Interferon-ß Overexpression in Adipose Tissue-Derived Stem Cells Induces HepG2 and Macrophage Cell Death in Liver Tumor Organoids via Induction of TNF-Related Apoptosis-Inducing Ligand Expression.

Liver tumor organoids derived from liver tumor tissues and pluripotent stem cells are used for liver tumor research but have several challenges in primary cell isolation and stem cell differentiation. Here, we investigated the potential of HepG2-based liver tumor organoids for screening anticancer drugs by evaluating their responsiveness to IFN-ß produced by mesenchymal stem cells (MSCs). Liver tumor organoids were prepared in three days on Matrigel using HepG2, primary liver sinusoidal epithelial cells (LSECs), LX-2 human hepatic stellate cells, and THP-1-derived macrophages at a ratio of 4:4:1:1, with 105 total cells. Hepatocyte-related and M2 macrophage-associated genes increased in liver tumor organoids. IFN-ß treatment decreased the viability of liver tumor organoids and increased M1 macrophage marker expression (i.e., TNF-α and iNOS) and TRAIL. TRAIL expression was increased in all four cell types exposed to IFN-ß, but cell death was only observed in HepG2 cells and macrophages. Further, MSCs overexpressing IFN-ß (ASC-IFN-ß) also expressed TRAIL, contributing to the reduced viability of liver tumor organoids. In summary, IFN-ß or ASC-IFN-ß can induce TRAIL-dependent HepG2 and macrophage cell death in HepG2-based liver tumor organoids, highlighting these liver tumor organoids as suitable for anticancer drug screening and mechanistic studies.

Subclinical diabetes confirmed by 75-g OGTT influence on the prognosis of decompensated cirrhosis.

BACKGROUND AND AIM: Disorders of glucose metabolism, such as impaired glucose tolerance (IGT) and diabetes mellitus (DM), frequently occur in cirrhosis. We aimed to evaluate who needs to be undertaken a 75-g oral glucose tolerance test (OGTT) to find underlying subclinical diabetes. METHODS: This prospective study included 713 patients with either compensated (Child-Turcotte-Pugh [CTP] class A) or decompensated cirrhosis (CTP class B/C) without previous DM history. All patients underwent a 75-g OGTT. The patients were divided into three groups: normal glucose tolerance (NGT), IGT, and newly diagnosed DM (subclinical DM). RESULTS: Among 713 patients, NGT was diagnosed in 139 (19.5%), IGT in 252 (35.3%), and subclinical DM in 322 (45.2%) patients, respectively. During a median follow-up period of 42.0 months, the cumulative survival rates of patients were as follows: NGT, 75.6%; IGT, 57.6%; and subclinical DM, 54.8%. Overall, IGT (adjusted hazard ratio [aHR], 1.605; 95% confidence interval [CI] = 1.009-2.553; P = 0.046) and subclinical DM (aHR, 1.840; 95% CI = 1.183-2.861; P = 0.001) were identified as independent predictors of mortality. In patients with compensated cirrhosis (n = 415), neither IGT nor subclinical DM conferred a higher mortality risk. However, among patients with decompensated cirrhosis (n = 298), those with IGT (aHR, 2.394; P = 0.015) and subclinical DM (aHR, 2.211; P = 0.022) showed a survival rate worse than those with NGT. In addition, subclinical DM was identified as an independent risk factor for infection (aHR, 2.508; P = 0.007). CONCLUSIONS: IGT and subclinical diabetes by OGTT are associated with an unfavorable prognosis in cirrhosis, and the effect is pronounced in the decompensated state. CLINICALTRIALS: gov, Number NCT04828512 (https://clinicaltrials.gov/ct2/show/NCT04828512).

Generation of Fibrotic Liver Organoids Using Hepatocytes, Primary Liver Sinusoidal Endothelial Cells, Hepatic Stellate Cells, and Macrophages.

Liver organoids generated with single or multiple cell types have been used to investigate liver fibrosis development, toxicity, pathogenesis, and drug screening. However, organoid generation is limited by the availability of cells isolated from primary tissues or differentiated from various stem cells. To ensure cell availability for organoid formation, we investigated whether liver organoids could be generated with cell-line-based Huh-7 hepatocellular carcinoma cells, macrophages differentiated from THP-1 monocytes, and LX-2 hepatic stellate cells (HSCs) and primary liver sinusoidal endothelial cells (LSECs). In liver organoids, hepatocyte-, LSEC-, macrophage-, and HSC-related gene expression increased relative to that in two-dimensional (2D)-cultured Huh-7/LSEC/THP-1/LX-2 cells without Matrigel. Thioacetamide (TAA) increased α-smooth muscle actin expression in liver organoids but not in 2D-cultured cells, whereas in TAA-treated organoids, the expression of hepatic and LSEC markers decreased and that of macrophage and HSC markers increased. TAA-induced fibrosis was suppressed by treatment with N-acetyl-L-cysteine or tumor-necrosis-factor-stimulated gene 6 protein. The results showed that liver toxicants could induce fibrotic and inflammatory responses in liver organoids comprising Huh-7/LSEC/macrophages/LX-2 cells, resulting in fibrotic liver organoids. We propose that cell-line-based organoids can be used for disease modeling and drug screening to improve liver fibrosis treatment.

[Pulmonary Complications in Patients with Liver Cirrhosis].

Portal hypertension is a clinical syndrome defined by an increased portal venous pressure. The most frequent cause of portal hypertension is liver cirrhosis, and many of the complications of cirrhosis, such as ascites and gastroesophageal variceal bleeding, are related to portal hypertension. Portal hypertension is a pathological condition caused by the accumulation of blood flow in the portal system. This blood flow retention reduces the effective circulation volume. To compensate for these changes, neurotransmitter hormone changes and metabolic abnormalities occur, which cause complications in organs other than the liver. A hepatic hydrothorax is fluid accumulation in the pleural space resulting from increased portal pressure. Hepatopulmonary syndrome and portopulmonary hypertension are the pulmonary complications in cirrhosis by deforming the vascular structure. Symptoms, such as dyspnea and hypoxia, affect the survival and the quality of life of patients. These lung complications are usually underestimated in the management of cirrhosis. This review briefly introduces the type of lung complications of cirrhosis.

Associations of Serum Uric Acid Level With Liver Enzymes, Nonalcoholic Fatty Liver Disease, and Liver Fibrosis in Korean Men and Women: A Cross-Sectional Study Using Nationally Representative Data.

BACKGROUND: This study aimed to determine whether serum uric acid (SUA) levels are associated with various indices of liver damage in the adult Korean population. METHODS: We used the Seventh (VII) Korean National Health and Nutritional Examination Surveys. Our study population comprised 6,007 men and 8,488 women. Levels of SUA were divided into four groups (≤ 5.3, 5.3-6.0, 6.0-7.0, and > 7.0 mg/dL for men and ≤ 4.0, 4.0-4.8, 4.8-6.0, and > 6.0 mg/dL for women). Elevated liver enzyme levels were defined as > 35 (men) and > 31 (women) IU/L for aspartate aminotransferase (AST), > 45 (men) and > 34 (women) IU/L for alanine aminotransferase (ALT). Hepatic steatosis index and fibrosis (FIB)-4 index was used to determine nonalcoholic fatty liver disease (NAFLD) and liver FIB, respectively. Adjusted odds ratios (aORs) were calculated by logistic regression analysis for liver enzymes, NAFLD, and liver FIB, according to the SUA level. RESULTS: Among women, the 4.8-6.0 and > 6.0 mg/dL SUA groups showed higher ORs of elevated AST (aOR, 1.78 and 2.03; 95% confidence interval [CI], 1.37-2.32 and 1.40-2.96, respectively; P < 0.001) and the 4.0-4.8, 4.8-6.0, and > 6.0 mg/dL SUA groups showed a higher ORs of ALT elevation (aOR, 1.35, 2.26, and 2.37; 95% CI, 1.02-1.79, 1.72-2.97, and 1.60-3.50, respectively; P < 0.001) compared to the lowest level SUA group. Among women with normal ALT, > 6.0 mg/dL SUA group showed higher OR of NAFLD status (aOR, 1.52; 95% CI, 1.06-2.19). Among men and women with NAFLD, hyperuricemia showed higher ORs of liver FIB (aOR, 2.25 and 1.89; 95% CI, 1.21-4.19 and 1.09-3.27, respectively) than the lowest level SUA group. CONCLUSION: High SUA levels may be associated with elevated liver enzymes and NAFLD, mainly in women. Even in women with normal ALT levels, SUA levels may predict the NAFLD status. Hyperuricemia may predict advanced liver FIB in both men and women with NAFLD. Further studies investigating the causal effects of SUA on liver damage are required.

Response-Guided Therapy With Cefotaxime, Ceftriaxone, or Ciprofloxacin for Spontaneous Bacterial Peritonitis: A Randomized Trial: A Validation Study of 2021 AASLD Practice Guidance for SBP.

INTRODUCTION: For the treatment of spontaneous bacterial peritonitis (SBP), cefotaxime, ceftriaxone, and ciprofloxacin were used as first-line agents. However, considering the increasing rate of antibiotic resistance, it is unclear which of these drugs can be initially recommended. This study aimed to compare the current efficacy of the 3 antibiotics, namely cefotaxime, ceftriaxone, and ciprofloxacin, for the treatment of SBP in patients with cirrhosis with ascites, when guided by therapeutic responses. METHODS: This study was a multicenter, prospective, randomized controlled trial. The inclusion criteria were 16- to 75-year-old patients with liver cirrhosis with ascites, having polymorphonuclear cell count of >250/mm 3 . We performed a follow-up paracentesis at 48 hours to decide continuing or changing the assigned antibiotics and then assessed the resolution rates at 120 and 168 hours of treatment. RESULTS: A total of 261 patients with cirrhosis who developed SBP were enrolled. Most of the patients were diagnosed as those with SBP within 48 hours of admission. The resolution rates at 120 hours, which is the primary endpoint, were 67.8%, 77.0%, and 73.6% in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively ( P = 0.388), by intension-to-treat analysis. The 1-month mortality was similar among the groups ( P = 0.770). The model for end-stage liver disease score and the SBP resolution were significant factors for survival. CONCLUSION: The efficacy of empirical antibiotics, such as cefotaxime, ceftriaxone, and ciprofloxacin, against SBP was not significantly different. In addition, these antibiotics administered based on response-guided therapy were still efficacious as initial treatment for SBP, especially in those with community-acquired infections.

Non-alcoholic fatty liver disease: Definition and subtypes.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, with a global prevalence of approximately 30%. However, the prevalence of NAFLD has been variously reported depending on the comorbidities. The rising prevalence of obesity in both the adult and pediatric populations is projected to consequently continue increasing NAFLD prevalence. It is a major cause of chronic liver disease worldwide, including cirrhosis and hepatocellular carcinoma (HCC). NAFLD has a variety of clinical phenotypes and heterogeneity due to the complexity of pathogenesis and clinical conditions of its occurrence, resulting in various clinical prognoses. In this article, we briefly described the basic definition of NAFLD and classified the subtypes based on current knowledge in this field.

Role of TGF-ß and p38 MAPK in TSG-6 Expression in Adipose Tissue-Derived Stem Cells In Vitro and In Vivo.

Mesenchymal stem cells (MSCs) regulate immune cell activity by expressing tumor necrosis factor-α (TNF-α)-stimulated gene 6 (TSG-6) in inflammatory environments; however, whether anti-inflammatory responses affect TSG-6 expression in MSCs is not well understood. Therefore, we investigated whether transforming growth factor-ß (TGF-ß) regulates TSG-6 expression in adipose tissue-derived stem cells (ASCs) and whether effective immunosuppression can be achieved using ASCs and TGF-ß signaling inhibitor A83-01. TGF-ß significantly decreased TSG-6 expression in ASCs, but A83-01 and the p38 inhibitor SB202190 significantly increased it. However, in septic C57BL/6 mice, A83-01 further reduced the survival rate of the lipopolysaccharide (LPS)-treated group and ASC transplantation did not improve the severity induced by LPS. ASC transplantation alleviated the severity of sepsis induced by LPS+A83-01. In co-culture of macrophages and ASCs, A83-01 decreased TSG-6 expression whereas A83-01 and SB202190 reduced Cox-2 and IDO-2 expression in ASCs. These results suggest that TSG-6 expression in ASCs can be regulated by high concentrations of pro-inflammatory cytokines in vitro and in vivo, and that A83-01 and SB202190 can reduce the expression of immunomodulators in ASCs. Therefore, our data suggest that co-treatment of ASCs with TGF-ß or p38 inhibitors is not adequate to modulate inflammation.

Outcome of Intermittent Thoracentesis versus Pigtail Catheter Drainage for Hepatic Hydrothorax.

Background/Aims: The management of hepatic hydrothorax (HH) remains a challenging clinical scenario with suboptimal options. We investigated the effect and safety of pigtail catheter drainage compared to intermittent thoracentesis. Methods: This multicenter, retrospective study included 164 cirrhotic patients with recurrent pleural effusion from March 2012 to June 2017. Patients with neoplasms, cardiopulmonary disease, and infectious conditions were excluded. We compared the clinical outcomes of pigtail catheter drainage versus thoracentesis for variables including complications related to procedures, overall survival, and re-admission rates. Results: A total of 164 patients were divided into pigtail catheter (n = 115) and thoracentesis (n = 49) groups. During the follow-up period of 6.93 months after discharge, 98 patients died (pigtail; n = 47 vs. thoracentesis; n = 51). The overall survival (p = 0.61) and 30-day mortality (p = 0.77) rates were similar between the pigtail catheter and thoracentesis groups. Only MELD scores were associated with overall survival (adjusted HR, 1.08; p < 0.01) in patients with HH. Spontaneous pleurodesis occurred in 59 patients (51.3%) in the pigtail catheter group. Re-admission rates did not differ between the pigtail catheter and thoracentesis groups (13.2% vs 19.6% p = 0.7). A total of five complications occurred, including four total cases of bleeding (one patient in the pigtail catheter group and three in the thoracentesis group) and one case of empyema in the pigtail catheter group. Conclusions: Pigtail catheter drainage is not inferior to that of intermittent thoracentesis for the management of HH, proving it may be an effective and safe clinical option.

Antifibrotic TSG-6 Expression Is Synergistically Increased in Both Cells during Coculture of Mesenchymal Stem Cells and Macrophages via the JAK/STAT Signaling Pathway.

The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1ß upregulate TNF-α-stimulated gene 6 (TSG-6); however, current knowledge about the optimal conditions for TSG-6 expression in mesenchymal stem cells (MSCs) is limited. Here, we investigated whether TSG-6 expression varies depending on the polarization state of macrophages co-cultured with adipose tissue-derived stem cells (ASCs) and analyzed the optimal conditions for TSG-6 expression in ASCs. TSG-6 expression increased in ASCs co-cultured with M0, M1, and M2 macrophages indirectly; among them, M1 macrophages resulted in the highest increase in TSG-6 expression in ASCs. TSG-6 expression in ASCs dramatically increased by combination (but not single) treatment of TNF-α, IL-1ß, interferon-gamma (IFN-γ), and lipopolysaccharide (LPS). In addition, phosphorylation of signal transducer and activator of transcription (STAT) 1/3 was observed in response to IFN-γ and LPS treatment but not TNF-α and/or IL-1ß. STAT1/3 activation synergistically increased TNF-α/IL-1ß-dependent TSG-6 expression, and JAK inhibitors suppressed TSG-6 expression both in ASCs and macrophages. In LX-2 hepatic stellate cells, TSG-6 inhibited TGF-ß-induced Smad3 phosphorylation, resulting in decreased α-smooth muscle actin (SMA) expression. Moreover, fibrotic activities of LX-2 cells induced by TGF-ß were dramatically decreased after indirect co-culture with ASCs and M1 macrophages. These results suggest that a comprehensive inflammatory microenvironment may play an important role in determining the therapeutic properties of ASCs by increasing TSG-6 expression through STAT1/3 activation.

Metabolic Stress Index Including Mitochondrial Biomarker for Noninvasive Diagnosis of Hepatic Steatosis.

Background: Mitochondrial dysfunction with oxidative stress contributes to nonalcoholic fatty liver disease (NAFLD) progression. We investigated the steatosis predictive efficacy of a novel non-invasive diagnostic panel using metabolic stress biomarkers. Methods: Altogether, 343 subjects who underwent magnetic resonance imaging-based liver examinations from a population-based general cohort, and 41 patients enrolled in a biopsy-evaluated NAFLD cohort, participated in the development and validation groups, respectively. Serologic stress biomarkers were quantitated by enzyme-linked immunosorbent assay. Results: Multivariate regression showed that waist-to-hip ratio, fibroblast growth factor (FGF) 21, FGF19, adiponectin-to-leptin ratio, insulin, albumin, triglyceride, total-cholesterol, and alanine-aminotransferase were independent predictors of steatosis (rank-ordered by Wald). The area under receiver-operator characteristics curve [AUROC (95%CI)] of the metabolic stress index for steatosis (MSI-S) was 0.886 (0.85-0.92) and 0.825 (0.69-0.96) in development and validation groups, respectively. MSI-S had higher diagnostic accuracy (78.1%-81.1%) than other steatosis indices. MSI-S notably differentiated steatosis severities, while other indices showed less discrimination. Conclusion: MSI-S, as a novel non-invasive index, based on mitochondrial stress biomarker FGF21 effectively predicted steatosis. Furthermore, MSI-S may increase the population that could be excluded from further evaluation, reducing unnecessary invasive investigations more effectively than other indices.

Reappraisal of sepsis-3 and CLIF-SOFA as predictors of mortality in patients with cirrhosis and infection presenting to the emergency department: A multicenter study.

BACKGROUND/AIMS: Sepsis-3 criteria and quick Sequential Organ Failure Assessment (qSOFA) have been advocated to be used in defining sepsis in the general population. We aimed to compare the Sepsis-3 criteria and Chronic Liver Failure-SOFA (CLIF-SOFA) scores as predictors of in-hospital mortality in cirrhotic patients admitted to the emergency department (ED) for infections. METHODS: A total of 1,622 cirrhosis patients admitted at the ED for infections were assessed retrospectively. We analyzed their demographic, laboratory, and microbiological data upon diagnosis of the infection. The primary endpoint was inhospital mortality rate. The predictive performances of baseline CLIF-SOFA, Sepsis-3, and qSOFA scores for in-hospital mortality were evaluated. RESULTS: The CLIF-SOFA score proved to be significantly better in predicting in-hospital mortality (area under the receiver operating characteristic curve [AUROC], 0.80; 95% confidence interval [CI], 0.78-0.82) than the Sepsis-3 (AUROC, 0.75; 95% CI, 0.72-0.77, P<0.001) and qSOFA (AUROC, 0.67; 95% CI, 0.64-0.70; P<0.001) score. The CLIF-SOFA, CLIF-C-AD scores, Sepsis-3 criteria, septic shock, and qSOFA positivity were significantly associated with in-hospital mortality (adjusted hazard ratio [aHR], 1.24; 95% CI, 1.19-1.28; aHR, 1.13; 95% CI, 1.09-1.17; aHR, 1.19; 95% CI, 1.15-1.24; aHR, 1.88; 95% CI, 1.42-2.48; aHR, 2.06; 95% CI, 1.55-2.72; respectively; all P<0.001). For CLIF-SOFA scores ≥6, in-hospital mortality was >10%; this is the cutoff point for the definition of sepsis. CONCLUSION: Among cirrhosis patients presenting with infections at the ED, CLIF-SOFA scores showed a better predictive performance for mortality than both Sepsis-3 criteria and qSOFA scores, and can be a useful tool of risk stratification in cirrhotic patients requiring timely intervention for infection.

Autoimmune Hepatitis Following Vaccination for SARS-CoV-2 in Korea: Coincidence or Autoimmunity?

Autoimmune hepatitis (AIH) is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells, causing the liver to be inflamed. AIH is one of the manifestations of a coronavirus disease 2019 (COVID-19), as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Few cases of AIH have been described after vaccination with two messenger RNA (mRNA)-based vaccines-BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-against SARS-CoV-2. Herein, we report a case of AIH occurring after Pfizer-BioNTech COVID-19 vaccine. A 27-year-old female presented with jaundice and hepatomegaly, appearing 14 days after receiving the second dose of Pfizer-BioNTech vaccine. Her laboratory results showed abnormal liver function with high total immunoglobulin G level. She was diagnosed with AIH with histologic finding and successfully treated with oral prednisolone. We report an AIH case after COVID-19 vaccination in Korea.

Application of ultrasound for the diagnosis of cirrhosis/portal hypertension.

With advances in technologic approaches in patients with cirrhosis, including the improvement of management, a simple, one-step approach for advanced fibrotic state of the liver is clinically useful. Although refining the diagnosis of cirrhosis to reflect disease heterogeneity is essential, current diagnostic tests have not kept pace with the progression of this new paradigm. There are unmet needs in primary care centers with respect to patients with cirrhosis. Liver biopsy and measurement of hepatic venous pressure gradient in patients with cirrhosis are the gold standards for the estimation of hepatic fibrosis, and they have diagnostic and prognostic value. However, both approaches are invasive and cannot be used repeatedly in clinical practice. Ultrasonography (US) is safe, easy to perform, inexpensive, and yields numerical and accurate results. Conventionally, the size of the liver and spleen, bluntness of the liver edge, nodularity of the liver surface, and coarseness of the liver parenchyma have been known as useful parameters for hepatic fibrosis or portal hypertension (PHT) in chronic liver disease. Additionally, some functional US indices including Doppler and CEUS-based examination have been suggested as promising markers for diagnosing cirrhosis and PHT. Identification of the reproducibility and long-term prognostic value through further investigations can demonstrate the clinical usefulness of functional US indices, which are characterized as quantitative parameters for hepatic fibrosis and PHT.

Multidimensional Biomarker Analysis Including Mitochondrial Stress Indicators for Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.

12-O-tetradecanoylphorbol-13-acetate Reduces Activation of Hepatic Stellate Cells by Inhibiting the Hippo Pathway Transcriptional Coactivator YAP.

Although protein kinase C (PKC) regulates various biological activities, including cell proliferation, differentiation, migration, tissue remodeling, gene expression, and cell death, the antifibrotic effect of PKC in myofibroblasts is not fully understood. We investigated whether 12-O-tetradecanoylphorbol-13-acetate (TPA), a PKC activator, reduced the activation of hepatic stellate cells (HSCs) and explored the involvement of the Hippo pathway transcriptional coactivator YAP. We analyzed the effect of TPA on the proliferation and expression of α-smooth muscle actin (SMA) in the LX-2 HSC line. We also analyzed the phosphorylation of the Hippo pathway molecules YAP and LATS1 and investigated YAP nuclear translocation. We examined whether Gö 6983, a pan-PKC inhibitor, restored the TPA-inhibited activities of HSCs. Administration of TPA decreased the growth rate of LX-2 cells and inhibited the expression of α-SMA and collagen type I alpha 1 (COL1A1). In addition, TPA induced phosphorylation of PKCδ, LATS1, and YAP and inhibited the nuclear translocation of YAP compared with the control. These TPA-induced phenomena were mostly ameliorated by Gö 6983. Our results indicate that PKCδ exerts an antifibrotic effect by inhibiting the Hippo pathway in HSCs. Therefore, PKCδ and YAP can be used as therapeutic targets for the treatment of fibrotic diseases.

Increased Phosphatase of Regenerating Liver-1 by Placental Stem Cells Promotes Hepatic Regeneration in a Bile-Duct-Ligated Rat Model.

Phosphatase of regenerating liver-1 (PRL-1) controls various cellular processes and liver regeneration. However, the roles of PRL-1 in liver regeneration induced by chorionic-plate-derived mesenchymal stem cells (CP-MSCs) transplantation remain unknown. Here, we found that increased PRL-1 expression by CP-MSC transplantation enhanced liver regeneration in a bile duct ligation (BDL) rat model by promoting the migration and proliferation of hepatocytes. Engrafted CP-MSCs promoted liver function via enhanced hepatocyte proliferation through increased PRL-1 expression in vivo and in vitro. Moreover, higher increased expression of PRL-1 regulated CP-MSC migration into BDL-injured rat liver through enhancement of migration-related signals by increasing Rho family proteins. The dual effects of PRL-1 on proliferation of hepatocytes and migration of CP-MSCs were substantially reduced when PRL-1 was silenced with siRNA-PRL-1 treatment. These findings suggest that PRL-1 may serve as a multifunctional enhancer for therapeutic applications of CP-MSC transplantation.

Association between chronic hepatitis B infection and COVID-19 outcomes: A Korean nationwide cohort study.

BACKGROUND/AIMS: We measured the association between underlying chronic hepatitis B (CHB) and antiviral use with infection rates among patients who underwent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. METHODS: In total, 204,418 patients who were tested for SARS-CoV-2 between January and June 2020 were included. For each case patient (n = 7,723) with a positive SARS-CoV-2 test, random controls (n = 46,231) were selected from the target population who had been exposed to someone with coronavirus disease 2019 (COVID-19) but had a negative SARS-CoV-2 test result. We merged claim-based data from the Korean National Health Insurance Service database collected. Primary endpoints were SARS-CoV-2 infection and severe clinical outcomes of COVID-19. RESULTS: The proportion of underlying CHB was lower in COVID-19 positive patients (n = 267, 3.5%) than in COVID-19 negative controls (n = 2482, 5.4%). Underlying CHB was associated with a lower SARS-CoV-2 positivity rate, after adjusting for comorbidities (adjusted odds ratio [aOR] 0.65; 95% confidence interval [CI], 0.57-0.74). Among patients with confirmed COVID-19, underlying CHB tended to confer a 66% greater risk of severe clinical outcomes of COVID-19, although this value was statistically insignificant. Antiviral treatment including tenofovir and entecavir was associated with a reduced SARS-CoV-2 positivity rate (aOR 0.49; 95% CI, 0.37-0.66), while treatment was not associated with severe clinical outcomes of COVID-19. CONCLUSIONS: Underlying CHB and antiviral agents including tenofovir decreased susceptibility to SARS-CoV-2 infection. HBV coinfection did not increase the risk of disease severity or lead to a worse prognosis in COVID-19.

Hepatopulmonary syndrome is related to the development of acute-on-chronic liver failure and poor prognosis in cirrhotic patients.

BACKGROUND AND AIMS: Long-term prospective data on hepatopulmonary syndrome (HPS) from a large number of patients, especially in Asian patients, are lacking. We evaluated the long-term prognosis of HPS and the development of acute-on-chronic liver failure (ACLF), and related factors. METHODS: A total of 142 patients with cirrhosis who underwent saline-agitated contrast echocardiography for the diagnosis of HPS were enrolled and observed prospectively from 2014 to 2019. RESULTS: A total of 59 patients (41%) were diagnosed with HPS (24 grade 1, 23 grade 2, 12 grade 3). Thirty-eight and 37 patients died in the HPS and non-HPS groups, respectively (p < 0.01). The 5-year survival rate was 47% in the HPS group and 62% in the non-HPS group. In the Cox proportional hazards model, HPS and Model for End-stage Liver Disease (MELD) score ≥ 18, and Child-Turcotte-Pugh (CTP) class B/C were significant risk factors for mortality after adjusting for other risk factors (HPS hazard ratio [HR] = 1.9, p = 0.01; MELD score ≥ 18 HR = 2.3, p < 0.01; CTP class B/C HR = 2.9, p < 0.01). Compared to that in non-HPS group, the HPS group had a significantly higher incidence of ACLF during follow-up (p < 0.01) and more frequently presented with lung involvement of ACLF (p = 0.03). CONCLUSIONS: In the long-term follow-up cohort, patients with HPS showed poorer prognosis than that of patients without HPS. HPS was a risk factor for ACLF development independent of hepatic dysfunction, and lung involvement was significantly common than without ACLF.