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The coronavirus disease (COVID-19) pandemic caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the global healthcare system. Drug repurposing is a feasible method for emergency treatment. As low-molecular-weight drugs have high potential to completely match interactions with essential SARS-CoV-2 targets, we propose a strategy to identify such drugs using the fragment-based approach. Herein, using ligand- and protein-observed fragment screening approaches, we identified niacin and hit 1 binding to the catalytic pocket of the main protease of the SARS-CoV-2 (Mpro), thereby modestly inhibiting the enzymatic activity of Mpro. Chemical shift perturbations induced by niacin and hit 1 indicate a partial overlap of their binding sites, i.e., the catalytic pocket of Mpro may accommodate derivatives with large molecular sizes. Therefore, we searched for drugs containing niacin or hit 1 pharmacophores and identified carmofur, bendamustine, triclabendazole, and emedastine; these drugs are highly capable of inhibiting protease activity. Our study demonstrates that the fragment-based approach is a feasible strategy for identifying low-molecular-weight drugs against the SARS-CoV-2 and other potential targets lacking specific drugs.
ABSTRACT
Small cell lung cancer is a special type of neuroendocrine tumor in the lungs,which has a poor therapeutic effect,and a short time for resistance to relapse,recurrence and distant metastasis.Therefore,searching for readily available predictive parameters is important for clinical treatment strategy.Some indicators of blood cell parameters have been extensively studied in malignant tumors such as non-small cell lung cancer,breast cancer,gastric cancer and colorectal cancer.In-depth understanding of the role of blood cell parameters in small cell lung cancer and its possible mechanisms are of great value in predicting the curative effect and prognosis of small cell lung cancer.
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Objective To explore miR-21 regulation of Smad7 in lung cancer A549 cell line as well as its impact on the proliferation of lung cancer A549 cell line. Methods miR-21 mimic and inhibitors in lung cancer A549 cell line were transfected by using Lipofectamine 2000 Reagent. After 48 h, Western blot and qRT-PCR were applied to assess the expression of protein and mRNA of Smad7 . MTT assay was used to determine the proliferation influence of the transfected lung cancer A549 cell line. Results Western blot and qRT-PCR showed that A549 cell trans-fected miR-21 mimic exhibited down-regulated Smad7 protein and mRNA expression, and A549 cell transfected miR-21 inhibitor exhibited up-regulated Smad7 protein and mRNA expression. The A549 cell proliferation activity decreased significantly after transfected miR-21 inhibitors. Conclusion miR-21 inhibitors can increase Smad7 pro-tein and mRNA expression, and suppress the proliferation activity of lung cancer A549 cell significantly.
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Objective To investigate the combined effect of exemestane and low-dose methotrexate on exemestane-resistant MCF-7 human breast cancer cells( MCF-7/EXE). Methods Antiproliferative effects of exemestane and low-dose of methotrexate, alone and in combination on growth of MCF-7/EXE cells were assessed by using the MTT assay. Synergistic interaction between the two drugs was evaluated in vitro by using the combination index ( CI) method. The cell cycle distribution was analyzed by flow cytometry in a half inhibitory concentration of exemestane and low-dose of methotrexate . The changes of apoptosis on MCF-7/EXE cells exposed to two drugs alone or in com-bination were observed by fluorescence microscope. The expression of Bcl-2,AKT,P-AKT and cyclooxygenase-2 was investigated by Western blot. Results MTT assays indicated that the combination treatment apparently decreased the viability of MCF-7/EXE cells compared to single drug treatment (CI<0. 9). In addition, the combination of exemestane and low-dose methotrexate exhibited a synergistic inhibition of cell proliferation, arrested the cell cycle in the S phase significantly and produced a stronger inhibitory effects on P-AKT, Bcl-2 and cyclooxygenase-2 ex-pression than control or individual drug treatment. Conclusion The combination of the two inhibitors significantly increases the response as compared to single agent treatment, suggesting that combination treatment which can re-verse the resistance of exemestane could be a more effective approach to breast cancer.
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Objective To evaluate the efficacy and safety of low-dose dexamethasone pretreatment regimen in prevention of hypersensitive reaction (HR) related to docetaxel in elderly tumor patients. Methods According to the order for admission and the ratio of 3:2, 91 elderly patients with docetaxel weekly therapy were randomly divided into two groups: experimental group and control group. All patients aged from 65 to 82 years with a median age of 68 years old. There were 54 patients in the experimental group and 37 patients in the control group. In the experimental group, patients received oral dexamethasone 4. 5 mg once daily on 1 day before treatment, the day of treatment and continuing for 3 days after treatment, while patients received 8 mg twice daily in the control group. All patients were scored according to MCIRS by the physician. The side effects were evaluated by NCI-CTCAE3.0. Results Four cases in the experimental group (7.4 %) and three cases in the control group (8. 1%) occurred HR, and there was no significant statistical difference (P=1. 000). Conclusions The low dose dexamethasone is efficient and safe compared with the conventional dose dexamethasone, and there is no significant difference in HR incidence between two groups.
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Currently targeted therapy of breast cancer therapy has become the hot research field and a kind of brand-new biological treatment mode after three traditional pattern of the surgery, radiotherapy and chemotherapy for breast cancer. Molecular targeted therapy is aimed at the target that may cause cancer cells, such as protocarcinogenic genes and tumor-suppressor genes, cell signaling pathways, cytokines and receptors, antiangiogenesis etc. It can reverse malignant biology behavior to inhibit tumor cell growth from the molecular level and has the advantages of high specific effects and low side effects. This paper focuses on the drug of the molecular targeted therapy for breast cancer and the latest progress of targeted therapy.
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1.15).It had marked difference between the combined group and the ADM group alone(P
