ABSTRACT
OBJECTIVE：To study the improvement effects of Weijing deco ction on AECOPD model rats and its possibile mechanism. METHODS ：Totally 55 male SD rats were randomly divided into normal group ，model group ，Weijing decoction low-dose and high-dose groups （8.37，16.74 g/kg，by crude drug ），dexamethasone group （positive control group ，0.09 mg/kg），with 11 rats in each group. Except for normal group ，AECOPD model was induced by cigarettes combined with lipopolysaccharide in other groups. After modeling ，normal group and model group were given constant volume of water intragastrically ，and other groups were given relevant medicine intragastrocally ，twice a day ，for 14 days. After last intragastric administration ，the serum level of IL- 1 β was determined，and pathological changes of lung tissue and bronchus were observed in each group ；mRNA expression of MMP-9 and TIMP- 1 genes in lung tissue were detected ；protein expression of Ras homologous gene family member （RhoA）， dishevelled associated activator of morphogenesis- 1（DAAM1）and hyperplasic suppress gene （HSG）in lung tissue were also determined. RESULTS ：Compared with normal group ，the levels of IL- 1β in serum，mRNA expression of MMP- 9 and TIMP-1 as well as protein expression of RhoA and DAAM 1 in lung tissue were increased significantly in the model group（P＜0.05），while protein expression of HSG in lung tissue was decreased significantly （P＜0.05）；there were many chronic inflammatory cells infiltrating around the bronchus ，some airway mucosa epithelium exfoliating ，alveolar compensatory dilation，pulmonary septal capillary dilation and hyperemia. Compared with model group ，the levels of IL- 1β in serum，mRNA expression of MMP- 9 and TIMP- 1 in lung tissue were decreased significantly in Weijing decoction high-dose group （P＜0.05）；the protein expression of RhoA and DAAM 1 in lung tissue were decreased significantly in Weijing decoction low-dose and high-dose groups（P＜0.05），while the protein expression of HSG in lung tissue was increased （P＜0.05）；the pathological changes of Weijing decoction high-dose group ，such as inflammatory cells infiltrating around the bronchus and shedding of airway mucosa ， were improved significantly ， and there was complete alveolar epithelium structure but no obvious pulmonary dilation. CONCLUSIONS：Weijing decoction can improve AECOPD model rats to certain extent ；its mechanism may be associated with down-regulating mRNA expression of MMP- 9 and TIMP -1 as well as protein expression of RhoA and DAAM 1 in lung tissue ， up-regulating protein expression of HSG in lung tissue so as to inhibit the airway remodeling.
ABSTRACT
To interfere with the biology of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, we focused on restoring the transcriptional response induced by infection. Utilizing expression patterns of SARS-CoV-2-infected cells, we identified a region in gene expression space that was unique to virus infection and inversely proportional to the transcriptional footprint of known compounds characterized in the Library of Integrated Network-based Cellular Signatures. Here we demonstrate the successful identification of compounds that display efficacy in blocking SARS-CoV-2 replication based on their ability to counteract the virus-induced transcriptional landscape. These compounds were found to potently reduce viral load despite having no impact on viral entry or modulation of the host antiviral response in the absence of virus. RNA-Seq profiling implicated the induction of the cholesterol biosynthesis pathway as the underlying mechanism of inhibition and suggested that targeting this aspect of host biology may significantly reduce SARS-CoV-2 viral load.
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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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Summary ParagraphThe current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.
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Objective: To analyze the clinical]features of the patient with nephrotic syndrome who developed Pneumocystis carinii pneumonia (PCP) and cytomegalovirus pneumonia (CMP) after oral administration of tacrolimus caspsules, and to discuss the correlations between immunosuppressive patient and Pneumocystis carinii (Pc) and cytomegalovirus (CMV) infection, and to provide the basis for the reasonable treatment plan in the early stage. Methods: The clinical materials of one patient with nephrotic syndrome who developed PCP and CMP after oral administration of tacrolimus capsules were collected and the clinical symptoms, past medical history and outcomes, auxiliary examination, treatment plan and prognosis were analyzed; the relevant literatures were reviewed. Results: The male 47-year-old patient was admitted to hospital because of cough for 1 month, shortness of breath for 1 week and fever for 3 d. The patient had the history of diabetes mellitus and took the medication regularly , and the level of blood sugar was well controlled. At the beginning of 2018, the patient received renal biopsy due to edema of the lower extremities and was diagnosed as stage II membranous nephropathy accompanying with mild mesangial proliferative diabetic nephropathy; the patient was orally administrated with glucocorticoid. In July 2018, the patient was diagnosed as nephrotic syndrome and stage II membranous nephropathy, and had been orally administrated with tacrolimus capsules after discharge. After admission, the patient developed acute respiratory distress syndrome rapidly; the multiple exudation and nodular foci of both lungs were found on the chest imaging, and the infectious lesions were considered. The IgM antibody and IgG antibody of CMV of the patient were both positive. The high throughput gene detection results of the infection pathogens in blood showed Pneumocystis jiroveci of Pneumocystis and human herpesvirus 5 (HHV-5). PCP complicated with CMP was diagnosed definitively. The patient was treated with sulfamethoxazole combined with ganciclovir and noninvasive ventilation. The patient was discharged after the condition was improved. Conclusion: The patient with low immunity should be alert to the mixed infection of PCP and CMP if he develops rapidly progressive hypoxemia.
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Objective To investigate the distribution of traditional Chinese medical syndromes and clinical characteristics of influenza in South of Five Ridges.Methods A retrospective analysis was carried out in 162 cases of influenza patients admitted from outpatient department,emergency department and inpatient department of the First Affiliated Hospital of Guangzhou University of Chinese Medicine from 2014 to 2016.The distribution of clinical manifestations and syndrome types of the included influenza patients was analyzed.Results The average age of the included influenza patients was 35.76 ± 11.4 years old.The clinical syndromes were mainly characterized by fever,aversion to cold and chills,fatigue and weakness.And damp-accumulation manifestations of heaviness in the body,poor appetite,dry mouth without willing to drink,nausea and vomiting were also predominant.The main syndrome types were wind-heat attacking defense phase syndrome,wind-cold fettering exterior syndrome,heat-toxin attacking lung syndrome,heat-toxin accumulating lung syndrome,and damp syndrome.Of the syndrome types,wind-heat attacking defense phase syndrome and heat-toxin attacking lung syndrome were the leading types,accounting for 77.79％ and interweaving with damp syndrome and heat-damp syndrome.Conclusion The syndromes of influenza patients in South of Five Ridges are usually complicated by damp syndrome or damp-heat syndrome,and the predominant syndrome type is wind-heat interweaved with damp syndrome,which is correlated with the climate being damp and hot in South of Five Ridges.
