scholarly journals Identification of Candidate COVID-19 Therapeutics using hPSC-derived Lung Organoids

2020 ◽  
Author(s):  
Yuling Han ◽  
Liuliu Yang ◽  
Xiaohua Duan ◽  
Fuyu Duan ◽  
Benjamin E. Nilsson-Payant ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Lung Cells ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Interferon Signaling ◽  
Pulmonary Infections ◽  
Drug Candidates ◽  
Approved Drugs ◽  
Fda Approved Drugs

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.

scholarly journals CD95 death-inducing signaling complex formation and internalization occur in lipid rafts of type I and type II cells

2004 ◽  
Vol 34 (7) ◽  
pp. 1930-1940 ◽  
Author(s):  
Adriana Eramo ◽  
Massimo Sargiacomo ◽  
Lucia Ricci-Vitiani ◽  
Matilde Todaro ◽  
Giorgio Stassi ◽  
...  
Keyword(s):  
Complex Formation ◽  
Lipid Rafts ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Signaling Complex

The Roles Potassium Currents Play in Regulating the Electrical Activity of Ventral Cochlear Nucleus Neurons

2003 ◽  
Vol 89 (6) ◽  
pp. 3097-3113 ◽  
Author(s):  
Jason S. Rothman ◽  
Paul B. Manis
Keyword(s):  
Cochlear Nucleus ◽  
Auditory Nerve ◽  
Threshold Current ◽  
Repetitive Firing ◽  
Resting Membrane Potential ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Ventral Cochlear Nucleus ◽  
Discharge Patterns

Using kinetic data from three different K+ currents in acutely isolated neurons, a single electrical compartment representing the soma of a ventral cochlear nucleus (VCN) neuron was created. The K+ currents include a fast transient current ( IA), a slow-inactivating low-threshold current ( ILT), and a noninactivating high-threshold current ( IHT). The model also includes a fast-inactivating Na+ current, a hyperpolarization-activated cation current ( Ih), and 1–50 auditory nerve synapses. With this model, the role IA, ILT, and IHT play in shaping the discharge patterns of VCN cells is explored. Simulation results indicate that IHT mainly functions to repolarize the membrane during an action potential, and IA functions to modulate the rate of repetitive firing. ILT is found to be responsible for the phasic discharge pattern observed in Type II cells (bushy cells). However, by adjusting the strength of ILT, both phasic and regular discharge patterns are observed, demonstrating that a critical level of ILT is necessary to produce the Type II response. Simulated Type II cells have a significantly faster membrane time constant in comparison to Type I cells (stellate cells) and are therefore better suited to preserve temporal information in their auditory nerve inputs by acting as precise coincidence detectors and having a short refractory period. Finally, we demonstrate that modulation of Ih, which changes the resting membrane potential, is a more effective means of modulating the activation level of ILT than simply modulating ILT itself. This result may explain why ILT and Ih are often coexpressed throughout the nervous system.

Disparate cytokine regulation of ICAM-1 in rat alveolar epithelial cells and pulmonary endothelial cells in vitro

1995 ◽  
Vol 269 (1) ◽  
pp. L127-L135 ◽  
Author(s):  
W. W. Barton ◽  
S. Wilcoxen ◽  
P. J. Christensen ◽  
R. Paine
Keyword(s):  
Endothelial Cells ◽  
Epithelial Cells ◽  
Inflammatory Cytokines ◽  
Alveolar Epithelial Cells ◽  
Normal Lung ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Epithelial

Intercellular adhesion molecule-1 (ICAM-1) is expressed at high levels on type I alveolar epithelial cells in the normal lung and is induced in vitro as type II cells spread in primary culture. In contrast, in most nonhematopoetic cells ICAM-1 expression is induced in response to inflammatory cytokines. We have formed the hypothesis that the signals that control ICAM-1 expression in alveolar epithelial cells are fundamentally different from those controlling expression in most other cells. To test this hypothesis, we have investigated the influence of inflammatory cytokines on ICAM-1 expression in isolated type II cells that have spread in culture and compared this response to that of rat pulmonary artery endothelial cells (RPAEC). ICAM-1 protein, determined both by a cell-based enzyme-linked immunosorbent assay and by Western blot analysis, and mRNA were minimally expressed in unstimulated RPAEC but were significantly induced in a time- and dose-dependent manner by treatment with tumor necrosis factor-alpha, interleukin-1 beta, or interferon-gamma. In contrast, these cytokines did not influence the constitutive high level ICAM-1 protein expression in alveolar epithelial cells and only minimally affected steady-state mRNA levels. ICAM-1 mRNA half-life, measured in the presence of actinomycin D, was relatively long at 7 h in alveolar epithelial cells and 4 h in RPAEC. The striking lack of response of ICAM-1 expression by alveolar epithelial cells to inflammatory cytokines is in contrast to virtually all other epithelial cells studied to date and supports the hypothesis that ICAM-1 expression by these cells is a function of cellular differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Sulfation of extracellular matrices modifies responses of alveolar type II cells to fibroblast growth factors

1996 ◽  
Vol 271 (5) ◽  
pp. L688-L697 ◽  
Author(s):  
P. L. Sannes ◽  
J. Khosla ◽  
P. W. Cheng
Keyword(s):  
Growth Factors ◽  
Biological Significance ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Fibroblast Growth ◽  
Alveolar Type Ii Cells ◽  
Proliferation And Differentiation ◽  
Type Ii Cell

The pulmonary alveolar basement membrane (BM) associated with alveolar type II cells has been shown to be significantly less sulfated than that of type I cells. To examine the biological significance of this observation, we measured the incorporation of 5-bromodeoxyuridine (BrdU) as an indicator of DNA synthesis in isolated rat type II cells cultured for 72-120 h on substrata that were naturally sulfated, not sulfated, or chemically desulfated in serum-free, hormonally defined media, with and without selected growth factors. The percentage of cells incorporating BrdU was significantly elevated by desulfated chondroitin sulfate in the presence of fibroblast growth factor-2 (FGF-2 or basic FGF) and depressed by heparin in the presence of either FGF-1 or acidic FGF or FGF-2. This depressive effect was lost by removing sulfate from the heparin. Some responses were dependent on the period of time in culture and concentration and molecular weight of the substrata. These observations support the notion that sulfation per se of certain components of BM is a key determinant of type II cell responses to select growth factors that may define patterns of proliferation and differentiation.

scholarly journals Differential Response of Primary Alveolar Type I and Type II Cells to LPS Stimulation

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e55545 ◽  
Author(s):  
Mandi H. Wong ◽  
Meshell D. Johnson
Keyword(s):  
Differential Response ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii

scholarly journals PS4DR: A multimodal workflow for identification and prioritization of drugs based on pathway signatures

2020 ◽  
Author(s):  
Mhammad Asif Emon ◽  
Daniel Domingo-Fernández ◽  
Charles Tapley Hoyt ◽  
Martin Hofmann-Apitius
Keyword(s):  
Gene Expression ◽  
Genome Wide Association Study ◽  
Drug Repositioning ◽  
Heterogeneous Data ◽  
New Drugs ◽  
Gwas Data ◽  
Drug Candidates ◽  
Gene Expression Signatures ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Background: During the last decade, there has been a surge towards computational drug repositioning owing to constantly increasing -omics data in the biomedical research field. While numerous existing methods focus on the integration of heterogeneous data to propose candidate drugs, it is still challenging to substantiate their results with mechanistic insights of these candidate drugs. Therefore, there is a need for more innovative and efficient methods which can enable better integration of data and knowledge for drug repositioning. Results: Here, we present a customizable workflow ( PS4DR) which not only integrates high-throughput data such as genome-wide association study (GWAS) data and gene expression signatures from disease and drug perturbations but also takes pathway knowledge into consideration to predict drug candidates for repositioning. We have collected and integrated publicly available GWAS data and gene expression signatures for several diseases and hundreds of FDA-approved drugs or those under clinical trial in this study. Additionally, different pathway databases were used for mechanistic knowledge integration in the workflow. Using this systematic consolidation of data and knowledge, the workflow computes pathway signatures that assist in the prediction of new indications for approved and investigational drugs. Conclusion: We showcase PS4DR with applications demonstrating how this tool can be used for repositioning and identifying new drugs as well as proposing drugs that can simulate disease dysregulations. We were able to validate our workflow by demonstrating its capability to predict FDA-approved drugs for their known indications for several diseases. Further, PS4DR returned many potential drug candidates for repositioning that were backed up by epidemiological evidence extracted from scientific literature. Source code is freely available at https://github.com/ps4dr/ps4dr .

scholarly journals Screening of FDA Approved Drugs Against COVID-19 Main Protease: Coronavirus Disease

2020 ◽  
Author(s):  
Vijayakumar Balakrishnan ◽  
Karthik Lakshminarayanan
Keyword(s):  
Vaccine Development ◽  
New Drugs ◽  
World Health ◽  
Wuhan City ◽  
Drug Candidates ◽  
Human Contact ◽  
Main Protease ◽  
Potent Drug ◽  
Approved Drugs ◽  
Fda Approved Drugs

In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger’s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.

Distinct Roles Of NF-?B RelA In Mediating Cytokine Expression From Type I And Type II Cells In The Lung

2011 ◽  
Author(s):  
Joseph D. Ferrari ◽  
Kazuko Yamamoto ◽  
Matthew T. Blahna ◽  
Lee J. Quinton ◽  
Matthew R. Jones ◽  
...  
Keyword(s):  
Cytokine Expression ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii

Ascorbate uptake by isolated rat alveolar macrophages and type II cells

1983 ◽  
Vol 54 (1) ◽  
pp. 208-214 ◽  
Author(s):  
V. Castranova ◽  
J. R. Wright ◽  
H. D. Colby ◽  
P. R. Miles
Keyword(s):  
Alveolar Macrophages ◽  
Membrane Surface ◽  
Lung Cells ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Sodium Influx ◽  
Saturation Kinetics ◽  
Ascorbate Uptake ◽  
Isolated Rat

Studies were conducted to measure intracellular ascorbate content and to characterize ascorbate uptake in three fractions of isolated rat pneumocytes (i.e., alveolar macrophages, alveolar type II epithelial cells, and another fraction of small pneumocytes that contains neither macrophages nor type II cells). When cells are incubated in medium containing 0.1 mM ascorbate (i.e., the concentration normally found in plasma), intracellular ascorbate concentrations are 3.2 mM in alveolar macrophages and type II cells and 0.9 mM in other lung cells; ascorbate influx is 1.5 nmol . 10(7) cells-1 . h-1 for alveolar macrophages, 0.24 nmol . 10(7) cells-1 . h-1 for type II cells, and very slow in other pneumocytes. Ascorbate influx displays saturation kinetics in both alveolar macrophages (K1/2 = 2 mM; Vmax = 32.2 nmol . 10(7) cells-1 . h-1) and type II cells (K1/2 = 5 mM; Vmax = 14.2 nmol . 10(7) cells-1 . h-1). After correction for differences in the membrane surface areas of these two types of lung cells, the rates for maximum ascorbate influx (Vmax) are similar in alveolar macrophages and type II cells. In addition, ascorbate uptake by alveolar macrophages and type II cells is dependent on metabolic activity and extracellular sodium. In contrast, ascorbate uptake in other lung cells does not exhibit saturation kinetics and is not dependent on metabolism or sodium. Thus alveolar macrophages and type II cells possess an energy-dependent cotransport system for ascorbate and sodium influx. The high ascorbate content and the existence of a specialized transport mechanism for ascorbate uptake may explain the relative resistance of alveolar macrophages and type II cells to oxidant injury.

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