medical definition of cholestasis is a retaining bile excreted substances into
the bile itself again. There are caused
by many different causes underly this condition including inherited and
acquired pathologies. Inherited
cholestasis is an autosomal recessive disease
while, the acquired cholestasis refers to bile secretion caused via several
defects such as bile duct obstruction, hepatitis,
biliary cirrhosis, cholangiocarcinoma or via hormonal disturbances during
and Lammert, 2013; Zollner and Trauner, 2008). Consequently, these conditions
lead to bile acids accumulation in hepatic tissues causing a potential to hepatotoxicity
and Gores; Perez and Briz, 2009).
obstructive cholestasis increases biliary pressure which leads to rupture in cholangioles
leading to bile reflux back into hepatic tissues causing hepatotoxicity (Fickert
et al., 2002). Hepatotoxicity initiates inflammatory response via secretion
of osteopontin and CXC chemokines by hepatocytes which in turn leading to an extensive neutrophil accumulation which induces liver injury (Gujral
et al., 2003; Kim et al., 2006; Kountouras et al., 1984; Licata et al., 2013;
O’Brien et al., 2013; Saito and Maher, 2000).
acid (LCA) is one of these bile acids
that essentially acts as a detergent for dietary fat solubilization and
et al., 1982; Hofmann, 2004). LCA is a secondary bile acid
formed by colon bacterial enzyme called 7 alpha-dehydroxylase (Reddy
et al.). LCA
is a hydrophobic compound implicated in several diseases such as colon cancer,
hepatotoxicity and liver injury (Ajouz
et al., 2014; Lucangioli et al., 2009). Experimentally, LCA feeding was
used as a model of liver injury by Fickert et al. in which LCA precipitates in
both hepatic and biliary tissues causing obstructive cholestasis and initiates
inflammatory cycle (Fickert
et al., 2002).
On the other hand, Artemisinin is a chemical compound synthesized either naturally by a plant
called Artemisia annua or artificially (Guo,
2016). It is a sesquiterpene lactone
containing a peroxide bridge which might be responsible for its action (Avery
et al., 1993).
Artemisinin and its derivatives have been reported to be effective treatment
for several viral infections, toxoplasmosis and
against Pnuemocystis carinii as well as these compounds have been shown
to be effective against some human cancer cell lines (Efferth,
2007; Efferth et al., 2008; Merali and Meshnick, 1991). Furthermore, artemisinin have been
shown to be a good treatment for different parasitic diseases such as malaria, leishmaniosis,
and African sleeping sickness (Mishina
et al., 2007; Posner et al., 1999; Sen et al., 2007; White, 1997). In the same context, artemisinin
has also anti-inflammatory and immunomodulatory effect (Ferreira
et al., 2010). In terms of liver injury Chin Q et
al have reported that dihydroartemisinin prevents liver fibrosis due to its action
on both apoptosis pathway and PDGF/MAPK pathway in experimental animals (Chen
et al., 2016a; Chen et al., 2016b).
the objective of this project is to study the effect of artemisinin on LCA- induced
liver injury in animal model on both cellular and molecular scales.