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Being the most common solid malignant tumor in the digestive system and the third leading cause of cancer-related death worldwide， hepatocellular carcinoma （HCC） is characterized by insidious onset， early recurrence/metastasis and poor prognosis. With the advantages of targeted precision， high specificity， minimal drug resistance， remarkable therapeutic efficacy and fewer side effects， molecular targeted drugs have become the hotspot and focus of tumor therapy research in recent years. As more is learned about the mechanism and clinical efficacy， some molecular targeted drugs have been recommended by HCC treatment guidelines. This paper reviewed the mechanism of HCC targeted therapy， molecular targeted drugs， relevant therapeutic protocols and outcomes so as to provide reference and evidence for subsequent research.
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Based on the research system of computer-aided drug design combined with complex network analysis, the potential mechanism of Dunhuang Dabupi Decoction in preventing and treating gastric cancer (GC) is analyzed, and the scientific connotation of its prescription rules is explored through the efficacy grouping. To study the effect of Dabupi Decoction freeze-dried powder solution on the proliferation activity of gastric cancer cells through cell experiments; the TCMSP and TCMID databases were used to collect the compound components of Dabupi Decoction. Swiss Target Prediction is used to predict potential targets of compounds. DrugBank, GeneCards, TTD, and DisGeNET were used to collect potential targets for gastric cancer. Analyze protein interactions of potential targets through the STRING database. DAVID database was used for KEGG enrichment analysis; Dabupi Decoction was divided into Wenzhong group (dried ginger), Yiqi group (ginseng, licorice, Atractylodes macrocephala), nourishing Yin group (Ophiopogon japonicus, Schisandra) and Jiangni group according to its efficacy characteristics. The inverse group (inula) has 4 functional compatibility groups. Cytoscape was used to construct a network of "medicinal flavor-potential active ingredient-key target" respectively, and the network was used to analyze the scientific connotation of the compatibility of efficacy groups. The Schrödinger software was used to verify the molecular docking of the core components and the core targets. The material basis of the Dabupi Decoction to prevent and treat gastric cancer was discovered through the combination of pattern analysis and combined free energy calculation. The core drug was analyzed from the perspective of dynamics through molecular dynamics simulation. Potential targets and representative potential compounds interact with each other. Cell experiments confirmed that Dabupitang freeze-dried powder solution can down-regulate the mitochondrial membrane potential of AGS gastric cancer cells, block the cell cycle in the G0/G1 phase (P < 0.05), and inhibit its proliferation (P < 0.05). The pathways enriched by the four functional groups contained in Dabupi Decoction are mainly distributed in the body's energy metabolism, inflammation-immune system regulation, and cycle-apoptotic functions. Each module is connected by a common target gene and has its own focus. The results of molecular docking showed that the compounds liquiritigenin, quercetin, kaempferol, isorhamnetin, methylophiopogonanone A, etc. may be the effective multi-target components of Dabupi Decoction. Estrogen receptor 1, androgen receptor, ATP-binding cassette superfamily G member 2, epidermal growth factor receptor, glycogen synthase kinase-3 beta and other targets have good affinity with each potential active compound, which may be a potential target of Dabupi Decoction for preventing and treating gastric cancer. Among them, kaempferol and the drug target EGFR not only have good binding ability, but also have good binding stability. This study is based on computer-aided drug design combined with complex network analysis strategies to initially reveal the material basis and molecular mechanism of Dabupi Decoction in the prevention and treatment of gastric cancer. It also explores the scientific connotation of Dabupi Decoction in the prevention and treatment of gastric cancer with different efficacy groups, and its clinical application provide chemical bioinformatics basis.
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Angelicae Sinensis Radix excels in activating blood, but the scientific mechanism has not been systematically analyzed, thus limiting the development of the medicinal. This study employed the computer-aided drug design methods, such as structural similarity-based target reverse prediction, complex network analysis, molecular docking, binding free energy calculation, cluster analysis, and ADMET(absorption, distribution, metabolism, excretion, toxicity) calculation, and enzyme activity assay in vitro, to explore the components and mechanism of Angelicae Sinensis Radix in activating blood. Target reverse prediction and complex network analysis yielded 40 potential anticoagulant targets of the medicinal. Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis indicated that the targets mainly acted on the complement and coagulation cascade signaling pathway to exert the anticoagulant function. Among them, the key enzymes thrombin(THR) and coagulation factor Xa(FXa) in coagulation cascade and thrombosis were the drug targets for thromboembolic diseases. At the same time, molecular docking and cluster analysis showed that the medicinal had high selectivity for FXa. According to binding free energy score, 8 potential active components were selected for enzyme activity assay in vitro. The results demonstrated that 8 components inhibited THR and FXa, and the inhibition was stronger on FXa than on THR. The pharmacophore model of 8 active compounds was constructed, which suggested that the components had the common pharmacophore AAHH. The ADMET calculation result indicated that they had good pharmacokinetic properties and were safe. Based on target reverse prediction, complex network analysis, molecular docking and binding free energy calculation, anticoagulant activity in vitro, spatial binding conformation of molecules and targets, pharmacophore model construction, and ADMET calculation, this study preliminarily clarified the material basis and molecular mechanism of Angelicae Sinensis Radix in activating blood from the perspective of big data, and calculated the pharmacology and toxicology parameters of the active components. Our study, for the first time, revealed that the medicinal had obvious selectivity and pertinence for different coagulation proteins, reflecting the unique effect of different Chinese medicinals and the biological basis. Therefore, this study can provide clues for precision application of Angelicae Sinensis Radix and the development of the blood-activating components with modern technology.
Subject(s)
Anticoagulants/pharmacology , Blood Coagulation , Drug Design , Drugs, Chinese Herbal/pharmacology , Molecular Docking SimulationABSTRACT
Objective:To investigate the antitumor effect and the mechanism of Dunhuang Pingweiwan and its decomposed recipes based on phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）/mammalian target of rapamycin （mTOR） signaling pathway in SCG-7901 gastric cancer-mice. Method:The subcutaneous tumor bearing model of SCG-7901 gastric cancer in mice was established， and the the mice were randomized into model group， Dunhuang Pingweiwan group （14.04 g·kg<sup>-1</sup>·d<sup>-1</sup>）， Huoxue Jiedu group （6.50 g·kg<sup>-1</sup>·d<sup>-1</sup>）， Wenzhong Sanhan group （3.64 g·kg<sup>-1</sup>·d<sup>-1</sup>） and cisplatin group （2 mg·kg<sup>-1</sup>·d<sup>-1</sup>）， with 8 mice in each group. From the 8<sup>th</sup> day of inoculation， the mice were administered for 10 consecutive days. The mice were weighed and the general conditions were observed every other day. On the next day of the last administration， the mice were sacrificed， and the tumor was removed and weighed to calculate the anti-tumor rate. The histopathological changes were observed by hematoxylin-eosin （HE） staining， and the mRNA and protein expressions of PI3K， Akt， and mTOR in tumor tissues were detected by real-time polymerase chain reaction（Real-time PCR） and immunohistochemistry （IHC）， respectively. Result:From the 10<sup>th</sup> day of inoculation， the mice in cisplatin group were generally in poor condition and their body mass decreased. The mice in model group， Dunhuang Pingweiwan group， Huoxue Jiedu group and Wenzhong Sanhan group were generally fair， and their body mass increased without significant difference among groups. The tumor inhibition rates of Dunhuang Pingweiwan， Huoxue Jiedu， Wenzhong Sanhan and cisplatin groups were 30.74%， 24.80%， 4.19% and 63.84%， respectively. Except for Wenzhong Sanhan group， tumor weight of the other treatment groups was significantly lower than that of the model group （<italic>P</italic><0.01）， and there was no significant difference between the Dunhuang Pingweiwan and Huoxue Jiedu group. Dunhuang Pingweiwan and Huoxue Jiedu group could significantly reduce tumor cell density and cause tumor cell necrosis. Compared with the model group， the expressions of PI3K， Akt， and mTOR mRNA and protein in the Dunhuang Pingweiwan， Huoxue Jiedu and cisplatin groups significantly decreased （<italic>P</italic><0.05， <italic>P</italic><0.01）， and there was no significant difference between the Dunhuang Pingweiwan group and Huoxue Jiedu group. Conclusion:Dunhuang Pingweiwan and its decomposed recipes （Huoxue Jiedu） have a certain anti-tumor effect on the SCG-7901 gastric cancer-mice， and the mechanism may be related to the down-regulation of key molecules in the PI3K/Akt/mTOR signaling pathway.
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The pathological anatomical results of coronavirus disease-2019 (COVID-19) patients showed that excessive inflammatory reaction in the lungs is one of the important causes for such complications as acute lung injury or acute respiratory distress syndrome. Therefore, regulation of immune response may be an effective measure for COVID-19. Alveolar macrophages have a high heterogeneity and plasticity. The dynamic changes of subsets balance and function of M1/M2 alveolar macrophages have a significant effect on pulmonary inflammatory response during the early and late stages of infection. This paper reviews the classification and function of macrophages and explores the mechanism of alveolar macrophage in the pathological process of COVID-19 at different stages and the pharmacodynamic mechanism of traditional Chinese medicine. Besides, it provides ideas for the treatment of COVID-19 with traditional Chinese medicine and other drugs' research and development based on the regulation of macrophage polarization.
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Objective::To study the protective effect of astragalus polysaccharide (APS) on micronucleus and sister chromatid exchange (SCE) in human bone marrow mesenchyml stem cell (BMSCs) exposed to formaldehyde, in order to initially explore the potential mechanism. Method::BMSCs were cultured in vitro, cells were randomly divided into five groups: control group, formaldehyde group, and APS 40, 100, 400 mg·L-1 groups. BMSCs were infected with 120 μmol·L-1 formaldehyde, meanwhile, APS 40, 100, 400 mg·L-1 groups were co-cultured with 40, 100, 400 mg·L-1 APS. Cell morphology was observed by inverted phase contrast microscope, micronucleus were detected by micronucleus test, SCE was detected by SCE test, and mRNA and protein expressions of proliferating cell nuclear antigen (PCNA), xeroderma pigmentosum B, D, F, G (XPB, XPD, XPF, XPG) were detected by quantitative real-time fluorescence polymerase chain reaction(Real-time PCR)and Western blot. Result::Compared with control group, cell counts decreased, and cell morphology of BMSCs in formaldehyde group significantly changed, they were all recovered gradually in 40, 100, 400 mg·L-1 APS groups. Compared with control group, the micronucleus and SCE increased significantly (P<0.01), PCNA mRNA and protein expressions down-regulated significantly (P<0.05), while XPB, XPD, XPF, XPG mRNA and protein expressions up-regulated significantly (P<0.05, P<0.01). Compared with formaldehyde group, BMSCs were treated with APS at 40, 100, 400 mg·L-1, micronucleus and SCE decreased significantly (P<0.01), and mRNA and protein expressions of PCNA, XPB, XPD, XPF and XPG up-regulated significantly (P<0.05, P<0.01). Among them, the 100 mg·L-1 APS group had the most obvious effect. Conclusion::APS can protect formaldehyde-induced BMSCs micronucleus and SCE, especially 100 mg·L-1 APS has the most obvious effect. The mechanism may be associated with the up-regulation of expressions of PCNA, XPB, XPD, XPF and XPG in the nucleotide exicision repair pathway (NER), which promoted the damage repair.
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<p><b>OBJECTIVE</b>To investigate the effects of minimally invasive esophagectomy (MIE) and open esophagectomy (OE) on the level of circulating tumor cells (CTCs) in patients with esophageal cancer (EC).</p><p><b>METHODS</b>A total of 73 patients with EC undergoing MIE (n=38) or OE (n=35) in our department between October, 2015 and October, 2017 were enrolled, with 10 patients with benign esophagus disease and 10 healthy volunteers as controls. The levels of CTCs in the peripheral blood of the participants were detected using CanPatrol technique and analyzed for their association with the operation methods and perioperative complications.</p><p><b>RESULTS</b>CTCs were detected in 60.3% (44/73) of the EC patients but in none of the control subjects. CTC level after the surgery was significantly higher than that during the surgery, and CTC level during the surgery was significantly higher than that before surgery (P<0.001). The preoperative and intra-operative CTC levels were not significantly different between MIE and OE groups (P>0.05), but the postoperative CTC level was significantly lower in MIE group than in OE group, and postoperative increment of CTC level (from the preoperative level) was significantly lower in MIE group than in OE group (P<0.001). The total incidence of postoperative complications was significantly lower in MIE group than in OE group (28.9% vs 54.3%, P=0.023), and in both groups, CTC levels in patients with complications were significantly higher than those in patients without complications (P=0.001 and P=0.005 in MIE and OE groups, respectively).</p><p><b>CONCLUSION</b>MIE may help to reduce the number of peripheral blood CTCs early after the operation, and dynamic monitoring CTCs level assists in evaluation of the prognosis of EC patients. CTC level may serve as an indicator for monitoring the prognosis of EC.</p>
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<p><b>OBJECTIVE</b>Multivariate analysis was used to select the risk factors in non-insulin dependent diabetes mellitus (NIDDM) patients with oral candidosis, and to establish the forecasting equation, aimed to detect the risk of oral candidosis among NIDDM patients.</p><p><b>METHODS</b>140 NIDDM patients were included in this study. 11 clinical parameters including gender, age, course smoking, fasting blood glucose, oral hygiene status, systemic manifestation, oral mucous membrane status, and denture were recorded respectively. Oral rinse technique was used to detect the salivary candidal carriage. The isolates were identified using CHROM agar Candida test. The Logistic multivariate regression analysis was carried our for risk factors analysis.</p><p><b>RESULTS</b>Candida was found in 69 out of 140 NIDDM cases, and Candida albicans was the major species isolated. The poor glycemic control, poor oral hygiene, and dry mouth were the risk factors of oral candidosis in NIDDM patients, and the forecasting equation was established. Using substitution method, the veracity of the forecasting equation was 82.1%.</p><p><b>CONCLUSION</b>Poor glycemic control, poor oral hygiene and dry mouth were risk factors of oral candidosis among NIDDM patients. The probability obtained from the forecasting equation may offer references for predicting and preventing the oral candidosis in NIDDM patients.</p>
Subject(s)
Adult , Female , Humans , Male , Middle Aged , Candida , Candida albicans , Candidiasis, Oral , Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Logistic Models , Oral Hygiene , Risk Factors , SmokingABSTRACT
<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of amiodarone and metoprolol in the treatment of ventricular premature beats.</p><p><b>METHODS</b>Controlled randomized clinical trials from 1999 through 2009 were retrieved in China HowNet, VIP Web, Pubmed home. Using Rev Man4.2 software provided by Cochrane Collaboration, Meta-analysis was conducted of 30 articles meeting the inclusion criteria involving a total of 1188 patients.</p><p><b>RESULTS</b>Merged analysis of amiodarone and metoprolol in the treatment of premature ventricular merge showed a comprehensive test results of Z=1.25, P=0.21, OR=1.18, 95%CI: 0.91-1.54; funnel plot analysis suggested the possible presence of publication bias. The comprehensive test of the incidence of adverse reactions in relation to the two drugs resulted in an OR of 1.96 (95%CI: 1.39-2.77), and funnel plot analysis also indicated publication bias.</p><p><b>CONCLUSIONS</b>The total response rate of amiodarone does not seem to be superior to metoprolol in the treatment of premature ventricular contractions, and amiodarone is associated with higher incidence of adverse reactions.</p>
Subject(s)
Humans , Amiodarone , Therapeutic Uses , Drug Therapy, Combination , Metoprolol , Therapeutic Uses , Treatment Outcome , Ventricular Premature Complexes , Drug TherapyABSTRACT
<p><b>OBJECTIVE</b>To evaluate the effect of soluble total proteins of Zaocys dhumnades on the expressions of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and IL-10 in human fibroblast-like synoviocytes (FLS) cultured in vitro.</p><p><b>METHODS</b>Primary cultured FLS isolated from the synovium of patients with rheumatoid arthritis (RA) were incubated in the presence of different concentrations (50, 150 and 450 microg/ml) of soluble total proteins of Zaocys dhumnades, with Tripterygium hypoglaucum Hutch (THH) and DMEM as the positive and negative controls, respectively. Enzyme-linked immunosorbent assay (ELISA) and RT-PCR were used to detect the expressions of IL-1beta, IL-10 and TNF-alpha in the FLS.</p><p><b>RESULTS</b>The protein and mRNA levels of IL-1beta and TNF-alpha in the supernatant of the FLS exposed to 150 and 450 microg/ml of the soluble total proteins of Zaocys dhumnades decreased, while IL-10 protein and mRNA increased significantly as compared with those in the negative control group (P<0.01).</p><p><b>CONCLUSION</b>The soluble total proteins of Zaocys dhumnades produce therapeutic effect on RA possibly by inhibiting IL-1beta and TNF-alpha and promoting IL-10 expressions in the FLS.</p>