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All Studies   Meta Analysis    Recent:   

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

Liu et al., Stem Cell Research & Therapy, doi:10.1186/s13287-023-03485-3
Sep 2023  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
 
*, now known with p < 0.00000000001 from 102 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments. c19ivm.org
In Vitro study showing that ivermectin and meclizine mitigated cardiac cell death and dysfunction caused by SARS-CoV-2 viral genes.
Authors found that SARS-CoV-2 viral genes Nsp6, Nsp8, and M had harmful effects on human cardiomyocytes (heart muscle cells) derived from human pluripotent stem cells.
SARS-CoV-2 infection and overexpression of these genes depleted cellular ATP, activated genes related to cell death and inflammation, suppressed genes important for heart contraction, and compromised calcium handling.
Ivermectin and meclizine restored ATP levels and mitigated the negative effects of the SARS-CoV-2 viral genes.
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Jitobaom, Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Jitobaom, Yang, West Nile Yang, Yellow Fever Mastrangelo, Varghese, Japanese encephalitis Mastrangelo, Chikungunya Varghese, Semliki Forest virus Varghese, Human papillomavirus Li, Epstein-Barr Li, BK Polyomavirus Bennett, and Sindbis virus Varghese.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), inhibits SARS-CoV-2 3CLpro Mody, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing Fauquet, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, Scheim, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 via IMPase inhibition Jitobaom, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, may inhibit SARS-CoV-2 RdRp activity Parvez (B), may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation Liu (C), shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-19 DiNicolantonio, Zhang, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage Zhao, may minimize SARS-CoV-2 induced cardiac damage Liu, Liu (B), increases Bifidobacteria which play a key role in the immune system Hazan, has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.
Liu et al., 13 Sep 2023, peer-reviewed, 7 authors. Contact: juliliu@outlook.com, lyang7@iu.edu.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
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
Juli Liu, Shiyong Wu, Yucheng Zhang, Cheng Wang, Sheng Liu, Jun Wan, Lei Yang
Stem Cell Research & Therapy, doi:10.1186/s13287-023-03485-3
Background Cardiovascular complications significantly augment the overall COVID-19 mortality, largely due to the susceptibility of human cardiomyocytes (CMs) to SARS-CoV-2 virus. SARS-CoV-2 virus encodes 27 genes, whose specific impacts on CM health are not fully understood. This study elucidates the deleterious effects of SARS-CoV-2 genes Nsp6, M, and Nsp8 on human CMs. Methods CMs were derived from human pluripotent stem cells (hPSCs), including human embryonic stem cells and induced pluripotent stem cells, using 2D and 3D differentiation methods. We overexpressed Nsp6, M, or Nsp8 in hPSCs and then applied whole mRNA-seq and mass spectrometry for multi-omics analysis. Co-immunoprecipitation mass spectrometry was utilized to map the protein interaction networks of Nsp6, M, and Nsp8 within host hiPSC-CMs. Results Nsp6, Nsp8, and M globally perturb the transcriptome and proteome of hPSC-CMs. SARS-CoV-2 infection and the overexpression of Nsp6, Nsp8, or M coherently upregulated genes associated with apoptosis and immune/ inflammation pathways, whereas downregulated genes linked to heart contraction and functions. Global interactome analysis revealed interactions between Nsp6, Nsp8, and M with ATPase subunits. Overexpression of Nsp6, Nsp8, or M significantly reduced cellular ATP levels, markedly increased apoptosis, and compromised Ca 2+ handling in hPSC-CMs. Importantly, administration of FDA-approved drugs, ivermectin and meclizine, could restore ATP levels, thereby mitigating apoptosis and dysfunction in hPSC-CMs overexpressing Nsp6, Nsp8, or M. Conclusion Overall, our findings uncover the extensive damaging effects of Nsp6, Nsp8, and M on hPSC-CMs, underlining the crucial role of ATP homeostasis in CM death and functional abnormalities induced by these SARS-CoV-2 genes, and reveal the potential therapeutic strategies to alleviate these detrimental effects with FDA-approved drugs.
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s13287-023-03485-3. Additional file 1. Supplementary Figures. S1 . mRNA expression profiling of Nsp6OE, Nsp8OE, or MOE and control hESC-CMs. Additional file 2. Table Additional file 3. Table S2 . Protein expression profiling of Nsp6OE, Nsp8OE, or MOE and control hESC-CMs. Additional file 4. Table S3 . CoIP-MS of Nsp6OE, Nsp8OE, or MOE and control hESC-CMs. Additional file 5. Table S4 . Primers for RT-qPCR. Author contributions JL initiated and designed the studies. JL and SW performed all experiments, and data collection and analyses. YZ, SL, and JW conducted bioinformatics analyses. CW assisted in CM functional studies. JL, SW, JW, and LY wrote the manuscript. All authors read and approved the final manuscript. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year • At BMC, research is always in progress. Learn more biomedcentral.com/submissions Ready to submit your research..
References
Bailey, Dmytrenko, Greenberg, Bredemeyer, Ma et al., SARS-CoV-2 infects human engineered heart tissues and models COVID-19 myocarditis, JACC Basic Transl Sci
Banerjee, Blanco, Bruce, Honson, Chen et al., 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, Aslan, Saleem et al., SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes, Cardiovasc Res
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Res
Clerkin, Fried, Raikhelkar, Sayer, Griffin et al., 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, Davis, Schlesinger, Drenkow, Zaleski et al., STAR: ultrafast universal RNA-seq aligner, Bioinformatics
Fearnley, Roderick, Bootman, Calcium signaling in cardiac myocytes, Cold Spring Harb Perspect Biol
Gibbs, Cardiac energetics, Physiol Rev
Gohil, Sheth, Nilsson, Wojtovich, Lee et al., Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis, Nat Biotechnol
Gordon, Jang, Bouhaddou, Xu, Obernier et al., A SARS-CoV-2 protein interaction map reveals targets for drug repurposing, Nature
Guo, Fan, Chen, Wu, Zhang et al., 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, Kruger, Herrler et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell
Huang, Wang, Li, Ren, Zhao et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet
Lian, Zhang, Azarin, Zhu, Hazeltine et al., 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
Lin, Kim, Li, Pan, Vergara et al., High-purity enrichment of functional cardiovascular cells from human iPS cells, Cardiovasc Res
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, Han, Chu et al., Genome-wide studies reveal the essential and opposite roles of ARID1A in controlling human cardiogenesis and neurogenesis from pluripotent stem cells, Genome Biol
Liu, Zhang, Han, Guo, Wu 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 Rep
Lu, Lin, Li, Arora, Han et al., Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways, J Mol Cell Cardiol
Ludwig, Bergendahl, Levenstein, Yu, Probasco et al., Feeder-independent culture of human embryonic stem cells, Nat Methods
Ludwig, Levenstein, Jones, Berggren, Mitchen et al., Derivation of human embryonic stem cells in defined conditions, Nat Biotechnol
Marchiano, Hsiang, Khanna, Higashi, Whitmore et al., SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function, Stem Cell Rep
Miyoshi, Oubrahim, Chock, Stadtman, Age-dependent cell death and the role of ATP in hydrogen peroxide-induced apoptosis and necrosis, Proc Natl Acad Sci
Nagai, Satomi, Abiru, Miyamoto, Nagasawa et al., Antihypertrophic effects of small molecules that maintain mitochondrial atp levels under hypoxia, EBioMedicine
Nalbandian, Sehgal, Gupta, Madhavan, Mcgroder et al., Post-acute COVID-19 syndrome, Nat Med
Nishiga, Wang, Han, Lewis, Wu, COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives, Nat Rev Cardiol
Palazzuoli, Beltrami, Mccullough, Acute COVID-19 management in heart failure patients: a specific setting requiring detailed inpatient and outpatient hospital care, Biomedicines
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
Perez-Bermejo, Kang, Rockwood, Simoneau, Joy et al., SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19, Sci Transl Med
Raman, Bluemke, Lüscher, Neubauer, Long COVID: postacute sequelae of COVID-19 with a cardiovascular focus, Eur Heart J
Robinson, Mccarthy, Smyth, edgeR: a Bioconductor package for differential expression analysis of digital gene expression data, Bioinformatics
Shang, Wan, Luo, Ye, Geng et al., Cell entry mechanisms of SARS-CoV-2, Proc Natl Acad Sci
Sharma, Garcia, Jr, Wang, Plummer et al., Human iPSC-derived cardiomyocytes are susceptible to SARS-CoV-2 infection, Cell Rep Med
Shi, Qin, Shen, Cai, Liu et al., Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, JAMA Cardiol
Shi, Qin, Yang, Coronavirus disease 2019 (COVID-19) and cardiac injury-reply, JAMA Cardiol
Suga, Ventricular energetics, Physiol Rev
Sun, Liu, Huang, Xu, Hu et al., SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1, Cell Death Differ
Tatsumi, Shiraishi, Keira, Akashi, Mano et al., Intracellular ATP is required for mitochondrial apoptotic pathways in isolated hypoxic rat cardiac myocytes, Cardiovasc Res
Tohyama, Hattori, Sano, Hishiki, Nagahata et al., 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
Xie, Xu, Bowe, Al-Aly, Long-term cardiovascular outcomes of, Nat Med
Yang, Han, Nilsson-Payant, Gupta, Wang et al., 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, Soonpaa, Adler, Roepke, Kattman et al., Human cardiovascular progenitor cells develop from a KDR+ embryonicstem-cell-derived population, Nature
Yang, Wu, Meng, Wang, Younis et al., SARS-CoV-2Membrane protein causes the mitochondrial apoptosis and pulmonary edema via targeting BOK, Cell Death Differ
Zang, Castro, Mccune, Zeng, Rothlauf et al., TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes, Sci Immunol
Zhou, Yang, Wang, Hu, Zhang et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature
Zhu, Wang, Huang, Lee, Lee et al., SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis, Commun Biol
Zhu, Zhang, Li, Yang, Song, A novel coronavirus from patients with pneumonia in China, 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
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