Hepatology Communications最新文献

{"title":"Cholestatic insult triggers alcohol-associated hepatitis in mice.","authors":"Shengmin Yan, Zhen Lin, Michelle Ma, Ailar Arasteh, Xiao-Ming Yin","doi":"10.1097/HC9.0000000000000566","DOIUrl":"10.1097/HC9.0000000000000566","url":null,"abstract":"<p><strong>Background: </strong>Alcohol-associated hepatitis (AH) is a severe, potentially life-threatening form of alcohol-associated liver disease with limited therapeutic options. Existing evidence shows that biliary dysfunction and cholestasis are common in patients with AH and are associated with poorer prognosis. However, the role of cholestasis in the development of AH is largely unknown. We aimed to examine the hypothesis that cholestasis can be an important etiology factor for AH.</p><p><strong>Methods: </strong>To study the interaction of cholestasis and alcohol, chronically ethanol (EtOH)-fed mice were challenged with a subtoxic dose of α-naphthylisothiocyanate (ANIT), a well-studied intrahepatic cholestasis inducer. Liver injury was measured by biochemical and histological methods. RNAseq was performed to determine hepatic transcriptomic changes. The impact of inflammation was assessed using an anti-LY6G antibody to deplete the neutrophils and DNase I to degrade neutrophil extracellular traps.</p><p><strong>Results: </strong>ANIT synergistically enhanced liver injury following a 4-week EtOH feeding with typical features of AH, including increased serum levels of ALT, AST, and total bile acids, cholestasis, necrosis, neutrophil infiltration, and accumulation of neutrophil extracellular traps. RNAseq revealed multiple genes uniquely altered in the livers of EtOH/ANIT-treated mice. Analysis of differentially expressed genes suggested an enrichment of genes related to inflammatory response. Anti-LY6G antibody or DNase I treatment significantly inhibited liver damage in EtOH/ANIT-treated mice.</p><p><strong>Conclusions: </strong>Our results support the hypothesis that cholestasis can be a critical contributor to the pathogenesis of AH. A combined treatment of EtOH and ANIT in mice presents biochemical, histological, and molecular features similar to those found in patients with AH, suggesting that this treatment scheme can be a useful model for studying Alcohol-associated Cholestasis and Hepatitis (AlChoHep).</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulating intestinal neuroimmune VIPergic signaling attenuates the reduction in ILC3-derived IL-22 and hepatic steatosis in MASLD.","authors":"Henry H Nguyen, Jhimmy Talbot, Dayi Li, Varsha Raghavan, Dan R Littman","doi":"10.1097/HC9.0000000000000528","DOIUrl":"10.1097/HC9.0000000000000528","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as NAFLD) is a major driver of cirrhosis and liver-related mortality. However, therapeutic options for MASLD, including prevention of liver steatosis, are limited. We previously described that vasoactive intestinal peptide-producing neurons (VIP-neurons) regulate the efficiency of intestinal dietary fat absorption and IL-22 production by type 3 innate lymphoid cells (ILC3) in the intestine. Given the described hepatoprotective role of IL-22, we hypothesize that modulation of this neuroimmune circuit could potentially be an innovative approach for the control of liver steatosis.</p><p><strong>Methods: </strong>We used a model of diet-induced MASLD by exposing mice to a high-fat diet (HFD) for 16 weeks, when the development of liver steatosis was first observed in our animals. We characterized IL-22 production by intestinal ILC3 at this dietary endpoint. We then evaluated whether communication between VIP-neurons and ILC3 affected IL-22 production and MASLD development by exposing mice with a conditional genetic deletion of Vipr2 in ILC3 (Rorc(t)CreVipr2fl/fl) to the HFD. We also performed intermittent global inhibition of VIP-neurons using a chemogenetic inhibitory approach (VipIres-CrehM4DiLSL) in HFD-fed mice.</p><p><strong>Results: </strong>Production of IL-22 by intestinal ILC3 is reduced in steatotic mice that were exposed to an HFD for 16 weeks. Targeted deletion of VIP receptor 2 in ILC3 resulted in higher production of IL-22 in ILC3 and was associated with a significant reduction in liver steatosis in mice under HFD. Global inhibition of VIP-producing neurons also resulted in a significant reduction in liver steatosis.</p><p><strong>Conclusions: </strong>Modulating VIPergic neuroimmune signaling can ameliorate the development of hepatic steatosis induced by a surplus of fat ingestion in the diet. This neuroimmune pathway should be further investigated as a potential therapeutic avenue in MASLD.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-translational modifications drive the effects of HMGB1 in alcohol-associated liver disease.","authors":"Xiaodong Ge, Nithyananthan Subramaniyam, Zhuolun Song, Romain Desert, Hui Han, Sukanta Das, Sai Santosh Babu Komakula, Chao Wang, Daniel Lantvit, Zhiyan Ge, Yujin Hoshida, Natalia Nieto","doi":"10.1097/HC9.0000000000000549","DOIUrl":"10.1097/HC9.0000000000000549","url":null,"abstract":"<p><strong>Background: </strong>We previously identified that high-mobility group box-1 (HMGB1) is increased and undergoes post-translational modifications (PTMs) in response to alcohol consumption. Here, we hypothesized that specific PTMs, occurring mostly in hepatocytes and myeloid cells, could contribute to the pathogenesis of alcohol-associated liver disease (AALD).</p><p><strong>Methods: </strong>We used the Lieber-DeCarli (LD) model of early alcohol-induced liver injury, combined with engineered viral vectors and genetic approaches to regulate the expression of HMGB1, its PTMs (reduced [H], oxidized [O], acetylated [Ac], both [O + Ac]), and its receptors (RAGE, TLR4) in a cell-specific manner (hepatocytes and/or myeloid cells).</p><p><strong>Results: </strong>Hmgb1 ablation in hepatocytes or myeloid cells partially protected, while ablation in both prevented steatosis, inflammation, IL1B production, and alcohol-induced liver injury. Hepatocytes were a major source of [H], [O], and [Ac] HMGB1, whereas myeloid cells produced only [H] and [Ac] HMGB1. Neutralization of HMGB1 prevented, whereas injection of [H] HMGB1 increased AALD, which was worsened by injection of [O] HMGB1. While [O] HMGB1 induced liver injury, [Ac] HMGB1 protected and counteracted the effects of [O] HMGB1 in AALD. [O] HMGB1 stimulated macrophage (MF) migration, activation, IL1B production, and secretion. Ethanol-fed RageΔMye but not Tlr4ΔMye, RageΔHep, or Tlr4ΔHep mice were protected from AALD, indicating a crucial role of RAGE in myeloid cells for AALD. [O] HMGB1 recruited and activated myeloid cells through RAGE and contributed to steatosis, inflammation, and IL1B production in AALD.</p><p><strong>Conclusions: </strong>These results provide evidence for targeting [O] HMGB1 of hepatocyte origin as a ligand for RAGE signaling in myeloid cells and a driver of steatosis, inflammatory cell infiltration, and IL1B production in AALD. Importantly, we reveal that [Ac] HMGB1 offsets the noxious effects of [O] HMGB1 in AALD.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of gut microbiota and gut metabolites and adverse outcomes in biliary atresia: A longitudinal prospective study.","authors":"Vandana Jain, Matthew J Dalby, Emma C Alexander, Charlotte Burford, Holly Acford-Palmer, Iliana R Serghiou, Nancy M Y Teng, Raymond Kiu, Konstantinos Gerasimidis, Konstantina Zafeiropoulou, Michael Logan, Anita Verma, Mark Davenport, Lindsay J Hall, Anil Dhawan","doi":"10.1097/HC9.0000000000000550","DOIUrl":"10.1097/HC9.0000000000000550","url":null,"abstract":"<p><strong>Background: </strong>The Kasai portoenterostomy (KPE) aims to re-establish bile flow in biliary atresia (BA); however, BA remains the commonest indication for liver transplantation in pediatrics. Gut microbiota-host interplay is increasingly associated with outcomes in chronic liver disease. This study characterized fecal microbiota and fatty acid metabolites in BA.</p><p><strong>Methods: </strong>Fecal samples were prospectively collected in newly diagnosed BA infants (n = 55) before and after KPE. Age-matched healthy control (n = 19) and cholestatic control (n = 21) fecal samples were collected. Fecal 16S rRNA gene amplicon sequencing for gut microbiota and gas chromatography for fecal fatty acids was performed.</p><p><strong>Results: </strong>Increased abundance of Enterococcus in pre-KPE BA and cholestatic control infants, compared to healthy infants, was demonstrated. At the early post-KPE time points, increased alpha diversity was revealed in BA versus healthy cohorts. A lower relative abundance of Bifidobacterium and increased Enterococcus, Clostridium, Fusobacterium, and Pseudomonas was seen in infants with BA. Fecal acetate was reduced, and fecal butyrate and propionate were elevated in early post-KPE BA infants. Higher post-KPE alpha diversity was associated with nonfavorable clinical outcomes (6-month jaundice and liver transplantation). A higher relative abundance of post-KPE Streptococcus and Fusobacterium and a lower relative abundance of Dorea, Blautia, and Oscillospira were associated with nonfavorable clinical outcomes. Blautia inversely correlated to liver disease severity, and Bifidobacterium inversely correlated to fibrosis biomarkers. Bifidobacterium abundance was significantly lower in infants experiencing cholangitis within 6 months after KPE.</p><p><strong>Conclusions: </strong>Increased diversity, enrichment of pathogenic, and depletion of beneficial microbiota early post-KPE are all factors associated with nonfavorable BA outcomes. Manipulation of gut microbiota in the early postsurgical period could provide therapeutic potential.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial mapping of the HCC landscape identifies unique intratumoral perivascular-immune neighborhoods.","authors":"Felix Marsh-Wakefield, Cositha Santhakumar, Angela L Ferguson, Thomas M Ashhurst, Joo-Shik Shin, Fiona H X Guan, Nicholas J Shields, Barry J Platt, Givanna H Putri, Ruta Gupta, Michael Crawford, Carlo Pulitano, Charbel Sandroussi, Jerome M Laurence, Ken Liu, Geoffrey W McCaughan, Umaimainthan Palendira","doi":"10.1097/HC9.0000000000000540","DOIUrl":"10.1097/HC9.0000000000000540","url":null,"abstract":"<p><strong>Background: </strong>HCC develops in the context of chronic inflammation; however, the opposing roles the immune system plays in both the development and control of tumors are not fully understood. Mapping immune cell interactions across the distinct tissue regions could provide greater insight into the role individual immune populations have within tumors.</p><p><strong>Methods: </strong>A 39-parameter imaging mass cytometry panel was optimized with markers targeting immune cells, stromal cells, endothelial cells, hepatocytes, and tumor cells. We mapped the immune landscape of tumor, invasive margin, and adjacent nontumor regions across 16 resected tumors comprising 144 regions of interest. X-shift clustering and manual gating were used to characterize cell subsets, and Spectre quantified the spatial environment to identify cellular neighborhoods. Ligand-receptor communication was quantified on 2 single-cell RNA-sequencing data sets and 1 spatial transcriptomic data set.</p><p><strong>Results: </strong>We show immune cell densities remain largely consistent across these 3 regions, except for subsets of monocyte-derived macrophages, which are enriched within the tumors. Mapping cellular interactions across these regions in an unbiased manner identifies immune neighborhoods comprised of tissue-resident T cells, dendritic cells, and various macrophage populations around perivascular spaces. Importantly, we identify multiple immune cells within these neighborhoods interacting with VEGFA+ perivascular macrophages. VEGFA was further identified as a ligand for communication between perivascular macrophages and CD34+ endothelial cells.</p><p><strong>Conclusions: </strong>Immune cell neighborhood interactions, but not cell densities, differ between intratumoral and adjacent nontumor regions in HCC. Unique intratumoral immune neighborhoods around the perivascular space point to an altered landscape within tumors. Enrichment of VEGFA+ perivascular macrophages within these tumors could play a key role in angiogenesis and vascular permeability.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum amyloid P (PTX2) attenuates hepatic fibrosis in mice by inhibiting the activation of fibrocytes and HSCs.","authors":"Min Cong, Raquel Carvalho Gontijo Weber, Sadatsugu Sakane, Vivian Zhang, Chunyan Jiang, Kojiro Taura, Yuzo Kodama, Samuele DeMinicis, Souradipta Ganguly, David Brafman, Shu Chien, Michael Kramer, Mark Lupher, David A Brenner, Jun Xu, Tatiana Kisseleva","doi":"10.1097/HC9.0000000000000557","DOIUrl":"10.1097/HC9.0000000000000557","url":null,"abstract":"<p><strong>Background: </strong>Liver fibrosis is caused by chronic toxic or cholestatic liver injury. Fibrosis results from the recruitment of myeloid cells into the injured liver, the release of inflammatory and fibrogenic cytokines, and the activation of myofibroblasts, which secrete extracellular matrix, mostly collagen type I. Hepatic myofibroblasts originate from liver-resident mesenchymal cells, including HSCs and bone marrow-derived CD45+ collagen type I+ expressing fibrocytes. Recombinant human serum amyloid P (hSAP), a natural inhibitor of fibrocyte activation into myofibroblasts, was shown to ameliorate experimental renal, lung, skin, and cardiac fibrosis. We investigated if hSAP can ameliorate the development of liver fibrosis of different etiologies.</p><p><strong>Methods: </strong>Reporter Collagen-α(1)I-GFP mice were subjected to cholestatic liver injury (by ligation of the common bile duct) or toxic liver injury (by carbon tetrachloride administration) and treated prophylactically or therapeutically with hSAP (12.5 μg/g). Primary cultures of mouse fibrocytes and HSCs were stimulated to activate with or without incubation with hSAP.</p><p><strong>Results: </strong>We demonstrate that treatment with hSAP suppressed hepatic fibrosis by ≈50% through dual mechanisms. hSAP prevented the recruitment of fibrocytes into the injured liver and their differentiation into myofibroblasts. Remarkably, hSAP also inhibited the activation of HSCs into myofibroblasts.</p><p><strong>Conclusions: </strong>Since HSCs serve as a major source of collagen type I-producing myofibroblasts and fibrocytes stimulate fibrosis, hSAP may become part of the therapy of liver fibrosis of different etiologies.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neighborhood-level deprivation mediates racial and ethnic disparities in HCC diagnosis in Texas.","authors":"Itunu O Sokale, Aaron P Thrift, Hashem B El-Serag, Abiodun O Oluyomi","doi":"10.1097/HC9.0000000000000536","DOIUrl":"10.1097/HC9.0000000000000536","url":null,"abstract":"<p><strong>Background: </strong>Texas has the highest HCC rates in the United States, and the greatest burden is among Hispanics. Racial and ethnic disparities in HCC incidence have multiple underpinning factors. We conducted a mediation analysis to examine the role of neighborhood disadvantage (Area Deprivation Index) as a potential mediator of the association between neighborhood race and ethnicity distribution and neighborhood HCC case counts in Texas.</p><p><strong>Methods: </strong>The primary outcome measure was counts of new HCC diagnoses per census tract based on Texas Department of State Health Services Texas Cancer Registry data. The primary exposure of interest was the race and ethnicity-based Index of Concentration at the Extremes (non-Hispanic Black ICE or Hispanic ICE). We assessed Area Deprivation Index as a potential mediator of the association between Black/Hispanic ICE and HCC case counts. We adjusted the analyses for selected census tract characteristics.</p><p><strong>Results: </strong>We analyzed 4934 census tracts containing 13,632 new HCC diagnoses reported to Texas Cancer Registry between 2016 and 2020. Racial minority (Black/Hispanic ICE)-concentrated neighborhoods had a higher socioeconomic disadvantage. The results of the mediation analyses showed that compared to non-Hispanic White-concentrated census tracts, non-Hispanic Black-concentrated census tracts and Hispanic-concentrated census tracts had higher case counts of HCC (total effects: adjusted case count ratio: 1.03 [95% CI, 1.02-1.04] and adjusted case count ratio: 1.09 [95% CI, 1.08-1.10], respectively). Approximately 48% and 15% of the neighborhood-level disparity in HCC case counts were attributable to neighborhood socioeconomic disadvantage in Black and Hispanic minoritized neighborhoods, respectively.</p><p><strong>Conclusions: </strong>Neighborhood HCC case counts varied by neighborhood race and ethnicity distribution. The variations were partly explained by neighborhood deprivation, with a stronger effect among Black-concentrated census tracts.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAK inhibition delays liver repair after acetaminophen-induced acute liver injury by suppressing hepatocyte proliferation and macrophage recruitment.","authors":"Qing Li, Qi Xu, Jialin Shi, Wei Dong, Junfei Jin, Chong Zhang","doi":"10.1097/HC9.0000000000000531","DOIUrl":"10.1097/HC9.0000000000000531","url":null,"abstract":"<p><strong>Background: </strong>Overdose of acetaminophen (APAP), a commonly used antipyretic analgesic, can lead to severe liver injury and failure. Current treatments are only effective in the early stages of APAP-induced acute liver injury (ALI). Therefore, a detailed examination of the mechanisms involved in liver repair following APAP-induced ALI could provide valuable insights for clinical interventions.</p><p><strong>Methods: </strong>4D-label-free proteomics analysis was used to identify dysregulated proteins in the liver of APAP-treated mice. RNA-Seq, hematoxylin-eosin staining, immunohistochemical staining, immunofluorescence staining, quantitative PCR, western blotting, transwell were used to explore the underlying mechanisms.</p><p><strong>Results: </strong>Utilizing high throughput 4D-label-free proteomics analysis, we observed a notable increase in proteins related to the \"focal adhesion\" pathway in the livers of APAP-treated mice. Inhibiting focal adhesion kinase (FAK) activation with a specific inhibitor, 1,2,4,5-Benzenetetraamine tetrahydrochloride (also called Y15), resulted in reduced macrophage numbers, delayed necrotic cell clearance, and inhibited liver cell proliferation in the necrotic regions of APAP-treated mice. RNA-Seq analysis demonstrated that Y15 downregulated genes associated with \"cell cycle\" and \"phagosome\" pathways in the livers of APAP-treated mice. Furthermore, blocking extracellular matrix (ECM)-integrin activation with a competitive peptide inhibitor, Gly-Arg-Gly-Asp-Ser (GRGDS), suppressed FAK activation and liver cell proliferation without affecting macrophage recruitment to necrotic areas. Mechanistically, ECM-induced FAK activation upregulated growth-promoting cell cycle genes, leading to hepatocyte proliferation, while CCL2 enhanced FAK activation and subsequent macrophage recruitment via F-actin rearrangement.</p><p><strong>Conclusions: </strong>Overall, these findings underscore the pivotal role of FAK activation in liver repair post-APAP overdose by promoting liver cell proliferation and macrophage recruitment.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tyrosine kinase Yes1 is a druggable host factor of HEV.","authors":"Jil Alexandra Haase, Abarna Baheerathan, Xin Zhang, Rebecca Menhua Fu, Maximilian Klaus Nocke, Charlotte Decker, Viet Loan Dao Thi, Daniel Todt, Johan Neyts, Suzanne J F Kaptein, Eike Steinmann, Volker Kinast","doi":"10.1097/HC9.0000000000000553","DOIUrl":"10.1097/HC9.0000000000000553","url":null,"abstract":"<p><strong>Background: </strong>HEV is a positive-sense, single-stranded RNA virus of the Hepeviridae family. Although HEV accounts for more than 3 million symptomatic cases of viral hepatitis per year, specific anti-HEV therapy and knowledge about HEV pathogenesis are scarce.</p><p><strong>Methods: </strong>To gain a deeper understanding of the HEV infectious cycle and guide the development of novel antiviral strategies, we here used an RNAi mini screen targeting a selection of kinases, including mitogen-activated protein kinases, receptor tyrosine kinases, and Src-family kinases. Further, we used state-of-the-art HEV infection models, including primary human hepatocytes and athymic nude rats.</p><p><strong>Results: </strong>Upon knockdown of the Src-family kinase Yes1, a significant reduction of HEV susceptibility could be observed, suggesting an important role of Yes1 in the HEV infectious cycle. Selective inhibition of Yes1 kinase activity resulted in significant inhibition of HEV infection in hepatoma cells and primary human hepatocytes, as well as in a rat HEV in vivo model system. Subsequent analysis of Y1KI during the HEV infectious life cycle indicated a role of Yes1 kinase activity in the early onset of HEV infection.</p><p><strong>Conclusions: </strong>We identified the dependence of HEV on Yes1 signaling, which may contribute to the so far scarce knowledge of HEV's pathogenesis in the future. Moreover, we provide Y1KI as a novel antiviral drug candidate specifically targeting an HEV host factor.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum levels of total bile acids are associated with an increased risk of HCC in patients with cirrhosis.","authors":"Hashem B El-Serag, Aaron P Thrift, Hao Duong, Jing Ning, Saira Khaderi, Amit G Singal, Sumeet K Asrani, Jorge A Marrero, Hannah Powell, Kinza Rizwan, Omar Najjar, Christopher I Amos, Michelle Luster, Abeer Al-Sarraj, Emad Salem, Michael E Scheurer, Jagpreet Chhatwal, Salma Kaochar, Fasiha Kanwal","doi":"10.1097/HC9.0000000000000545","DOIUrl":"10.1097/HC9.0000000000000545","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have reported higher circulating bile acid levels in patients with HCC compared to healthy controls. However, the association between prediagnostic bile acid levels and HCC risk among patients with cirrhosis is unclear.</p><p><strong>Methods: </strong>We measured total BA (TBA) concentration in serum samples collected from a prospective cohort of patients with cirrhosis who were followed until the development of HCC, death, or last study date. Competing risk proportional hazard-adjusted models were used to estimate the association between tertiles of serum TBA levels and the risk of developing HCC. We quantified the incremental predictive value of serum bile acid when added to a previously validated clinical model.</p><p><strong>Results: </strong>We analyzed data from 940 patients with cirrhosis, of whom 68 patients progressed to HCC during 3406 person-years of follow-up. Higher baseline serum TBA level was significantly associated with an increased risk of developing HCC with an adjusted HR of 3.69 (95% CI = 1.85-7.37) for the highest versus lowest tertile. TBA levels significantly increased predictive ability for progression to HCC at 2 years of follow-up; the c statistic increased from 0.74 to 0.80 (p < 0.001). There was evidence for a significant interaction between TBA level and hepatitis C (p = 0.04).</p><p><strong>Conclusions: </strong>In a large prospective cohort study, the prediagnostic serum level of TBAs was associated with a significant increase in the risk of developing HCC among patients with multi-etiology cirrhosis. The TBA-associated risk was additive to that of established demographic and clinical predictors.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11469875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}