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Background: Previously, we demonstrated that Spp1−/− mice exhibit a greater susceptibility to alcohol‐induced liver injury than wild‐type (WT) mice. Notably, alcohol triggers the expression of osteopontin (encoded by SPP1) in hepatocytes. However, the specific role of hepatocyte‐derived SPP1 in either mitigating or exacerbating alcohol‐associated liver disease (AALD) has yet to be elucidated. We hypothesized that hepatocyte‐derived SPP1 plays a role in AALD by modulating the regulation of steatosis. Methods: We analyzed hepatic SPP1 expression using four publicly available datasets from patients with alcoholic hepatitis (AH). Additionally, we examined SPP1 expression in the livers of WT mice subjected to either a control or ethanol Lieber‐DeCarli (LDC) diet for 6 weeks. We compared the relationship between SPP1 expression and significantly dysregulated genes in AH with controls using correlation and enrichment analyses. To investigate the specific impact of hepatocyte‐derived SPP1, we generated hepatocyte‐specific Spp1 knock‐out (Spp1ΔHep) mice and subjected them to either a control or ethanol Lieber‐DeCarli diet for 6 weeks. Results: Alcohol induced hepatic SPP1 expression in both humans and mice. Our analysis, focusing on genes correlated with SPP1, revealed an enrichment of fatty acid oxidation (FAO) in three datasets, and peroxisome proliferator‐activated receptor signaling in one dataset. Notably, FAO genes correlating with SPP1 were downregulated in patients with AH. Ethanol‐fed WT mice exhibited higher serum‐free fatty acids (FFAs), adipose tissue lipolysis, and hepatic fatty acid (FA) transporters. In contrast, ethanol‐fed Spp1ΔHep mice displayed lower liver triglycerides, FFAs, and serum alanine transaminase and greater FAO gene expression than WT mice, indicating a protective effect against AALD. Primary hepatocytes from Spp1∆Hep mice exhibited heightened expression of genes encoding proteins involved in FAO. Conclusions: Alcohol induces the expression of SPP1 in hepatocytes, leading to impaired FAO and contributing to the development of AALD. [ABSTRACT FROM AUTHOR]

Neutrophils are associated with pro‐inflammation and contribute to pathophysiology of ischemic stroke. Prevention of neutrophils from infiltrating into ischemic area can be a potential approach for stroke therapy. In this study, a rod‐shaped polylactic acid polyglycolic acid (PLGA) nanoparticles encapsulated with piceatannol is developed to target and intervene the interaction of neutrophils with inflamed endothelial cells. In contrast to macrophages, neutrophils exhibit enhanced endocytosis of elongated particles. The nanoparticles with aspect ratio (AR) of 5 display higher internalization by neutrophils compared to other nanoparticles. Thus, AR5 nanoparticles are screened out to load with piceatannol (Pic@AR5) for investigating the therapeutic effect against middle cerebral artery occlusion model. It is demonstrated that Pic@AR5 can block the adherence of neutrophils to endothelial cells, inhibiting the infiltration of neutrophils into blood‐brain barrier (BBB). Besides, the inflammatory cytokine of ischemic brain can also be reduced even if a small part of Pic@AR5‐carried neutrophils enter BBB. The nanoparticles release piceatannol within the ischemic region, which inhibit microglial Syk signal and result in alleviation of neuroinflammation. This strategy provides new insights into ischemic stroke therapy. [ABSTRACT FROM AUTHOR]

Introduction: Subclinical rejection (SCR) is a common injury in protocol biopsy after pediatric liver transplantation (pLT), but its effect on the recipient is not clearly understood. We herein investigated the incidence and risk factors involved in SCR and analyzed the relationship between SCR and allograft fibrosis (AF). Methods: We retrospectively reviewed the biopsy results from 507 children between May 2013 and May 2019, and 352 patients underwent protocol biopsy 2 years after pLT, 203 underwent protocol biopsy 5 years after pLT, and 48 underwent protocol biopsy both 2 and 5 years after pLT. Results: The incidence of SCR in the 5‐year group was higher than that in the 2‐year group (20.2% vs.13.4%, respectively, p =.033). The number of patients with mild and moderate SCR in the 5‐year group was also higher than that in the 2‐year group (p =.039). Logistic regression analysis showed that acute rejection before liver biopsy and deceased donor liver transplantation (DDLT) were independent risk factors for SCR in the two groups, and that the incidence and severity of AF in protocol biopsies at both periods in the SCR group were higher than those in the non‐SCR group (p <.05). Conclusions: The incidence and severity of SCR increased with the prolongation of protocol biopsy time. We postulate that acute rejection and DDLT are independent risk factors for SCR after transplantation. As the occurrence of SCR also augmented the incidence and severity of AF. [ABSTRACT FROM AUTHOR]

We investigated the clinical characteristics and therapeutic strategies for paediatric liver transplant (PLT) recipients who experienced de novo hepatitis B virus infection and the features of HBsAg seroconversion. A total of 821 PLT were performed in HBV‐free recipients between January 2013 and January 2019 in Paediatric Organ Transplant Center, Tianjin First Central Hospital. Twenty‐one recipients developed de novo HBV infection, the clinical data were analysed. The overall incidence of de novo HBV infection was 2.5%. Only one recipient received an HBcAb‐negative graft, 20 recipients received HBcAb‐positive grafts. The incidence of de novo HBV infection in HBcAb‐negative and HBcAb‐positive graft recipients were 0.2% and 6.3%, respectively. Fifteen de novo HBV‐infected recipients showed HBsAg seroconversion, the incidence of HBsAg seroconversion was 71.4%. The median time from the diagnosis of de novo HBV infection to HBsAg seroconversion was 15 (1, 73) months. Recipients with hepatitis B surface antigen (HBsAg) titre <1000 IU/L and negative hepatitis B e antigen (HBeAg) at the time of de novo HBV infection diagnosis were more likely to achieve HBsAg seroconversion. Nucleotide analogues were effective in treating recipients with de novo HBV infection. De novo HBV infection does not impact liver graft function as well as recipient and graft survival rate. De novo HBV infection does not impact PLT recipient outcomes under close monitoring and appropriate treatment. High incidence of HBsAg seroconversion can be achieved after anti‐viral therapy. [ABSTRACT FROM AUTHOR]

Silencing the Hippo kinases mammalian sterile 20‐like 1 and 2 (MST1/2) activates the transcriptional coactivator yes‐associated protein (YAP) in human hepatocellular carcinoma (HCC). Hepatocyte‐derived high‐mobility group box‐1 (HMGB1) regulates YAP expression; however, its contribution to HCC in the context of deregulated Hippo signaling is unknown. Here, we hypothesized that HMGB1 is required for hepatocarcinogenesis by activating YAP in Hippo signaling‐deficient (Mst1/2ΔHep) mice. Mst1/2ΔHep mice developed HCC within 3.5 months of age and had increased hepatic expression of HMGB1 and elevated YAP activity compared to controls. To understand the contribution of HMGB1, we generated Mst1/2&Hmgb1ΔHep mice. They exhibited decreased YAP activity, cell proliferation, inflammation, fibrosis, atypical ductal cell expansion, and HCC burden at 3.5 months compared to Mst1/2∆Hep mice. However, Mst1/2&Hmgb1ΔHep mice were smaller, developed hyperbilirubinemia, had more liver injury with intrahepatic biliary defects, and had reduced hemoglobin compared to Mst1/2ΔHep mice. Conclusion: Hepatic HMGB1 promotes hepatocarcinogenesis by regulation of YAP activity; nevertheless, it maintains intrahepatic bile duct physiology under Hippo signaling deficiency. [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) expression correlates with tumor progression in many cancers, including hepatocellular carcinoma (HCC); however, its role in the onset of HCC remains unclear. We hypothesized that increased hepatocyte‐derived OPN is a driver of hepatocarcinogenesis. Analysis of a tissue microarray of 366 human samples revealed a continuous increase in OPN expression during hepatocarcinogenesis. In patients with cirrhosis, a transcriptome‐based OPN correlation network was associated with HCC incidence along 10 years of follow‐up, together with messenger RNA (mRNA) signatures of carcinogenesis. After diethylnitrosamine (DEN) injection, mice with conditional overexpression of Opn in hepatocytes (OpnHep transgenic [Tg]) showed increased tumor burden. Surprisingly, mice with conditional ablation of Opn in hepatocytes (OpnΔHep) expressed a similar phenotype. The acute response to DEN was reduced in OpnΔHep, which also showed more cancer stem/progenitor cells (CSCs, CD44+AFP+) at 5 months. CSCs from OpnHep Tg mice expressed several mRNA signatures known to promote carcinogenesis, and mRNA signatures from OpnHep Tg mice were associated with poor outcome in human HCC patients. Treatment with rOPN had little effect on CSCs, and their progression to HCC was similar in Opn−/− compared with wild‐type mice. Finally, ablation of Cd44, an OPN receptor, did not reduce tumor burden in Cd44−/−OpnHep Tg mice. Conclusions: Hepatocyte‐derived OPN acts as a tumor suppressor at physiological levels by controlling the acute response to DEN and the presence of CSCs, while induction of OPN is pro‐tumorigenic. This is primarily due to intracellular events rather that by the secretion of the protein and receptor activation. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to analyze the risk factors, causes, and management of intestinal obstruction after pediatric liver transplantation. Methods: Retrospective analysis was performed on pediatric liver transplantation recipients from January 1st 2013 to December 31st 2019 at Organ Transplant Center, Tianjin First Central Hospital. The cases of intestinal obstruction were analyzed. Results: A total of 1034 pediatric liver transplantations were performed during the study period, 66 intestinal obstructions were diagnosed in 61 recipients. Three recipients suffered intestinal obstructions twice, and one recipient suffered three times. Forty of the 66 cases were treated with non‐surgical treatment, including fasting, gastrointestinal decompression, purgation, enema, and parenteral nutrition. Surgical intervention was performed in 26 cases. Diaphragmatic hernia, intestinal inflammatory stenosis, PTLD, and intestine perforation are essential causes of intestinal obstruction in pediatric liver transplant recipients. Diaphragmatic hernia was independent risk factors for intestinal obstruction. The 1‐, 2‐ and 3‐year survival rate of the recipients with or without intestinal obstruction were 98.4%, 96.5%, 96.5% and 95.3%, 94.4%, 94.0%, respectively, without significant difference. Conclusions: Most cases of intestinal obstruction after liver transplantation in children can be remitted by non‐surgical treatment, but there are still some cases need to be treated by surgery. Both measures are related to ideal outcomes, intestinal obstruction does not increase the mortality rate in pediatric liver transplantation. [ABSTRACT FROM AUTHOR]

Alcohol‐associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol‐induced liver injury, female and male wild‐type mice were fed the control or ethanol Lieber‐DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho‐GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator–activated receptor signaling. During resolution from ALD, there was up‐regulation of vitamin D receptor/retinoid X receptor, toll‐like receptor, p38 and Stat3, and down‐regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune‐response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl‐L‐leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen‐activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender‐specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD. [ABSTRACT FROM AUTHOR]

Capecitabine (CAP) is now widely used in the comprehensive treatment of digestive system tumors. Some clinical observations have shown that CAP may have immunosuppressive effects, but there is still a lack of clear experimental verification. In this study, different doses of CAP were administered to normal mice by gavage. Our results confirmed that CAP did not cause myelosuppression in bone marrow tissue; CAP selectively reduced the proportion of T cells and the concentration of related pro-inflammatory cytokines, while it increased the concentration of anti-inflammatory cytokines. Thymidylate phosphorylase (TP) is the key enzyme for the transformation of CAP in vivo ; this study confirmed that T cells express TP, but the bone marrow tissue lacks TP expression, which explains the selectivity in pharmacodynamic effects of CAP. In addition, it was confirmed that CAP can induce T cell apoptosis in vivo and in vitro. In vitro experiments showed that CAP-induced T cell apoptosis was related to TP expression, endoplasmic reticulum stress (ERS) induction, reactive oxygen species (ROS) production, and mitochondria-mediated apoptosis activation. Therefore, this study confirmed that the differential expression of TP in cells and tissues explains why CAP avoids the toxic effects of myelosuppression while inducing T cell apoptosis to exert the immunosuppressive effect. Therefore, CAP may become an immunosuppressive agent with a simultaneous anti-cancer effect, which is worthy of further studies. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus (HBV) infection changes the composition of the extracellular matrix (ECM) and enables the onset and progression of hepatocellular carcinoma (HCC). The ensemble of ECM proteins and associated factors is a major component of the tumor microenvironment. Our aim was to unveil the matrisome genes from HBV‐related HCC. Transcriptomic and clinical profiles from 444 patients with HBV‐related HCC were retrieved from the Gene Expression Omnibus (GEO) and Cancer Genome Atlas (TCGA) repositories. Matrisome genes associated with HBV‐related hepatocarcinogenesis, matrisome gene modules, HCC subgroups, and liver‐specific matrisome genes were systematically analyzed, followed by identification of their biological function and clinical relevance. Eighty matrisome genes, functionally enriched in immune response, ECM remodeling, or cancer‐related pathways, were identified as associated with HBV‐related HCC, which could robustly discriminate HBV‐related HCC tumor from nontumor samples. Subsequently, four significant matrisome gene modules were identified as showing functional homogeneity linked to cell cycle activity. Two subgroups of patients with HBV‐related HCC were classified based on the highly correlated matrisome genes. The high‐expression subgroup (15.0% in the TCGA cohort and 17.9% in the GEO cohort) exhibited favorable clinical prognosis, activated metabolic activity, exhausted cell cycle, strong immune infiltration, and lower tumor purity. Four liver‐specific matrisome genes (F9, HPX [hemopexin], IGFALS [insulin‐like growth‐factor‐binding protein, acid labile subunit], and PLG [plasminogen]) were identified as involved in HBV‐related HCC progression and prognosis. Conclusion: This study identified the expression and function of matrisome genes from HBV‐related hepatocarcinogenesis, providing major insight to understand HBV‐related HCC and develop potential therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Background: Dietary polyphenols including anthocyanins target multiple organs.Objective: We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G).Methods: Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2).Results: In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P < 0.05). In Exp. 2, Cy3G attenuated HFD-induced body-weight gain (20.3% at week 16), and improved glucose tolerance (26.5% at week 15) but not insulin tolerance. Although Cy3G had no effect on glucose tolerance in LFD mice, LFD/Cy3G/AB mice showed better glucose tolerance than LFD/Cy3G mice (23%). In contrast, HFD/Cy3G/AB mice showed worse glucose tolerance compared with HFD/Cy3G mice (15%). Beneficial effects of Cy3G in HFD mice were not associated with changes in plasma leptin, insulin or GLP-1 concentrations. However, Cy3G increased hepatic Fgf21 expression in mice in Exp. 1 by 4-fold and attenuated Fgf21 overexpression in HFD mice (Exp. 2, 22%), associated with increased expression of genes that encode FGFR1 and β-klotho (>3-fold, P < 0.05).Conclusions: Dietary Cy3G may reduce body weight and exert metabolic homeostatic effects in mice via changes in hepatic FGF21. [ABSTRACT FROM AUTHOR]

Background and Aim: We aim to investigate the risk factors of de novo hepatitis B virus (HBV) infection in pediatric liver transplantation recipients receiving hepatitis B core antibody positive grafts and to evaluate the efficacy of our prophylactic strategies. Methods: One hundred thirty‐nine pediatric recipients receiving hepatitis B core antibody positive grafts operated from September 2016 to September 2018 were retrospectively enrolled, and all the patients received prophylactic treatment to prevent de novo HBV infection. Donor and recipient features, operative information along with graft, and recipient outcomes were compared between recipients with or without de novo HBV infection. Univariate and multivariate analyses were applied to identify the risk factors of de novo HBV infection. Results: The mean follow‐up time was 23.5 ± 15.7 months, and the overall incidence of de novo HBV infection was 3.6%. Recipients with de novo HBV infection showed equal graft and recipient outcome compared with the recipients without de novo HBV infection during the follow‐up time. Recipient preoperative hepatitis B surface antibody titer of < 1000 IU/L (odds ratio [OR] = 9.652, P = 0.024), graft HBV DNA of > 1000 copies (OR = 9.050, P = 0.032), and intraoperative fresh‐frozen plasma transfusion of > 400 mL (OR = 10.462, P = 0.023) were identified as independent risk factors for de novo HBV infection. Conclusion: Hepatitis B core antibody positive grafts can safely be used in pediatric liver transplantation under rational prophylactic therapy. [ABSTRACT FROM AUTHOR]

Donors with low-body-weight were previously reported to be related to inferior recipient outcomes in pediatric liver transplantation. However, the scarce availability of age and size-matched organs has encouraged us to re-evaluate the feasibility and safety of using low-body-weight donors. We retrospectively analyzed 91 deceased donor pediatric liver transplantation between January 2014 and December 2016, donor weight less than 5 kg was defined as low-body-weight donors. The recipients were divided into two groups according to donor weight. (≤ 5 kg and 5 kg < to ≤ 20 kg). Donor and recipient characteristics, perioperative data, postoperative complications as well as graft and recipient survival rate were compared The recipients and grafts recovery after transplantation were comparable between two groups. The recipients receiving low-body-weight donors showed higher risk of hepatic artery thrombosis and small-for-size syndrome, however, these complications can effectively be treated by our strategies. The 2-year patient survival rates were 92.9% and 95.2%, 2-year graft survival rates were 92.9% and 93.7% in Groups 1 and 2, without significant difference. Our finding suggested that the utility of livers from low-body-weight donors is a potential strategy to increase donor availability in well-selected pediatric recipients. III [ABSTRACT FROM AUTHOR]

The bipartite transcription factor β-catenin (β-cat)/T cell factor (TCF), formed by free β-cat and a given TCF family member, serves as the effector of the developmental Wnt signaling cascade. β-cat/TCFs also serve as effectors of certain peptide hormones or growth factors during adulthood. We reported that liver-specific expression of dominant-negative Transcription factor 7 like 2 (TCF7L2DN) led to impaired glucose disposal. Here we show that, in this LTCFDN transgenic mouse model, serum and hepatic lipid contents were elevated in male but not in female mice. In hepatocytes, TCF7L2DN adenovirus infection led to stimulated expression of genes that encode lipogenic transcription factors and lipogenic enzymes, while estradiol (E2) treatment attenuated the stimulation, associated with Wnt-target gene activation. Mechanistically, this E2-mediated activation can be attributed to elevated β-cat Ser675 phosphorylation and TCF expression. In wild-type female mice, ovariectomy (OVX) plus high-fat diet (HFD) challenge impaired glucose disposal and insulin tolerance, associated with increased hepatic lipogenic transcription factor sterol regulatory element-binding protein 1-c (SREBP-1c) expression. In wild-type mice with OVX, E2 reconstitution attenuated HFD-induced metabolic defects. Some of the attenuation effects, including insulin intolerance, elevated liver-weight gain, and hepatic SREBP-1c expression, were not affected by E2 reconstitution in HFD-fed LTCFDN mice with OVX. Finally, the effects of E2 in hepatocytes on β-cat/TCF activation can be attenuated by the G-protein-coupled estrogen receptor (GPER) antagonist G15. Our study thus expanded the scope of functions of the Wnt pathway effector β-cat/TCF, as it can also mediate hepatic functions of E2 during adulthood. This study also enriches our mechanistic understanding of gender differences in the risk and pathophysiology of metabolic diseases. [ABSTRACT FROM AUTHOR]

Abstract: Defective regeneration of small‐for‐size (SFS) liver remnants and partial grafts remains a key limiting factor in the application of liver surgery and transplantation. Exogenous melatonin (MLT) has protective effects on hepatic ischemia‐reperfusion injury (IRI), but its influence on graft regeneration is unknown. The aim of the study is to investigate the role of MLT in IRI and graft regeneration in settings of partial liver transplantation. We established three mouse models to study hepatic IRI and regeneration associated with partial liver transplantation: (I) IR+PH group: 60 minutes liver ischemia (IR) plus 2/3 hepatectomy (PH); (II) IR+exPH group: 60 minutes liver IR plus extended hepatectomy (exPH) associated with the SFS syndrome; (III) SFS‐LT group: Arterialized 30% SFS liver transplant. Each group was divided into MLT or vehicle‐treated subgroups. Hepatic injury, inflammatory signatures, liver regeneration, and animal survival rates were assessed. MLT reduced liver injury, enhanced liver regeneration, and promoted interleukin (IL) 6, IL10, and tumor necrosis factor‐α release by infiltrating, inflammatory Ly6C+ F4/80+ monocytes in the IR+PH group. MLT‐induced IL6 significantly improved hepatic microcirculation and survival in the IR+exPH model. In the SFS‐LT group, MLT promoted graft regeneration and increased recipient survival along with increased IL6/GP130‐STAT3 signaling. In IL6−/− mice, MLT failed to promote liver recovery, which could be restored through recombinant IL6. In the IR+exPH and SFS‐LT groups, inhibition of the IL6 co‐receptor GP130 through SC144 abolished the beneficial effects of MLT. MLT ameliorates SFS liver graft IRI and restores regeneration through monocyte‐released IL6 and downstream IL6/GP130‐STAT3 signaling. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine whether dietary curcumin intervention targets both white adipose tissue (WAT) inflammation and brown adipose tissue (BAT)-mediated energy expenditure.Methods: C57BL/6J mice were fed with a low-fat diet, high-fat diet (HFD), or HFD plus curcumin. In addition to assessing the effect of curcumin intervention on metabolic profiles, this study assessed WAT macrophage infiltration and composition and inflammatory cytokine production. Metabolic cages were applied for determining energy expenditure. Raw264.7 (ATCC, Manassas, Virginia) and other cell models were utilized to test the in vitro effect of curcumin treatment.Results: Curcumin intervention reduced WAT macrophage infiltration and altered macrophage functional polarity, as the ratio of M2-like versus M1-like macrophages increased after curcumin intervention. Curcumin treatment reduced M1-like macrophage markers or proinflammation cytokine expression in both macrophages and adipocytes. Curcumin intervention also increased energy expenditure and body temperature in response to a cold challenge. Finally, the in vivo and in vitro investigations suggested that curcumin increased expression of uncoupling protein 1 (UCP1), possibly involving PPAR-dependent and -independent mechanisms.Conclusions: Curcumin intervention targets both WAT inflammation and BAT UCP1 expression. These observations advanced our knowledge on the metabolic beneficial effects of the curry compound curcumin, bringing us a novel perspective on dietary polyphenol research. [ABSTRACT FROM AUTHOR]

Background: The lack of age‐ and size‐matched organs result in higher waiting list mortality in pediatric recipients than adults. Organs from deceased newborns and infants are a valuable source to increase donor pool in pediatric liver transplantation. However, the feasibility and safety of using neonatal donors have not been well evaluated. Methods: From 2014 to 2016, 48 deceased donor pediatric liver transplantations with donor age younger than 1 year old in our center were enrolled in this study. The recipients were divided into three groups based on the donor age (<1 month, 1 month ≤ to <3 months, and 3 months ≤ to <1 year). Recipient's characteristics, perioperative data, and postoperative complications were compared. Results: Two‐year patient survival rates were 87.5%, 94.4%, and 95.5%, and 2‐year graft survival rates were 75%, 94.4%, and 95.5%, respectively, without significant difference. The liver grafts from donors younger than 3 months were more advantageous in terms of acute rejection and virus infection, while the young grafts were related to slight higher incidence of hepatic artery thrombosis and SFSS. Those complications could be effectively prevented or treated by our perioperative care strategies. In addition, eight recipients who received neonatal livers achieved comparable outcomes with recipients with older livers. Conclusion: Our data revealed that the application of liver grafts from donors younger than 1 year old could achieve excellent outcome. In particular, neonatal donors could be safely used in well‐selected patients. [ABSTRACT FROM AUTHOR]

Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules can also promote inflammation in the context of liver disease. Herein, we provide a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury. We consider the role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, as well as how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer. In addition, we discuss the role of damage-associated molecular patterns in ischaemia reperfusion injury and liver transplantation and highlight current studies in which blockade of specific damage-associated molecular patterns has proven beneficial in humans and mice. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether radiomics signature can identify aggressive behavior and predict recurrence of hepatocellular carcinoma (HCC) after liver transplantation.Methods: Our study consisted of a training dataset (n = 93) and a validation dataset (40) with clinically confirmed HCC after liver transplantation from October 2011 to December 2016. Radiomics features were extracted by delineating regions-of-interest (ROIs) around the lesion in four phases of CT images. A radiomics signature was generated using the least absolute shrinkage and selection operator (LASSO) Cox regression model. The association between radiomics signature and recurrence-free survival (RFS) was assessed. Preoperative clinical characteristics potentially associated with RFS were evaluated to develop a clinical model. A combined model incorporating clinical risk factors and radiomics signature was built.Results: The stable radiomics features associated with the recurrence of HCC were simply found in arterial phase and portal phase. The prediction model based on the radiomics features extracted from the arterial phase showed better prediction performance than the portal vein phase or the fusion signature combining both of arterial and portal vein phase. A radiomics nomogram based on combined model consisting of the radiomics signature and clinical risk factors showed good predictive performance for RFS with a C-index of 0.785 (95% confidence interval [CI]: 0.674-0.895) in the training dataset and 0.789 (95% CI: 0.620-0.957) in the validation dataset. The calibration curves showed agreement in both training (p = 0.121) and validation cohorts (p = 0.164).Conclusions: Radiomics signature extracted from CT images may be a potential imaging biomarker for liver cancer invasion and enable accurate prediction of HCC recurrence after liver transplantation. [ABSTRACT FROM AUTHOR]

Background: Optimizing the immunosuppressive regimen is essential to improve the long-term outcomes of pediatric liver transplant recipients., Methods: We conducted a prospective, randomized, open-label study to compare the safety and efficacy of 2 treatment approaches during pediatric liver transplantation: tacrolimus monotherapy following basiliximab induction (the study group) and a dual regimen of tacrolimus plus steroids (the control group). A total of 150 patients were enrolled, with 75 patients allocated to each group., Results: In both groups, recipients achieved graft and recipient overall survival rates exceeding 93%, with no statistically significant differences between them. However, the study group exhibited a significantly lower incidence of acute cellular rejection (ACR), delayed occurrence of ACR, and an improved ACR-free survival rate at 2 y compared with the control group. Notably, the study group also showed a significant reduction in the incidence of de novo donor-specific antibodies at 3-mo and 2-y posttransplant. Furthermore, 6 mo after the transplant, the study group demonstrated significant improvements in weight-for-age Z score and height-for-age Z score. No notable differences were observed in postoperative complications or the incidence of liver fibrosis between the 2 groups., Conclusions: Basiliximab induction combine with tacrolimus (TAC) monotherapy is a safe and effective immunosuppressive regimen to reduce the episodes of ACR without influencing the development of liver fibrosis and graft and recipient survival rate after pediatric liver transplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background Aims: Excessive deposition and crosslinking of extracellular matrix increases liver density and stiffness, promotes fibrogenesis, and increases resistance to fibrinolysis. An emerging therapeutic opportunity in liver fibrosis is to target the composition of the extracellular matrix or block pathogenic communication with surrounding cells. However, the type and extent of extracellular changes triggering liver fibrosis depend on the underlying etiology. Our aim was to unveil matrisome genes not dependent on etiology, which are clinically relevant to liver fibrosis., Approach Results: We used transcriptomic profiles from liver fibrosis cases of different etiologies to identify and validate liver fibrosis-specific matrisome genes (LFMGs) and their clinical and biological relevance. Dysregulation patterns and cellular landscapes of LFMGs were further explored in mouse models of liver fibrosis progression and regression by bulk and single-cell RNA sequencing. We identified 35 LFMGs, independent of etiology, representing an LFMG signature defining liver fibrosis. Expression of the LFMG signature depended on histological severity and was reduced in regressive livers. Patients with liver fibrosis, even with identical pathological scores, could be subclassified into LFMG Low and LFMG High , with distinguishable clinical, cellular, and molecular features. Single-cell RNA sequencing revealed that microfibrillar-associated protein 4 + activated HSC increased in LFMG High patients and were primarily responsible for the LFMG signature expression and dysregulation., Conclusions: The microfibrillar-associated protein 4 + -activated HSC-derived LFMG signature classifies patients with liver fibrosis with distinct clinical and biological characteristics. Our findings unveil hidden information from liver biopsies undetectable using traditional histologic assessments., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: This study aimed to explore whether serum CXCL8 concentration can be used as a noninvasive marker of subclinical rejection (SCR) after pediatric liver transplantation (pLT)., Methods: Firstly, RNA sequencing (RNA-seq) was performed on 22 protocol liver biopsy samples. Secondly, several experimental methods were used to verify the RNA-seq results. Finally, the clinical data and serum samples of 520 LT patients in the Department of Pediatric Transplantation of Tianjin First Central Hospital from January 2018 to December 2019 were collected., Results: RNA-seq results indicated that CXCL8 was significantly increased in the SCR group. The results of the 3 experimental methods were consistent with RNA-seq results. According to the 1:2 propensity score matching, 138 patients were divided into the SCR (n = 46) and non-SCR (n = 92) groups. Serological test results indicated that there was no difference in preoperative CXCL8 concentration between the SCR and non-SCR groups ( P  > 0.05). However, during protocol biopsy, CXCL8 in the SCR group was significantly higher than in the non-SCR group ( P  < 0.001). In diagnosing SCR, receiver operating characteristic curve analysis showed that the area under the curve of CXCL8 was 0.966 (95% confidence interval, 0.938-0.995), sensitivity was 95%, and specificity was 94.6%. In differentiating nonborderline from borderline rejection, the area under the curve of CXCL8 was 0.853 (95% confidence interval, 0.718-0.988), sensitivity was 86.7%, and specificity was 94.6%., Conclusions: This study demonstrates that serum CXCL8 concentration has high accuracy for the diagnosis and disease stratification of SCR after pLT., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: HCC, the third leading cause of cancer-related death, arises in the context of liver fibrosis. Although HCC is generally poorly fibrogenic, some tumors harbor focal intratumor extracellular matrix (ECM) deposits called "fibrous nests." To date, the molecular composition and clinical relevance of these ECM deposits have not been fully defined., Approach and Results: We performed quantitative matrisome analysis by tandem mass tags mass spectrometry in 20 human cancer specific matrisome (HCCs) with high or low-grade intratumor fibrosis and matched nontumor tissues, as well as in 12 livers from mice treated with vehicle, carbon tetrachloride, or diethylnitrosamine. We found 94 ECM proteins differentially abundant between high and low-grade fibrous nests, including interstitial and basement membrane components, such as several collagens, glycoproteins, proteoglycans, enzymes involved in ECM stabilization and degradation, and growth factors. Pathway analysis revealed a metabolic switch in high-grade fibrosis, with enhanced glycolysis and decreased oxidative phosphorylation. Integrating the quantitative proteomics with transcriptomics from HCCs and nontumor livers (n = 2,285 samples), we identified a subgroup of fibrous nest HCCs, characterized by cancer-specific ECM remodeling, expression of the WNT/TGFB (S1) subclass signature, and poor patient outcome. Fibrous nest HCCs abundantly expressed an 11-fibrous-nest - protein signature, associated with poor patient outcome, by multivariate Cox analysis, and validated by multiplex immunohistochemistry., Conclusions: Matrisome analysis highlighted cancer-specific ECM deposits, typical of the WNT/TGFB HCC subclass, associated with poor patient outcomes. Hence, histologic reporting of intratumor fibrosis in HCC is of clinical relevance., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background and Aims: Early allograft dysfunction (EAD) is a severe event leading to graft failure after liver transplant (LT). Extracellular high-mobility group box-1 (HMGB1) is a damage-associated molecular pattern that contributes to hepatic ischemia-reperfusion injury (IRI). However, the contribution of intracellular HMGB1 to LT graft injury remains elusive. We hypothesized that intracellular neutrophil-derived HMGB1 from recipients protects from post-LT EAD., Approach and Results: We generated mice with conditional ablation or overexpression of Hmgb1 in hepatocytes, myeloid cells, or both. We performed LTs and injected lipopolysaccharide (LPS) to evaluate the effect of intracellular HMGB1 in EAD. Ablation of Hmgb1 in hepatocytes and myeloid cells of donors and recipients exacerbated early allograft injury after LT. Ablation of Hmgb1 from liver grafts did not affect graft injury; however, lack of Hmgb1 from recipient myeloid cells increased reactive oxygen species (ROS) and inflammation in liver grafts and exacerbated injury. Neutrophils lacking HMGB1 were more activated, showed enhanced pro-oxidant and pro-inflammatory signatures, and reduced biosynthesis and metabolism of inositol polyphosphates (InsPs). On LT reperfusion or LPS treatment, there was significant neutrophil mobilization and infiltration into the liver and enhanced production of ROS and pro-inflammatory cytokines when intracellular Hmgb1 was absent. Depletion of neutrophils using anti-Ly6G antibody attenuated graft injury in recipients with myeloid cell Hmgb1 ablation., Conclusions: Neutrophil HMGB1 derived from recipients is central to regulate their activation, limits the production of ROS and pro-inflammatory cytokines, and protects from early liver allograft injury., (Copyright © 2023 American Association for the Study of Liver Diseases.)

The lower limit of body weight for "splitable" liver grafts remains unknown. To examine the outcome of split-liver transplantation (SLT) from pediatric donors ≤25 kg relative to conventional graft-type liver transplantation from deceased donors under corresponding conditions, a total of 158 patients who received primary liver transplantation, including 22 SLTs from donors ≤25 kg, 46 SLTs from donors >25 kg, 76 whole-liver transplantations, and 14 reduced-liver transplantations in donors ≤25 kg between January 2018 and December 2019, were included in the study. There was no significant difference in the complications, patient survival, and graft survival between each of the latter three groups and the SLT ≤25 kg group. Pediatric End-Stage Liver Disease (PELD) score was the independent predictor of graft loss (death or retransplantation). Graft weight was the independent predictor of hepatic artery thrombosis. SLT using well-selected pediatric donors ≤25 kg is an effective strategy to increase organ availability, especially for low-body-weight recipients, compared with conventional graft type from deceased donors under the condition of corresponding donor weight without increasing morbidity and mortality., (Copyright © 2022 American Association for the Study of Liver Diseases.)

Hydrodynamic tail vein injection (HTV) is the "gold standard" for delivering naked DNA vectors to mouse liver, thereby transfecting predominately perivenous hepatocytes. While HTV corrects metabolic liver defects such as phenylketonuria or cystathionine β-synthase deficiency, correction of spf ash mice with ornithine transcarbamylase (OTC) deficiency was not possible despite overexpression in the liver, as the OTC enzyme is primarily expressed in periportal hepatocytes. To target periportal hepatocytes, we established hydrodynamic retrograde intrabiliary injection (HRII) in mice and optimized minicircle (MC) vector delivery using luciferase as a marker gene. HRII resulted in a transfection efficiency below 1%, 100-fold lower than HTV. While HRII induced minimal liver toxicity compared with HTV, overexpression of luciferase by both methods, but not of a natural liver-specific enzyme, elicited an immune response that led to the elimination of luciferase expression. Further testing of MC vectors delivered via HRII in spf ash mice did not result in sufficient therapeutic efficacy and needs further optimization and/or selection of the corrected cells. This study reveals that luciferase expression is toxic for the liver. Furthermore, physical delivery of MC vectors via the bile duct has the potential to treat defects restricted to periportal hepatocytes, which opens new doors for non-viral liver-directed gene therapy., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Gamma-aminobutyric acid (GABA) administration attenuates streptozotocin (STZ)-induced diabetes in rodent models with unclear underlying mechanisms. We found that GABA and Sitagliptin possess additive effect on pancreatic β-cells, which prompted us to ask the existence of common or unique targets of GLP-1 and GABA in pancreatic β-cells. Effect of GABA on expression of thioredoxin-interacting protein (TxNIP) was assessed in the INS-1 832/13 (INS-1) cell line, WT and GLP-1R-/- mouse islets. GABA was also orally administrated in STZ-challenged WT or GLP-1R-/- mice, followed by immunohistochemistry assessment of pancreatic islets. Effect of GABA on Wnt pathway effector β-catenin (β-cat) was examined in INS-1 cells, WT and GLP-1R-/- islets. We found that GABA shares a common feature with GLP-1 on inhibiting TxNIP, while this function was attenuated in GLP-1R-/- islets. In WT mice with STZ challenge, GABA alleviated several 'diabetic syndromes', associated with increased β-cell mass. These features were virtually absent in GLP-1R-/- mice. Knockdown TxNIP in INS-1 cells increased GLP-1R, Pdx1, Nkx6.1 and Mafa levels, associated with increased responses to GABA or GLP-1 on stimulating insulin secretion. Cleaved caspase-3 level can be induced by high-glucose, dexamethasone, or STZ in INS-1 cell, while GABA treatment blocked the induction. Finally, GABA treatment increased cellular cAMP level and β-cat S675 phosphorylation in WT but not GLP-1R-/- islets. We, hence, identified TxNIP as a common target of GABA and GLP-1 and suggest that, upon STZ or other stress challenge, the GLP-1R-cAMP-β-cat signaling cascade also mediates beneficial effects of GABA in pancreatic β-cell, involving TxNIP reduction.

The ability of the liver to restore its original volume following tissue loss has been associated with the Hippo-YAP1 pathway, a key controller of organ size. Yes-associated protein 1 (YAP1)-a growth effector usually restrained by Hippo signaling-is believed to be of particular importance; however, its role in liver regeneration remains ill-defined. To explore its function, we knocked down YAP1 prior to standard 70%-hepatectomy (sHx) using a hepatocyte-specific nanoformulation. Knockdown was effective during the major parenchymal growth phase (S-phase/M-phase peaks at 32 hours/48 hours post-sHx). Liver weight gain was completely suppressed by the knockdown at 32 hours, but was reaccelerated toward 48 hours. Likewise, proliferative markers, Ccna2/b2 and YAP1 target gene expression were downregulated at 32 hours, but re-elevated at 48 hours post-sHx. Nonetheless, knockdown slightly compromised survival after sHx. When assessing a model of resection-induced liver failure (extended 86%-hepatectomy, eHx) featuring deficient S- and M-phase progression, YAP1 was not induced at 32 hours, but upregulated at 48 hours post-eHx, confirming its dissociation from M-phase regulation. Therefore, YAP1 is vital to push hepatocytes into cycle and through the S-phase, but is not required for further cell cycle progression during liver regeneration. The examination of YAP1 in human livers suggested its function is conserved in the regenerating mammalian liver.