Alleviation of Hepatic Steatosis by 4-azidophlorizin via the Degradation of Geranylgeranyl Diphosphate Synthase by the Ubiquitin-Proteasome Pathway in Vivo and in Vitro.

There are no known approved pharmacotherapies for non-alcoholic fatty liver disease (NAFLD) in the clinical setting. Although studies have provided substantial evidence that geranylgeranyl diphosphate synthase (GGPPS) is a potential therapeutic target for the treatment of NAFLD corresponding drug screening is rare. A GGPPS-targeted inhibitor is identified using a structure-based virtual small molecule screening method.

Serum proteome profiling reveals differentially expressed proteins between subjects with metabolically healthy obesity and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the leading risk factor for common chronic liver disease and is often regarded as a prevalent metabolic disorder tightly associated with obesity. However, the existence of metabolically healthy obesity (MHO) indicates that some important factors may participate in protecting individuals with MHO free of NAFLD, even with excessive adiposity. To explore factors independent of obesity that may be involved in the occurrence of NAFLD, we performed an iTRAQ-based proteomic study to identify proteins differentially expressed in serum between NAFLD and MHO subjects.

WIPI2 depletion inhibits the growth of hepatocellular carcinoma cells through the AMPK signaling pathway.

WD‑repeat domain phosphoinositide‑interacting protein 2 (WIPI2) is a protein that regulates the assembly of multiprotein complexes by presenting a beta‑propeller platform for simultaneous and reversible protein‑protein interactions. This study was designed to investigate the association between the expression of WIPI2 and the growth of hepatocellular carcinoma (HCC). Publicly‑available data from the UALCAN platform revealed that WIPI2 is upregulated in tumor tissues compared with that noted in normal tissues in many types of tumors especially in HCC, and high WIPI2 expression predicts a poor patient prognosis.

Protective Properties of FOXO1 Inhibition in a Murine Model of Non-alcoholic Fatty Liver Disease Are Associated With Attenuation of ER Stress and Necroptosis.

Aim: The pathogenesis of non-alcoholic fatty liver disease is currently unclear, however, lipid accumulation leading to endoplasmic reticulum stress appears to be pivotal in the process. At present, FOXO1 is known to be involved in NAFLD progression. The relationship between necroptosis and non-alcoholic steatohepatitis has been of great research interest more recently.

Zoledronic acid inhibits TSC2-null cell tumor growth via RhoA/YAP signaling pathway in mouse models of lymphangioleiomyomatosis.

Background: This study is to investigate the effects of zoledronic acid (ZA) on TSC2-null cell proliferation and on the tumor progression and recurrence in mouse models of lymphangioleiomyomatosis (LAM).

Methods: Subcutaneous mouse models and LAM mouse models were established. Immunohistochemistry and immunofluorescence were performed to detect the protein expression levels.

Proteomic analysis to identify differentially expressed proteins between subjects with metabolic healthy obesity and non-alcoholic fatty liver disease.

Obese subjects with non-alcoholic fatty liver disease (NAFLD) and considered metabolically healthy have not been well differentiated. In this study, obese subjects were divided into metabolic healthy obesity (MHO) and NAFLD groups. Liver tissues were sampled from these two types of subjects undergoing bariatric surgery, and proteins in the liver tissues that expressed differently between the two groups of subjects were identified by Tandem Mass Tags (TMT) assay.

Liver governs adipose remodelling via extracellular vesicles in response to lipid overload.

Lipid overload results in lipid redistribution among metabolic organs such as liver, adipose, and muscle; therefore, the interplay between liver and other organs is important to maintain lipid homeostasis. Here, we show that liver responds to lipid overload first and sends hepatocyte-derived extracellular vesicles (EVs) targeting adipocytes to regulate adipogenesis and lipogenesis. Geranylgeranyl diphosphate synthase (Ggpps) expression in liver is enhanced by lipid overload and regulates EV secretion through Rab27A geranylgeranylation.

ER-stress regulates macrophage polarization through pancreatic EIF-2alpha kinase.

During the process of NAFLD progression, ER-stress is activated in macrophages and induces the pro-inflammatory polarization of macrophage. As one of the three ER membrane resident proteins, pancreatic eIF-2alpha kinase (PERK) plays an important role in ER stress, but its participation in macrophage polarization is largely unknown. In this study, we found that the PA mediated ER-stress activation could induce M1-type polarization in macrophages, and this phenotype polarization could be inhibited by ER-stress inhibitor 4-PBA as well as GSK2656157, an inhibitor of PERK.

Prostaglandin E secreted by mesenchymal stem cells protects against acute liver failure via enhancing hepatocyte proliferation.

Bone marrow-derived mesenchymal stem cells (MSCs) have been recently used in clinical trials as treatment for liver diseases. However, the underlying mechanism of their effectiveness remains largely unexplored. In the present study, we confirmed that the protective effects of MSCs on mouse model of acute liver failure (ALF) were based on MSC-secreted prostaglandin (PG)E.

IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells.

Fatty liver is one of the widely accepted marginal donor for liver transplantation, but is also more sensitive to ischemia and reperfusion injury (IRI) and produces more reactive oxygen species (ROS). Moreover, so far, no effective method has been developed to alleviate it. Endoplasmic reticulum stress (ER-stress) of hepatocyte is associated with the occurrence of fatty liver disease, but ER-stress of kupffer cells (KCs) in fatty liver is not clear at all.

Mesenchymal Stem Cells Enhance Liver Regeneration via Improving Lipid Accumulation and Hippo Signaling.

The liver has the potential to regenerate after injury. It is a challenge to improve liver regeneration (LR) after liver resection in clinical practice. Bone morrow-derived mesenchymal stem cells (MSCs) have shown to have a role in various liver diseases.

MicroRNA-122 Inhibits Lipid Droplet Formation and Hepatic Triglyceride Accumulation via Yin Yang 1.

Background/aims: An increase in intracellular lipid droplet formation and hepatic triglyceride (TG) content usually results in nonalcoholic fatty liver disease. However, the mechanisms underlying the regulation of hepatic TG homeostasis remain unclear.

Methods: Oil red O staining and TG measurement were performed to determine the lipid content.

Interleukin-10 secreted by mesenchymal stem cells attenuates acute liver failure through inhibiting pyroptosis.

Aim: Recently, the benefit of mesenchymal stem cells (MSCs) as a cell-based therapy for acute liver failure (ALF) has gained much attention, although the mechanism of action of MSCs in the treatment of ALF remains elusive. Pyroptosis is a novel form of programmed cell death with an intense inflammatory response. The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects through inhibiting pyroptosis in ALF.

USP39 regulates the growth of SMMC-7721 cells via FoxM1.

The present study investigated ubiquitin specific peptidase 39 (USP39) gene knockdown on SMMC-7721 cells and , and the role of USP39 in regulating the growth of hepatocellular carcinoma (HCC). Two small interfering RNAs (siRNA) were constructed, which targeted the USP39 gene and control sequences were synthesized and inserted into a pGCSIL-GFP lentiviral vector. The full length of USP39 cDNA was amplified by polymerase chain reaction (PCR) and cloned into pEGFP-N2, and the recombinant plasmids were transfected into cells.

USP39 promotes colorectal cancer growth and metastasis through the Wnt/β-catenin pathway.

In the present study, we first examined the expression of USP39 protein using tissue array containing 90 colorectal cancer (CRC) tissues and 9 clinical samples, and observed that it has significantly higher expression in cancer tissues as compared to the corresponding adjacent normal tissues. Also, we tested USP39 expression level in four CRC cancer cell lines and identified that it indeed had higher expression in all these CRC cell lines. In addition, its knockdown inhibited not only the cell growth of SW480 and HT29 cells, but also the cell migration and invasion.

Combined treatment with MSC transplantation and neutrophil depletion ameliorates D-GalN/LPS-induced acute liver failure in rats.

Background: The imbalance of immunity is an important pathogenesis of acute liver failure (ALF). Neutrophils are the hallmark of acute inflammation, which have an essential role in immune regulation. Mesenchymal stem cell (MSC) transplantation is a promising therapy in ALF treatment.

Interleukin-10 Contributes to Therapeutic Effect of Mesenchymal Stem Cells for Acute Liver Failure via Signal Transducer and Activator of Transcription 3 Signaling Pathway.

Background: Mesenchymal stem cells (MSCs) transplantation has been proven to have therapeutic potential for acute liver failure (ALF). However, the mechanism remains controversial. Recently, modulation of inflammation by MSCs has been regarded as a crucial mechanism.

IL-1β siRNA adenovirus benefits liver regeneration by improving mesenchymal stem cells survival after acute liver failure.

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Background: Uncontrolled hapatic inflammatory response is regarded as the primary pathological mechanism of acute liver failure and impairs the regeneration of hepatocytes and stem cell grafts. Interleukin-1 plays a key role for activating immune and inflammatory response. Recently, siRNA has made quite a few progresses in treating inflammatory response.

No transmission of porcine endogenous retrovirus in an acute liver failure model treated by a novel hybrid bioartificial liver containing porcine hepatocytes.

Background: A novel hybrid bioartificial liver (HBAL) was constructed using an anionic resin adsorption column and a multi-layer flat-plate bioreactor containing porcine hepatocytes co-cultured with bone marrow mesenchymal stem cells (MSCs). This study aimed to evaluate the microbiological safety of the HBAL by detecting the transmission of porcine endogenous retroviruses (PERVs) into canines with acute liver failure (ALF) undergoing HBAL.

Methods: Eight dogs with ALF received a 6-hour HBAL treatment on the first day after the modeling by D-galactosamine administration.

USP39 promotes the growth of human hepatocellular carcinoma in vitro and in vivo.

Ubiquitin specific protease 39 (USP39) plays an important role in mRNA splicing. In the present study, we investigated the role of USP39 in regulating the growth of hepatocellular carcinoma (HCC). We detected USP39 expression in more than 100 HCC clinical samples.

Targeted migration of mesenchymal stem cells modified with CXCR4 to acute failing liver improves liver regeneration.

Aim: To improve the colonization rate of transplanted mesenchymal stem cells (MSCs) in the liver and effect of MSC transplantation for acute liver failure (ALF).

Methods: MSC was modified with the chemokine CXC receptor 4 (CXCR4) gene (CXCR4-MSC) or not (Null-MSC) through lentiviral transduction. The characteristics of CXCR4-MSCs and Null-MSCs were determined by real-time quantitative polymerase chain reaction, Western blotting and flow cytometry.

Evaluation of two decellularization methods in the development of a whole-organ decellularized rat liver scaffold.

Aim: Hepatic tissue engineering is considered as a possible alternative to liver transplantation for end-stage liver disease. Several methods of decellularization of xenogeneic liver are available to produce three-dimensional organ scaffolds for engineering liver tissues. However, rare studies have examined and compared the effectiveness of different methods on the structure and composition of intact decellularized liver extracellular matrix.

Endothelial precursor cells promote angiogenesis in hepatocellular carcinoma.

Aim: To investigate the role of bone marrow-derived endothelial progenitor cells (EPCs) in the angiogenesis of hepatocellular carcinoma (HCC).

Methods: The bone marrow of HCC mice was reconstructed by transplanting green fluorescent protein (GFP) + bone marrow cells. The concentration of circulating EPCs was determined by colony-forming assays and fluorescence-activated cell sorting.

The mobilization, recruitment and contribution of bone marrow-derived endothelial progenitor cells to the tumor neovascularization occur at an early stage and throughout the entire process of hepatocellular carcinoma growth.

Obvious neovascularization is a key feature of hepatocellular carcinoma (HCC) and the status of neovascularization in HCC is closely correlated with the tumor growth and patient prognosis. The actual effect of current antivascular treatment including embolization to HCC is not satisfactory. Compensatory angiogenesis is one of the primary causes responsible for failure of antiangiogenic therapy.