\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Angiotensin converting enzyme 2 activation: a novel potential Covid-19
therapeutic strategy}



\author[1]{Haidy Michel}%
\affil[1]{Ain Shams University Faculty of Pharmacy}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Not applicable%
\end{abstract}%



\sloppy


\textbf{Angiotensin converting enzyme 2 activation: a novel potential
Covid-19 therapeutic strategy}

In late December 2019, the Covid-19 epidemic, caused by a novel
coronavirus SARS-CoV-2, emerged in Wuhan, Hubei province, China. This
epidemic has a doubling period of 1.8 days, and there are concerns about
its progression to pandemic scales due to its exponential rate of
spread. No specific drugs or vaccines are currently available for the
treatment and/or prevention of SARS-CoV-2 infection. Hence, there is an
imperative need to search for a safe and effective therapeutic strategy
for Covid-19 infected patients, especially the critically ill
individuals.

Angiotensin-converting enzyme 2 (ACE2) is a crucial component of the
renin-angiotensin-system (RAS) axis because it converts Angiotensin II
into angiotensin (1--7), which exerts an antifibrotic, antihypertrophic
and vasodilatory effect. ACE2 is a membrane-bound aminopeptidase which
has been reported to be a functional receptor for coronaviruses,
including SARS-CoV and SARS-CoV-2. The first step of SARS-CoV-2
infection is binding of the spike protein of the virus to ACE2 which is
widely distributed on the alveolar type II cells and capillary
endothelium (Lu et al., 2020). It has been demonstrated that SARS-CoV
downregulates ACE2 protein in mice, contributing to severe lung injury
(Kuba et al., 2005). This suggests that augmented ACE2 activation may
result in enhanced binding with SARS-CoV-2. Thus, increasing ACE2
activation may have a dual function to both neutralize the virus and
rescue cellular ACE2 activity protecting the lung from damage.

Diminazene (DIZE) is an antitripanosomal drug which has been shown to
serve as an ACE2 activator and reduce bleomycin-induced pulmonary
fibrosis (Shenoy, Qi, Gupta, Katovich \& Raizada, 2012). In addition, it
has been reported that activation of ACE2 by DIZE prevented asthma
progression in rats by altering AKT, p38, NF-\selectlanguage{greek}κ\selectlanguage{english}B and other inflammatory
markers. DIZE also halted the development and progression of
experimentally induced pulmonary hypertension in rats, improved right
ventricular function, and diminished proinflammatory cytokines effects
that were accompanied with increased lung ACE2 activity. Given the
reported safety of DIZE administration in humans (Hutchinson \& Watson,
1962; Pepin \& Milord, 1994) and the pressing need for Covid-19
therapeutic, in addition to the well-documented pharmacological effects
of DIZE, clinical studies are warranted to elucidate the potential
safety and efficacy of DIZE in Covid-19 infected patients.

In conclusion, SARS-CoV-2 represents a global health challenge.
Unfortunately, no specific therapeutic options are currently available.
Thus, there is an imperative need for a safe and effective drug in order
to put this pandemic to an end. DIZE has a reported acceptable safety
profile. Moreover, DIZE increased lung ACE2 activity in different
experimental models, an effect which conferred lung protection against
various insults. Taking into consideration the reported effect of
SARS-CoV-2 on pulmonary ACE2 activity, it could be suggested that DIZE
administration could offer some therapeutic merit for SARS-CoV-2
infected patients. However, clinical studies are required to unravel the
potential safety and efficacy of DIZE administration in Covid-19
infected patients.

\textbf{Competing interests} The author declares no competing interests.

\textbf{Role of the funding source~}The present work did not receive any
specific grant from funding agencies in the public, commercial, or
not-for-profit sectors.

\textbf{References}

Hutchinson M, \& Watson H (1962). Berenil in the treatment of
Trypanosoma gambiense infection in man. Transactions of the Royal
Society of Tropical Medicine and Hygiene 56\textbf{:} 227-230.

Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B\emph{, et al.} (2005). A
crucial role of angiotensin converting enzyme 2 (ACE2) in SARS
coronavirus--induced lung injury. Nature medicine 11\textbf{:} 875-879.

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H\emph{, et al.} (2020). Genomic
characterisation and epidemiology of 2019 novel coronavirus:
implications for virus origins and receptor binding. The Lancet
395\textbf{:} 565-574.

Pepin J, \& Milord F (1994). The treatment of human African
trypanosomiasis. Advances in parasitology 33\textbf{:} 1-47.

Shenoy V, Qi Y, Gupta D, Katovich M, \& Raizada M (2012). Small
moleculae ACE2 activator, diminazene aceturate attenuates
bleomycin-induced pulmonary fibrosisEur Respiratory Soc.

\selectlanguage{english}
\FloatBarrier
\end{document}

