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Abstract Background Alcohol-related liver disease (ALD) is a major health concern worldwide, but effective therapeutics for ALD are still lacking. Tumor necrosis factor-inducible gene 6 protein (TSG-6), a cytokine released from mesenchymal stem cells, was shown to reduce liver fibrosis and promote successful liver repair in mice with chronically damaged livers. However, the effect of TSG-6 and the mechanism underlying its activity in ALD remain poorly understood. Methods To investigate its function in ALD mice with fibrosis, male mice chronically fed an ethanol (EtOH)-containing diet for 9 weeks were treated with TSG-6 (EtOH + TSG-6) or PBS (EtOH + Veh) for an additional 3 weeks. Results Severe hepatic injury in EtOH-treated mice was markedly decreased in TSG-6-treated mice fed EtOH. The EtOH + TSG-6 group had less fibrosis than the EtOH + Veh group. Activation of cluster of differentiation 44 (CD44) was reported to promote HSC activation. CD44 and nuclear CD44 intracellular domain (ICD), a CD44 activator which were upregulated in activated HSCs and ALD mice were significantly downregulated in TSG-6-exposed mice fed EtOH. TSG-6 interacted directly with the catalytic site of MMP14, a proteolytic enzyme that cleaves CD44, inhibited CD44 cleavage to CD44ICD, and reduced HSC activation and liver fibrosis in ALD mice. In addition, a novel peptide designed to include a region that binds to the catalytic site of MMP14 suppressed CD44 activation and attenuated alcohol-induced liver injury, including fibrosis, in mice. Conclusions These results demonstrate that TSG-6 attenuates alcohol-induced liver damage and fibrosis by blocking CD44 cleavage to CD44ICD and suggest that TSG-6 and TSG-6-mimicking peptide could be used as therapeutics for ALD with fibrosis.

Liver disease: Inflammation-related receptor offers new drug target Drugs directed at a receptor protein implicated in the body’s inflammatory responses could help protect the liver against fibrosis, cancer and other disorders. Youngmi Jung and Chanbin Lee from Pusan National University, South Korea, review how the formyl peptide receptor (FPR) family of proteins plays important roles in mediating immune responses to infection, injury and stress. One such family member, FPR2, is particularly active in certain liver diseases, including non-alcoholic fatty liver disease and hepatocellular carcinoma. However, there is laboratory evidence linking FPR2 expression both to the production and suppression of disease-provoking inflammatory molecules, depending on the type of cell and signaling molecules that interact with FPR2. A better understanding of this dual mechanism of action could help drug developers design FPR2-targeted therapies that protect against liver injury and fibrosis.

Prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) higher in men than premenopausal women. Here the authors report that formyl peptide receptor 2 (FPR2) levels are regulated by estrogen, and that FPR2 contributes to NAFLD resistance in female mice.

Liver fibrosis is the most common feature of liver disease, and activated hepatic stellate cells (HSCs) are the main contributors to liver fibrosis. Thus, finding key targets that modulate HSC activation is important to prevent liver fibrosis. Previously, we showed that thymosin β4 (Tβ4) influenced HSC activation by interacting with the Hedgehog pathway in vitro. Herein, we generated Tβ4 conditional knockout (Tβ4-flox) mice to investigate in vivo functions of Tβ4 in liver fibrosis. To selectively delete Tβ4 in activated HSCs, double-transgenic (DTG) mice were generated by mating Tβ4-flox mice with α-smooth muscle actin (α-Sma)-Cre-ERT2 mice, and these mice were administered carbon tetrachloride (CCl4) or underwent bile duct ligation to induce liver fibrosis. Tβ4 was selectively suppressed in the activated HSCs of DTG mouse liver, and this reduction attenuated liver injury, including fibrosis, in both fibrotic models by repressing Hedgehog (Hh) signaling. In addition, the re-expression of Tβ4 by an adeno-associated virus reversed the effect of HSC-specific Tβ4 deletion and led to liver fibrosis with Hh activation in CCl4-exposed mice treated with tamoxifen. In conclusion, our results demonstrate that Tβ4 is a crucial regulator of HSC activation, suggesting it as a novel therapeutic target for curing liver fibrosis.

Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The therapeutic efficiency of current therapies for ALD is limited, and there is no FDA-approved therapy for ALD at present. Various strategies targeting pathogenic events in the progression of ALD are being investigated in preclinical and clinical trials. Recently, mesenchymal stem cells (MSCs) have emerged as a promising candidate for ALD treatment and have been tested in several clinical trials. MSC-released factors have captured attention, as they have the same therapeutic function as MSCs. Herein, we focus on current therapeutic options, recently proposed strategies, and their limitations in ALD treatment. Also, we review the therapeutic effects of MSCs and those of MSC-related secretory factors on ALD. Although accumulating evidence suggests the therapeutic potential of MSCs and related factors in ALD, the mechanisms underlying their actions in ALD have not been well studied. Further investigations of the detailed mechanisms underlying the therapeutic role of MSCs in ALD are required to expand MSC therapies to clinical applications. This review provides information on current or possible treatments for ALD and contributes to our understanding of the development of effective and safe treatments for ALD.

Extracellular vesicles (EVs) are membrane-bound endogenous nanoparticles released by the majority of cells into the extracellular space. Because EVs carry various cargo (protein, lipid, and nucleic acids), they transfer bioinformation that reflects the state of donor cells to recipient cells both in healthy and pathologic conditions, such as liver disease. Chronic liver disease (CLD) affects numerous people worldwide and has a high mortality rate. EVs released from damaged hepatic cells are involved in CLD progression by impacting intercellular communication between EV-producing and EV-receiving cells, thereby inducing a disease-favorable microenvironment. In patients with CLD, as well as in the animal models of CLD, the levels of released EVs are elevated. Furthermore, these EVs contain high levels of factors that accelerate disease progression. Therefore, it is important to understand the diverse roles of EVs and their cargoes to treat CLD. Herein, we briefly explain the biogenesis and types of EVs and summarize current findings presenting the role of EVs in the pathogenesis of CLD. As the role of microRNAs (miRNAs) within EVs in liver disease is well documented, the effects of miRNAs detected in EVs on CLD are reviewed. In addition, we discuss the therapeutic potential of EVs to treat CLD.

Background/Aims: Malaria is the most deadly parasitic infection in the world, resulting in damage to various organs, including the liver, of the infected organism; however, the mechanism causing this damage in the liver remains unclear. Liver fibrosis, a major characteristic of liver diseases, occurs in response to liver injury and is regulated by a complex network of signaling pathways. Hedgehog (Hh) signaling orchestrates a number of hepatic responses including hepatic fibrogenesis. Therefore, we investigated whether Hh signaling influenced the liver’s response to malarial infection. Methods: Eight-week-old male C57BL/6 mice inoculated with blood containing Plasmodium berghei ANKA (PbA)-infected erythrocytes were sacrificed when the level of parasitemia in the blood reached 10% or 30%, and the livers were collected for biochemical analysis. Liver responses to PbA infection were examined by hematoxylin and eosin staining, real-time polymerase chain reaction, immunohistochemistry and western blot. Results: Severe hepatic injury, such as ballooned hepatocytes, sinusoidal dilatation, and infiltrated leukocytes, was evident in the livers of the malaria-infected mice. Hypoxia was also induced in 30% parasitemia group. With the accumulation of Kupffer cells, inflammation markers, TNF-α, interleukin-1β, and chemokine (C-X-C motif) ligand 1, were significantly upregulated in the infected group compared with the control group. Expression of fibrotic markers, including transforming growth factor-β, α-smooth muscle actin (α-SMA), collagen 1a1, thymosin β4, and vimentin, were significantly higher in the infected groups than in the control group. With increased collagen deposition, hepatic stellate cells expressing α-SMA accumulated in the liver of the PbA-infected mice, whereas those cells were rarely detected in the livers of the control mice. The levels of Hh signaling and Yes-associated protein (YAP), two key regulators for hepatic fibrogenesis, were significantly elevated in the infected groups compared with the control group. Treatment of mice with Hh inhibitor, GDC-0449, reduced hepatic inflammation and fibrogenesis with Hh suppression in PbA-infected mice. Conclusion: Our results demonstrate that HSCs are activated in and Hh and YAP signaling are associated with this process, contributing to increased hepatic fibrosis in malaria-infected livers.

Liver fibrosis is a common feature of chronic liver disease. Activated hepatic stellate cells (HSCs) are the main drivers of extracellular matrix accumulation in liver fibrosis. Hence, a strategy for regulating HSC activation is crucial in treating liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent stem cells derived from various post-natal organs. Therapeutic approaches involving MSCs have been studied extensively in various diseases, including liver disease. MSCs modulate hepatic inflammation and fibrosis and/or differentiate into hepatocytes by interacting directly with immune cells, HSCs, and hepatocytes and secreting modulators, thereby contributing to reduced liver fibrosis. Cell-free therapy including MSC-released secretomes and extracellular vesicles has elicited extensive attention because they could overcome MSC transplantation limitations. Herein, we provide basic information on hepatic fibrogenesis and the therapeutic potential of MSCs. We also review findings presenting the effects of MSC itself and MSC-based cell-free treatments in liver fibrosis, focusing on HSC activation. Growing evidence supports the anti-fibrotic function of either MSC itself or MSC modulators, although the mechanism underpinning their effects on liver fibrosis has not been established. Further studies are required to investigate the detailed mechanism explaining their functions to expand MSC therapies using the cell itself and cell-free treatments for liver fibrosis.

Abstract The molecular mechanisms of thymosin beta-4 (TB4) involved in regulating hepatic stellate cell (HSC) functions remain unclear. Therefore, we hypothesize that TB4 influences HSC activation through hedgehog (Hh) pathway. HSC functions declined in a TB4 siRNA-treated LX-2. TB4 suppression down-regulated both integrin linked kinase (ILK), an activator of smoothened, and phosphorylated glycogen synthase kinase 3 beta (pGSK-3B), an inactive form of GSK-3B degrading glioblastoma 2 (GLI2), followed by the decreased expression of both smoothened and GLI2. A TB4 CRISPR also blocked the activation of primary HSCs, with decreased expression of smoothened, GLI2 and ILK compared with cells transfected with nontargeting control CRISPR. Double immunostaining and an immunoprecipitation assay revealed that TB4 interacted with either smoothened at the cytoplasm or GLI2 at the nucleus in LX-2. Smoothened suppression in primary HSCs using a Hh antagonist or adenovirus transduction decreased TB4 expression with the reduced activation of HSCs. Tb4-overexpressing transgenic mice treated with CCl4 were susceptible to the development hepatic fibrosis with higher levels of ILK, pGSK3b, and Hh activity, as compared with wild-type mice. These findings demonstrate that TB4 regulates HSC activation by influencing the activity of Smoothened and GLI2, suggesting TB4 as a novel therapeutic target in liver disease.

Nonalcoholic fatty liver disease (NAFLD) caused by fat accumulation in the liver is globally the most common cause of chronic liver disease. Simple steatosis can progress to nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD. The most potent driver for NASH is hepatocyte death induced by lipotoxicity, which triggers inflammation and fibrosis, leading to cirrhosis and/or liver cancer. Despite the significant burden of NAFLD, there is no therapy for NAFLD/NASH. Accumulating evidence indicates gender-related NAFLD progression. A higher incidence of NAFLD is found in men and postmenopausal women than premenopausal women, and the experimental results, showing protective actions of estradiol in liver diseases, suggest that estrogen, as the main female hormone, is associated with the progression of NAFLD/NASH. However, the mechanism explaining the functions of estrogen in NAFLD remains unclear because of the lack of reliable animal models for NASH, the imbalance between the sexes in animal experiments, and subsequent insufficient results. Herein, we reviewed the pathogenesis of NAFLD/NASH focused on gender and proposed a feasible association of estradiol with NAFLD/NASH based on the findings reported thus far. This review would help to expand our knowledge of the gender differences in NAFLD and for developing gender-based treatment strategies for NAFLD/NASH.

Even though a patterned sapphire substrate (PSS) has been used for the growth of a high-quality epilayer because of its many advantages, it has not been successfully used to grow an AlN epilayer for ultraviolet (UV) light-emitting diodes (LEDs) on a PSS up to now. We report the growth of a high-quality AlN epilayer on a PSS, as a substrate for the manufacture of UV LEDs, by hydride vapor phase epitaxy (HVPE). The X-ray diffraction (XRD) peaks for the AlN epilayer grown on the PSS indicate that crystalline AlN with a wurtzite structure was grown successfully on the PSS. Furthermore, HVPE combining both in situ HVPE technology and liquid-phase epitaxy (LPE) using a mixed source is proposed as a novel method for the growth of a flat AlN epilayer on a PSS. [ABSTRACT FROM AUTHOR]