82.5%) than in paracancerous tissues (vs. 45.0%; x2 = 12.170, P less than 0.001) and non-cancerous tissues (vs. 0%; x2 = 56.170, P less than 0.001). IGF-II overexpression in HCC was significantly associated with degree of differentiation, extent of infiltrated serosa, size of tumor, and HBV-positive infection status. Epigenetic alterations in the IGF-II gene regulate its transcription and expression and are closely associated with HCC development and progression.
Subject(s)
Adult , Humans , Middle Aged , Carcinoma, Hepatocellular , Genetics , Metabolism , Pathology , CpG Islands , Genetics , DNA Methylation , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Immunohistochemistry , Insulin-Like Growth Factor II , Genetics , Metabolism , Liver , Metabolism , Pathology , Liver Neoplasms , Genetics , Metabolism , Pathology , Polymerase Chain Reaction , Methods , Promoter Regions, Genetic , RNA, Messenger , Genetics , Metabolism , Transcription, GeneticABSTRACT
This study investigates whether kappa-opioid receptor and ORL1 receptor may interact to form a heterodimer. In immunofluorescence and co-immunoprecipitation experiments, differentially epitope-tagged receptors, colocalization and heterodimerization of kappa-opioid receptor and ORL1 receptor were used and examined in primary culturing rat neurons, Chinese hamster ovary (CHO) or human embryonic kidney 293 (HEK293) cells. The results show that fluorescence of both kappa-opioid receptor and ORL1 receptor were overlapping in primary culturing hippocampal and cortical neurons. Similarly in co-expressing CHO or HEK293 cells, HA-KOR and Myc-ORL1 were almost exclusively confined to the membranes, revealing extensive colocalization. When Flag-KOR and Myc-ORL1 were co-expressing in CHO cells, heterodimerization was identified to have the ability to co-immunoprecipitate ORL1-receptors with kappa-opioid receptor and vice versa. In the current study, further evidence was provided for the direct interaction of two subtypes of opioid receptors, kappa-opioid receptor and ORL1-receptor, to form the heterodimerization. The finding represents the novel pharmacological mechanism for modulation of opioid receptor function as well as diversity of G protein-coupled receptors.
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Animals , Cricetinae , Female , Humans , Male , Rats , CHO Cells , Cells, Cultured , Cerebral Cortex , Cell Biology , Metabolism , Cricetulus , Dimerization , HEK293 Cells , Hippocampus , Cell Biology , Metabolism , Immunoprecipitation , Neurons , Cell Biology , Metabolism , Rats, Wistar , Receptors, Opioid , Metabolism , Receptors, Opioid, kappa , MetabolismABSTRACT
Objective: To observe the effect of intrathecal p38 MAPK inhibitor (SB203580) treatment on neuropathic pain and the expression of p38 MAPK and BDNF in dorsal horn of spinal cord in rats with chronic constriction injury (CCI), So as to investigate the possible mechanisms of neuropathic pain. Methods: Totally 30 SD rats were evenly randomized into 3 groups (n=10): sham group receiving intrathecal injection of sodium chloride, control group receiving intrathecal injection of sodium chloride and CCI surgery, and SB203580 group receiving intrathecal injection of SB203580 and CCI surgery. SB203580 (0.1 ml/kg) was administered 0.5 h before and 1-14 d after CCI surgery. The mechanical thresholds were tested 24 h before and 4-14 d after CCI surgery. p38 MAPK expression and BDNF release in the dorsal horn were determined using immunohistochemistry method 14 d after CCI surgery. Results: The mechanical thresholds in the control and SB203580 groups were significantly lower after CCI surgery compared with that before CCI surgery (P0.05). Compared with the sham operation group, the mechanical thresholds were significantly lower in the other two groups after CCI surgery (P<0.05). The mechanical threshold of SB203580 group was significantly higher than that of the control group after CCI surgery (P<0.05). The p38 MAPK expression and BDNF release were significantly higher in the control and SB203580 groups compared with those in the sham operation group (P<0.05), and those in the SB203580 group were significantly lower than those in the control group (P<0.05). Conclusion: Intrathecal injection of p38 MAPK inhibitor SB203580 can attenuate hyperalgesia in CCI rats through decreasing p38 MAPK expression and BDNF release.
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The pharmacokinetics of 6beta-naltrexol (6beta-NOL) following single intramuscular administration and multiple intramuscular injection once per day for seven days was studied in 4 Beagle dogs. Plasma concentration of 6beta-NOL in dogs was analyzed by a combination of high performance liquid chromatography (HPLC) and electrochemical detection with naloxone (NLX) as internal standard. After single intramuscular injection of 0.2 mg x kg(-1) 6beta-NOL, the plasma concentration-time curve of the drug was found to fit to a two compartment model with first-order absorption. The main parameters of single dosing were as follows: t1/2alpha was (0.26 +/- 0.23) h, t1/2beta was (4.77 +/- 1.65) h, C(max) was (81.65 +/- 5.61) ng x mL(-1), t(peak) was (0.27 +/- 0.07) h, CL(s) was (1.20 +/- 0.06) L x kg(-1) x h(-1), V/F(c) was (1.94 +/- 0.15) L x kg(-1), and AUC(0-t) was (166.82 +/- 7.68) ng x h x mL(-1), separately. After multiple intramuscular injection of 0.2 mg x kg(-1) 6beta-NOL once per day for seven days, the plasma concentration-time curve of the drug fitted to a two compartment model with first-order absorption too. The main parameters of the last dosing were as follows: t1/2alpha was (0.19 +/- 0.18) h, t1/2beta was (5.79 +/- 1.50) h, C(max) was (79.82 +/- 10.5) ng x mL(-1), t(peak) was (0.18 +/- 0.08) h, CL(s) was (1.12 +/- 0.07) L x kg(-1) x h(-1), V/F(c) was (2.10 +/- 0.27) L x kg(-1), and AUC(0-t) was (173.23 +/- 9.49) ng x h x mL(-1), separately. The difference of the parameters between the first and the last dosing was not significant, showing that the plasma kinetics of 6beta-naltrexol was not changed after multiple administrations. In the course of multiple administration, the peak and valley concentration of plasma 6beta-naltrexol were (79.03 +/- 10.3) and (1.50 +/- 0.93) ng x mL(-1), respectively. No clear adverse events were noted during this study. These results showed that plasma 6beta-naltrexol fits to a two compartment model with first-order absorption in dog after intramuscular administration and their pharmacokinetic parameters were reported. There was no remarkable change on plasma pharmacokinetics of 6beta-naltrexol after multiple intramuscular administrations.
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Animals , Dogs , Male , Chromatography, High Pressure Liquid , Half-Life , Injections, Intramuscular , Naltrexone , PharmacokineticsABSTRACT
Thienorphine is a chemically-new opioid developed in Beijing Institute of Pharmacology and Toxicology. To elucidate the chemical basis for the unique pharmacological effects of thienorphine, 15 derivatives were synthesized according to combinatorial chemistry and the structure-activity relationships of these compounds were studied. It is demonstrated that thienorphine is a potent long-acting partial agonist. N-Cyclopropylmethyl is responsible for the antagonist effect of thienorphine. More importantly, thiophene at the end of side chain is most likely the pharmacophore accounts for the long-lasting effect of thienorphine. Change of the connection of thiophene and the side chain does not result in changes in the antinociceptive activity.
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Animals , Female , Male , Mice , Rats , Buprenorphine , Pharmacokinetics , Pharmacology , Combinatorial Chemistry Techniques , Dose-Response Relationship, Drug , Mice, Inbred Strains , Morphine , Pharmacology , Rats, Wistar , Receptors, Opioid , Structure-Activity RelationshipABSTRACT
<p><b>OBJECTIVE</b>To investigate the effect of intra- and out-anorectal drainage in the prevention of anastomotic leakage after low anterior resection (LAR).</p><p><b>METHODS</b>Two hundred and thirty-five patients undergone LAR were divided into two groups according to two periods, the former group from Mar. 2003 to Aug. 2004 and the later group from Sep. 2004 to Nov. 2007. Technique advances were adopted in the later group, especially the routine intra- and out-anorectal drainage. Incidence of anastomotic leakage and clinicopathological data of two groups were compared.</p><p><b>RESULTS</b>Anastomotic leakage occurred in 4 patients of the former group (4/89) and 1 of the later group (1/146). Logistic analysis found that intra- and out-anorectal drainage was the main issue which prevented anastomotic leakage.</p><p><b>CONCLUSION</b>Intra- and out-anorectal drainage is useful for the prevention of anastomotic leakage after low anterior resection.</p>
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Anal Canal , General Surgery , Anastomosis, Surgical , Drainage , Methods , Postoperative ComplicationsABSTRACT
Objective To explore the relationship between size,shape and function of the left atrium appendage (LAA) and its thrombosis in patients with atrial fibrillation (AF) by transesophageal echocardiography (TEE) to provide evidence for clinical risk assessment,prognosis evaluation and treatment guidance.Method Length,diameter,end-diastolic volume (EDV) and ejection velocity (PEV) of LAA were measured in 41 patients with AF,and thrombus in LAA was detected by TEE.Results Thrombus in LAA was detected in seven of 41 patients of AF (17%).No significant difference in size and EDV was found between the patients with and without thrombus,but there was significant difference in PEV between them (P
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<p><b>OBJECTIVE</b>To evaluate the possibility of dissemination of lung cancer cells through blood during the operation for lung cancer.</p><p><b>METHODS</b>The blood samples were taken from 52 patients with non-small cell lung cancer (NSCLC) and 5 patients with benign lung diseases at four different intervals during the operation. The transcription of carcinoembryonic antigen (CEA) messenger ribonucleic acid was assayed by means of nested reverse transcriptase polymerase chain reaction (RT-PCR). A549 (a human adenocarcinoma cell line) served as positive control. The sensitivity has been tested using quantificationally diluted A549 cells.</p><p><b>RESULTS</b>The CEA mRNA positive rates of all four time spots are as follows: 31% (16/52) at beginning of the operation (sample taken from peripheral vein), 54% (28/52) at ligating the pulmonary vein (peripheral vein), 54% (28/52) at ligating the pulmonary vein (pulmonary vein) and 54% (28/52) at 1 hour after ligating the pulmonary vein (peripheral vein). There is no relationship between the tumor identity and the positive rate of CEA mRNA. The positive rate of CEA mRNA is higher in patients with centrally located lung cancer than that in patients with peripherally located lung cancer, similar phenomenon is also found between patients with advanced lung cancer and the patients with early stage of lung cancer. No negative control samples was found to be positive for CEA mRNA, the sensitivity of our test was 1 x 10(-6).</p><p><b>CONCLUSIONS</b>The cancer cell dissemination during operation was demonstrated indirectly in our study, the time of pulmonary vein ligation (later or earlier) may affect the quantity of tumor cells released into circulation. Patients with lung cancer of central type and late TNM stage have more possibility of cancer cell dissemination during operation. More effective means may be needed to avoid the dissemination of cancer cells.</p>