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Review
22 December 2021
Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19
Keiji Kuba
1 more and 
Josef M. Penninger
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Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.

13,424 views
54 citations
5,397 views
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Perspective
22 September 2021
Will Auranofin Become a Golden New Treatment Against COVID-19?
Karine Sonzogni-Desautels
 and 
Momar Ndao
Auranofin inhibits dimerization of toll-like receptor (TLR) 4, activation of IκB kinase (IKK), degradation of IκB, IL-6-induced phosphorylation of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3), and STAT3 translocation to the nucleus. In addition, auranofin inhibits thioredoxin reductase (TrxR) and, consequently, TrxR-dependent activation of thioredoxin (Trx); auranofin therefore inhibits the Trx-induced promotion of NF-κB transactivation.

Auranofin is an FDA-approved disease-modifying anti-rheumatic drug that has been used for decades for treatment of rheumatoid arthritis. This gold(I) compound has anti-inflammatory properties because it reduces IL-6 expression via inhibition of the NF-κB-IL-6-STAT3 signaling pathway. Also, by inhibiting redox enzymes such as thioredoxin reductase, auranofin increases cellular oxidative stress and promotes apoptosis. Auranofin also possesses antiviral properties. Recently, it was reported that auranofin reduced by 95% SARS-CoV-2 RNA in infected human cells in vitro and decreased SARS-CoV-2-induced cytokine expression, including IL-6. During SARS-CoV-2 infection, a cytokine storm involving IL-6 increases severity of illness and worsens prognosis. Therefore, auranofin could, in our point of view, reduce pathology due to SARS-CoV-2-induced IL-6. COVID-19 is a rapidly-evolving respiratory disease now distributed worldwide. Strikingly high numbers of new COVID-19 cases are reported daily. We have begun a race to vaccinate people, but due to the complex logistics of this effort, the virus will continue to spread before all humans can be immunized, and new variants that may be less well contained by current vaccines are of concern. The COVID-19 pandemic has overwhelmed health care systems and new treatments to reduce mortality are urgently needed. We encourage to further evaluate the potential of auranofin in the treatment of COVID-19 in vitro and in animal models of SARS-CoV-2 infection and, if preliminary data are promising, in clinical trials with COVID-19 patients. In our opinion, auranofin has the potential to become a valuable addition to available therapies in this pandemic.

9,341 views
17 citations
The virus quantitative detection results were expressed by CT value for the SARS-CoV-2 gene by quantitative real-time reverse transcription-PCR as previously described. Viral loads from 35 patients within 2 weeks after disease onset were acquired. The levels of 3 cytokines, including IP-10, HGF and IL-10, were positively correlated with the virus titers.
8,461 views
73 citations
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Frontiers in Microbiology

Multi-Omics Research in Disease Microbiology
Edited by Chandrajit Lahiri, Chirajyoti Deb, Datta Madamwar
Deadline
30 November 2024
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Frontiers Logo

Frontiers in Microbiology

Multi-Omics Research in Disease Microbiology
Edited by Chandrajit Lahiri, Chirajyoti Deb, Datta Madamwar
Deadline
30 November 2024
Submit a paper