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Loss of mucosal p32/gC1qR/HABP1 triggers energy deficiency and impairs goblet cell differentiation in ulcerative colitis Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-27 Annika Sünderhauf; Maren Hicken; Heidi Schlichting; Kerstin Skibbe; Mohab Ragab; Annika Raschdorf; Misa Hirose; Holger Schäffler; Arne Bokemeyer; Dominik Bettenworth; Anne G. Savitt; Sven Perner; Saleh Ibrahim; Ellinor l. Peerschke; Berhane Ghebrehiwet; Stefanie Derer; Christian Sina
Background & Aims Cell differentiation in the colonic crypt is driven by a metabolic switch from glycolysis to mitochondrial oxidation. Mitochondrial and goblet cell dysfunction have been attributed to the pathology of ulcerative colitis (UC). We hypothesized that p32/gC1qR/HABP1, which critically maintains oxidative phosphorylation, is involved in goblet cell differentiation and hence in the pathogenesis
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Sox9EGFP defines biliary epithelial heterogeneity downstream of Yap activity Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-23 Deepthi Y. Tulasi; Diego Martinez Castaneda; Kortney Wager; Connor B. Hogan; Karel P. Alcedo; Jesse R. Raab; Adam D. Gracz
Background & Aims Defining the genetic heterogeneity of intrahepatic biliary epithelial cells (BECs) is challenging and tools for identifying BEC subpopulations are limited. Here, we characterize the expression of a Sox9EGFP transgene in the liver and demonstrate that GFP expression levels are associated with distinct cell types. Methods Sox9EGFP BAC transgenic mice were assayed by immunofluorescence
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Inhibition of Dot1L Alleviates Fulminant Hepatitis through Myeloid Derived Suppressor Cells Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-23 Wanlin Yang; Hongshuang Yu; Jiefang Huang; Xiang Miao; Qiwei Wang; Yanan Wang; Yiji Cheng; Shan He; Fang Zhao; Lijun Meng; Bei Wang; Fengtao Qian; Xiaohui Ren; Min Jin; Yuting Gu; Yanyun Zhang; Wei Cai
Background & Aims Fulminant hepatitis (FH) is a clinical syndrome characterized by sudden and severe liver dysfunction. Dot1L, a histone methyltransferase, is implicated in various physiologic and pathologic processes, including transcription regulation and leukemia. However, the role of Dot1L in regulating inflammatory responses during FH remains elusive. Methods Propionibacterium acnes (P. acnes)-primed
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p53-independent induction of p21 fails to control regeneration and hepatocarcinogenesis in a murine liver injury model Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-21 Laura Elisa Buitrago-Molina; Silke Marhenke; Diana Becker; Robert Geffers; Timo Itzel; Andreas Teufel; Hartmut Jaeschke; André Lechel; Kristian Unger; Jovana Markovic; Amar Deep Sharma; Jens U. Marquardt; Michael Saborowski; Anna Saborowski; Arndt Vogel
Background and aims A coordinated stress and regenerative response is important following hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the CHK2/p53/p21-pathway in a murine model of metabolic liver injury. Methods NTBC was reduced or withdrawn in Fah-/- mice lacking Chk2, p53 or p21, and survival, tumor development, liver injury
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Pharmacological normalization of pancreatic cancer-associated fibroblast secretome impairs pro-metastatic cross-talk with macrophages Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-20 R. Samain; A. Brunel; T. Douché; M. Fanjul; S. Cassant-Sourdy; J. Rochotte; J. Cros; C. Neuzillet; J. Raffenne; C. Duluc; A. Perraud; J. Nigri; V. Gigoux; I. Bieche; M. Ponzo; G. Carpentier; I. Cascone; R. Tomasini; C. Bousquet
Background & Aims Cancer associated fibroblasts (CAFs) from pancreatic adenocarcinoma (PDA) present high protein synthesis rates. CAFs express the G protein-coupled somatostatin receptor sst1. The sst1 agonist SOM230 blocks CAF pro-tumoral features in vitro and in immunocompromised mice. We have explored here the therapeutic potential of SOM230, and underlying mechanisms, in immunocompetent models
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Exposure to p40 in early life prevents intestinal inflammation in adulthood through inducing a long-lasting epigenetic imprint on TGFβ Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-19 Yilin Deng; Oliver G. McDonald; Anna L. Means; Richard M. Peek; M. Kay Washington; Sari A. Acra; D. Brent Polk; Fang Yan
Background & Aims Colonization by the gut microbiota in early life confers beneficial effects on immunity throughout the host lifespan. We sought to elucidate the mechanisms whereby neonatal supplementation with p40, a probiotic functional factor, reprograms intestinal epithelial cells (IECs) for protection against adult-onset intestinal inflammation. Methods p40 was used to treat young adult mouse
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The ubiquitin E3 ligase TRIM21 promotes hepatocarcinogenesis by suppressing the p62-Keap1-Nrf2 antioxidant pathway Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-19 Fang Wang; Ye Zhang; Jianliang Shen; Bin Yang; Weiwei Dai; Junrong Yan; Sara Maimouni; Heineken Q. Daguplo; Sara Coppola; Yingtang Gao; Yijun Wang; Zhi Du; Kesong Peng; Hui Liu; Qin Zhang; Fei Tang; Peng Wang; Shenglan Gao; Wei-Xing Zong
Background and Aims TRIM21 is a ubiquitin E3 ligase that is implicated in numerous biological processes including immune response, cell metabolism, redox homeostasis, and cancer development. We recently reported that TRIM21 can negatively regulate the p62-Keap1-Nrf2 antioxidant pathway by ubiquitylating p62 and prevents its oligomerization and protein sequestration function. As redox homeostasis plays
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Complement-5 inhibition deters progression of fulminant hepatitis to acute liver failure in murine models Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-12 Jiro Kusakabe; Koichiro Hata; Hidetaka Miyauchi; Tetsuya Tajima; Yi Wang; Ichiro Tamaki; Junya Kawasoe; Yusuke Okamura; Xiangdong Zhao; Tatsuya Okamoto; Tatsuaki Tsuruyama; Shinji Uemoto
Background & Aims Acute liver failure (ALF) is a life-threatening condition with limited treatment alternatives. ALF pathogenesis seemingly involves the complement system. However, no complement-targeted intervention has been clinically applied. In this study, we aimed to investigate the potential of Complement-5 (C5)-targeted ALF treatment. Methods ALF was induced in C5-knockout (KO, B10D2/oSn) mice
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Hepatocyte-specific loss of PPARγ protects mice from NASH, and increases the therapeutic effects of rosiglitazone in the liver. Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-11 Samuel M. Lee; Carolina M. Pusec; Gregory H. Norris; Adam De Jesus; Alberto Diaz-Ruiz; Jose Muratalla; Andre Sarmento-Cabral; Grace Guzman; Brian T. Layden; Jose Cordoba-Chacon
Background and aims Non-alcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and ALT, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma
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scRNA-sequencing reveals new enteric nervous system roles for GDNF, NRTN, and TBX3 Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-11 Christina M. Wright; Sabine Schneider; Kristen M. Smith-Edwards; Fernanda Mafra; Anita J.L. Leembruggen; Michael V. Gonzalez; Deepika R. Kothakapa; Jessica B. Anderson; Beth A. Maguire; Tao Gao; Tricia A. Missall; Marthe J. Howard; Joel C. Bornstein; Brian M. Davis; Robert O. Heuckeroth
Background and aims Bowel function requires coordinated activity of diverse enteric neuron subtypes. Our aim was to define gene expression in these neuron subtypes to facilitate development of novel therapeutic approaches to treat devastating enteric neuropathies, and to learn more about enteric nervous system function. Methods To identify subtype-specific genes, we performed single-nucleus RNA-seq
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Norovirus-Specific CD8+ T Cell Responses in Human Blood and Tissues Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-11 Ajinkya Pattekar; Lena S. Mayer; Chi Wai Lau; Chengyang Liu; Olesya Palko; Meenakshi Bewtra; H.P.A.P. Consortium; Lisa C. Lindesmith; Paul D. Brewer-Jensen; Ralph S. Baric; Michael R. Betts; Ali Naji; E. John Wherry; Vesselin T. Tomov
Background & Aims Noroviruses (NoVs) are the leading cause of acute gastroenteritis worldwide and are associated with significant morbidity and mortality. Moreover, an asymptomatic carrier state can persist following acute infection, promoting NoV spread and evolution. Thus, defining immune correlates of NoV protection and persistence is needed to guide the development of future vaccines and limit
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Interleukin-1β Suppresses Gastrin via Primary Cilia and Induces Antral Hyperplasia Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-10 Lin Ding; Erica A. Sontz; Milena Saqui-Salces; Juanita L. Merchant
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Preventing Colitis-associated Colon Cancer with antioxidants: A systematic Review Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2021-01-05 Thergiory Irrazabal; Bhupesh K. Thakur; Kenneth Croitoru; Alberto Martin
Inflammatory bowel disease (IBD) patients have an increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Several studies have shown that IBD patients have signs of increased oxidative damage, which could be a result of genetic and environmental factors, such as an excess in oxidant molecules
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Predicting HCC Response to Multikinase Inhibitors with In Vivo Cirrhotic Mouse Model for Personalized Therapy Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-12-16 Daniel Q. Huang; Mark D. Muthiah; Lei Zhou; Halisah Jumat; Wan Xin Tan; Guan Huei Lee; Seng Gee Lim; Alfred Kow; Glenn Bonney; Iyer Shridhar; Yi Ting Lim; Aileen Wee; Yin Huei Pang; Gwyneth Soon; Pierce Chow; Yock Young Dan
Background & Aims Hepatocellular carcinoma (HCC) arises in a cirrhotic, pro-angiogenic microenvironment. Inhibiting angiogenesis is a key mode of action of multikinase inhibitors and current non-cirrhotic models are unable to predict treatment response. We present a novel mouse cirrhotic model of xenotransplant that predicts the natural biology of HCC and allows personalized therapy. Methods Cirrhosis
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Single-cell transcriptomics reveals zone-specific alterations of liver sinusoidal endothelial cells in cirrhosis Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-12-16 Tingting Su; Yilin Yang; Sanchuan Lai; Jain Jeong; Yirang Jung; Matthew McConnell; Teruo Utsumi; Yasuko Iwakiri
Background Dysfunction of liver sinusoidal endothelial cells (LSECs) is permissive for the progression of liver fibrosis/cirrhosis and responsible for its clinical complications. Here, we have mapped the spatial distribution of heterogeneous liver ECs in normal versus cirrhotic mouse livers and identified zone-specific transcriptomic changes of LSECs associated with liver cirrhosis using single-cell
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Mesenteric neural crest cells are the embryological basis of skip segment Hirschsprung’s disease Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-12-16 Qi Yu; Mengjie Du; Wen Zhang; Li liu; Zhigang Gao; Wei Chen; Yan Gu; Kun Zhu; Xueyuan Niu; Qiming Sun; Liang Wang
BACKGROUND & AIMS Defective rostrocaudal colonization of the gut by vagal neural crest cells (vNCCs) results in Hirschsprung's disease (HSCR), which is characterized by aganglionosis in variable lengths of the distal bowel. Skip segment Hirschsprung’s disease (SSHD), referring to a ganglionated segment within an otherwise aganglionic intestine, contradicts HSCR pathogenesis and underscores a significant
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The glucocorticoid receptor in intestinal epithelial cells alleviates colitis and associated colorectal cancer in mice Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-12-13 Chiara Muzzi; Norika Watanabe; Eric Twomey; Garrit K. Meers; Holger M. Reichardt; Hanibal Bohnenberger; Sybille D. Reichardt
Background & Aims Inflammatory bowel disease is commonly treated by administration of glucocorticoids. While the importance of intestinal epithelial cells for the pathogenesis of this disorder is widely accepted, their role as target cells for glucocorticoids has not been explored. To address this issue, we induced colonic inflammation in GRvillin mice, which carry an inducible deletion of the glucocorticoid
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MAdCAM-1/α4β7 Integrin-Mediated Lymphocyte/Endothelium Interactions Exacerbate Acute Immune-Mediated Hepatitis in Mice Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-12-13 Angela Schippers; Jessica Hübel; Felix Heymann; Thomas Clahsen; Sreepradha Eswaran; Sarah Schlepütz; Robin Püllen; Nikolaus Gaßler; Klaus Tenbrock; Frank Tacke; Norbert Wagner
BACKGROUND & AIMS Aberrant lymphocyte homing could potentially link inflammatory processes in the intestine and the liver, as distinct hepatobiliary diseases frequently develop as extra-intestinal manifestations in inflammatory bowel disease. In this study, we examined the role of the gut-tropic leukocyte adhesion molecule β7 integrin and its endothelial ligand mucosal addressin cell-adhesion molecule-1
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Cholangiopathy and biliary fibrosis in Cyp2c70-deficient mice are fully reversed by ursodeoxycholic acid Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-12-10 J.F. de Boer; H.D. de Vries; A. Palmiotti; R. Li; M. Doestzada; J.A. Hoogerland; J. Fu; A.M. La Rose; M. Westerterp; N.L. Mulder; M.V. Hovingh; M. Koehorst; N.J. Kloosterhuis; J.C. Wolters; V.W. Bloks; J.T. Haas; D. Dombrowicz; B. Staels; F. Kuipers
Background and Aims Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential
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Innate lymphoid cells and celiac disease: current perspective Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-12-10 Xuechen Yu; Justin Vargas; Peter HR. Green; Govind Bhagat
Celiac disease (CD) is a common autoimmune disease triggered by the ingestion of gluten in genetically susceptible individuals. Although the mechanisms underlying gliadin-mediated activation of adaptive immunity in CD have been well characterized, regulation of innate immune responses and functional roles of different immune cell populations within the epithelium and lamina propria are not well understood
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A mitochondrial DNA variant elevates the risk of gallstone disease by altering mitochondrial function Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-12-04 Dayan Sun; Zhenmin Niu; Hong-Xiang Zheng; Fei Wu; Liuyiqi Jiang; Tian-Quan Han; Yang Wei; Jiucun Wang; Li Jin
Background and aims Gallstone disease (cholelithiasis) is a cholesterol-related metabolic disorders with strong familial predisposition. Mitochondrial DNA (mtDNA) variants accumulated during human evolution are associated with some metabolic disorders related to modified mitochondrial function. The mechanistic links between mtDNA variants and gallstone formation need further exploration. Methods In
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The A150V polymorphism of genotype 3 hepatitis C virus polymerase inhibits interferon alfa by suppressing protein kinase R activation. Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-26 Wing-Yiu Jason Lee; Meleri Jones; Peter A.C. Wing; Swathi Rajagopal; Graham R. Foster
Background and aims Despite recent advances in antiviral therapy for HCV, a proportion of patients with genotype 3 (G3) HCV infection do not respond to current all oral treatment regimens [1,2]. Genomic analyses have identified key polymorphisms correlating with increased resistance to direct-acting antivirals (DAAs). We previously reported that amino acid polymorphisms (A150V and K206E) in the polymerase
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Acute intestinal inflammation depletes/recruits histamine-expressing myeloid cells from the bone marrow leading to exhaustion of MB-HSCs Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-26 Na Fu; Feijing Wu; Zhengyu Jiang; Woosook Kim; Tuo Ruan; Ermanno Malagola; Yosuke Ochiai; Osmel Companioni Nápoles; Giovanni Valenti; Ruth A. White; Bryana R. Belin; Leah B. Zamechek; Jonathan S. LaBella; Timothy C. Wang
AIM Histidine decarboxylase (HDC), the histamine-synthesizing enzyme, is expressed in a subset of myeloid cells but also marks quiescent myeloid-biased hematopoietic stem cells (MB-HSCs) that are activated upon myeloid demand injury. However, the role of MB-HSCs in dextran sulfate sodium (DSS) - induced acute colitis has not been addressed. Method We investigated HDC+ MB-HSCs and myeloid cells by flow
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Controversies Surrounding the Origin of Hepatocytes in Adult Livers and the in Vitro Generation or Propagation of Hepatocytes Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-28 Nicole Min Qian Pek; Kevin J. Liu; Massimo Nichane; Lay Teng Ang
Epithelial cells in the liver (known as hepatocytes) are high-performance engines of myriad metabolic functions and versatile responders to liver injury. As hepatocytes metabolize amino acids, alcohol, drugs, and other substrates, they produce and are exposed to a milieu of toxins and harmful byproducts that can damage themselves. In the healthy liver, hepatocytes generally divide slowly. However,
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Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-24 Yoshimi Nakagawa; Yunong Wang; Song-iee Han; Kanako Okuda; Asayo Oishi; Yuka Yagishita; Kae Kumagai; Hiroshi Ohno; Yoshinori Osaki; Yuhei Mizunoe; Masaya Araki; Yuki Murayama; Hitoshi Iwasaki; Morichika Konishi; Nobuyuki Itoh; Takashi Matsuzaka; Hirohito Sone; Nobuhiro Yamada; Hitoshi Shimano
Background and Aims cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis
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Intestinal Phospholipid Disequilibrium Initiates an ER Stress Response that Drives Goblet Cell Necroptosis and Spontaneous Colitis in Mice Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-22 John P. Kennelly; Stephanie Carlin; Tingting Ju; Jelske N. van der Veen; Randal C. Nelson; Jean Buteau; Aducio Thiesen; Caroline Richard; Ben P. Willing; René L. Jacobs
Background and aims Patients with ulcerative colitis have low concentrations of the major membrane lipid phosphatidylcholine (PC) in gastrointestinal mucus, suggesting that defects in colonic PC metabolism might be involved in the development of colitis. To determine the precise role that PC plays in colonic barrier function, we examined mice with intestinal epithelial cell (IEC)-specific deletion
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Propionate Enhances Cell Speed and Persistence to Promote Intestinal Epithelial Turnover and Repair Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-22 Anthony J. Bilotta; Chunyan Ma; Wenjing Yang; Yanbo Yu; Yu Yu; Xiaojing Zhao; Zheng Zhou; Suxia Yao; Sara M. Dann; Yingzi Cong
Background and Aims Gut bacteria-derived short-chain fatty acids (SCFAs) play crucial roles in the maintenance of intestinal homeostasis. However, how SCFAs regulate epithelial turnover and tissue repair remain incompletely understood. In this study, we investigated how the SCFA propionate regulates cell migration to promote epithelial renewal and repair. Methods Mouse small intestinal epithelial cells
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Distinct and overlapping roles of Hippo effectors YAP and TAZ during human and mouse hepatocarcinogenesis Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-21 Haichuan Wang; Jingxiao Wang; Shanshan Zhang; Jiaoyuan Jia; Xianqiong Liu; Jie Zhang; Pan Wang; Xinhua Song; Li Che; Ke Liu; Silvia Ribback; Antonio Cigliano; Matthias Evert; Hong Wu; Diego F. Calvisi; Yong Zeng; Xin Chen
Background & Aims Yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ) are two co-activators downstream of Hippo tumor suppressor cascade. Both have been implicated in the development of hepatocellular carcinoma (HCC). However, whether YAP and TAZ have distinct or overlapping functions during hepatocarcinogenesis remains unknown. Methods Expression
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A novel PAK1-Notch1 axis regulates crypt homeostasis in intestinal inflammation Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-12 Adrian Frick; Vineeta Khare; Kristine Jimenez; Kyle Dammann; Michaela Lang; Anita Krnjic; Christina Gmainer; Maximilian Baumgartner; Ildiko Mesteri; Christoph Gasche
Background&Aims PAK1 belongs to a family of serine-threonine kinases and contributes to cellular pathways like NFκB, MAPK, PI3K/AKT and Wnt/ β-catenin all of which are involved in intestinal homeostasis. Overexpression of PAK1 is linked to IBD as well as colitis-associated cancer (CAC) and similar was observed in IL-10 KO mice, a model of colitis and CAC. Here we tested the effects of PAK1 deletion
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Intestinal dysbiosis amplifies acetaminophen induced acute liver injury Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-12 Kai Markus Schneider; Carsten Elfers; Ahmed Ghallab; Carolin Victoria Schneider; Eric JC. Galvez; Antje Mohs; Wenfang Gui; Lena Susanna Candels; Theresa Hildegard Wirtz; Sebastian Zuehlke; Michael Spiteller; Maiju Myllys; Alain Roulet; Amirouche Ouzerdine; Benjamin Lelouvier; Konrad Kilic; Lijun Liao; Anika Nier; Christian Trautwein
Background&Aims Acute liver failure (ALF) represents an unmet medical need in Western countries. While the link between intestinal dysbiosis and chronic liver disease is well established, there is little evidence for a functional role of gut-liver interaction during ALF. Here, we hypothesized that intestinal dysbiosis may affect ALF. Methods To test this hypothesis, we assessed the association of proton
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Loss of RNF43 function contributes to gastric carcinogenesis by impairing DNA damage response Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-11 Victoria Neumeyer; Anna Brutau-Abia; Michael Allgäuer; Nicole Pfarr; Wilko Weichert; Christina Falkeis-Veits; Elisabeth Kremmer; Michael Vieth; Markus Gerhard; Raquel Mejías-Luque
Background & Aims RING Finger Protein 43 (RNF43) is a tumor suppressor that is frequently mutated in gastric tumors. The link between RNF43 and modulation of WNT signaling has not been clearly demonstrated in the stomach. As mutations in RNF43 are highly enriched in microsatellite-instable gastric tumors, which show defects in DDR, we investigated whether RNF43 is involved in DDR in the stomach. Methods
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Drug inhibition of SARS-CoV-2 replication in human pluripotent stem cell-derived intestinal organoids Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-10 Jana Krüger; Rüdiger Groß; Carina Conzelmann; Janis A. Müller; Lennart Koepke; Konstantin M.J. Sparrer; Tatjana Weil; Desirée Schütz; Thomas Seufferlein; Thomas F.E. Barth; Steffen Stenger; Sandra Heller; Jan Münch; Alexander Kleger
Background and aims The COVID-19 pandemic has spread worldwide and poses a severe health risk. While most patients present mild symptoms, descending pneumonia can lead to severe respiratory insufficiency. Up to 50% of patients show gastrointestinal symptoms like diarrhea or nausea, intriguingly associating with prolonged symptoms and increased severity. Thus, models to understand and validate drug
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Inflammation-associated senescence promotes Helicobacter pylori-induced atrophic gastritis Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-11-05 Qinbo Cai; Peng Shi; Yujie Yuan; Jianjun Peng; Xinde Ou; Wen Zhou; Jin Li; Taiqiang Su; Liangliang Lin; Shirong Cai; Yulong He; Jianbo Xu
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Chaperones and ubiquitin ligases balance mutant p53 protein stability in esophageal and other digestive cancers Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-31 May San Martinho; Derek J. Nancarrow; Theodore S. Lawrence; David G. Beer; Dipankar Ray
The incidence of esophageal adenocarcinoma (EAC) and other gastrointestinal (GI) cancers have risen dramatically, thus defining the oncogenic drivers to develop effective therapies are necessary. Patients with Barrett’s Esophagus (BE), have an elevated risk of developing EAC. Around 70-80% of BE cases that progress to dysplasia and cancer have detectable TP53 mutations. Similarly, in other GI cancers
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Hepatic autophagy deficiency remodels gut microbiota for an adaptive protection via FGF15-FGFR4 signaling Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-23 Shengmin Yan; Bilon Khambu; Xiaoyun Chen; Zheng Dong; Grace Guo; Xiao-Ming Yin
Background & Aims The functions of the liver and the intestine are closely tied in both physiological and pathological conditions. The gut microbiota (GM) often causes deleterious effects during hepatic pathogenesis. Autophagy is essential for liver homeostasis, but the impact of hepatic autophagy function on liver-gut interaction remains unknown. Here, we investigated the effect of hepatic autophagy
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Confusion on cell fusion Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-22 Rana Ramadan; Louis Vermeulen
Cell fusion, whereby two cells merge to create one, has been widely described in development, but the role of cell fusion in tissue regeneration and homeostasis remains an open debate. We propose that the regenerative capacity of the gut can be fully attributed to extensive plasticity of the intestinal epithelium.
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The Fragile X Mental Retardation Protein regulates RIP1K and colorectal cancer resistance to necroptosis Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-19 Antonio Di Grazia; Irene Marafini; Giorgia Pedini; Davide Di Fusco; Federica Laudisi; Vincenzo Dinallo; Eleonora Rosina; Carmine Stolfi; Eleonora Franzè; Pierpaolo Sileri; Giuseppe Sica; Giovanni Monteleone; Claudia Bagni; Ivan Monteleone
Background & Aims The Fragile X Mental Retardation Protein (FMRP) affects multiple steps of the mRNA metabolism during brain development and in different neoplastic processes. However, the contribution of FMRP in colon carcinogenesis has not been investigated. Methods FMRP transcripts and proteins expression were analyzed in human colon samples derived from patients with sporadic CRC and healthy subjects
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Nanoparticle-Mediated Delivery of 2-Deoxy-D-Glucose Induces Antitumor Immunity and Cytotoxicity in Liver Tumors in Mice Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-24 Kyo Sasaki; Sohji Nishina; Akira Yamauchi; Kotaro Fukuda; Yuichi Hara; Masahiro Yamamura; Kensuke Egashira; Keisuke Hino
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Claudin-18 Loss Alters Transcellular Chloride Flux but not Tight Junction Ion Selectivity in Gastric Epithelial Cells Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-16 Tyler J. Caron; Kathleen E. Scott; Nishita Sinha; Sureshkumar Muthupalani; Mahnoor Baqai; Lay-Hong Ang; Yue Li; Jerrold R. Turner; James G. Fox; Susan J. Hagen
Background & aims Tight junctions form a barrier to the paracellular passage of luminal antigens. Although most tight junction proteins reside within the apical tight junction complex, claudin-18 localizes mainly to the basolateral membrane where its contribution to paracellular ion transport is undefined. Claudin-18 loss in mice results in gastric neoplasia development and tumorigenesis that may or
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Deficient Endoplasmic Reticulum Acetyl-CoA Import in Pancreatic Acinar Cells Leads to Chronic Pancreatitis Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-17 Michelle M. Cooley; Diana D.H. Thomas; Kali Deans; Yajing Peng; Aurelia Lugea; Stephen J. Pandol; Luigi Puglielli; Guy E. Groblewski
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S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-17 Linqiang Zhang; Zhiguo Zhang; Chengbin Li; Tingting Zhu; Jing Gao; Hu Zhou; Yingzhuan Zheng; Qing Chang; Mingshan Wang; Jieyu Wu; Liyuan Ran; Yingjie Wu; Huilai Miao; Xiaoju Zou; Bin Liang
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Fibrinogen/AKT/Microfilament Axis Promotes Colitis by Enhancing Vascular Permeability Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-17 Chong Zhang; Honglv Chen; Qiaoling He; Yiqin Luo; Andong He; Ailin Tao; Jie Yan
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Soluble epoxide hydrolase hepatic deficiency ameliorates alcohol-associated liver disease Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-15 Aline Mello; Ming-Fo Hsu; Shinichiro Koike; Bryan Chu; Jeff Cheng; Jun Yang; Christophe Morisseau; Natalie J. Torok; Bruce D. Hammock; Fawaz G. Haj
Background & Aims Alcohol-associated liver disease (ALD) is a significant cause of liver-related morbidity and mortality worldwide and with limited therapies. Soluble epoxide hydrolase (sEH; Ephx2) is a largely cytosolic enzyme that is highly expressed in the liver and is implicated in hepatic function, but its role in ALD has heretofore remained uncharted. Methods To decipher the role of hepatic sEH
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Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-16 Chiara Lasconi; Matthew C. Pahl; Diana L. Cousminer; Claudia A. Doege; Alessandra Chesi; Kenyaita M. Hodge; Michelle E. Leonard; Sumei Lu; Matthew E. Johnson; Chun Su; Reza K. Hammond; James A. Pippin; Natalie A. Terry; Louis R. Ghanem; Rudolph L. Leibel; Andrew D. Wells; Struan F.A. Grant
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Impaired duodenal Palmitoylethanolamide release underlies acid-induced mast cells activation in Functional Dyspepsia Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-14 Giovanni Sarnelli; Marcella Pesce; Luisa Seguella; Jie Lu; Eleonora Efficie; Jan Tack; Fatima Domenica Elisa De Palma; Alessandra D’Alessandro; Giuseppe Esposito
Background and aims Acid hypersensitivity is claimed to be a symptomatic trigger in functional dyspepsia (FD); however, the neuroimmune pathway(s) and the mediators involved in this process have not been systematically investigated. Palmitoylethanolamide (PEA) is an endogenous compound, able to modulate nociception and inflammation, but its role in FD has never been assessed. Methods Duodenal biopsies
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SARS-CoV-2 induces a more robust innate immune response and replicates less efficiently than SARS-CoV in the human intestines: an ex vivo study with implications on pathogenesis of COVID-19 Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-10-01 Hin Chu; Jasper Fuk-Woo Chan; Yixin Wang; Terrence Tsz-Tai Yuen; Yue Chai; Huiping Shuai; Dong Yang; Bingjie Hu; Xiner Huang; Xi Zhang; Yuxin Hou; Jian-Piao Cai; Anna Jinxia Zhang; Jie Zhou; Shuofeng Yuan; Kelvin Kai-Wang To; Ivan Fan-Ngai Hung; Tan To Cheung; Kwok-Yung Yuen
Background And Aims Besides prominent respiratory involvement, gastrointestinal manifestations are commonly reported in Coronavirus Disease 2019 (COVID-19) patients. We compared infection of ex vivo human intestinal tissues by SARS-CoV-2 and SARS-CoV with respect to their replication kinetics and immune activation profile. Methods Human intestinal tissues were obtained from patients while undergoing
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Crohn’s disease pathobiont adherent-invasive E. coli disrupts epithelial mitochondrial networks with implications for gut permeability Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-28 Nicole L. Mancini; Sruthi Rajeev; Timothy S. Jayme; Arthur Wang; Åsa V. Keita; Matthew L. Workentine; Samira Hamed; Johan D. Söderholm; Fernando Lopes; Timothy E. Shutt; Jane Shearer; Derek M. McKay
Background & Aims Adherent-invasive E. coli (AIEC) are implicated in inflammatory bowel disease (IBD), and mitochondrial dysfunction has been observed in IBD-patient biopsies. As a novel aspect of AIEC-epithelial interaction we hypothesized that E. coli (strain LF82) would elicit substantial disruption of epithelial mitochondrial form and function. Methods Monolayers of human colon-derived epithelial
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Findings of Severe Hepatic SARS-CoV-2 Infection Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-28 M. Isabel Fiel; Siraj M. El Jamal; Alberto Paniz-Mondolfi; Ronald E. Gordon; Jason Reidy; Jela Bandovic; Rashmi Advani; Saikiran Kilaru; Kamron Pourmand; Stephen Ward; Swan N. Thung; Thomas Schiano
Background and Aims Liver injury due to COVID-19 is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients. Methods: The current report details the clinical courses of two patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light
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Inducible deletion of YAP and TAZ in adult mouse smooth muscle causes rapid and lethal colonic pseudo-obstruction Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-28 Fatima Daoud; Johan Holmberg; Azra Alajbegovic; Mario Grossi; Catarina Rippe; Karl Swärd; Sebastian Albinsson
Background & Aims YAP (Yap1) and TAZ (Wwtr1) are transcriptional co-activators and downstream effectors of the Hippo pathway, which play crucial roles in organ size control and cancer pathogenesis. Genetic deletion of YAP/TAZ has revealed their critical importance for embryonic development of the heart, vasculature and gastrointestinal mesenchyme. The aim of this study was to determine the functional
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Tristetraprolin promotes hepatic inflammation and tumor initiation but restrains cancer progression to malignancy. Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-25 Dobrochna Dolicka; Cyril Sobolewski; Monika Gjorgjieva; Marta Correia de Sousa; Flavien Berthou; Claudio De Vito; Didier J. Colin; Olivia Bejuy; Margot Fournier; Christine Maeder; Perry J. Blackshear; Laura Rubbia-Brandt; Michelangelo Foti
Background & Aims Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular
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Aspirin rescues Wnt-driven stem-like phenotype in human intestinal organoids and increases the Wnt antagonist Dickkopf-1 Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-22 Karen Dunbar; Asta Valanciute; Ana Lima; Paz Freile Vinuela; Thomas Jamieson; Vidya Rajasekaran; James Blackmur; Anna-Maria Ochocka-Fox; Alice Guazzelli; Patrizia Cammareri; Mark J. Arends; Owen J. Sansom; Kevin B. Myant; Susan M. Farrington; Malcolm G. Dunlop; Farhat V.N. Din
Background & aims Aspirin reduces colorectal cancer (CRC) incidence and mortality. Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use. Wnt signalling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations (CSC). Here, we
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Vitamin A in Nonalcoholic Fatty Liver Disease: A Key Player in an Offside Position? Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-21 Carmen Berasain,Matias A Avila
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Dietary Fructose Alters the Composition, Localization and Metabolism of Gut Microbiota in Association with Worsening Colitis. Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-20 David C Montrose,Ryohei Nishiguchi,Srijani Basu,Hannah A Staab,Xi Kathy Zhou,Hanhan Wang,Lingsong Meng,Melanie Johncilla,Juan R Cubillos-Ruiz,Diana K Morales,Martin T Wells,Kenneth W Simpson,Shiying Zhang,Belgin Dogan,Chen Jiao,Zhangjun Fei,Akihiko Oka,Jeremy W Herzog,R Balfour Sartor,Andrew J Dannenberg
Background & Aims The incidence of inflammatory bowel diseases has increased over the last half century, suggesting a role for dietary factors. Fructose consumption has increased in recent years. Recently, a high fructose diet (HFrD) was shown to enhance DSS-induced colitis in mice. The primary objectives of the current study were to elucidate the mechanism(s) underlying the pro-colitic effects of
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Oxidized Low-Density Lipoprotein drives dysfunction of the liver lymphatic system. Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-19 Matthew A Burchill,Jeffrey M Finlon,Alyssa R Goldberg,Austin E Gillen,Petra A Dahms,Rachel H McMahan,Anne Tye,Andrew B Winter,Julie A Reisz,Eric Bohrnsen,Johnathon B Schafer,Angelo D'Alessandro,David J Orlicky,Michael S Kriss,Hugo R Rosen,Rebecca L McCullough,Beth A Jirón Tamburini
Background and Aims As the incidence of nonalcoholic steatohepatitis (NASH) continues to rise, understanding how normal liver functions are affected during disease is required before developing novel therapeutics which could reduce morbidity and mortality. However, very little is understood about how the transport of proteins and cells from the liver by the lymphatic vasculature is affected by inflammatory
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Liver Pyruvate Kinase Promotes NAFLD/NASH in both Mice and Humans in a Sex-Specific Manner. Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-14 Karthickeyan Chella Krishnan,Raquel R Floyd,Simon Sabir,Dulshan W Jayasekera,Paola V Leon-Mimila,Anthony E Jones,Angel A Cortez,Varun Shravah,Miklós Péterfy,Linsey Stiles,Samuel Canizales-Quinteros,Ajit S Divakaruni,Adriana Huertas-Vazquez,Aldons J Lusis
BACKGROUND AND AIMS The etiology of non-alcoholic fatty liver disease (NAFLD) is poorly understood, with males and certain populations exhibiting markedly increased susceptibility. Using a systems genetics approach, involving multi-omic analysis of ∼100 diverse inbred strains of mice, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these, liver pyruvate
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Aryl hydrocarbon receptor activity in hepatocytes sensitizes to hyperacute acetaminophen-induced hepatotoxicity in mice. Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-12 Fenja A Schuran,Christoph Lommetz,Andreas Steudter,Ahmed Ghallab,Björn Wieschendorf,Dorothee Schwinge,Sebastian Zuehlke,Joerg Reinders,Joerg Heeren,Ansgar W Lohse,Christoph Schramm,Johannes Herkel,Antonella Carambia
Background & Aims Acetaminophen (APAP)-induced liver injury is one of the most common causes of acute liver failure, however, a clear definition of sensitizing risk factors is lacking. Here, we investigated the role of the ligand-activated transcription factor aryl hydrocarbon receptor (Ahr) in APAP-induced liver injury. We hypothesized that Ahr, which integrates environmental, dietary, microbial and
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Cancer-associated fibroblasts provide a stromal niche for liver cancer organoids that confers trophic effects and therapy resistance. Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-12 Jiaye Liu,Pengfei Li,Ling Wang,Meng Li,Zhouhong Ge,Lisanne Noordam,Ruby Lieshout,Monique M A Verstegen,Buyun Ma,Junhong Su,Qin Yang,Ruyi Zhang,Guoying Zhou,Lucia Campos Carrascosa,Dave Sprengers,Jan N M IJzermans,Ron Smits,Jaap Kwekkeboom,Luc J W van der Laan,Maikel P Peppelenbosch,Qiuwei Pan,Wanlu Cao
Background & Aims Cancer associated fibroblasts (CAFs) play a key role in cancer process, but the research progress is hampered by the paucity of preclinical models essential for mechanistic dissection of cancer cell-CAF interactions. Here, we aim to establish a 3D organotypic co-cultures of primary liver tumor-derived organoids with CAFs, and to understand their interactions and the response to treatment
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NTCP deficiency causes gallbladder abnormalities in mouse and human. Cell. Mol. Gastroenterol. Hepatol. (IF 7.076) Pub Date : 2020-09-09 Fengfeng Mao,Meng-Xuan Wang,Xinfeng Hou,Zhongmin Zhou,Yan-Yan Yan,Ling-Juan Fang,Zexi Tan,Wei-Yuan Fang,Teng Liu,Wenhui He,Cong Li,Xin-Bao Xie,Shi-Qi Lu,Jianhua Sui,Fengchao Wang,Lun Han,Jian-She Wang,Wenhui Li
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