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Summary ParagraphThe SARS-CoV-2 virus has caused already over 3.5 million COVID-19 cases and 250,000 deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 using human disease-relevant cells to understand key features of virus biology and facilitate drug screening. As primary SARS-CoV-2 infection is respiratory-based, we developed a lung organoid model using human pluripotent stem cells (hPSCs) that could be adapted for drug screens. The lung organoids, particularly aveolar type II cells, express ACE2 and are permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection revealed a robust induction of chemokines and cytokines with little type I/III interferon signaling, similar to that observed amongst human COVID-19 pulmonary infections. We performed a high throughput screen using hPSC-derived lung organoids and identified FDA-approved drug candidates, including imatinib and mycophenolic acid, as inhibitors of SARS-CoV-2 entry. Pre- or post-treatment with these drugs at physiologically relevant levels decreased SARS-CoV-2 infection of hPSC-derived lung organoids. Together, these data demonstrate that hPSC-derived lung cells infected by SARS-CoV-2 can model human COVID-19 disease and provide a valuable resource to screen for FDA-approved drugs that might be repurposed and should be considered for COVID-19 clinical trials.
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Objective To investigate the changes in ATPase activity of diaphragm in rats with acute organophosphorus poisoning (AOPP) and to explore the effect of Xuebijing injection on the ATPase activity. Methods 24 clean healthy Spraue-Dawley(SD)rats were divided into control group,model group and Xuebijing treatment group by means of random number table,with 8 rats in each group. AOPP model was established by intra-gastrical administration of 50 mg/kg oxide dimethoate. In Xuebijing treatment group,after oxide dimethoate administration,intraperitoneal injection of Xuebijing(10 mL/kg)was given at the same time,while in control group and model group,equal amount of normal saline(NS)was injected via the same route. The rats were sacrificed at 6 hours after model formation,and their diaphragms were taken sterilely. The activities of Na+-K+-ATPase and Ca2+-ATPsae of diaphragms were detected by enzyme linked immunosorbent assay(ELISA). The histopathological changes in diaphragms of rats were observed with light microscopy. Results 6 hours after intoxication,the diaphragm Na+-K+-ATPase activity of rats in model group was markedly lower than that in control group(mmol?h-1?g-1:5.22±0.74 vs. 9.98±0.37,P<0.01),while the Na+-K+-ATPase activity in Xuebijing treatment group(6.93±1.14) was markedly higher than that in model group(P<0.05). The diaphragm Ca2+-ATPase activity of rats in model group was markedly lower than that in control group(mmol?h-1?g-1:7.45±0.74 vs. 12.08±0.74,P<0.01),while the Ca2+-ATPase activity in Xuebijing treatment group(9.35±1.67)was obviously higher than that in model group(P<0.05)after intoxication for 6 hours. Light microscope observation indicated that there were swelling and necrosis in diaphragm in model group,while in Xuebijing treatment group no necrosis was found. Conclusion The diaphragm was degenerated and necrotic in AOPP rats,Xuebijing injection can lessen the injury in such rats,and the curative effect may be related to the improvement of the Na+-K+-ATPase and Ca2+-ATPsae activities of diaphragm.
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AIM:To investigate the ameliorative effect of ischemic postconditioning (I-postC) on pia mater microcirculation in rats subjected to cerebral ischemia reperfusion (I/R) and its mechanisms. METHODS:Thirty-two male Wistar rats were randomly divided into sham,I/R,I-postC,and ischemic preconditioning (IPC) groups. The global cerebral I/R injury was induced by shunting carotid artery in rats. Pia mater microcirculation and cerebral microcirculatory perfusion were measured after reperfusion. The content of soluble intercellular adhesion molecule-1 (sICAM-1) in plasma was detected using enzyme linked-immunosorbent assay (ELISA). Myeloperoxidase (MPO),malondialdehyde (MDA),and superoxide dismutase (SOD) in cerebral tissue were detected. The expressions of vascular endothelial cell cadherin (VE-cadherin) and NF-?B p65 in cerebral tissue were assayed by Western blotting. RESULTS:(1) The disturbance of the blood flow in microvessel induced by I/R was improved significantly by I-postC. In addition,I-postC alleviated significantly the decrease in diameters of microvesseles,cerebral microcirculatory perfusion and cerebral VE-cadherin content induced by I/R (P