Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes
et al., Stem Cell Reports, doi:10.1016/j.stemcr.2022.01.014, Jan 2022 (preprint)
Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.00000000001 from 106 studies, recognized in 24 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
|
In vitro study showing that ivermectin and meclizine treatment may minimize SARS-CoV-2-induced cardiac damage by reducing Orf9c-induced apoptosis and dysfunction. Using human pluripotent stem cell-derived cardiomyocytes, authors show that the SARS-CoV-2 gene Orf9c may play a key role in the detrimental effects of the virus on cardiomyocytes by reducing ATP levels.
74 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N771, Dengue37,72,73 , HIV-173, Simian virus 4074, Zika37,75,76 , West Nile76, Yellow Fever77,78, Japanese encephalitis77, Chikungunya78, Semliki Forest virus78, Human papillomavirus57, Epstein-Barr57, BK Polyomavirus79, and Sindbis virus78.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins71,73,74,80 , shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing38, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination41,81, shows dose-dependent inhibition of wildtype and omicron variants36, exhibits dose-dependent inhibition of lung injury61,66, may inhibit SARS-CoV-2 via IMPase inhibition37, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation9, inhibits SARS-CoV-2 3CLpro54, may inhibit SARS-CoV-2 RdRp activity28, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages60, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation82, may interfere with SARS-CoV-2's immune evasion via ORF8 binding4, may inhibit SARS-CoV-2 by disrupting CD147 interaction83-86, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1959,87, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage8, may minimize SARS-CoV-2 induced cardiac damage40,48, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation88, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses1, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways35, increases Bifidobacteria which play a key role in the immune system89, has immunomodulatory51 and anti-inflammatory70,90 properties, and has an extensive and very positive safety profile91.
1.
Gayozo et al., Binding affinities analysis of ivermectin, nucleocapsid and ORF6 proteins of SARS-CoV-2 to human importins α isoforms: A computational approach, Biotecnia, doi:10.18633/biotecnia.v27.2485.
2.
Lefebvre et al., Characterization and Fluctuations of an Ivermectin Binding Site at the Lipid Raft Interface of the N-Terminal Domain (NTD) of the Spike Protein of SARS-CoV-2 Variants, Viruses, doi:10.3390/v16121836.
3.
Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.
4.
Bagheri-Far et al., Non-spike protein inhibition of SARS-CoV-2 by natural products through the key mediator protein ORF8, Molecular Biology Research Communications, doi:10.22099/mbrc.2024.50245.2001.
5.
de Oliveira Só et al., In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease, Preprints, doi:10.20944/preprints202404.1825.v1.
6.
Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.
7.
Oranu et al., Validation of the binding affinities and stabilities of ivermectin and moxidectin against SARS-CoV-2 receptors using molecular docking and molecular dynamics simulation, GSC Biological and Pharmaceutical Sciences, doi:10.30574/gscbps.2024.26.1.0030.
8.
Zhao et al., Identification of the shared gene signatures between pulmonary fibrosis and pulmonary hypertension using bioinformatics analysis, Frontiers in Immunology, doi:10.3389/fimmu.2023.1197752.
9.
Vottero et al., Computational Prediction of the Interaction of Ivermectin with Fibrinogen, Molecular Sciences, doi:10.3390/ijms241411449.
10.
Chellasamy et al., Docking and molecular dynamics studies of human ezrin protein with a modelled SARS-CoV-2 endodomain and their interaction with potential invasion inhibitors, Journal of King Saud University - Science, doi:10.1016/j.jksus.2022.102277.
11.
Umar et al., Inhibitory potentials of ivermectin, nafamostat, and camostat on spike protein and some nonstructural proteins of SARS-CoV-2: Virtual screening approach, Jurnal Teknologi Laboratorium, doi:10.29238/teknolabjournal.v11i1.344.
12.
Alvarado et al., Interaction of the New Inhibitor Paxlovid (PF-07321332) and Ivermectin With the Monomer of the Main Protease SARS-CoV-2: A Volumetric Study Based on Molecular Dynamics, Elastic Networks, Classical Thermodynamics and SPT, Computational Biology and Chemistry, doi:10.1016/j.compbiolchem.2022.107692.
13.
Aminpour et al., In Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds, Computation, doi:10.3390/computation10040051.
14.
Parvez et al., Insights from a computational analysis of the SARS-CoV-2 Omicron variant: Host–pathogen interaction, pathogenicity, and possible drug therapeutics, Immunity, Inflammation and Disease, doi:10.1002/iid3.639.
15.
Francés-Monerris et al., Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection, Physical Chemistry Chemical Physics, doi:10.1039/D1CP02967C.
16.
González-Paz et al., Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach, Biophysical Chemistry, doi:10.1016/j.bpc.2021.106677.
17.
González-Paz (B) et al., Structural Deformability Induced in Proteins of Potential Interest Associated with COVID-19 by binding of Homologues present in Ivermectin: Comparative Study Based in Elastic Networks Models, Journal of Molecular Liquids, doi:10.1016/j.molliq.2021.117284.
18.
Rana et al., A Computational Study of Ivermectin and Doxycycline Combination Drug Against SARS-CoV-2 Infection, Research Square, doi:10.21203/rs.3.rs-755838/v1.
19.
Muthusamy et al., Virtual Screening Reveals Potential Anti-Parasitic Drugs Inhibiting the Receptor Binding Domain of SARS-CoV-2 Spike protein, Journal of Virology & Antiviral Research, www.scitechnol.com/abstract/virtual-screening-reveals-potential-antiparasitic-drugs-inhibiting-the-receptor-binding-domain-of-sarscov2-spike-protein-16398.html.
20.
Qureshi et al., Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1906750.
21.
Schöning et al., Highly-transmissible Variants of SARS-CoV-2 May Be More Susceptible to Drug Therapy Than Wild Type Strains, Research Square, doi:10.21203/rs.3.rs-379291/v1.
22.
Bello et al., Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1911857.
23.
Udofia et al., In silico studies of selected multi-drug targeting against 3CLpro and nsp12 RNA-dependent RNA-polymerase proteins of SARS-CoV-2 and SARS-CoV, Network Modeling Analysis in Health Informatics and Bioinformatics, doi:10.1007/s13721-021-00299-2.
24.
Choudhury et al., Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach, Future Medicine, doi:10.2217/fvl-2020-0342.
25.
Kern et al., Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing, Frontiers in Pharmacology, doi:10.3389/fphar.2021.625678.
26.
Saha et al., The Binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2, Structural Chemistry, doi:10.1007/s11224-021-01776-0.
27.
Eweas et al., Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2, Frontiers in Microbiology, doi:10.3389/fmicb.2020.592908.
28.
Parvez (B) et al., Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach, International Journal of Biological Macromolecules, doi:10.1016/j.ijbiomac.2020.09.098.
29.
Francés-Monerris (B) et al., Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent, ChemRxiv, doi:10.26434/chemrxiv.12782258.v1.
30.
Kalhor et al., Repurposing of the approved small molecule drugs in order to inhibit SARS-CoV-2 S protein and human ACE2 interaction through virtual screening approaches, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2020.1824816.
31.
Swargiary, A., Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against SARS-CoV2: Evidence from in silico studies, Research Square, doi:10.21203/rs.3.rs-73308/v1.
32.
Maurya, D., A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients, American Chemical Society (ACS), doi:10.26434/chemrxiv.12630539.v1.
33.
Lehrer et al., Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2, In Vivo, 34:5, 3023-3026, doi:10.21873/invivo.12134.
34.
Suravajhala et al., Comparative Docking Studies on Curcumin with COVID-19 Proteins, Preprints, doi:10.20944/preprints202005.0439.v3.
35.
Kofler et al., M-Motif, a potential non-conventional NLS in YAP/TAZ and other cellular and viral proteins that inhibits classic protein import, iScience, doi:10.1016/j.isci.2025.112105.
36.
Shahin et al., The selective effect of Ivermectin on different human coronaviruses; in-vitro study, Research Square, doi:10.21203/rs.3.rs-4180797/v1.
37.
Jitobaom et al., Identification of inositol monophosphatase as a broad‐spectrum antiviral target of ivermectin, Journal of Medical Virology, doi:10.1002/jmv.29552.
38.
Fauquet et al., Microfluidic Diffusion Sizing Applied to the Study of Natural Products and Extracts That Modulate the SARS-CoV-2 Spike RBD/ACE2 Interaction, Molecules, doi:10.3390/molecules28248072.
39.
García-Aguilar et al., In Vitro Analysis of SARS-CoV-2 Spike Protein and Ivermectin Interaction, International Journal of Molecular Sciences, doi:10.3390/ijms242216392.
40.
Liu et al., SARS-CoV-2 viral genes Nsp6, Nsp8, and M compromise cellular ATP levels to impair survival and function of human pluripotent stem cell-derived cardiomyocytes, Stem Cell Research & Therapy, doi:10.1186/s13287-023-03485-3.
41.
Boschi et al., SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects, bioRxiv, doi:10.1101/2022.11.24.517882.
42.
De Forni et al., Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients, PLoS ONE, doi:10.1371/journal.pone.0276751.
43.
Saha (B) et al., Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder, Pharmaceutics, doi:10.3390/pharmaceutics14071432.
44.
Jitobaom (B) et al., Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations, BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8.
45.
Croci et al., Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin, International Journal of Biomaterials, doi:10.1155/2016/8043983.
46.
Zheng et al., Red blood cell-hitchhiking mediated pulmonary delivery of ivermectin: Effects of nanoparticle properties, International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121719.
47.
Delandre et al., Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, Pharmaceuticals, doi:10.3390/ph15040445.
48.
Liu (B) et al., Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes, Stem Cell Reports, doi:10.1016/j.stemcr.2022.01.014.
49.
Segatori et al., Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients, Viruses, doi:10.3390/v13102084.
50.
Jitobaom (C) et al., Favipiravir and Ivermectin Showed in Vitro Synergistic Antiviral Activity against SARS-CoV-2, Research Square, doi:10.21203/rs.3.rs-941811/v1.
51.
Munson et al., Niclosamide and ivermectin modulate caspase-1 activity and proinflammatory cytokine secretion in a monocytic cell line, British Society For Nanomedicine Early Career Researcher Summer Meeting, 2021, web.archive.org/web/20230401070026/https://michealmunson.github.io/COVID.pdf.
52.
Mountain Valley MD, Mountain Valley MD Receives Successful Results From BSL-4 COVID-19 Clearance Trial on Three Variants Tested With Ivectosol™, www.globenewswire.com/en/news-release/2021/05/18/2231755/0/en/Mountain-Valley-MD-Receives-Successful-Results-From-BSL-4-COVID-19-Clearance-Trial-on-Three-Variants-Tested-With-Ivectosol.html.
53.
Yesilbag et al., Ivermectin also inhibits the replication of bovine respiratory viruses (BRSV, BPIV-3, BoHV-1, BCoV and BVDV) in vitro, Virus Research, doi:10.1016/j.virusres.2021.198384.
54.
Mody et al., Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents, Communications Biology, doi:10.1038/s42003-020-01577-x.
55.
Jeffreys et al., Remdesivir-ivermectin combination displays synergistic interaction with improved in vitro activity against SARS-CoV-2, International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2022.106542.
56.
Surnar et al., Clinically Approved Antiviral Drug in an Orally Administrable Nanoparticle for COVID-19, ACS Pharmacol. Transl. Sci., doi:10.1021/acsptsci.0c00179.
57.
Li et al., Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment, J. Cellular Physiology, doi:10.1002/jcp.30055.
58.
Caly et al., The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Research, doi:10.1016/j.antiviral.2020.104787.
59.
Zhang et al., Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice, Inflammation Research, doi:10.1007/s00011-008-8007-8.
60.
Gao et al., Ivermectin ameliorates acute myocarditis via the inhibition of importin-mediated nuclear translocation of NF-κB/p65, International Immunopharmacology, doi:10.1016/j.intimp.2024.112073.
61.
Abd-Elmawla et al., Suppression of NLRP3 inflammasome by ivermectin ameliorates bleomycin-induced pulmonary fibrosis, Journal of Zhejiang University-SCIENCE B, doi:10.1631/jzus.B2200385.
62.
Uematsu et al., Prophylactic administration of ivermectin attenuates SARS-CoV-2 induced disease in a Syrian Hamster Model, The Journal of Antibiotics, doi:10.1038/s41429-023-00623-0.
63.
Albariqi et al., Pharmacokinetics and Safety of Inhaled Ivermectin in Mice as a Potential COVID-19 Treatment, International Journal of Pharmaceutics, doi:10.1016/j.ijpharm.2022.121688.
64.
Errecalde et al., Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model, Journal of Pharmaceutical Sciences, doi:10.1016/j.xphs.2021.01.017.
65.
Madrid et al., Safety of oral administration of high doses of ivermectin by means of biocompatible polyelectrolytes formulation, Heliyon, doi:10.1016/j.heliyon.2020.e05820.
66.
Ma et al., Ivermectin contributes to attenuating the severity of acute lung injury in mice, Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.113706.
67.
de Melo et al., Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin, EMBO Mol. Med., doi:10.15252/emmm.202114122.
68.
Arévalo et al., Ivermectin reduces in vivo coronavirus infection in a mouse experimental model, Scientific Reports, doi:10.1038/s41598-021-86679-0.
69.
Chaccour et al., Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats, Scientific Reports, doi:10.1038/s41598-020-74084-y.
70.
Yan et al., Anti-inflammatory effects of ivermectin in mouse model of allergic asthma, Inflammation Research, doi:10.1007/s00011-011-0307-8.
71.
Götz et al., Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import, Scientific Reports, doi:10.1038/srep23138.
72.
Tay et al., Nuclear localization of dengue virus (DENV) 1–4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin, Antiviral Research, doi:10.1016/j.antiviral.2013.06.002.
73.
Wagstaff et al., Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochemical Journal, doi:10.1042/BJ20120150.
74.
Wagstaff (B) et al., An AlphaScreen®-Based Assay for High-Throughput Screening for Specific Inhibitors of Nuclear Import, SLAS Discovery, doi:10.1177/1087057110390360.
75.
Barrows et al., A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection, Cell Host & Microbe, doi:10.1016/j.chom.2016.07.004.
76.
Yang et al., The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antiviral Research, doi:10.1016/j.antiviral.2020.104760.
77.
Mastrangelo et al., Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug, Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dks147.
78.
Varghese et al., Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses, Antiviral Research, doi:10.1016/j.antiviral.2015.12.012.
79.
Bennett et al., Role of a nuclear localization signal on the minor capsid Proteins VP2 and VP3 in BKPyV nuclear entry, Virology, doi:10.1016/j.virol.2014.10.013.
80.
Kosyna et al., The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways, Biological Chemistry, doi:10.1515/hsz-2015-0171.
81.
Scheim et al., Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19, International Journal of Molecular Sciences, doi:10.3390/ijms242317039.
82.
Liu (C) et al., Crosstalk between neutrophil extracellular traps and immune regulation: insights into pathobiology and therapeutic implications of transfusion-related acute lung injury, Frontiers in Immunology, doi:10.3389/fimmu.2023.1324021.
83.
Shouman et al., SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147, Cell Communication and Signaling, doi:10.1186/s12964-024-01718-3.
84.
Scheim (B), D., Ivermectin for COVID-19 Treatment: Clinical Response at Quasi-Threshold Doses Via Hypothesized Alleviation of CD147-Mediated Vascular Occlusion, SSRN, doi:10.2139/ssrn.3636557.
85.
Scheim (C), D., From Cold to Killer: How SARS-CoV-2 Evolved without Hemagglutinin Esterase to Agglutinate and Then Clot Blood Cells, Center for Open Science, doi:10.31219/osf.io/sgdj2.
86.
Behl et al., CD147-spike protein interaction in COVID-19: Get the ball rolling with a novel receptor and therapeutic target, Science of The Total Environment, doi:10.1016/j.scitotenv.2021.152072.
87.
DiNicolantonio et al., Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19, Open Heart, doi:10.1136/openhrt-2020-001350.
88.
Mothae et al., SARS-CoV-2 host-pathogen interactome: insights into more players during pathogenesis, Virology, doi:10.1016/j.virol.2025.110607.
89.
Hazan et al., Treatment with Ivermectin Increases the Population of Bifidobacterium in the Gut, ACG 2023, acg2023posters.eventscribe.net/posterspeakers.asp.
Liu et al., 23 Jan 2022, peer-reviewed, 11 authors.
Contact: lyang7@iu.edu (corresponding author).
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
SARS-CoV-2 Viral Genes Compromise Survival and Functions of Human Pluripotent Stem Cell-derived Cardiomyocytes via Reducing Cellular ATP Level
doi:10.1101/2022.01.20.477147
Cardiac manifestations are commonly observed in COVID-19 patients and prominently contributed to overall mortality. Human myocardium could be infected by SARS-CoV-2, and human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are susceptible to SARS-CoV-2 infection. However, molecular mechanisms of SARS-CoV-2 gene-induced injury and dysfunction of human CMs remain elusive. Here, we find overexpression of three SARS-CoV-2 coding genes, Nsp6, Nsp8 and M, could globally compromise transcriptome of hPSC-CMs. Integrated transcriptomic analyses of hPSC-CMs infected by SARS-CoV-2 with hPSC-CMs of Nsp6, Nsp8 or M overexpression identified concordantly activated genes enriched into apoptosis and immune/inflammation responses, whereas reduced genes related to heart contraction and functions. Further, Nsp6, Nsp8 or M overexpression induce prominent apoptosis and electrical dysfunctions of hPSC-CMs. Global interactome analysis find Nsp6, Nsp8 and M all interact with ATPase subunits, leading to significantly reduced cellular ATP level of hPSC-CMs. Finally, we find two FDA-approved drugs, ivermectin and meclizine, could enhance the ATP level, and ameliorate cell death and dysfunctions of hPSC-CMs overexpressing Nsp6, Nsp8 or M. Overall, we uncover the global detrimental impacts of SARS-CoV-2 genes Nsp6, Nsp8 and M on the whole transcriptome and interactome of hPSC-CMs, define the crucial role of ATP level reduced by SARS-CoV-2 genes in CM death and functional abnormalities, and explore the potentially pharmaceutical approaches to ameliorate SARS-CoV-2 genes-induced CM injury and abnormalities.
Author contributions JL and LY initiated and designed studies. JL performed all experiments and data analyses. SW, LH, CW, ES, YW and YLL assisted in whole RNA-seq. YZ and JW assisted in bioinformatics. YL, WS and ML supported calcium handling and MEA experiments and data analyses. JL, JW, ML and LY wrote the manuscript.
Declaration of interest The authors declare no competing interests. Supplementary Figure 1
Supplemental Information acquisition a minimum AGC of 2e3 and charge exclusion of 1, and ≥7 were used.
References
Bailey, Dmytrenko, Greenberg, SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis, J Am Coll Cardiol Basic Trans Science
Bailey, Dmytrenko, Greenberg, SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis, J Am Coll Cardiol Basic Transl Science
Banerjee, Blanco, Bruce, SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses, Cell
Bers, Calcium cycling and signaling in cardiac myocytes, Annu Rev Physiol
Bers, Guo, Calcium signaling in cardiac ventricular myocytes, Ann N Y Acad Sci
Bojkova, Wagner, Shumliakivska, SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes, Cardiovasc Res
Brinton, Replication cycle and molecular biology of the West Nile virus, Viruses
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Res
Clerkin, Fried, Raikhelkar, COVID-19 and Cardiovascular Disease, Circulation
Dhakal, Sweitzer, Indik, Acharya, William, SARS-CoV-2 Infection and Cardiovascular Disease: COVID-19 Heart, Heart Lung Circ
Dobin, STAR: ultrafast universal RNA-seq aligner, Bioinformatics, doi:10.1093/bioinformatics/bts635
Eguchi, Shimizu, Tsujimoto, Intracellular ATP levels determine cell death fate by apoptosis or necrosis, Cancer Res
Fearnley, Roderick, Bootman, Calcium signaling in cardiac myocytes, Cold Spring Harb Perspect Biol
Gohil, Sheth, Nilsson, Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis, Nat Biotechnol
Gordon, Jang, Bouhaddou, A SARS-CoV-2 protein interaction map reveals targets for drug repurposing, Nature
Guo, Fan, Chen, Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19), JAMA Cardiol
Hikmet, Mear, Edvinsson, Micke, Uhlen et al., The protein expression profile of ACE2 in human tissues, Mol Syst Biol
Hoffmann, Kleine-Weber, Schroeder, SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell
Huang, Wang, Li, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet
Knight, Kotecha, Razvi, COVID-19: Myocardial Injury in Survivors, Circulation
Lian, Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/beta-catenin signaling under fully defined conditions, Nat Protoc, doi:10.1038/nprot.2012.150
Lian, Zhang, Azarin, Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/beta-catenin signaling under fully defined conditions, Nat Protoc
Liao, Smyth, Shi, The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads, Nucleic Acids Res, doi:10.1093/nar/gkz114
Lin, High-purity enrichment of functional cardiovascular cells from human iPS cells, Cardiovasc Res, doi:10.1093/cvr/cvs185
Liu, Li, Lin, Sheng, Yang, HBL1 Is a Human Long Noncoding RNA that Modulates Cardiomyocyte Development from Pluripotent Stem Cells by Counteracting MIR1, Dev Cell
Liu, Liu, Gao, Genome-wide studies reveal the essential and opposite roles of ARID1A in controlling human cardiogenesis and neurogenesis from pluripotent stem cells, Genome Biol
Lu, Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways, J Mol Cell Cardiol, doi:10.1016/j.yjmcc.2013.07.019
Ludwig, Bergendahl, Levenstein, Yu, Probasco et al., Feeder-independent culture of human embryonic stem cells, Nat Methods
Ludwig, Derivation of human embryonic stem cells in defined conditions, Nat Biotechnol, doi:10.1038/nbt1177
Ludwig, Feeder-independent culture of human embryonic stem cells, Nat Methods, doi:10.1038/nmeth902
Ludwig, Levenstein, Jones, Derivation of human embryonic stem cells in defined conditions, Nat Biotechnol
Marchiano, Hsiang, Khanna, SARS-CoV-2 Infects Human Pluripotent Stem Cell-Derived Cardiomyocytes, Impairing Electrical and Mechanical Function, Stem Cell Reports
Medigeshi, Hirsch, Streblow, Nikolich-Zugich, Nelson, West Nile virus entry requires cholesterol-rich membrane microdomains and is independent of alphavbeta3 integrin, J Virol
Miyoshi, Oubrahim, Chock, Stadtman, Age-dependent cell death and the role of ATP in hydrogen peroxide-induced apoptosis and necrosis, Proc Natl Acad Sci U S A
Nagai, Satomi, Abiru, Antihypertrophic Effects of Small Molecules that Maintain Mitochondrial ATP Levels Under Hypoxia, EBioMedicine
Nishiga, Wang, Han, Lewis, Wu, COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives, Nat Rev Cardiol
Peltier, Latham, Normalization of microRNA expression levels in quantitative RT-PCR assays: identification of suitable reference RNA targets in normal and cancerous human solid tissues, RNA, doi:10.1261/rna.939908
Perez-Bermejo, Kang, Rockwood, SARS-CoV-2 infection of human iPSC-derived cardiac cells predicts novel cytopathic features in hearts of COVID-19 patients, bioRxiv
Rajter, Sherman, Fatteh, Vogel, Sacks et al., Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease, Chest
Robinson, Mccarthy, Smyth, edgeR: a Bioconductor package for differential expression analysis of digital gene expression data, Bioinformatics, doi:10.1093/bioinformatics/btp616
Shang, Wan, Luo, Cell entry mechanisms of SARS-CoV-2, Proc Natl Acad Sci U S A
Sharma, Garcia, Wang, Human iPSC-Derived Cardiomyocytes Are Susceptible to SARS-CoV-2 Infection, Cell Rep Med
Shi, Qin, Shen, Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China, JAMA Cardiol
Shi, Qin, Yang, Coronavirus Disease 2019 (COVID-19) and Cardiac Injury-Reply, JAMA Cardiol
Tatsumi, Shiraishi, Intracellular ATP is required for mitochondrial apoptotic pathways in isolated hypoxic rat cardiac myocytes, Cardiovasc Res
Tohyama, Hattori, Sano, Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes, Cell Stem Cell
Tsujimoto, Apoptosis and necrosis: intracellular ATP level as a determinant for cell death modes, Cell Death Differ
Yang, Han, Nilsson-Payant, A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids, Cell Stem Cell
Yang, Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population, Nature, doi:10.1038/nature06894
Yang, Soonpaa, Adler, Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population, Nature
Zang, Castro, Mccune, TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes, Sci Immunol
Zhou, Yang, Wang, A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature
Zhu, Zhang, A Novel Coronavirus from Patients with Pneumonia in China, 2019, N Engl J Med
Zhuo, Gorgun, Englander, Augmentation of glycolytic metabolism by meclizine is indispensable for protection of dorsal root ganglion neurons from hypoxia-induced mitochondrial compromise, Free Radic Biol Med
DOI record:
{
"DOI": "10.1016/j.stemcr.2022.01.014",
"ISSN": [
"2213-6711"
],
"URL": "http://dx.doi.org/10.1016/j.stemcr.2022.01.014",
"alternative-id": [
"S2213671122000583"
],
"assertion": [
{
"label": "This article is maintained by",
"name": "publisher",
"value": "Elsevier"
},
{
"label": "Article Title",
"name": "articletitle",
"value": "Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes"
},
{
"label": "Journal Title",
"name": "journaltitle",
"value": "Stem Cell Reports"
},
{
"label": "CrossRef DOI link to publisher maintained version",
"name": "articlelink",
"value": "https://doi.org/10.1016/j.stemcr.2022.01.014"
},
{
"label": "Content Type",
"name": "content_type",
"value": "article"
},
{
"label": "Copyright",
"name": "copyright",
"value": "© 2022 The Author(s)."
}
],
"author": [
{
"affiliation": [],
"family": "Liu",
"given": "Juli",
"sequence": "first"
},
{
"affiliation": [],
"family": "Zhang",
"given": "Yucheng",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Han",
"given": "Lei",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Guo",
"given": "Shuai",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Wu",
"given": "Shiyong",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Doud",
"given": "Emma Helen",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Wang",
"given": "Cheng",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Chen",
"given": "Hanying",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Rubart-von der Lohe",
"given": "Michael",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Wan",
"given": "Jun",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0002-1479-2374",
"affiliation": [],
"authenticated-orcid": false,
"family": "Yang",
"given": "Lei",
"sequence": "additional"
}
],
"container-title": "Stem Cell Reports",
"container-title-short": "Stem Cell Reports",
"content-domain": {
"crossmark-restriction": true,
"domain": [
"cell.com",
"elsevier.com",
"sciencedirect.com"
]
},
"created": {
"date-parts": [
[
2022,
2,
17
]
],
"date-time": "2022-02-17T15:33:09Z",
"timestamp": 1645111989000
},
"deposited": {
"date-parts": [
[
2022,
5,
30
]
],
"date-time": "2022-05-30T18:24:34Z",
"timestamp": 1653935074000
},
"indexed": {
"date-parts": [
[
2023,
7,
6
]
],
"date-time": "2023-07-06T05:30:47Z",
"timestamp": 1688621447937
},
"is-referenced-by-count": 1,
"issue": "3",
"issued": {
"date-parts": [
[
2022,
3
]
]
},
"journal-issue": {
"issue": "3",
"published-print": {
"date-parts": [
[
2022,
3
]
]
}
},
"language": "en",
"license": [
{
"URL": "https://www.elsevier.com/tdm/userlicense/1.0/",
"content-version": "tdm",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2022,
3,
1
]
],
"date-time": "2022-03-01T00:00:00Z",
"timestamp": 1646092800000
}
},
{
"URL": "http://creativecommons.org/licenses/by/4.0/",
"content-version": "vor",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2022,
1,
18
]
],
"date-time": "2022-01-18T00:00:00Z",
"timestamp": 1642464000000
}
}
],
"link": [
{
"URL": "https://api.elsevier.com/content/article/PII:S2213671122000583?httpAccept=text/xml",
"content-type": "text/xml",
"content-version": "vor",
"intended-application": "text-mining"
},
{
"URL": "https://api.elsevier.com/content/article/PII:S2213671122000583?httpAccept=text/plain",
"content-type": "text/plain",
"content-version": "vor",
"intended-application": "text-mining"
}
],
"member": "78",
"original-title": [],
"page": "522-537",
"prefix": "10.1016",
"published": {
"date-parts": [
[
2022,
3
]
]
},
"published-print": {
"date-parts": [
[
2022,
3
]
]
},
"publisher": "Elsevier BV",
"reference": [
{
"DOI": "10.1152/ajpcell.00426.2020",
"article-title": "Mitochondrial metabolic manipulation by SARS-CoV-2 in peripheral blood mononuclear cells of patients with COVID-19",
"author": "Ajaz",
"doi-asserted-by": "crossref",
"first-page": "C57",
"journal-title": "Am. J. Physiol. Cell Physiol.",
"key": "10.1016/j.stemcr.2022.01.014_bib1",
"volume": "320",
"year": "2021"
},
{
"article-title": "SARS-CoV-2 ORF9c is a membrane-associated protein that suppresses antiviral responses in cells",
"author": "Andres",
"journal-title": "bioRxiv",
"key": "10.1016/j.stemcr.2022.01.014_bib2",
"year": "2020"
},
{
"DOI": "10.1016/j.jacbts.2021.01.002",
"article-title": "SARS-CoV-2 infects human engineered heart tissues and models COVID-19 myocarditis",
"author": "Bailey",
"doi-asserted-by": "crossref",
"first-page": "331",
"journal-title": "JACC Basic Transl. Sci.",
"key": "10.1016/j.stemcr.2022.01.014_bib3",
"volume": "6",
"year": "2021"
},
{
"DOI": "10.1146/annurev.physiol.70.113006.100455",
"article-title": "Calcium cycling and signaling in cardiac myocytes",
"author": "Bers",
"doi-asserted-by": "crossref",
"first-page": "23",
"journal-title": "Annu. Rev. Physiol.",
"key": "10.1016/j.stemcr.2022.01.014_bib4",
"volume": "70",
"year": "2008"
},
{
"DOI": "10.1196/annals.1341.008",
"article-title": "Calcium signaling in cardiac ventricular myocytes",
"author": "Bers",
"doi-asserted-by": "crossref",
"first-page": "86",
"journal-title": "Ann. N. Y. Acad. Sci.",
"key": "10.1016/j.stemcr.2022.01.014_bib5",
"volume": "1047",
"year": "2005"
},
{
"DOI": "10.1093/cvr/cvaa267",
"article-title": "SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes",
"author": "Bojkova",
"doi-asserted-by": "crossref",
"first-page": "2207",
"journal-title": "Cardiovasc. Res.",
"key": "10.1016/j.stemcr.2022.01.014_bib6",
"volume": "116",
"year": "2020"
},
{
"DOI": "10.1016/j.antiviral.2020.104787",
"article-title": "The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro",
"author": "Caly",
"doi-asserted-by": "crossref",
"first-page": "104787",
"journal-title": "Antivir. Res.",
"key": "10.1016/j.stemcr.2022.01.014_bib7",
"volume": "178",
"year": "2020"
},
{
"DOI": "10.1038/nature09005",
"article-title": "Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome",
"author": "Carvajal-Vergara",
"doi-asserted-by": "crossref",
"first-page": "808",
"journal-title": "Nature",
"key": "10.1016/j.stemcr.2022.01.014_bib8",
"volume": "465",
"year": "2010"
},
{
"DOI": "10.1016/j.kint.2020.03.005",
"article-title": "Kidney disease is associated with in-hospital death of patients with COVID-19",
"author": "Cheng",
"doi-asserted-by": "crossref",
"first-page": "829",
"journal-title": "Kidney Int.",
"key": "10.1016/j.stemcr.2022.01.014_bib9",
"volume": "97",
"year": "2020"
},
{
"DOI": "10.1016/j.hlc.2020.05.101",
"article-title": "SARS-CoV-2 infection and cardiovascular disease: COVID-19 heart",
"author": "Dhakal",
"doi-asserted-by": "crossref",
"first-page": "973",
"journal-title": "Heart Lung Circ.",
"key": "10.1016/j.stemcr.2022.01.014_bib10",
"volume": "29",
"year": "2020"
},
{
"article-title": "Intracellular ATP levels determine cell death fate by apoptosis or necrosis",
"author": "Eguchi",
"first-page": "1835",
"journal-title": "Cancer Res.",
"key": "10.1016/j.stemcr.2022.01.014_bib11",
"volume": "57",
"year": "1997"
},
{
"DOI": "10.1101/cshperspect.a004242",
"article-title": "Calcium signaling in cardiac myocytes",
"author": "Fearnley",
"doi-asserted-by": "crossref",
"first-page": "a004242",
"journal-title": "Cold Spring Harb. Perspect. Biol.",
"key": "10.1016/j.stemcr.2022.01.014_bib12",
"volume": "3",
"year": "2011"
},
{
"DOI": "10.1038/s41576-018-0008-z",
"article-title": "Heterogeneity and specialized functions of translation machinery: from genes to organisms",
"author": "Genuth",
"doi-asserted-by": "crossref",
"first-page": "431",
"journal-title": "Nat. Rev. Genet.",
"key": "10.1016/j.stemcr.2022.01.014_bib13",
"volume": "19",
"year": "2018"
},
{
"DOI": "10.1038/nbt.1606",
"article-title": "Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis",
"author": "Gohil",
"doi-asserted-by": "crossref",
"first-page": "249",
"journal-title": "Nat. Biotechnol.",
"key": "10.1016/j.stemcr.2022.01.014_bib14",
"volume": "28",
"year": "2010"
},
{
"DOI": "10.1038/s41586-020-2286-9",
"article-title": "A SARS-CoV-2 protein interaction map reveals targets for drug repurposing",
"author": "Gordon",
"doi-asserted-by": "crossref",
"first-page": "459",
"journal-title": "Nature",
"key": "10.1016/j.stemcr.2022.01.014_bib15",
"volume": "583",
"year": "2020"
},
{
"DOI": "10.1001/jamacardio.2020.1017",
"article-title": "Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19)",
"author": "Guo",
"doi-asserted-by": "crossref",
"first-page": "811",
"journal-title": "JAMA Cardiol.",
"key": "10.1016/j.stemcr.2022.01.014_bib16",
"volume": "5",
"year": "2020"
},
{
"DOI": "10.15252/msb.20209610",
"article-title": "The protein expression profile of ACE2 in human tissues",
"author": "Hikmet",
"doi-asserted-by": "crossref",
"first-page": "e9610",
"journal-title": "Mol. Syst. Biol.",
"key": "10.1016/j.stemcr.2022.01.014_bib17",
"volume": "16",
"year": "2020"
},
{
"DOI": "10.1016/j.cell.2020.02.052",
"article-title": "SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor",
"author": "Hoffmann",
"doi-asserted-by": "crossref",
"first-page": "271",
"journal-title": "Cell",
"key": "10.1016/j.stemcr.2022.01.014_bib18",
"volume": "181",
"year": "2020"
},
{
"DOI": "10.1016/S0140-6736(20)30183-5",
"article-title": "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China",
"author": "Huang",
"doi-asserted-by": "crossref",
"first-page": "497",
"journal-title": "Lancet",
"key": "10.1016/j.stemcr.2022.01.014_bib19",
"volume": "395",
"year": "2020"
},
{
"DOI": "10.1016/j.bbabio.2004.05.007",
"article-title": "\"Wages of fear\": transient threefold decrease in intracellular ATP level imposes apoptosis",
"author": "Izyumov",
"doi-asserted-by": "crossref",
"first-page": "141",
"journal-title": "Biochim. Biophys. Acta",
"key": "10.1016/j.stemcr.2022.01.014_bib20",
"volume": "1658",
"year": "2004"
},
{
"DOI": "10.1161/CIRCULATIONAHA.120.047969",
"article-title": "The COVID-19 pandemic A massive threat for those living with cardiovascular disease among the poorest billion",
"author": "Klassen",
"doi-asserted-by": "crossref",
"first-page": "1887",
"journal-title": "Circulation",
"key": "10.1016/j.stemcr.2022.01.014_bib21",
"volume": "142",
"year": "2020"
},
{
"DOI": "10.3390/cells8050508",
"article-title": "Regulation of ribosomal proteins on viral infection",
"author": "Li",
"doi-asserted-by": "crossref",
"first-page": "508",
"journal-title": "Cells",
"key": "10.1016/j.stemcr.2022.01.014_bib22",
"volume": "8",
"year": "2019"
},
{
"DOI": "10.1038/nprot.2012.150",
"article-title": "Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/beta-catenin signaling under fully defined conditions",
"author": "Lian",
"doi-asserted-by": "crossref",
"first-page": "162",
"journal-title": "Nat. Protoc.",
"key": "10.1016/j.stemcr.2022.01.014_bib23",
"volume": "8",
"year": "2013"
},
{
"DOI": "10.1093/cvr/cvs185",
"article-title": "High-purity enrichment of functional cardiovascular cells from human iPS cells",
"author": "Lin",
"doi-asserted-by": "crossref",
"first-page": "327",
"journal-title": "Cardiovasc. Res.",
"key": "10.1016/j.stemcr.2022.01.014_bib24",
"volume": "95",
"year": "2012"
},
{
"DOI": "10.1001/jama.2021.3071",
"article-title": "Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19 A randomized clinical trial",
"author": "Lopez-Medina",
"doi-asserted-by": "crossref",
"first-page": "1426",
"journal-title": "JAMA",
"key": "10.1016/j.stemcr.2022.01.014_bib25",
"volume": "325",
"year": "2021"
},
{
"DOI": "10.1038/nmeth902",
"article-title": "Feeder-independent culture of human embryonic stem cells",
"author": "Ludwig",
"doi-asserted-by": "crossref",
"first-page": "637",
"journal-title": "Nat. Methods",
"key": "10.1016/j.stemcr.2022.01.014_bib26",
"volume": "3",
"year": "2006"
},
{
"DOI": "10.1038/nbt1177",
"article-title": "Derivation of human embryonic stem cells in defined conditions",
"author": "Ludwig",
"doi-asserted-by": "crossref",
"first-page": "185",
"journal-title": "Nat. Biotechnol.",
"key": "10.1016/j.stemcr.2022.01.014_bib27",
"volume": "24",
"year": "2006"
},
{
"DOI": "10.1016/j.stemcr.2021.02.008",
"article-title": "SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function",
"author": "Marchiano",
"doi-asserted-by": "crossref",
"first-page": "478",
"journal-title": "Stem Cell Rep.",
"key": "10.1016/j.stemcr.2022.01.014_bib28",
"volume": "16",
"year": "2021"
},
{
"DOI": "10.1073/pnas.0510346103",
"article-title": "Age-dependent cell death and the role of ATP in hydrogen peroxide-induced apoptosis and necrosis",
"author": "Miyoshi",
"doi-asserted-by": "crossref",
"first-page": "1727",
"journal-title": "Proc. Natl. Acad. Sci. U S A",
"key": "10.1016/j.stemcr.2022.01.014_bib29",
"volume": "103",
"year": "2006"
},
{
"DOI": "10.1016/j.ebiom.2017.09.022",
"article-title": "Antihypertrophic effects of small molecules that maintain mitochondrial ATP levels under hypoxia",
"author": "Nagai",
"doi-asserted-by": "crossref",
"first-page": "147",
"journal-title": "Ebiomedicine",
"key": "10.1016/j.stemcr.2022.01.014_bib30",
"volume": "24",
"year": "2017"
},
{
"DOI": "10.1038/s41569-020-0413-9",
"article-title": "COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives",
"author": "Nishiga",
"doi-asserted-by": "crossref",
"first-page": "543",
"journal-title": "Nat. Rev. Cardiol.",
"key": "10.1016/j.stemcr.2022.01.014_bib31",
"volume": "17",
"year": "2020"
},
{
"article-title": "SARS-CoV-2 infection of human iPSC-derived cardiac cells predicts novel cytopathic features in hearts of COVID-19 patients",
"author": "Perez-Bermejo",
"first-page": "eabf7872",
"journal-title": "Sci. Transl. Med.",
"key": "10.1016/j.stemcr.2022.01.014_bib32",
"volume": "590",
"year": "2020"
},
{
"DOI": "10.1016/j.xcrm.2020.100052",
"article-title": "Human iPSC-derived cardiomyocytes are susceptible to SARS-CoV-2 infection",
"author": "Sharma",
"doi-asserted-by": "crossref",
"first-page": "100052",
"journal-title": "Cell Rep. Med.",
"key": "10.1016/j.stemcr.2022.01.014_bib33",
"volume": "1",
"year": "2020"
},
{
"DOI": "10.1001/jamacardio.2020.0950",
"article-title": "Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China",
"author": "Shi",
"doi-asserted-by": "crossref",
"first-page": "802",
"journal-title": "JAMA Cardiol.",
"key": "10.1016/j.stemcr.2022.01.014_bib34",
"volume": "5",
"year": "2020"
},
{
"DOI": "10.1001/jamacardio.2020.0950",
"article-title": "Coronavirus disease 2019 (COVID-19) and cardiac injury-reply",
"author": "Shi",
"doi-asserted-by": "crossref",
"first-page": "802",
"journal-title": "JAMA Cardiol.",
"key": "10.1016/j.stemcr.2022.01.014_bib35",
"volume": "7",
"year": "2020"
},
{
"DOI": "10.1152/ajpheart.2001.281.4.H1637",
"article-title": "Important role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis",
"author": "Shiraishi",
"doi-asserted-by": "crossref",
"first-page": "H1637",
"journal-title": "Am. J. Physiol. Heart Circ. Physiol.",
"key": "10.1016/j.stemcr.2022.01.014_bib36",
"volume": "281",
"year": "2001"
},
{
"DOI": "10.1007/s10495-006-5881-9",
"article-title": "Bioenergetic aspects of apoptosis, necrosis and mitoptosis",
"author": "Skulachev",
"doi-asserted-by": "crossref",
"first-page": "473",
"journal-title": "Apoptosis",
"key": "10.1016/j.stemcr.2022.01.014_bib37",
"volume": "11",
"year": "2006"
},
{
"DOI": "10.1016/S0008-6363(03)00391-2",
"article-title": "Intracellular ATP is required for mitochondrial apoptotic pathways in isolated hypoxic rat cardiac myocytes",
"author": "Tatsumi",
"doi-asserted-by": "crossref",
"first-page": "428",
"journal-title": "Cardiovasc. Res.",
"key": "10.1016/j.stemcr.2022.01.014_bib38",
"volume": "59",
"year": "2003"
},
{
"DOI": "10.1016/j.stem.2012.09.013",
"article-title": "Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes",
"author": "Tohyama",
"doi-asserted-by": "crossref",
"first-page": "127",
"journal-title": "Cell Stem Cell",
"key": "10.1016/j.stemcr.2022.01.014_bib39",
"volume": "12",
"year": "2013"
},
{
"DOI": "10.1038/sj.cdd.4400262",
"article-title": "Apoptosis and necrosis: intracellular ATP level as a determinant for cell death modes",
"author": "Tsujimoto",
"doi-asserted-by": "crossref",
"first-page": "429",
"journal-title": "Cell Death Differ.",
"key": "10.1016/j.stemcr.2022.01.014_bib40",
"volume": "4",
"year": "1997"
},
{
"DOI": "10.1016/j.stem.2020.06.015",
"article-title": "A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids",
"author": "Yang",
"doi-asserted-by": "crossref",
"first-page": "125",
"journal-title": "Cell Stem Cell",
"key": "10.1016/j.stemcr.2022.01.014_bib41",
"volume": "27",
"year": "2020"
},
{
"DOI": "10.1038/nature06894",
"article-title": "Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population",
"author": "Yang",
"doi-asserted-by": "crossref",
"first-page": "524",
"journal-title": "Nature",
"key": "10.1016/j.stemcr.2022.01.014_bib42",
"volume": "453",
"year": "2008"
},
{
"DOI": "10.1126/sciimmunol.abc3582",
"article-title": "TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes",
"author": "Zang",
"doi-asserted-by": "crossref",
"first-page": "eabc3582",
"journal-title": "Sci. Immunol.",
"key": "10.1016/j.stemcr.2022.01.014_bib43",
"volume": "47",
"year": "2020"
},
{
"DOI": "10.1056/NEJMoa2001017",
"article-title": "A novel coronavirus from patients with pneumonia in China, 2019",
"author": "Zhu",
"doi-asserted-by": "crossref",
"first-page": "727",
"journal-title": "N. Engl. J. Med.",
"key": "10.1016/j.stemcr.2022.01.014_bib44",
"volume": "382",
"year": "2020"
},
{
"DOI": "10.1016/j.freeradbiomed.2016.07.022",
"article-title": "Augmentation of glycolytic metabolism by meclizine is indispensable for protection of dorsal root ganglion neurons from hypoxia-induced mitochondrial compromise",
"author": "Zhuo",
"doi-asserted-by": "crossref",
"first-page": "20",
"journal-title": "Free Radic. Biol. Med.",
"key": "10.1016/j.stemcr.2022.01.014_bib45",
"volume": "99",
"year": "2016"
}
],
"reference-count": 45,
"references-count": 45,
"relation": {},
"resource": {
"primary": {
"URL": "https://linkinghub.elsevier.com/retrieve/pii/S2213671122000583"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [
"Cell Biology",
"Developmental Biology",
"Genetics",
"Biochemistry"
],
"subtitle": [],
"title": "Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes",
"type": "journal-article",
"update-policy": "http://dx.doi.org/10.1016/elsevier_cm_policy",
"volume": "17"
}