PMID- 36187008
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230510
IS  - 2297-055X (Print)
IS  - 2297-055X (Electronic)
IS  - 2297-055X (Linking)
VI  - 9
DP  - 2022
TI  - Robust therapeutic effects on COVID-19 of novel small molecules: Alleviation of 
      SARS-CoV-2 S protein induction of ACE2/TMPRSS2, NOX2/ROS, and MCP-1.
PG  - 957340
LID - 10.3389/fcvm.2022.957340 [doi]
LID - 957340
AB  - While new variants of severe acute respiratory syndrome coronavirus 2 
      (SARS-CoV-2) constantly emerge to prolong the pandemic of COVID-19, robust and 
      safe therapeutics are in urgent need. During the previous and ongoing fight 
      against the pandemic in China, Traditional Chinese Medicine (TCM) has proven to 
      be markedly effective in treating COVID-19. Among active ingredients of TCM 
      recipes, small molecules such as quercetin, glabridin, gallic acid, and 
      chrysoeriol have been predicted to target viral receptor angiotensin-converting 
      enzyme 2 (ACE2) via system pharmacology/molecular docking/visualization analyses. 
      Of note, endothelial dysfunction induced by oxidative stress and inflammation 
      represents a critical mediator of acute respiratory distress syndrome (ARDS) and 
      multi-organ injuries in patients with COVID-19. Hence, in the present study, we 
      examined whether quercetin, glabridin, gallic acide and chrysoeriol regulate 
      viral receptors of ACE2 and transmembrane serine protease 2 (TMPRSS2), redox 
      modulator NADPH oxidase isoform 2 (NOX2), and inflammatory protein of monocyte 
      chemoattractant protein-1 (MCP-1) in endothelial cells to mediate therapeutic 
      protection against COVID-19. Indeed, quercetin, glabridin, gallic acide and 
      chrysoeriol completely attenuated SARS-CoV-2 spike protein (S protein)-induced 
      upregulation in ACE2 protein expression in endothelial cells. In addition, these 
      small molecules abolished S protein upregulation of cleaved/active form of 
      TMPRSS2, while native TMPRSS2 was not significantly regulated. Moreover, these 
      small molecules completely abrogated S protein-induced upregulation in NOX2 
      protein expression, which resulted in alleviated superoxide production, 
      confirming their preventive efficacies against S protein-induced oxidative stress 
      in endothelial cells. In addition, treatment with these small molecules abolished 
      S protein induction of MCP-1 expression. Collectively, our findings for the first 
      time demonstrate that these novel small molecules may be used as novel and robust 
      therapeutic options for the treatment of patients with COVID-19, via effective 
      attenuation of S protein induction of endothelial oxidative stress and 
      inflammation.
CI  - Copyright (c) 2022 Youn, Wang, Li, Huang and Cai.
FAU - Youn, Ji Youn
AU  - Youn JY
AD  - Division of Molecular Medicine, Department of Anesthesiology, David Geffen School 
      of Medicine at University of California, Los Angeles, Los Angeles, CA, United 
      State.
AD  - Division of Cardiology, Department of Medicine, David Geffen School of Medicine 
      at University of California, Los Angeles, Los Angeles, CA, United States.
FAU - Wang, Jian
AU  - Wang J
AD  - Department of Cardiology, China-Japan Friendship Hospital, Beijing, China.
FAU - Li, Qian
AU  - Li Q
AD  - Division of Molecular Medicine, Department of Anesthesiology, David Geffen School 
      of Medicine at University of California, Los Angeles, Los Angeles, CA, United 
      State.
AD  - Division of Cardiology, Department of Medicine, David Geffen School of Medicine 
      at University of California, Los Angeles, Los Angeles, CA, United States.
FAU - Huang, Kai
AU  - Huang K
AD  - Division of Molecular Medicine, Department of Anesthesiology, David Geffen School 
      of Medicine at University of California, Los Angeles, Los Angeles, CA, United 
      State.
AD  - Division of Cardiology, Department of Medicine, David Geffen School of Medicine 
      at University of California, Los Angeles, Los Angeles, CA, United States.
FAU - Cai, Hua
AU  - Cai H
AD  - Division of Molecular Medicine, Department of Anesthesiology, David Geffen School 
      of Medicine at University of California, Los Angeles, Los Angeles, CA, United 
      State.
AD  - Division of Cardiology, Department of Medicine, David Geffen School of Medicine 
      at University of California, Los Angeles, Los Angeles, CA, United States.
LA  - eng
GR  - R01 HL142951/HL/NHLBI NIH HHS/United States
GR  - R01 HL154754/HL/NHLBI NIH HHS/United States
GR  - R01 HL162407/HL/NHLBI NIH HHS/United States
GR  - R01 HL088975/HL/NHLBI NIH HHS/United States
GR  - R01 HL077440/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20220915
PL  - Switzerland
TA  - Front Cardiovasc Med
JT  - Frontiers in cardiovascular medicine
JID - 101653388
PMC - PMC9520320
OTO - NOTNLM
OT  - COVID-19
OT  - NADPH oxidase isoform 2 (NOX2)
OT  - SARS-CoV-2
OT  - acute respiratory distress syndrome (ARDS)
OT  - endothelial dysfunction
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/10/04 06:00
MHDA- 2022/10/04 06:01
PMCR- 2022/09/15
CRDT- 2022/10/03 04:44
PHST- 2022/05/31 00:00 [received]
PHST- 2022/07/18 00:00 [accepted]
PHST- 2022/10/03 04:44 [entrez]
PHST- 2022/10/04 06:00 [pubmed]
PHST- 2022/10/04 06:01 [medline]
PHST- 2022/09/15 00:00 [pmc-release]
AID - 10.3389/fcvm.2022.957340 [doi]
PST - epublish
SO  - Front Cardiovasc Med. 2022 Sep 15;9:957340. doi: 10.3389/fcvm.2022.957340. 
      eCollection 2022.