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| Open AccessClinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease
This study characterizes expression of pharmacogenes across the histological NAFLD severity spectrum. Here, the authors show the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.
- Nicholas R. Powell
- , Tiebing Liang
- & Naga Chalasani
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Article
| Open AccessBlocking Dectin-1 prevents colorectal tumorigenesis by suppressing prostaglandin E2 production in myeloid-derived suppressor cells and enhancing IL-22 binding protein expression
The effect of β-glucans and their receptor Dectin-1 in tumor development remains controversial. Here the authors show that Dectin-1 signaling promotes the development of colorectal cancer (CRC) by inducing prostaglandin E2 production in myeloid-derived suppressor cells and by suppressing IL-22BP expression, suggesting dectin-1 blockade as a potential therapeutic target for CRC.
- Ce Tang
- , Haiyang Sun
- & Yoichiro Iwakura
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| Open AccessDeficiency of gluconeogenic enzyme PCK1 promotes metabolic-associated fatty liver disease through PI3K/AKT/PDGF axis activation in male mice
Phosphoenolpyruvate carboxykinase 1 (Pck1) is an enzyme involved in glucose production that also regulates lipogenesis and has been linked to liver steatosis. Here the authors report that deficiency of Pck1 in the liver leads to nonalcoholic fatty liver disease via activation of the RhoA/PI3K/AKT pathway in a study with male mice.
- Qian Ye
- , Yi Liu
- & Ni Tang
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| Open AccessMicrobiota alters the metabolome in an age- and sex- dependent manner in mice
Commensal microbes contribute considerably to mammalian metabolism. Here the authors report the relative contributions of microbiome, age and sex to metabolism throughout the body and uncover age- and sex- specificity in how microbes affect metabolite levels in mice.
- Kirsty Brown
- , Carolyn A. Thomson
- & Kathy D. McCoy
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| Open AccessGut microbiota alters host bile acid metabolism to contribute to intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy (ICP) is a liver disease that sometimes develops during pregnancy and is characterized by increased serum bile acid levels. Here the authors report that the gut microbiome species B. fragilis is enriched in patients with ICP and promotes ICP development in mice via inhibition of signalling though the bile acid receptor FXR.
- Bo Tang
- , Li Tang
- & Shiming Yang
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| Open AccessLong-term gastrointestinal outcomes of COVID-19
SARS-CoV-2 infection can lead to varied post-acute symptoms in the lungs and other organs, including the gastrointestinal system. Here the authors estimate the risks and 1-year burdens of a set of pre-specified incident gastrointestinal outcomes following SARS-CoV-2 infection in an electronic health care record-based cohort study.
- Evan Xu
- , Yan Xie
- & Ziyad Al-Aly
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| Open AccessMolecular imaging of liver inflammation using an anti-VCAM-1 nanobody
Here, the authors present a noninvasive tool to detect liver inflammation using nuclear imaging, as an alternative to biopsy. The prove the diagnostic power of this tool to detect liver inflammation in preclinical models of chronic liver disease.
- Maxime Nachit
- , Christopher Montemagno
- & Pascale Perret
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| Open AccessThe gut microbiome and early-life growth in a population with high prevalence of stunting
Here, using metagenomics, the authors show that the gut microbiome of rural Zimbabwean infants undergoes programmed maturation that is unresponsive to sanitation and nutrition interventions but is strongly associated with maternal HIV infection and can moderately predict linear growth.
- Ruairi C. Robertson
- , Thaddeus J. Edens
- & Amee R. Manges
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Article
| Open AccessSingle-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis
Peritoneal metastasis is one of the most common forms of death for gastrointestinal cancers, however, its cell composition is incompletely understood. Here, the authors use single cell RNA-seq of peritoneal metastases from 35 patients and show diversity in immune cells, and plasticity in cancer cell phenotypes and autophagy related genes as biomarkers of prognosis.
- Xuan-Zhang Huang
- , Min-Jiao Pang
- & Zhen-Ning Wang
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Article
| Open AccessIdentifying glycan consumers in human gut microbiota samples using metabolic labeling coupled with fluorescence-activated cell sorting
Dietary glycans are a major driver of the human gut microbiota composition. Here, the authors apply next-generation metabolic labeling coupled with fluorescence-activated cell sorting to identify and isolate gut bacteria consumers of dietary glycans in human stool samples, linking bacteria to the glycans they consume.
- Lharbi Dridi
- , Fernando Altamura
- & Bastien Castagner
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Article
| Open AccessMicrobially produced vitamin B12 contributes to the lipid-lowering effect of silymarin
Silymarin has been used for improving hepatic damage and lipid disorders, but its action mechanism remains to be clarified. Here, the authors reveal a mechanism of action underpinning the lipid-lowering effect of silymarin via the gut microbiota and its vitamin B12 producing capabilities.
- Wen-Long Sun
- , Sha Hua
- & Hong-Fang Ji
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Article
| Open AccessWestern diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol
Interplay of western diet and gut microbiota has been reported to be involved in the development of nonalcoholic steatohepatitis (NASH). Here the authors report that Blautia producta and 2-oleoylglycerol are bacterial and metabolic mediators that promote liver inflammation and hepatic fibrosis in male mice.
- Ming Yang
- , Xiaoqiang Qi
- & Guangfu Li
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Article
| Open AccessIn vivo detection of bile duct pre-cancer with endoscopic light scattering spectroscopy
Diagnosis of bile duct cancer often occur in advanced stages, leading to poor survival. Here, the authors combine light scattering and diffuse reflectance spectroscopies in a minimally invasive endoscopic technique for directly assessing the malignant potential of the bile duct lining, and demonstrate 97% detection accuracy.
- Douglas K. Pleskow
- , Mandeep S. Sawhney
- & Lev T. Perelman
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Article
| Open AccessSystematic review and individual-patient-data meta-analysis of non-invasive fibrosis markers for chronic hepatitis B in Africa
Authors carry out a systematic review and meta-analysis to evaluate the performance of fibrosis biomarkers for the diagnosis of fibrosis and cirrhosis in patients with chronic hepatitis B virus infection living in sub-Saharan Africa.
- Asgeir Johannessen
- , Alexander J. Stockdale
- & Maud Lemoine
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Article
| Open AccessPharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease
The Lin28/let-7 axis regulates metabolic pathways in normal and pathological contexts. Here the authors show that pharmacological inhibition of Lin28 protects against lipid accumulation in multiple preclinical models of nonalcoholic fatty liver disease.
- Evangelia Lekka
- , Aleksandra Kokanovic
- & Jonathan Hall
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Article
| Open AccessChronic exposure to synthetic food colorant Allura Red AC promotes susceptibility to experimental colitis via intestinal serotonin in mice
Allura Red AC is a dye used in food products. Here the authors report that chronic, long-term exposure to Allura Red AC increases susceptibility to experimental colitis in mice dependent on the serotonin biosynthetic enzyme TPH1, while intermittent exposure more typical for the human setting did not increase susceptibility to experimental colitis.
- Yun Han Kwon
- , Suhrid Banskota
- & Waliul I. Khan
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Article
| Open AccessThe role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction
Impaired liver metabolic function is related to mortality in severely malnourished children. Here the authors report a role for the tryptophan-NAD + pathway in reduced hepatic mitochondrial function and liver steatosis in a mouse model of severe malnutrition.
- Guanlan Hu
- , Catriona Ling
- & Robert H. J. Bandsma
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Article
| Open AccessA metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes
Hyperactivation of the toll-like receptors (TLRs) have been implicated as risk factors for more severe forms of disease in COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here the authors report that MBOAT7 is reduced in macrophages of patients with MAFLD and COVID-19, and acts as a negative regulator of TLR signalling.
- Jawaher Alharthi
- , Ali Bayoumi
- & Mohammed Eslam
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| Open AccessModular stimuli-responsive hydrogel sealants for early gastrointestinal leak detection and containment
Digestive surgical leaks manifesting days after a successful surgery can lead to severe complications and affect healthcare worldwide. Here, the authors address the problem holistically with a hydrogel patch capable of sealing tissues, while detecting imminent leaks via a smartphone-operated ultrasound probe.
- Alexandre H. C. Anthis
- , Maria Paulene Abundo
- & Inge K. Herrmann
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| Open AccessRestoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage
Drug induced liver injury (DILI) is an important cause acute liver failure. Here the authors report that serum Mg2+ serum levels decrease in patients with DILI as well as in preclinical animal models treated with acetaminophen overdose, and that early intervention targeting the Mg2+ transporter Cyclin M4 may be beneficial for acetaminophen overdose in preclinical models.
- Irene González-Recio
- , Jorge Simón
- & Maria L Martínez-Chantar
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Article
| Open AccessEnterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia
Enterotoxigenic Escherichia coli infections have been linked to non-diarrheal sequelae however, the reasons for this are unclear. Here, the authors present an additional role of heat-labile toxin in disrupting the structure and function of intestinal epithelial cells.
- Alaullah Sheikh
- , Brunda Tumala
- & James M. Fleckenstein
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| Open AccessMulti-kingdom gut microbiota analyses define COVID-19 severity and post-acute COVID-19 syndrome
Here, by performing an integrative multi-omics analysis coupled to clinical features of COVID-19 patients prospectively followed for up to 6 month, the authors identify specific gut microbiome patterns associated with disease severity and development of post-acute COVID-19 syndrome.
- Qin Liu
- , Qi Su
- & Siew C. Ng
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Article
| Open AccessHepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism
Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. Here the authors report that hepatic thyroid hormone receptor β mediates the effects of the thyroid hormone T3 on systemic glucose homeostasis by modulating GLP-1 levels through suppression of hepatic CYP8B1 expression and bile acid mediated inhibition of intestinal FXR signalling.
- Ying Yan
- , Zhoumin Niu
- & Hao Ying
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Article
| Open AccessDNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon
DNA methyltransferase 3 A (DNMT3A) is involved in DNA methylation, and genetic variants in the DNMT3 locus have been associated with inflammatory bowel disease. Here the authors report that DNMT3A controls intestinal epithelial barrier function and restoration of the gut barrier function after intestinal epithelial perturbation.
- Antonella Fazio
- , Dora Bordoni
- & Philip Rosenstiel
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| Open AccessReduced alcohol preference and intake after fecal transplant in patients with alcohol use disorder is transmissible to germ-free mice
Gut microbiota composition is altered in patients with alcohol use disorder, and fecal microbiota transplant reduced alcohol craving in patients with alcohol use disorder and liver cirrhosis in a phase 1 clinical trial. Here the authors used stool samples collected in the trial to report that this phenotype is transmissible via microbial transfer to germ free mice, as assessed by reduced ethanol acceptance, intake and preference.
- Jennifer T. Wolstenholme
- , Justin M. Saunders
- & Jasmohan S. Bajaj
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Article
| Open AccessA local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma
The changes in super-enhancer (SE) landscape of cancers are mainly attributed to cell-intrinsic genomic alterations. Here, the authors perform epigenomic profiling on primary colorectal cancers (CRCs) and their matched normal tissues and show that local tumour microenvironment induces a SE activation and that its target, PDZK1IP1 promotes CRC growth.
- Royce W. Zhou
- , Jia Xu
- & Ramon E. Parsons
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Article
| Open AccessHepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK
Mechanisms underlying the pathogenesis of nonalcoholic steatohepatitis are unclear. Here, the authors show that ROS-mediated DUSP22 degradation participates in the progression of fatty liver, contributing to the development of NASH and associated HCC via regulating FAK and its downstream ERK1/2 and NF-κB signaling cascade.
- Chenxu Ge
- , Jun Tan
- & Minxuan Xu
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Article
| Open AccessHelicobacter pylori shows tropism to gastric differentiated pit cells dependent on urea chemotaxis
The carcinogenic bacterium Helicobacter pylori infects gastric cells. Here, the authors show that H. pylori preferentially infects differentiated cells in the pit region of gastric units, and this relies on bacterial chemotaxis towards host cell-released urea, which scales with host cell size.
- Carmen Aguilar
- , Mindaugas Pauzuolis
- & Sina Bartfeld
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| Open AccessInterleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy
Mechanisms of non-response to ustekinumab, a biologic targeting IL-23, are currently unclear. Here, the authors show that the transcriptional program regulated by IL-22, an IL-23 responsive cytokine, is enriched in patients with ulcerative colitis unresponsive to ustekinumab and associated with higher colon neutrophil recruitment and activation of upstream IL-22 regulators.
- Polychronis Pavlidis
- , Anastasia Tsakmaki
- & Nick Powell
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Article
| Open AccessProteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies
The mechanisms of resistance to therapy in gastric cancer remain to be explored. Here, proteomic profiling of 206 tumour tissues from patients treated with chemotherapy and anti-HER2-based therapy results in the identification of four molecular subtypes and the development of prognostic models.
- Yan Li
- , Chen Xu
- & Chen Ding
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Article
| Open AccessInterferon regulatory factor 1 (IRF-1) promotes intestinal group 3 innate lymphoid responses during Citrobacter rodentium infection
Innate lymphoid cells (ILC) are involved with different immune responses. Here the authors show that Interferon regulatory factor 1 (IRF1) is important for intestinal ILC3 accumulation during Citrobacter rodentium infection and promotes release of the protective cytokine IL-22 and response to IL-23.
- Angelika Schmalzl
- , Tamara Leupold
- & Stefan Wirtz
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| Open AccessIn vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis
Management of ulcerative colitis can require a combination of treatments targeting different pathways. Here the authors design a therapy for ulcerative colitis based on a multitargeted genetic circuit to simultaneously target TNF-α, B7-1 and integrin α4, and show the therapy is effective in male mice with induced or spontaneous genetic colitis.
- Xinyan Zhou
- , Mengchao Yu
- & Xi Chen
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Article
| Open AccessTFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis
Matye el al. show that coenzyme-A and glutathione deficiency in NAFLD limits fatty acid oxidation and antioxidant defence capacity. The nutrient sensing transcription factor EB induces autophagy–lysosome proteolysis and methionine cycle-transsulfuration to maintain hepatic cysteine, coenzyme-A and glutathione availability.
- David Matye
- , Sumedha Gunewardena
- & Tiangang Li
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| Open AccessFunctional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis
Myofibroblasts contribute to the development of liver fibrosis. Here, the authors report that the transcription factor Basonuclin 2 (BNC2) integrates fibrogenic signals and drives myofibroblastic transcriptional activation in liver fibrosis.
- Marie Bobowski-Gerard
- , Clémence Boulet
- & Jérôme Eeckhoute
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Article
| Open AccessO-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis
Hyperammonemia occurs in liver diseases affecting ureagenesis, and is life-threatening. Here, the authors show that liver UDP-GlcNAc is increased during hyperammonemia, leading to O-GlcNAcylation of the rate-limiting ureagenesis enzyme CPS1, that enhanced ureagenesis and ammonia detoxification. They also showed that pharmacological increase of protein O-GlcNAcylation reduces hyperammonemia in mouse models of liver disease.
- Leandro R. Soria
- , Georgios Makris
- & Nicola Brunetti-Pierri
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Article
| Open AccessNeutralization of hepatitis B virus with vaccine-escape mutations by hepatitis B vaccine with large-HBs antigen
The hepatitis B vaccine is recognised as the most effective approach in reducing hepatitis-B-related morbidity; vaccine-escape mutations are however capable of infecting vaccinated individuals. In this work, authors aim to establish a hepatitis B vaccine candidate, which they assess in rhesus macaques in terms of efficacy and safety.
- Ayaka Washizaki
- , Asako Murayama
- & Takanobu Kato
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Article
| Open AccessIn vivo adenine base editing reverts C282Y and improves iron metabolism in hemochromatosis mice
Hemochromatosis is a metabolic disorder caused by mutations in the HFE gene. Here, the authors show that a single administration of AAV8 vectors expressing an Adenine Base Editor facilitates efficient in vivo gene correction in hepatocytes and leads to improvement of iron-specific parameters in the liver and the blood in mouse models of the disease.
- Alice Rovai
- , BoMee Chung
- & Michael Ott
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Article
| Open AccessSirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity
Host defense against helminth infection is mediated by mucosal type 2 immunity. Using gain- and loss-of-function mouse models, and mouse intestinal organoids, Xiong et al. show that SIRT6 modulates tuft and goblet cell expansion in intestinal epithelium by activating STAT6 to maintain type 2 mucosal immunity in response to helminth infection.
- Xiwen Xiong
- , Chenyan Yang
- & Qingzhi Wang
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Article
| Open AccessSpermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression
Spermidine, a polyamine reported to extend lifespan and reduce the risk of age-related diseases, serves as a substrate for the post-translational modification hypusination. Here the authors report that EIF5A hypusination, which regulates mitochondrial protein synthesis, is reduced during non-alcoholic steatohepatitis (NASH), which can be prevented by spermidine to inhibit the progression of NASH in mice.
- Jin Zhou
- , Jeremy Pang
- & Paul Michael Yen
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Article
| Open AccessBiliary NIK promotes ductular reaction and liver injury and fibrosis in mice
Excessive expansion of cholangiocytes in the liver leads to ductular reaction and liver disease. Here, the authors show that genetic ablation, or pharmacological inhibition, of biliary NIK blocks ductular reaction, liver inflammation, and liver fibrosis in mice by modulating secretion of cholangiokines that mediate liver inflammation and fibrosis.
- Zhiguo Zhang
- , Xiao Zhong
- & Liangyou Rui
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Article
| Open AccessPredicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment
Predictive methods for gastric cancer to try and differentiate between potential treatment response are required. Here the authors use a multiplexed immunohistochemistry method to propose the proximity of tumour infiltrating immune cells as an indicator of likely therapeutic response.
- Yang Chen
- , Keren Jia
- & Lin Shen
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Article
| Open AccessMannose ameliorates experimental colitis by protecting intestinal barrier integrity
New potential therapies for inflammatory bowel disease are needed as not all patients respond to or maintain a response to conventional therapies. Here the authors report that mannose supplementation ameliorates experimental colitis in male mice, potentially via effects on intestinal epithelium lysosomal integrity.
- Lijun Dong
- , Jingwen Xie
- & Daming Zuo
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Article
| Open AccessMettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a
m6A is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. Here the authors show a role for Mettl3-mediated RNA m6A modification in postnatal liver development by regulating the Hnf4a-centered transcriptional network
- Yan Xu
- , Zhuowei Zhou
- & Qi Zhang
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Article
| Open AccessDeficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH)
Ectopic lipid accumulation and inflammation are the essential signs of NASH. Here, the authors show that hepatic WTAP is a key integrative repressor of ectopic lipid accumulation and inflammation during NASH progression, and hepatic deletion of Wtap promotes both of them, leading to NASH
- Xinzhi Li
- , Kaixin Ding
- & Zheng Chen
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Article
| Open AccessIn mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response
The function of T regulatory cells in the tissue fibrosis in chronic pancreatitis is not fully understood. Here the authors use a mouse model of chronic pancreatitis to show that Treg cells reduce IL-4 mediated chronic inflammation in the pancreas associated with M2-like macrophages in vivo.
- Juliane Glaubitz
- , Anika Wilden
- & Matthias Sendler
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Article
| Open AccessCholesterol sulfate alleviates ulcerative colitis by promoting cholesterol biosynthesis in colonic epithelial cells
New treatment strategies are required for ulcerative colitis. Here the authors show in mouse models that cholesterol sulfate, an endogenous active cholesterol derivative, contributes to the healing of the mucosal barrier by promoting cholesterol biosynthesis in colonic epithelial cells and exhibits therapeutic efficacy against ulcerative colitis.
- Dongke Xu
- , Ruijun Ma
- & Xiaobo Li
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Article
| Open AccessLactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice
Triclosan is an antimicrobial additive in consumer products that has been detected in human breast milk. Here the authors report that exposure of pregnant mice to triclosan leads to lactational exposure to newborns and the development of liver steatosis.
- André A. Weber
- , Xiaojing Yang
- & Robert H. Tukey
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Article
| Open AccessPancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement
Pharmacological inhibition of the prolyl isomerase PIN1, highly expressed in cancer cells and cancer associated fibroblasts (CAF), has been proposed for cancer therapy. Here the authors report the design of a DNA-barcoded micellular system functionalized with antibodies targeting CAFs and a T cell recruiting aptamer to deliver the PIN1 inhibitor AG17724, showing antitumor response in preclinical models of pancreatic cancer.
- Jiaye Liu
- , Yang Wang
- & Yong Liu
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Article
| Open AccessLoss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity
Obesity is a major risk factor for fatty liver disease. Here, using a forward genetic screen, the authors identify the gene GM4951 as a GTPase involved in lipid oxidation and development of NAFLD in mice.
- Zhao Zhang
- , Yu Xun
- & Bruce Beutler