Xanthohumol suppresses inflammatory response to warm ischemia–reperfusion induced liver injury
Highlights
► Xanthohumol reduces oxidative stress in hepatic ischemia/reperfusion (I/R) injury. ► Xanthohumol (XN) ameliorates I/R induced NFkappaB activation in the liver. ► XN inhibits expression of genes, which affect I/R-induced liver damage.
Introduction
Hepatic ischemia/reperfusion (I/R) injury occurs in a variety of clinical scenarios, including transplantation, liver resection, trauma, and hypovolemic shock. The molecular mechanisms causing liver injury after I/R have been subject of several studies, which revealed a series of complex interactions of various participant inflammatory pathways (Walsh et al., 2009, Zwacka et al., 1998a). The process of hepatic I/R-injury can be divided into two phases; an acute phase (the first 6 h after reperfusion) and the following subacute phase (Fan et al., 1999). The acute phase is characterized by acute generation of reactive oxygen species (ROS) subsequent to reoxygenation of the liver leading to marked hepatocellular damage, measurable by an increase of serum alanine transaminase levels peaking 3 to 6 h after reperfusion (Parks and Granger, 1988, Rauen et al., 1994). The secondary subacute phase is associated with vigorous inflammatory responses and the progression of necrotic processes (Gujral et al., 2001, Zwacka et al., 1998a). This can lead to chronic liver inflammation, a decline in liver function, and eventually complete organ failure.
Whereas earlier studies suggested that hepatic I/R‐damage was mainly inflicted in the acute phase by ROS directly, more recent data indicate that oxidative stress may injure the tissue more indirectly by initiating a cascade of adverse cellular responses leading to inflammation, e.g. by activating redox-sensitive transcription factors such as NFκB (Jaeschke, 1995, Shin et al., 2008, Zwacka et al., 1998b). Antioxidant as well as anti-inflammatory therapies depict two practicable and medically sensible treatment options for preventing or ameliorating I/R-induced liver injury. Antioxidant substances could reduce I/R-induced tissue damage directly caused by ROS and, more importantly, attenuate the ROS-triggered inflammatory response which could be further suppressed by additional anti-inflammatory therapies.
Xanthohumol (XN), the principal prenylated chalcone of the hop plant (Humulus lupulus L.), has been discussed for its antioxidant (Gerhauser et al., 2002, Miranda et al., 2000, Yamaguchi et al., 2009) as well as anti-inflammatory properties (Dorn et al., 2010b, Lupinacci et al., 2009, Stevens and Page, 2004) suggesting this natural substance as a potential candidate for an I/R-damage-preventing treatment of the liver. In addition, XN is known as an inhibitor of the transcription factor NFκB (Albini et al., 2006, Colgate et al., 2007, Dorn et al., 2010c) whose activity increases upon hepatic I/R (Suetsugu et al., 2005, Tacke et al., 2009). Whereas it has been unclear for a long time whether NFκB-dependent signaling withholds a protective or damaging role in I/R, more recent data show that the NFκB pathway does not serve as a survival pathway in hepatic I/R, but instead can aggravate hepatocellular death and liver damage (Luedde et al., 2005, Suetsugu et al., 2005). NFκB-mediated expression of adhesion molecules like ICAM-1 (Inter-Cellular Adhesion Molecule-1) may be responsible for increased tissue damage inflicted by infiltrating neutrophils in the late phase of hepatic I/R-injury (Jaeschke, 2006, Jaeschke et al., 1996). However, as shown by Beraza et al. (2007), complete abolishment of NFκB activation in conditional NEMO-knockout mice resulted in massive hepatic inflammation and apoptosis after I/R indicating that suppression of NFκB induction is preferable to complete inhibition of basal NFκB activity for preventing I/R-induced liver injury.
The aim of this study was to investigate the effects of XN on oxidative stress, hepatocellular damage and inflammation in the acute phase of a murine model of warm I/R-injury.
Section snippets
Animal model of warm ischemia/reperfusion injury of the liver
Male BALB/c mice were purchased from Charles River Laboratories (Sulzfeld, Germany) at 8 weeks of age and housed in a 22 °C controlled room under a 12 h light–dark cycle with free access to food and water. After one week of acclimatization mice were fed either with standard diet (control) or standard diet supplemented with 0.5% (w/w) XN. XN was obtained from the Nookandeh Institute for Natural Chemicals (Homburg/Saar, Germany) with a purity ≥ 98% determined by HPLC. All chows were prepared by
Effect of xanthohumol on oxidative stress induced during the acute phase of hepatic ischemia–reperfusion
To assess the effect of XN on ischemia/reperfusion (I/R) injury, XN was applied orally to mice by supplementation of the standard diet with XN at a concentration of 5 mg/g chow starting 5 days prior to warm I/R. Previously we have shown that this XN-concentration in the chow did not affect food consumption of mice and led to a daily uptake of approximately 1 mg/g body weight (Dorn et al., 2010a). Since we aimed to assess the XN effect on the acute phase of hepatic I/R-injury mice were sacrificed 6
Discussion
The aim of this study was to investigate the effect of the prenylated chalcone xanthohumol (XN) on hepatic ischemia–reperfusion (I/R) injury, which is an important problem after liver transplantation and surgical resection (Bahde and Spiegel, 2010, Klune and Tsung, 2010). Based on the known pharmacological properties of XN we focused our analysis on the early phase of I/R-induced liver damage, which is characterized by ROS‐formation following reoxygenation (Parks and Granger, 1988, Rauen et
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
We want to thank Ruth Schewior and Marina Fink (Department of Internal Medicine I, University Hospital Regensburg) for the excellent technical assistance.
This project was supported in part by an unrestricted research grant from the Joh. Barth & Sohn GmbH (Nuremberg, Germany).
Financial relationships of the authors with Joh. Barth & Sohn GmbH are as follows: C.H. is a consultant, and C.D. is working in the laboratory of C.H.
S.M. and A.W. are employed by a Joh. Barth & Sohn subsidiary.
J.H. does
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