Nano-designed carbon monoxide donor SMA/CORM2 exhibits protective effect against acetaminophen induced liver injury through macrophage reprograming and promoting liver regeneration.

Acetaminophen (APAP) induced liver injury is the most common drug-induced liver injury, accounting for the top cause of acute liver failure in the United State, however the therapeutic options for it is very limited. Excess generation of reactive oxygen species (ROS) and the subsequent inflammatory responses are the major factors of the liver injury. Carbon monoxide (CO) is an important gaseous molecule with versatile functions including anti-oxidation and anti-inflammation, and we previous reported the therapeutic potential of a nano-designed CO donor SMA/CORM2 in a dextran sulphate sodium (DSS) induced mouse colitis model. In this context, we investigated the effect of SMA/CORM2 in an APAP-induced mouse acute liver injury model and tackled the mechanisms involved. We found upregulation of heme oxygenase-1 (HO-1, endogenous CO generating enzyme) and the dynamic changes of macrophage polarization (pro-inflammatory M1/anti-inflammatory M2), which played important roles in the process of live injury. SMA/CORM2 treatment remarkably increased the CO levels in the liver and circulation, by which oxidative stresses in the liver were significantly reduced, and more importantly, it remarkably suppressed the expression of M1 macrophages but alternatively increased M2 polarization. Consequently the liver injury was significantly ameliorated, and the proliferation and regeneration were greatly promoted through the Pi3k/Akt/mTOR signaling pathway. The shift of macrophage polarization accompanied with the downregulated hypoxia-inducible factor-1α (HIF-1α) level. These findings suggested CO released from SMA/CORM2 manipulated the macrophage reprogramming toward M2 phenotype by inhibiting HIF-1α, which subsequently protected liver against inflammatory injury and benefited tissue repair. Moreover, compared to native CORM2, SMA/CORM2 exhibited superior bioavailability and protective effect. We thus anticipate the application of SMA/CORM2 as a therapeutic regimen for APAP induced liver injury as well as other inflammatory diseases and disorders.

The protective effect of obeticholic acid on lipopolysaccharide-induced disorder of maternal bile acid metabolism in pregnant mice.

The disorder of bile acid metabolism is a common feature during pregnancy, which leads to adverse birth outcomes and maternal damage effects. However, the cause and therapy about the disorder of bile acid metabolism are still poor. Microbial infection often occurs in pregnant women, which can induce the disorder of bile acid metabolism in adult mice. Here, this study observed the acute effect of lipopolysaccharide (LPS) on maternal bile acid of pregnant mice at gestational day 17 and the protective effect of obeticholic acid (OCA) pretreatment, a potent agonist of bile acid receptor farnesoid X receptor (FXR). The results showed LPS significantly increased the level of maternal serum and disordered bile acids components of maternal serum and liver, which were ameliorated by OCA pretreatment with obviously reducing the contents of CA, TCA, DCA, TCDCA, CDCA, GCA and TDCA in maternal serum and DCA, TCA, TDCA, TUDCA, CDCA and TCDCA in maternal liver. Furthermore, we investigated the effects of OCA on LPS-disrupted bile acid metabolism in maternal liver. LPS disrupted maternal bile acid profile by decreasing transport and metabolism with hepatic tight junctions of bile acid in pregnant mice. OCA obviously increased the protein level of nuclear FXR and regulated its target genes involving in the metabolism of bile acid, which was characterized by the lower expression of bile acid synthase CYP7A1, the higher expression of CYP3A and the higher mRNA level of transporter Mdr1a/b. This study provided the evidences that LPS disrupted bile acid metabolism in the late stage of pregnant mice and OCA pretreatment played the protective role on it by activating FXR.

Inositol-Requiring Enzyme 1 Alpha Endoribonuclease Specific Inhibitor STF-083010 Alleviates Carbon Tetrachloride Induced Liver Injury and Liver Fibrosis in Mice.

Accumulating data demonstrated that hepatic endoplasmic reticulum (ER) stress was involved in the pathogenesis of liver fibrosis. Long-term chronic hepatocyte death contributed to liver fibrosis initiation and progression. Previous researches reported that ER stress sensor inositol-requiring enzyme 1 alpha (IRE1α) was first activated in the process of liver fibrosis. STF-083010 was an IRE1α RNase specific inhibitor. This study aimed to explore the effects of STF-083010 on carbon tetrachloride (CCl4)-induced liver injury and subsequent liver fibrosis. Mice were intraperitoneally (i.p.) injected with CCl4 (0.15 ml/kg) for 8 weeks. In STF-083010+CCl4 group, mice were injected with STF-083010 (30 mg/kg, i.p.), twice a week, beginning from the 6th week after CCl4 injection. CCl4 treatment markedly enhanced the levels of serum ALT, TBIL, DBIL and TBA, and STF-083010 had obviously extenuated CCl4-induced exaltation of ALT, DBIL, and TBA levels. CCl4-induced hepatic hydroxyproline and collagen I, major indicators of liver fibrosis, were alleviated by STF-083010. Additionally, CCl4-induced α-smooth muscle actin, a marker for hepatic stellate cells activation, was obviously attenuated in STF-083010-treated mice. Moreover, CCl4-induced upregulation of inflammatory cytokines was suppressed by STF-083010. Mechanistic exploration found that hepatic miR-122 was downregulated in CCl4-treated mice. Hepatic MCP1, CTGF, P4HA1, Col1α1, and Mmp9, target genes of miR-122, were upregulated in CCl4-treated mice. Interestingly, STF-083010 reversed CCl4-induced hepatic miR-122 downregulation. Correspondingly, STF-083010 inhibited CCl4-induced upregulation of miR-122 target genes. This study provides partial evidence that STF-083010 alleviated CCl4-induced liver injury and thus protected against liver fibrosis associated with hepatic miR-122.