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• Hepatocytes secrete Gal-9 to attenuate intrahepatic production of Th1 cytokines in AIH. • Gal-9 suppresses intrahepatic T cell activation through Tim-3 during AIH induction. • Gal-9 promotes Foxp3 expression and Treg function through TL1A but not TGF-β in AIH. • Gal-9 hinders the increase of activated T cells in liver in a Tim-3-independent way. • TLR2/4 ligands attenuate the effects of Gal-9 by increasing intrahepatic IL-6 and IL-12. Hepatocytes are the targets in autoimmune hepatitis (AIH) that results in T cell-dependent liver injury. However, hepatocytes may also affect the hepatic T cells in AIH, but the underlying mechanisms are not fully understood. Here we report that hepatocytes could secrete galectin-9 (Gal-9) to suppress the intrahepatic production of Th1 cytokine IFN-γ and restrict AIH development, but hepatocyte damage resulted in opposite effects due to release of TLR2/4 ligands that promoted the intrahepatic production of IL-1β, IL-6, and IL-12. Through Tim-3, Gal-9 could efficiently suppress the intrahepatic T cell activation despite presence of TLR2/4 ligands, thus attenuating Th1 response in AIH. Intriguingly, intrahepatic IL-6/IL-12 suppressed the effect of TGF-β on Treg cells. Therefore, in AIH, Gal-9 promoted Foxp3 expression and function of hepatic Treg cells through TL1A signaling, although Treg function was still impaired, compared with that in naive state. Due to its promoting effect on Treg function, together with its effect on T effector cells in a Tim-3-independent way, Gal-9 could attenuate intrahepatic IFN-γ production by hindering the increase of hepatic CD4+CD43+ T cells resulting from extrahepatic T cell activation. TLR2/4 ligands attenuated the effects of Gal-9 on Treg cells and CD4+CD43+ T cells by increasing intrahepatic IL-6 and IL-12. Blocking TLR2/4 ligands could efficiently suppress intrahepatic IFN-γ production, liver injury, and hepatic fibrosis. These findings suggest that hepatocytes paradoxically affect Th1 response in AIH due to Gal-9 expression and TLR2/4 ligands release, and that targeting TLR2/4 signaling may provide an important approach in the therapeutic strategy for AIH. [ABSTRACT FROM AUTHOR]

Abstract T cell-dependent liver injury is an important reason for the massive hepatic damage and cirrhosis. So far it is unclear whether the development of the disease could be efficiently suppressed by anti-inflammatory cytokine that modulates innate immune cells. Here we report that anti-inflammatory cytokine IL-37 could efficiently suppress the sustained hepatic expression of IFN-γ and TNF-α, two critical cytokines for inducing hepatocyte apoptosis and liver fibrosis in T cell-dependent liver injury. IL-37 could directly suppress IFN-γ/TLR4 ligand-induced M1 activation of macrophages, thus reducing the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-12. Moreover, IL-37 attenuated Th1 response in vivo and increased the expression of Th2 cytokines IL-4 and IL-13, which in turn promoted M2 activation of macrophages in the liver. The increase of M2 activation not only further reduced TNF-α, IL-1β and IL-12 expression, but also increased IL-10 and IL-1Ra expression in macrophages, thus more efficiently suppressing the hepatic IFN-γ expression. By suppressing IFN-γ/TNF-α expression, IL-37 suppressed the up-regulation and activation of MLKL that drives hepatocellular necrosis in T cell-dependent liver damage. Accordingly, IL-37 efficiently reduced liver injury and hepatic inflammation after the repeated ConA challenge and the induction of autoimmune hepatitis, and also suppressed hepatic fibrosis resulting from the sustained liver damage. This study showed that the direct and indirect effect of IL-37 on macrophages could reduce the hepatic TNF-α expression, and also modulate IL-1β/IL-12 and IL-10/IL-1Ra expression to suppress the hepatic IFN-γ expression, thus suppressing the development of T cell-dependent liver injury such as autoimmune hepatitis. Highlights • IL-37 suppresses M1 activation of macrophages to reduce hepatic production of TNF-α. • IL-37 alters Th1/Th2 responses to increase M2 activation of hepatic macrophages. • IL-37 reduces IL-1β/IL-12 and increases IL-10/IL-1Ra to reduce IFN-γ in the liver. • IL-37 suppresses the up-regulation and activation of MLKL by reducing IFN-γ/TNF-α. • IL-37 efficiently suppresses the sustained liver injury and hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Relationship between pKa of organic acid and TOF of co-catalysis was explored. • Oxalic acid (pKa = 1.25) gave the maximum TOF value (6.26 h−1). • Furfural was synthesized from D- xylose with oxalic acid plus SO 4 2−/SnO 2 -argil. • High furfural yield (50.8%) from D- xylose (50 g/L) was achieved. • An effective approach for one-pot synthesis of FOL from D -xylose was demonstrated. Abstract In this study, organic acid could be used as co-catalyst for assisting solid acid SO 4 2−/SnO 2 -argil to convert hemicellulose-derived D -xylose into furfural. The relationship between pKa of organic acid and turnover frequency (TOF) of co-catalysis with organic acid plus SO 4 2−/SnO 2 -argil was explored on the conversion of D- xylose to furfural. Oxalic acid (pKa = 1.25) (0.35 wt%) was found to be the optimum co-catalyst for assisting SO 4 2−/SnO 2 -argil (3.6 wt%) to synthesize furfural from D- xylose (20 g/L) at 180 °C for 20 min, and the furfural yield and TOF could be obtained at 57.07% and 6.26 h−1, respectively. Finally, the obtained furfural (107.6 mM) could be completely biotransformed to furfuralcohol by recombinant Escherichia coli CCZU-K14 whole-cells at 30 °C and pH 6.5 in the presence of 1.5 mol glucose/mol furfural and 400 mM D -xylose. Clearly, this strategy shows high potential application for the effective synthesis of furfuralcohol from biomass-derived D -xylose. [ABSTRACT FROM AUTHOR]

Summary Background & aims Non-alcoholic fatty liver disease (NAFLD) is a common and strong risk factor for cardiovascular disease and hepatocellular carcinoma. The rapid acceleration of the increase in NAFLD prevalence has exceeded the trends observed for obesity, and has been driven by multiple factors. The aim of this study was to investigate the correlation between the serum levels of folic acid, the endogenous source of methyl groups for DNA methylation, and NAFLD in Chinese adults. Methods The correlations between the serum folic acid levels and NAFLD were investigated in two independent cohorts of 70 subjects who underwent a liver biopsy and 130 subjects with varying liver fat contents, as measured using proton magnetic resonance spectroscopy (1H-MRS). Independent correlations between serum folic acid levels and liver steatosis grades were detected using a multivariate ordinal regression analysis. The diagnostic performances of serum folic acid levels alone and in combination with existing NAFLD prediction scores were compared with those of traditional NAFLD prediction parameters using receiver operating characteristic (ROC) curve analyses. Results Serum folic acid concentrations were inversely correlated with liver histological steatosis grades (ρ = −0.371, P < 0.001) and the 1H-MRS-measured liver fat content (r = −0.199, P = 0.038). According to the multivariate ordinal regression analysis, serum folic acid levels were inversely correlated with liver steatosis grades (OR 0.739 [0.594–0.918], P = 0.006) independent of age, gender, BMI, components of metabolic syndrome and the serum TC, LDL-c and HOMA-IR levels. The AUROC of serum folic acid for the diagnosis of NAFLD was 0.75 (0.65–0.83), and the addition of serum folic acid to NAFLD prediction scores significantly improved the diagnostic prediction of NAFLD (AUROC = 0.88 [0.81–0.94]). Conclusion Low serum folic acid levels were identified as an independent risk factor for NAFLD in the Chinese population. The addition of the serum folic acid levels to the current existing NAFLD prediction scores significantly improved the prediction of NAFLD. [ABSTRACT FROM AUTHOR]