A method of three-dimensional branching geometry to differentiate the intrahepatic vascular type in early-stage liver fibrosis using X-ray phase-contrast CT.

Purpose: Differentiating the intrahepatic vascular type is essential for the early diagnosis of liver fibrosis. X-ray phase-contrast computed tomography (PCCT) is a label-free, high-resolution imaging modality for imaging vascular networks in a whole liver lobe. This study explores the use of three-dimensional (3D) branching geometry to differentiate between the hepatic vein (HV) and portal vein (PV) in early-stage liver fibrosis with PCCT.

Selective depletion of hepatic stellate cells-specific LOXL1 alleviates liver fibrosis.

The role of LOXL1 in fibrosis via mediating ECM crosslinking and stabilization is well established; however, the role of hepatic stellate cells (HSCs)-specific LOXL1 in the development of fibrosis remains unknown. We generated HSCs-specific Loxl1-depleted mice (Loxl1 mice) to investigate the HSCs-specific contribution of LOXL1 in the pathogenesis of fibrosis. Loxl1 mice were used as the control.

Dietary Inorganic Nitrate Protects Hepatic Ischemia-Reperfusion Injury Through NRF2-Mediated Antioxidative Stress.

Hepatic ischemia-reperfusion injury (HIRI) is of common occurrence during liver surgery and liver transplantation and may cause hepatic impairment, resulting in acute liver dysfunction. Nitrate plays an important physiological regulatory role in the human body. Whether dietary nitrate could prevent HIRI is, however, unknown.

CD4 derived double negative T cells prevent the development and progression of nonalcoholic steatohepatitis.

Hepatic inflammation is the driving force for the development and progression of NASH. Treatment targeting inflammation is believed to be beneficial. In this study, adoptive transfer of CD4 T cells converted double negative T cells (cDNT) protects mice from diet-induced liver fat accumulation, lobular inflammation and focal necrosis.

EGF neutralization antibodies attenuate liver fibrosis by inhibiting myofibroblast proliferation in bile duct ligation mice.

The expression of epidermal growth factor (EGF) is increased during liver fibrogenesis, and EGF receptor (EGFR) antagonist could attenuate liver fibrosis. Since EGFR is highly expressed by hepatocytes and cholangiocytes in cirrhotic liver, whether hepatic stellate cells express EGFR in response to EGF still needs exploration. Although EGFR antagonist could attenuate liver fibrosis, many ligands with EGF-like domains, besides EGF, can function through EGFR.

Critical role of OX40 in drug-induced acute liver injury.

Background And Purpose: The innate and adaptive immune systems both play important roles in drug-induced liver injury (DILI). However, the crosstalk between the innate and adaptive immunity in DILI is largely unknown. Extensive crosstalk is likely mandated by co-stimulatory interactions between these immune systems.

OX40 expression in neutrophils promotes hepatic ischemia/reperfusion injury.

Neutrophils play critical roles during the initial phase of hepatic ischemia/reperfusion injury (HIRI). However, the regulation of neutrophil activation, infiltration, and proinflammatory cytokine secretion has not been fully elucidated. In this study, we revealed that OX40 was expressed by neutrophils, its expression in neutrophils was time-dependently upregulated following HIRI, and Ox40 knockout markedly alleviated liver injury.

Double negative T cells mediate Lag3-dependent antigen-specific protection in allergic asthma.

Allergic asthma is an inflammatory disorder of the airway without satisfactory traditional therapies capable of controlling the underlying pathology. New approaches that can overcome the detrimental effects of immune dysregulation are thus desirable. Here we adoptively transfer ovalbumin (OVA) peptide-primed CD4CD8 double negative T (DNT) cells intravenously into a mouse model of OVA-induced allergic asthma to find that OVA-induced airway hyperresponsiveness, lung inflammation, mucus production and OVA-specific IgG/IgE production are significantly suppressed.

ECM1 Prevents Activation of Transforming Growth Factor β, Hepatic Stellate Cells, and Fibrogenesis in Mice.

Background & Aims: Activation of TGFB (transforming growth factor β) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers.

Methods: We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1).

OX40 Regulates Both Innate and Adaptive Immunity and Promotes Nonalcoholic Steatohepatitis.

Both innate and adaptive immune cells are involved in the pathogenesis of nonalcoholic steatohepatitis (NASH), but the crosstalk between innate and adaptive immunity is largely unknown. Here we show that compared with WT mice, OX40 mice exhibit decreased liver fat accumulation, lobular inflammation, and focal necrosis after feeding with diets that induce NASH. Mechanistically, OX40 deficiency suppresses Th1 and Th17 differentiation, and OX40 deficiency in T cells inhibits monocyte migration, antigen presentation, and M1 polarization.

Ox40 regulates the conversion and suppressive function of double-negative regulatory T cells.

Naïve CD4 T cells can be converted to double-negative regulatory T cells (DNT) by mature dendritic cells (mDCs) and IL-2 stimulation, with IL-2 enhancing the proliferation and Perforin expression of DNT. However, the molecules that affect the conversion of DNT are still not clear. Here, we investigated the effects of Ox40 on the conversion and function of DNT in vitro and in vivo without IL-2.

Diethyldithiocarbamate, an anti-abuse drug, alleviates steatohepatitis and fibrosis in rodents through modulating lipid metabolism and oxidative stress.

Background And Purpose: Diethyldithiocarbamate (DDC) is a major metabolite of disulfiram that is a potential drug for alcoholism treatment. In the present study, we attempted to explore the possible effect of DDC on non-alcoholic fatty liver disease (NAFLD) and related fibrosis in vivo.

Experimental Approach: C57BL/6 mice and Sprague Dawley (SD) rats received a methionine/choline-deficient (MCD) diet to establish the model of NAFLD with or without DDC treatment.

Critical role of OX40 in the expansion and survival of CD4 T-cell-derived double-negative T cells.

CD4 T-cell-converted CD4CD8 double negative (cDNT) have strong suppressive activity in the maintenance of immune tolerance, whereas IL-2 promotes cDNT proliferation and enhances cDNT resistance to apoptosis. However, the intrinsic mechanisms that regulate the survival of cDNT are still unknown. Here we demonstrate that the OX40 molecule was highly expressed on cDNT.

Efficacy and Safety of Wei Bi Mei, a Chinese Herb Compound, as an Alternative to Bismuth for Eradication of .

Bismuth-containing quadruple therapy has been recommended as the first line of treatment in areas of high clarithromycin or metronidazole resistance. However, safety concerns of bismuth agents have long been raised. We first assessed the efficacy and safety of Wei Bi Mei granules, which are bismuth compounds consisting of three synthetic drugs and five medicinal herbs, compared to bismuth aluminate and colloidal bismuth subcitrate (CBS) in -infected mouse model.

Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation.

Background: Although they are expandable in vitro, hepatic progenitors are immature cells and share many immunomarkers with hepatocellular carcinoma, raising potential concerns regarding maltransformation after transplantation. This study investigated the effects of hepatic nuclear factor (HNF) 4α on the proliferation, migration, and maltransformation of hepatic progenitors and determined the feasibility of using these manipulated cells for transplantation.

Methods: The effects of HNF4α on rat hepatic progenitors (i.

Supersonic Shear Wave Imaging of the Spleen for Staging of Liver Fibrosis in Rats.

The goal of the work described here was to explore the cause of spleen stiffness (SS) in hepatic fibrogenesis and evaluate the value of SS in liver fibrosis (LF) staging. LF was induced with carbon tetrachloride (CCl) in rats (n = 40). Supersonic shear wave imaging and contrast-enhanced ultrasound were performed to determine liver stiffness (LS), SS and splenic hemodynamics.

OX40 promotes obesity-induced adipose inflammation and insulin resistance.

Adaptive immunity plays a critical role in IR and T2DM development; however, the biological mechanisms linking T cell costimulation and glucose metabolism have not been fully elucidated. In this study, we demonstrated that the costimulatory molecule OX40 controls T cell activation and IR development. Inflammatory cell accumulation and enhanced proinflammatory gene expression, as well as high OX40 expression levels on CD4 T cells, were observed in the adipose tissues of mice with diet-induced obesity.

Berberine blocks the relapse of Clostridium difficile infection in C57BL/6 mice after standard vancomycin treatment.

Vancomycin is a preferred antibiotic for treating Clostridium difficile infection (CDI) and has been associated with a rate of recurrence of CDI of as high as 20% in treated patients. Recent studies have suggested that berberine, an alternative medical therapy for gastroenteritis and diarrhea, exhibits several beneficial effects, including induction of anti-inflammatory responses and restoration of the intestinal barrier function. This study investigated the therapeutic effects of berberine on preventing CDI relapse and restoring the gut microbiota in a mouse model.