Lactulose accelerates liver regeneration in rats by inducing hydrogen

Oxidative stress and inflammation are implicated in the process of liver regeneration. Lactulose orally administered can be bacterially fermented and induces dramatic amounts of endogenous hydrogen. Hydrogen has been confirmed to have antioxidant and anti-inflammatory properties. This study investigated the potential influence of lactulose administration on liver regeneration. Antibiotics were used to suppress bacterial fermentation of lactulose, and hydrogen-rich saline was used as a supplementary measure of exogenous hydrogen. The liver regeneration model was produced in Sprague-Dawley rats through 70% partial hepatectomy. Compared with non-lactulose-treated group, lactulose administration remarkably increased the weights of remnant liver and inhibited increases in serum levels of transaminases more notably. In the lactulose-treated group, increases of markers for regeneration, such as proliferating cell nuclear antigen and cyclin D1, were highly elevated. Biochemically, lactulose administration increased liver superoxide dismutase activity and decreased malondialdehyde content. In the lactulose-treated group, excessive increases in inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α, were inhibited significantly. Increased heme oxygenase-1 and superoxide dismutase 2 expression were also observed after lactulose treatment. The antibiotics suppressed the regeneration-promoting effect of lactulose by reducing hydrogen production, whereas supplementing hydrogen by hydrogen-rich saline would get a similar regeneration-promoting effect as lactulose administration. Lactulose administration accelerates posthepatectomized liver regeneration in rats by inducing hydrogen, which may result from attenuation of the oxidative stress response and excessive inflammatory response. Copyright © 2015 Elsevier Inc. All rights reserved.

Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic cholangiocytes by activating Nrf2 expression

Hypoxia/reoxygenation (H/R) injury of cholangiocytes causes serious biliary complications during hepatobiliary surgeries. Molecular hydrogen (H2) has been shown to be effective in protecting various cells and organs against oxidative stress injury. Human liver cholangiocytes were used to determine the potential protective effects of hydrogen against cholangiocyte H/R injury and explore the underlying mechanisms. We found that H2 ameliorated H/R-induced cholangiocytes apoptosis. Our study revealed that H2 activated NF-E2-related factor 2 (Nrf2) and downstream cytoprotective protein expression. However, the protective function of H2 was abolished when Nrf2 was silenced. Apoptosis in cholangiocytes isolated from a rat model of liver ischemia/reperfusion injury indicated that H2 significantly attenuates ischemia/reperfusion cholangiocyte injury in vivo. In conclusion, our study shows that H2 protects intrahepatic cholangiocytes from hypoxia/reoxygenation-induced apoptosis in vitro or in vivo, and this phenomenon may depend on activating Nrf2 expression.

Molecular hydrogen accelerates the reversal of acute obstructive cholangitis‑induced liver dysfunction by restoring gap and tight junctions

Gap junctions (GJs) and tight junctions (TJs) are essential to maintain the function of hepatocytes. Changes in biliary tract pressure and the effect of lipopolysaccharide (LPS) may lead to acute obstructive cholangitis (AOC) and cause liver injury via GJ and TJ dysfunction. Hydrogen has been confirmed to have a protective role in various organs during pathological conditions and inflammation. The present study investigated the function of junction proteins and the potential application of H2 in AOC‑induced liver injury. An AOC rat model was established by LPS injection through a bile duct catheter, while the distal bile duct was closed. The catheter sealing caps were removed and bile was allowed to flow out from the catheters at 12 h after LPS infusion. The potential application of H2 was studied in the AOC rat model with biliary drainage. It was observed that AOC induced the disruption of junction proteins of both GJs and TJs. H2 administration reversed AOC‑induced disruption of GJs and TJs after biliary drainage. The mechanism of this phenomenon suggests that H2 may have effectively attenuated AOC‑induced inflammatory and oxidative damage, and decreased matrix metalloproteinase activity. H2 may accelerate the reversal of AOC‑induced liver dysfunction, and this phenomenon may depend on reversing the inhibition of GJs and TJs.