318 results on '"Fanyin Meng"'
Search Results
2. Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2−/− mouse model of primary sclerosing cholangitis (PSC)Research in context
- Author
-
Tianhao Zhou, Konstantina Kyritsi, Nan Wu, Heather Francis, Zhihong Yang, Lixian Chen, April O'Brien, Lindsey Kennedy, Ludovica Ceci, Vik Meadows, Praveen Kusumanchi, Chaodong Wu, Leonardo Baiocchi, Nicholas J. Skill, Romil Saxena, Amelia Sybenga, Linglin Xie, Suthat Liangpunsakul, Fanyin Meng, Gianfranco Alpini, and Shannon Glaser
- Subjects
Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Cholangiocytes are the target cells of cholangiopathies including primary sclerosing cholangitis (PSC). Vimentin is an intermediate filament protein that has been found in various types of mesenchymal cells. The aim of this study is to evaluate the role of vimentin in the progression of biliary damage/liver fibrosis and whether there is a mesenchymal phenotype of cholangiocytes in the Mdr2−/− model of PSC. Methods: In vivo studies were performed in 12 wk. Mdr2−/− male mice with or without vimentin Vivo-Morpholino treatment and their corresponding control groups. Liver specimens from human PSC patients, human intrahepatic biliary epithelial cells (HIBEpiC) and human hepatic stellate cell lines (HHSteCs) were used to measure changes in epithelial-to-mesenchymal transition (EMT). Findings: There was increased mesenchymal phenotype of cholangiocytes in Mdr2−/− mice, which was reduced by treatment of vimentin Vivo-Morpholino. Concomitant with reduced vimentin expression, there was decreased liver damage, ductular reaction, biliary senescence, liver fibrosis and TGF-β1 secretion in Mdr2−/− mice treated with vimentin Vivo-Morpholino. Human PSC patients and derived cell lines had increased expression of vimentin and other mesenchymal markers compared to healthy controls and HIBEpiC, respectively. In vitro silencing of vimentin in HIBEpiC suppressed TGF-β1-induced EMT and fibrotic reaction. HHSteCs had decreased fibrotic reaction and increased cellular senescence after stimulation with cholangiocyte supernatant with reduced vimentin levels. Interpretation: Our study demonstrated that knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes, which leads to decreased biliary senescence and liver fibrosis. Inhibition of vimentin may be a key therapeutic target in the treatment of cholangiopathies including PSC. Fund: National Institutes of Health (NIH) awards, VA Merit awards. Keywords: Ductular reaction, Fibroblast, Fibrosis, Senescence, Transforming growth factor beta 1
- Published
- 2019
- Full Text
- View/download PDF
3. Current Perspectives of Neuroendocrine Regulation in Liver Fibrosis
- Author
-
Bowen Li, Hui Wang, Yudian Zhang, Ying Liu, Tiejun Zhou, Bingru Zhou, Ying Zhang, Rong Chen, Juan Xing, Longfei He, Jennifer Mata Salinas, Sachiko Koyama, Fanyin Meng, and Ying Wan
- Subjects
neuroendocrine hormones ,neuroendocrine regulation ,hepatic stellate cells ,tissue homeostasis ,liver fibrosis ,Cytology ,QH573-671 - Abstract
Liver fibrosis is a complicated process that involves different cell types and pathological factors. The excessive accumulation of extracellular matrix (ECM) and the formation of fibrotic scar disrupt the tissue homeostasis of the liver, eventually leading to cirrhosis and even liver failure. Myofibroblasts derived from hepatic stellate cells (HSCs) contribute to the development of liver fibrosis by producing ECM in the area of injuries. It has been reported that the secretion of the neuroendocrine hormone in chronic liver injury is different from a healthy liver. Activated HSCs and cholangiocytes express specific receptors in response to these neuropeptides released from the neuroendocrine system and other neuroendocrine cells. Neuroendocrine hormones and their receptors form a complicated network that regulates hepatic inflammation, which controls the progression of liver fibrosis. This review summarizes neuroendocrine regulation in liver fibrosis from three aspects. The first part describes the mechanisms of liver fibrosis. The second part presents the neuroendocrine sources and neuroendocrine compartments in the liver. The third section discusses the effects of various neuroendocrine factors, such as substance P (SP), melatonin, as well as α-calcitonin gene-related peptide (α-CGRP), on liver fibrosis and the potential therapeutic interventions for liver fibrosis.
- Published
- 2022
- Full Text
- View/download PDF
4. Functional roles of gut bacteria imbalance in cholangiopathies
- Author
-
Keisaku Sato, Fanyin Meng, Giammarco Fava, Shannon Glaser, and Gianfranco Alpini
- Subjects
Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Cholangiopathies are caused by bile duct damage or inflammation followed by cholestasis leading to liver fibrosis. Bile duct epithelial cells, cholangiocytes, are a primary target for cholangiopathies. Ductular reaction is often observed in cholangiopathies and the proliferation of cholangiocytes is associated with ductular reaction and liver fibrogenesis. Accumulating evidence suggests that patients with cholangiopathies have different gut bacterial profiles from healthy individuals, indicating the association between gut microbiota and cholangiopathies. Bile acids are produced by hepatocytes and modified by gut bacteria. Bile acids regulate cholangiocyte proliferation but effects vary depending on the type of bile acids. Recent studies suggest that therapies targeting gut bacteria, such as antibiotics administration and gut bacteria depletion or therapies using gut bacteria-associated bile acids, such as ursodeoxycholic acid (UDCA) administration, may be useful for treatments of cholangiopathies, although data are controversial depending on animal models or cohorts. This review summarizes current understandings of functional roles of gut bacterial imbalance and strategies for treatments of cholangiopathies targeting gut bacteria. Keywords: Cholangiopathies, Bile acids, Gut bacteria, Cholangiocytes, Cholestasis, Inflammation
- Published
- 2019
- Full Text
- View/download PDF
5. Complex bile duct network formation within liver decellularized extracellular matrix hydrogels
- Author
-
Phillip L. Lewis, Jimmy Su, Ming Yan, Fanyin Meng, Shannon S. Glaser, Gianfranco D. Alpini, Richard M. Green, Beatriz Sosa-Pineda, and Ramille N. Shah
- Subjects
Medicine ,Science - Abstract
Abstract The biliary tree is an essential component of transplantable human liver tissue. Despite recent advances in liver tissue engineering, attempts at re-creating the intrahepatic biliary tree have not progressed significantly. The finer branches of the biliary tree are structurally and functionally complex and heterogeneous and require harnessing innate developmental processes for their regrowth. Here we demonstrate the ability of decellularized liver extracellular matrix (dECM) hydrogels to induce the in vitro formation of complex biliary networks using encapsulated immortalized mouse small biliary epithelial cells (cholangiocytes). This phenomenon is not observed using immortalized mouse large cholangiocytes, or with purified collagen 1 gels or Matrigel. We also show phenotypic stability via immunostaining for specific cholangiocyte markers. Moreover, tight junction formation and maturation was observed to occur between cholangiocytes, exhibiting polarization and transporter activity. To better define the mechanism of duct formation, we utilized three fluorescently labeled, but otherwise identical populations of cholangiocytes. The cells, in a proximity dependent manner, either branch out clonally, radiating from a single nucleation point, or assemble into multi-colored structures arising from separate populations. These findings present liver dECM as a promising biomaterial for intrahepatic bile duct tissue engineering and as a tool to study duct remodeling in vitro.
- Published
- 2018
- Full Text
- View/download PDF
6. Cyclic GMP-AMP Ameliorates Diet-induced Metabolic Dysregulation and Regulates Proinflammatory Responses Distinctly from STING Activation
- Author
-
Xin Guo, Chang Shu, Honggui Li, Ya Pei, Shih-Lung Woo, Juan Zheng, Mengyang Liu, Hang Xu, Rachel Botchlett, Ting Guo, Yuli Cai, Xinsheng Gao, Jing Zhou, Lu Chen, Qifu Li, Xiaoqiu Xiao, Linglin Xie, Ke K. Zhang, Jun-Yuan Ji, Yuqing Huo, Fanyin Meng, Gianfranco Alpini, Pingwei Li, and Chaodong Wu
- Subjects
Medicine ,Science - Abstract
Abstract Endogenous cyclic GMP-AMP (cGAMP) binds and activates STING to induce type I interferons. However, whether cGAMP plays any roles in regulating metabolic homeostasis remains unknown. Here we show that exogenous cGAMP ameliorates obesity-associated metabolic dysregulation and uniquely alters proinflammatory responses. In obese mice, treatment with cGAMP significantly decreases diet-induced proinflammatory responses in liver and adipose tissues and ameliorates metabolic dysregulation. Strikingly, cGAMP exerts cell-type-specific anti-inflammatory effects on macrophages, hepatocytes, and adipocytes, which is distinct from the effect of STING activation by DMXAA on enhancing proinflammatory responses. While enhancing insulin-stimulated Akt phosphorylation in hepatocytes and adipocytes, cGAMP weakens the effects of glucagon on stimulating hepatocyte gluconeogenic enzyme expression and glucose output and blunts palmitate-induced hepatocyte fat deposition in an Akt-dependent manner. Taken together, these results suggest an essential role for cGAMP in linking innate immunity and metabolic homeostasis, indicating potential applications of cGAMP in treating obesity-associated inflammatory and metabolic diseases.
- Published
- 2017
- Full Text
- View/download PDF
7. Diagnostic and therapeutic potentials of microRNAs in cholangiopathies
- Author
-
Lindsey Kennedy, Heather Francis, Fanyin Meng, Shannon Glaser, and Gianfranco Alpini
- Subjects
Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Cholangiopathies are a group of rare, devastating diseases that arise from damaged cholangiocytes, the cells that line the intra- and extra-hepatic bile ducts of the biliary epithelium. Cholangiopathies result in significant morbidity and mortality and are a major cause of liver transplantation. A better understanding of the underlying pathogenesis that influences cholangiocyte dysregulation and cholangiopathy progression is necessary, considering the dismal prognosis associated with these diseases.MicroRNAs are a class of small, non-coding RNAs that regulate post-transcriptional mRNA expression of specific genes. The role of microRNAs has expanded to include the initiation and development of many diseases, including cholangiopathies. Understanding microRNA regulation of cholangiopathies may provide diagnostic and therapeutic benefit for these diseases. In this review, the authors primarily focus on studies published within the last five years that help determine the diagnostic and therapeutic potential of microRNAs in cholangiopathies. Keywords: microRNAs, Cholangiopathies, Diagnosis, Therapy
- Published
- 2017
- Full Text
- View/download PDF
8. Neuroendocrine Changes in Cholangiocarcinoma Growth
- Author
-
Keisaku Sato, Heather Francis, Tianhao Zhou, Fanyin Meng, Lindsey Kennedy, Burcin Ekser, Leonardo Baiocchi, Paolo Onori, Romina Mancinelli, Eugenio Gaudio, Antonio Franchitto, Shannon Glaser, and Gianfranco Alpini
- Subjects
cholangiocarcinoma ,cholangiocytes ,ductular reaction ,liver fibrosis ,neurotransmitters ,neuropeptides ,hormones ,Cytology ,QH573-671 - Abstract
Cholangiocarcinoma (CCA) is a highly aggressive malignancy that emerges from the biliary tree. There are three major classes of CCA—intrahepatic, hilar (perihilar), or distal (extrahepatic)—according to the location of tumor development. Although CCA tumors are mainly derived from biliary epithelia (i.e., cholangiocytes), CCA can be originated from other cells, such as hepatic progenitor cells and hepatocytes. This heterogeneity of CCA may be responsible for poor survival rates of patients, limited effects of chemotherapy and radiotherapy, and the lack of treatment options and novel therapies. Previous studies have identified a number of neuroendocrine mediators, such as hormones, neuropeptides, and neurotransmitters, as well as corresponding receptors. The mediator/receptor signaling pathways play a vital role in cholangiocyte proliferation, as well as CCA progression and metastases. Agonists or antagonists for candidate pathways may lead to the development of novel therapies for CCA patients. However, effects of mediators may differ between healthy or cancerous cholangiocytes, or between different subtypes of receptors. This review summarizes current understandings of neuroendocrine mediators and their functional roles in CCA.
- Published
- 2020
- Full Text
- View/download PDF
9. Functional and Structural Features of Cholangiocytes in Health and DiseaseSummary
- Author
-
Luca Maroni, Bai Haibo, Debolina Ray, Tianhao Zhou, Ying Wan, Fanyin Meng, Marco Marzioni, and Gianfranco Alpini
- Subjects
Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Cholangiocytes are the epithelial cells that line the bile ducts. Along the biliary tree, two different kinds of cholangiocytes exist: small and large cholangiocytes. Each type has important differences in their biological role in physiologic and pathologic conditions. In response to injury, cholangiocytes become reactive and acquire a neuroendocrine-like phenotype with the secretion of a number of peptides. These molecules act in an autocrine/paracrine fashion to modulate cholangiocyte biology and determine the evolution of biliary damage. The failure of such mechanisms is believed to influence the progression of cholangiopathies, a group of diseases that selectively target biliary cells. Therefore, the understanding of mechanisms regulating cholangiocyte response to injury is expected to foster the development of new therapeutic options to treat biliary diseases. In this review, we discuss the most recent findings in the mechanisms driving cholangiocyte adaptation to damage, with particular emphasis on molecular pathways that are susceptible of therapeutic intervention. Morphogenic pathways (Hippo, Notch, Hedgehog), which have been recently shown to regulate biliary ontogenesis and response to injury, are also reviewed as well as the results of ongoing clinical trials evaluating new drugs for the treatment of cholangiopathies. Keywords: Biliary Epithelium, Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis
- Published
- 2015
- Full Text
- View/download PDF
10. Intercellular Communication between Hepatic Cells in Liver Diseases
- Author
-
Keisaku Sato, Lindsey Kennedy, Suthat Liangpunsakul, Praveen Kusumanchi, Zhihong Yang, Fanyin Meng, Shannon Glaser, Heather Francis, and Gianfranco Alpini
- Subjects
liver fibrosis ,extracellular vesicles ,hepatocytes ,macrophages ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Liver diseases are perpetuated by the orchestration of hepatocytes and other hepatic non-parenchymal cells. These cells communicate and regulate with each other by secreting mediators such as peptides, hormones, and cytokines. Extracellular vesicles (EVs), small particles secreted from cells, contain proteins, DNAs, and RNAs as cargos. EVs have attracted recent research interests since they can communicate information from donor cells to recipient cells thereby regulating physiological events via delivering of specific cargo mediators. Previous studies have demonstrated that liver cells secrete elevated numbers of EVs during diseased conditions, and those EVs are internalized into other liver cells inducing disease-related reactions such as inflammation, angiogenesis, and fibrogenesis. Reactions in recipient cells are caused by proteins and RNAs carried in disease-derived EVs. This review summarizes cell-to-cell communication especially via EVs in the pathogenesis of liver diseases and their potential as a novel therapeutic target.
- Published
- 2019
- Full Text
- View/download PDF
11. Dual Role of Bile Acids on the Biliary Epithelium: Friend or Foe?
- Author
-
Leonardo Baiocchi, Tianhao Zhou, Suthat Liangpunsakul, Ilaria Lenci, Francesco Santopaolo, Fanyin Meng, Lindsey Kennedy, Shannon Glaser, Heather Francis, and Gianfranco Alpini
- Subjects
bile acids ,cholangiocyte ,cholestasis ,TGR5 ,ABAT ,cholangiocarcinoma ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Bile acids are a family of amphipathic compounds predominantly known for their role in solubilizing and absorbing hydrophobic compounds (including liposoluble vitamins) in the intestine. Bile acids also are key signaling molecules and inflammatory agents that activate transcriptional factors and cell signaling pathways that regulate lipid, glucose, and energy metabolism in various human disorders, including chronic liver diseases. However, in the last decade increased awareness has been founded on the physiological and chemical heterogeneity of this category of compounds and their possible beneficial or injurious effects on the biliary tree. In this review, we provide an update on the current understanding of the molecular mechanism involving bile acid and biliary epithelium. The last achievements of the research in this field are summarized, focusing on the molecular aspects and the elements with relevance regarding human liver diseases.
- Published
- 2019
- Full Text
- View/download PDF
12. Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness
- Author
-
Elise Slevin, Sachiko Koyama, Kelly Harrison, Ying Wan, James E. Klaunig, Chaodong Wu, Ashok K. Shetty, and Fanyin Meng
- Subjects
Molecular Medicine ,Cell Biology - Published
- 2023
13. miR-34a regulates macrophage-associated inflammation and angiogenesis in alcohol-induced liver injury
- Author
-
Ying Wan, Elise Slevin, Sachiko Koyama, Chiung-Kuei Huang, Ashok K Shetty, Xuedong Li, Kelly Harrison, Tian Li, Bingru Zhou, Sugeily Ramos Lorenzo, Yudian Zhang, Jennifer Mata Salinas, Wenjuan Xu, James E. Klaunig, Chaodong Wu, Hidekazu Tsukamoto, and Fanyin Meng
- Subjects
Hepatology - Published
- 2023
14. Liver‐specific deletion of <scp>microRNA</scp> ‐34a alleviates ductular reaction and liver fibrosis during experimental cholestasis
- Author
-
Ying Wan, Tianhao Zhou, Elise Slevin, Sachiko Koyama, Xuedong Li, Kelly Harrison, Tian Li, Bingru Zhou, Sugeily Ramos Lorenzo, Yudian Zhang, Wenjuan Xu, James E. Klaunig, Chaodong Wu, Ashok K. Shetty, Chiung‐Kuei Huang, and Fanyin Meng
- Subjects
Liver Cirrhosis ,Cholestasis ,Liver Diseases ,Fibrosis ,Biochemistry ,Mice ,MicroRNAs ,Liver ,Genetics ,Humans ,Animals ,Bile Ducts ,Molecular Biology ,Biotechnology - Abstract
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammatory responses and fibrotic scar formation leading to cholestasis. Ductular reaction and liver fibrosis are typical liver changes seen in human PSC and cholestasis patients. The current study aimed to clarify the role of liver-specific microRNA-34a in the cholestasis-associated ductular reaction and liver fibrosis. We demonstrated that miR-34a expression was significantly increased in human PSC livers along with the enhanced ductular reaction, cellular senescence, and liver fibrosis. A liver-specific miR-34a knockout mouse was established by crossing floxed miR-34a mice with albumin-promoter-driven Cre mice. Bile duct ligation (BDL) induced liver injury characterized by necrosis, fibrosis, and immune cell infiltration. In contrast, liver-specific miR-34a knockout in BDL mice resulted in decreased biliary ductular pathology associated with the reduced cholangiocyte senescence and fibrotic responses. The miR-34a-mediated ductular reactions may be functioning through Sirt-1-mediated senescence and fibrosis. The hepatocyte-derived conditioned medium promoted LPS-induced fibrotic responses and senescence in cholangiocytes, and miR-34a inhibitor suppressed these effects, further supporting the involvement of paracrine regulation. In conclusion, we demonstrated that liver-specific miR-34a plays an important role in ductular reaction and fibrotic responses in a BDL mouse model of cholestatic liver disease.
- Published
- 2022
15. Up-regulation of the human-specific CHRFAM7A gene protects against renal fibrosis in mice with obstructive nephropathy
- Author
-
Bingru Zhou, Yudian Zhang, Xitong Dang, Bowen Li, Hui Wang, Shu Gong, Siwen Li, Fanyin Meng, Juan Xing, Tian Li, Longfei He, Ping Zou, and Ying Wan
- Subjects
Inflammation ,Epithelial-Mesenchymal Transition ,Mice, Transgenic ,Cell Biology ,Kidney ,Fibrosis ,Up-Regulation ,Transforming Growth Factor beta1 ,Mice ,Molecular Medicine ,Humans ,Animals ,Kidney Diseases ,Renal Insufficiency, Chronic ,Ureteral Obstruction - Abstract
Renal fibrosis is a major factor in the progression of chronic kidney diseases. Obstructive nephropathy is a common cause of renal fibrosis, which is also accompanied by inflammation. To explore the effect of human-specific CHRFAM7A expression, an inflammation-related gene, on renal fibrosis during obstructive nephropathy, we studied CHRFAM7A transgenic mice and wild type mice that underwent unilateral ureteral obstruction (UUO) injury. Transgenic overexpression of CHRFAM7A gene inhibited UUO-induced renal fibrosis, which was demonstrated by decreased fibrotic gene expression and collagen deposition. Furthermore, kidneys from transgenic mice had reduced TGF-β1 and Smad2/3 expression following UUO compared with those from wild type mice with UUO. In addition, the overexpression of CHRFAM7A decreased release of inflammatory cytokines in the kidneys of UUO-injured mice. In vitro, the overexpression of CHRFAM7A inhibited TGF-β1-induced increase in expression of fibrosis-related genes in human renal tubular epithelial cells (HK-2 cells). Additionally, up-regulated expression of CHRFAM7A in HK-2 cells decreased TGF-β1-induced epithelial-mesenchymal transition (EMT) and inhibited activation f TGF-β1/Smad2/3 signalling pathways. Collectively, our findings demonstrate that overexpression of the human-specific CHRFAM7A gene can reduce UUO-induced renal fibrosis by inhibiting TGF-β1/Smad2/3 signalling pathway to reduce inflammatory reactions and EMT of renal tubular epithelial cells.
- Published
- 2022
16. The Apelin–Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis
- Author
-
Heather Francis, Tori White, Lixian Chen, Sanjukta Chakraborty, Chaodong Wu, Lindsey Kennedy, Shannon Glaser, April O'Brien, Fanyin Meng, Gianfranco Alpini, Tianhao Zhou, Romil Saxena, Zhihong Yang, Suthat Liangpunsakul, and Qiaobing Huang
- Subjects
Liver Cirrhosis ,MAPK/ERK pathway ,medicine.medical_specialty ,Cholangitis, Sclerosing ,Cholangiocyte proliferation ,Article ,Cholangiocyte ,Mice ,Fibrosis ,Internal medicine ,Hepatic Stellate Cells ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Extracellular Signal-Regulated MAP Kinases ,Receptor ,Cell Proliferation ,Pyrans ,Apelin receptor ,Flavonoids ,Apelin Receptors ,Cholestasis ,Hepatology ,Chemistry ,Free Radical Scavengers ,medicine.disease ,Acetylcysteine ,Apelin ,Endocrinology ,NADPH Oxidase 4 ,Nitrobenzoates ,Hepatic stellate cell ,Reactive Oxygen Species ,Signal Transduction - Abstract
BACKGROUND AND AIMS Apelin (APLN) is the endogenous ligand of its G protein-coupled receptor, apelin receptor (APJ). APLN serum levels are increased in human liver diseases. We evaluated whether the APLN-APJ axis regulates ductular reaction and liver fibrosis during cholestasis. APPROACH AND RESULTS We measured the expression of APLN and APJ and serum APLN levels in human primary sclerosing cholangitis (PSC) samples. Following bile duct ligation (BDL) or sham surgery, male wild-type (WT) mice were treated with ML221 (APJ antagonist) or saline for 1 week. WT and APLN-/- mice underwent BDL or sham surgery for 1 week. Multidrug resistance gene 2 knockout (Mdr2-/- ) mice were treated with ML221 for 1 week. APLN levels were measured in serum and cholangiocyte supernatants, and cholangiocyte proliferation/senescence and liver inflammation, fibrosis, and angiogenesis were measured in liver tissues. The regulatory mechanisms of APLN-APJ in (1) biliary damage and liver fibrosis were examined in human intrahepatic biliary epithelial cells (HIBEpiCs) treated with APLN and (2) hepatic stellate cell (HSC) activation in APLN-treated human HSC lines (HHSteCs). APLN serum levels and biliary expression of APLN and APJ increased in PSC samples. APLN levels were higher in serum and cholangiocyte supernatants from BDL and Mdr2-/- mice. ML221 treatment or APLN-/- reduced BDL-induced and Mdr2-/- -induced cholangiocyte proliferation/senescence, liver inflammation, fibrosis, and angiogenesis. In vitro, APLN induced HIBEpiC proliferation, increased nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) expression, reactive oxygen species (ROS) generation, and extracellular signal-regulated kinase (ERK) phosphorylation. Pretreatment of HIBEpiCs with ML221, diphenyleneiodonium chloride (Nox4 inhibitor), N-acetyl-cysteine (NAC, ROS inhibitor), or PD98059 (ERK inhibitor) reduced APLN-induced cholangiocyte proliferation. Activation of HHSteCs was induced by APLN but reduced by NAC. CONCLUSIONS The APLN-APJ axis induces cholangiocyte proliferation through Nox4/ROS/ERK-dependent signaling and HSC activation through intracellular ROS. Modulation of the APLN-APJ axis may be important for managing cholangiopathies.
- Published
- 2021
17. Mast Cells Induce Ductular Reaction Mimicking Liver Injury in Mice Through Mast Cell–Derived Transforming Growth Factor Beta 1 Signaling
- Author
-
Gianfranco Alpini, Heather Francis, Karla Cerritos, Jennifer Demieville, Laura Hargrove, Vik Meadows, Debjyoti Kundu, Linh Pham, Lindsey Kennedy, Fanyin Meng, Konstantina Kyritsi, and Amelia Sybenga
- Subjects
0301 basic medicine ,Liver injury ,Hepatology ,biology ,Angiogenesis ,Transforming growth factor beta ,medicine.disease ,Molecular biology ,03 medical and health sciences ,chemistry.chemical_compound ,Liver disease ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Vascular endothelial growth factor C ,Fibrosis ,medicine ,Hepatic stellate cell ,biology.protein ,030211 gastroenterology & hepatology ,Sirius Red - Abstract
BACKGROUND AND AIMS Following liver injury, mast cells (MCs) migrate into the liver and are activated in patients with cholestasis. Inhibition of MC mediators decreases ductular reaction (DR) and liver fibrosis. Transforming growth factor beta 1 (TGF-β1) contributes to fibrosis and promotes liver disease. Our aim was to demonstrate that reintroduction of MCs induces cholestatic injury through TGF-β1. APPROACH AND RESULTS Wild-type, KitW-sh (MC-deficient), and multidrug resistance transporter 2/ABC transporter B family member 2 knockout mice lacking l-histidine decarboxylase were injected with vehicle or PKH26-tagged murine MCs pretreated with 0.01% dimethyl sulfoxide (DMSO) or the TGF-β1 receptor inhibitor (TGF-βRi), LY2109761 (10 μM) 3 days before sacrifice. Hepatic damage was assessed by hematoxylin and eosin (HE biliary senescence was evaluated by IF or qPCR for p16, p18, and p21. Fibrosis was evaluated by sirius red/fast green staining and IF for synaptophysin 9 (SYP-9), desmin, and alpha smooth muscle actin (α-SMA). TGF-β1 secretion/expression was measured by enzyme immunoassay and qPCR. Angiogenesis was detected by IF for von Willebrand factor and vascular endothelial growth factor C qPCR. In vitro, MC-TGF-β1 expression/secretion were measured after TGF-βRi treatment; conditioned medium was collected. Cholangiocytes and hepatic stellate cells (HSCs) were treated with MC-conditioned medium, and biliary proliferation/senescence was measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and qPCR; HSC activation evaluated for α-SMA, SYP-9, and collagen type-1a expression. MC injection recapitulates cholestatic liver injury characterized by increased DR, fibrosis/TGF-β1 secretion, and angiogenesis. Injection of MC-TGF-βRi reversed these parameters. In vitro, MCs induce biliary proliferation/senescence and HSC activation that was reversed with MCs lacking TGF-β1. CONCLUSIONS Our study demonstrates that reintroduction of MCs mimics cholestatic liver injury and that MC-derived TGF-β1 may be a target in chronic cholestatic liver disease.
- Published
- 2021
18. microRNA‐34a modulates the senescence of activated hepatic stellate cells in alcohol‐associated liver injury
- Author
-
Elise Slevin, Ying Wan, Kelly Harrison, Yudian Zhang, Xuedong Li, Tian Li, Sugeily R. Lorenzo, Wenjuan Xu, James E. Klaunig, Ashok K. Shetty, and Fanyin Meng
- Subjects
Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
19. Adipose Tissue Inflammation and Systemic Insulin Resistance in Mice with Diet-induced Obesity Is Possibly Associated with Disruption of PFKFB3 in Hematopoietic Cells
- Author
-
Hang Xu, Gianfranco Alpini, Tianhao Zhou, Shannon Glaser, Yina Wang, Xin Guo, Chaodong Wu, Qiongli Yin, Heather Francis, Honggui Li, Bilian Zhu, Fanyin Meng, Boxiong Jiang, and James J. Cai
- Subjects
0301 basic medicine ,obesity ,Phosphofructokinase-2 ,Adipose tissue ,White adipose tissue ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,PFKFB3 ,Adipocyte ,insulin resistance ,hematopoietic cells ,Adipocytes ,adipose tissue inflammation ,Diet, Fat-Restricted ,Cells, Cultured ,biology ,food and beverages ,030220 oncology & carcinogenesis ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Rosiglitazone ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Signal Transduction ,medicine.medical_specialty ,Adipose Tissue, White ,Inflammation ,Diet, High-Fat ,Article ,Pathology and Forensic Medicine ,Proinflammatory cytokine ,03 medical and health sciences ,Insulin resistance ,Internal medicine ,medicine ,Animals ,Molecular Biology ,business.industry ,Macrophages ,nutritional and metabolic diseases ,Cell Biology ,medicine.disease ,Insulin receptor ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,business - Abstract
Obesity-associated inflammation in white adipose tissue (WAT) is a causal factor of systemic insulin resistance; however, precisely how immune cells regulate WAT inflammation in relation to systemic insulin resistance remains to be elucidated. The present study examined a role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in hematopoietic cells in regulating WAT inflammation and systemic insulin sensitivity. Male C57BL/6J mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 12 weeks and examined for WAT inducible 6-phosphofructo-2-kinase (iPFK2) content, while additional HFD-fed mice were treated with rosiglitazone and examined for PFKFB3 mRNAs in WAT stromal vascular cells (SVC). Also, chimeric mice in which PFKFB3 was disrupted only in hematopoietic cells and control chimeric mice were also fed an HFD and examined for HFD-induced WAT inflammation and systemic insulin resistance. In vitro, adipocytes were co-cultured with bone marrow-derived macrophages and examined for adipocyte proinflammatory responses and insulin signaling. Compared with their respective levels in controls, WAT iPFK2 amount in HFD-fed mice and WAT SVC PFKFB3 mRNAs in rosiglitazone-treated mice were significantly increased. When the inflammatory responses were analyzed, peritoneal macrophages from PFKFB3-disrputed mice revealed increased proinflammatory activation and decreased anti-inflammatory activation compared with control macrophages. At the whole animal level, hematopoietic cell-specific PFKFB3 disruption enhanced the effects of HFD feeding on promoting WAT inflammation, impairing WAT insulin signaling, and increasing systemic insulin resistance. In vitro, adipocytes co-cultured with PFKFB3-disrupted macrophages revealed increased proinflammatory responses and decreased insulin signaling compared with adipocytes co-cultured with control macrophages. These results suggest that PFKFB3 disruption in hematopoietic cells only exacerbates HFD-induced WAT inflammation and systemic insulin resistance.
- Published
- 2021
20. Knockout of the Tachykinin Receptor 1 in the Mdr2−/− (Abcb4−/−) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis
- Author
-
Paolo Onori, Lindsey Kennedy, Heather Francis, Zhihong Yang, Gianfranco Alpini, Thao Giang, Burcin Ekser, Tianhao Zhou, Ludovica Ceci, Romina Mancinelli, Fanyin Meng, Amelia Sybenga, Konstantina Kyritsi, Suthat Liangpunsakul, Nan Wu, Vik Meadows, Chaodong Wu, Antonio Franchitto, Shannon Glaser, and Eugenio Gaudio
- Subjects
0301 basic medicine ,Senescence ,Chemistry ,Inflammation ,Substance P ,ABCB4 ,medicine.disease ,ATP binding cassette transporter ,subfamily B ,animals ,disease models ,gene knockdown techniques ,mice ,knockout ,receptors ,neurokinin-1 ,bile ducts ,cholangitis ,sclerosing ,liver cirrhosis ,Molecular biology ,Pathology and Forensic Medicine ,Primary sclerosing cholangitis ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Cholestasis ,Tachykinin receptor 1 ,medicine ,Immunohistochemistry ,030211 gastroenterology & hepatology ,medicine.symptom - Abstract
Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated and Mdr2−/− (alias Abcb4−/−) mice through enhanced transforming growth factor-β1 (TGF-β1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-β1–induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-β1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2−/− and NK1R−/ (alias Tacr1−/−) to further address the role of the SP/NK1R axis during chronic cholestasis. In vivo studies were performed in the following 12-week–old male mice: (i) NK1R−/−; (ii) Mdr2−/−; and (iii) NK1R−/−/Mdr2−/− (Tacr1−/−/Abcb4−/−) and their corresponding wild-type controls. Liver tissues and cholangiocytes were collected, and liver damage, changes in biliary mass/senescence, and inflammation as well as liver fibrosis were evaluated by both immunohistochemistry in liver sections and real-time PCR. miR-31 expression was measured by real-time PCR in isolated cholangiocytes. Decreased ductular reaction, liver fibrosis, biliary senescence, and biliary inflammation were observed in NK1R−/−/Mdr2−/− mice compared with Mdr2−/− mice. Elevated expression of miR-31 was observed in Mdr2−/− mice, which was reduced in NK1R−/−/Mdr2−/− mice. Targeting the SP/NK1R and/or miR-31 may be a potential approach in treating human cholangiopathies, including primary sclerosing cholangitis.
- Published
- 2020
21. Kupffer Cells
- Author
-
Shannon Glaser, Burcin Ekser, Lixian Chen, Wenjuan Xu, Keisaku Sato, Heather Francis, Sugeily R. Lorenzo, Leonardo Baiocchi, Gianfranco Alpini, Victoria Meadows, Tianhao Zhou, Ludovica Ceci, Fanyin Meng, Konstantina Kyritsi, Debiyoti Kundu, Elise Slevin, Emily Lin, Yuyan Han, Nan Wu, and Lindsey Kennedy
- Subjects
0301 basic medicine ,Liver injury ,business.industry ,Kupffer cell ,Macrophage polarization ,Inflammation ,medicine.disease ,Pathology and Forensic Medicine ,Proinflammatory cytokine ,03 medical and health sciences ,Liver disease ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,medicine ,Hepatic stellate cell ,Cancer research ,Macrophage ,medicine.symptom ,business - Abstract
Chronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease.
- Published
- 2020
22. Liver-specific deletion of microRNA-34a alleviates ductular reaction and liver fibrosis during experimental cholestasis.
- Author
-
Ying Wan, Tianhao Zhou, Slevin, Elise, Koyama, Sachiko, Xuedong Li, Harrison, Kelly, Tian Li, Bingru Zhou, Lorenzo, Sugeily Ramos, Yudian Zhang, Wenjuan Xu, Klaunig, James E., Chaodong Wu, Shetty, Ashok K., Chiung-Kuei Huang, and Fanyin Meng
- Published
- 2023
- Full Text
- View/download PDF
23. Hepatocyte Autophagy: Maintaining a Toxic‐Free Environment
- Author
-
Nan Wu, Fanyin Meng, Gianfranco Alpini, and Heather Francis
- Subjects
medicine.anatomical_structure ,Hepatology ,Chemistry ,Hepatocyte ,Autophagy ,medicine ,Cell biology - Published
- 2020
24. Indole Alleviates Diet‐Induced Hepatic Steatosis and Inflammation in a Manner Involving Myeloid Cell 6‐Phosphofructo‐2‐Kinase/Fructose‐2,6‐Biphosphatase 3
- Author
-
Jinbo Hu, Destiny Matthews, Heather Francis, Xiaoqiu Xiao, Jing Zhou, Rachel Botchlett, Honggui Li, Tianshu Zeng, Lulu Chen, Fanyin Meng, Shannon Glaser, Linqiang Ma, Chaodong Wu, Qifu Li, Gianfranco Alpini, Qingsheng Li, Giri Athrey, David W. Threadgill, and Juan Zheng
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Indoles ,Myeloid ,Phosphofructokinase-2 ,Cell ,Inflammation ,Diet, High-Fat ,Article ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,medicine ,Animals ,Humans ,Myeloid Cells ,Glycolysis ,Obesity ,Cells, Cultured ,Aged ,Aged, 80 and over ,Indole test ,Hepatology ,business.industry ,Lipogenesis ,Fatty liver ,nutritional and metabolic diseases ,Macrophage Activation ,Middle Aged ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Hepatocytes ,Female ,030211 gastroenterology & hepatology ,Steatosis ,medicine.symptom ,business - Abstract
Background and aims Indole is a microbiota metabolite that exerts anti-inflammatory responses. However, the relevance of indole to human non-alcoholic fatty liver disease (NAFLD) is not clear. It also remains largely unknown whether and how indole acts to protect against NAFLD. The present study sought to examine the association between the circulating levels of indole and liver fat content in human subjects and explore the mechanisms underlying indole actions in mice with diet-induced NAFLD. Approach and results In a cohort of 137 subjects, the circulating levels of indole were reversely correlated with body mass index. In addition, the circulating levels of indole in obese subjects were significantly lower than those in lean subjects and were accompanied with increased liver fat content. At the whole-animal level, treatment of high-fat diet (HFD)-fed C57BL/6J mice with indole caused significant decreases in the severity of hepatic steatosis and inflammation. In cultured cells, indole treatment stimulated the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a master regulatory gene of glycolysis, and suppressed macrophage proinflammatory activation in a PFKFB3-dependent manner. Moreover, myeloid cell-specific PFKFB3 disruption exacerbated the severity of HFD-induced hepatic steatosis and inflammation and blunted the effect of indole on alleviating diet-induced NAFLD phenotype. Conclusions Taken together, our results demonstrate that indole is relevant to human NAFLD and capable of alleviating diet-induced NAFLD phenotypes in mice in a myeloid cell PFKFB3-dependent manner. Therefore, indole mimetic and/or macrophage-specific PFKFB3 activation may be the viable preventive and/or therapeutic approaches for inflammation-associated diseases including NAFLD.
- Published
- 2020
25. Pro‐inflammatory signalling and gut‐liver axis in non‐alcoholic and alcoholic steatohepatitis: Differences and similarities along the path
- Author
-
Lindsey Kennedy, Leonardo Baiocchi, Giuseppe Grassi, Ilaria Lenci, Heather Francis, Shannon Glaser, Gianfranco Alpini, Suthat Liangpunsakul, Fanyin Meng, Tianhao Zhou, and Trenton Glaser
- Subjects
0301 basic medicine ,Cirrhosis ,ASH ,NASH ,gut-liver axis ,inflammation ,microRNA ,steatohepatitis ,Reviews ,Inflammation ,Review ,Disease ,Bioinformatics ,Pathogenesis ,Settore MED/12 ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,medicine ,Humans ,business.industry ,Fatty liver ,Cell Biology ,medicine.disease ,Gastrointestinal Tract ,030104 developmental biology ,Liver ,030220 oncology & carcinogenesis ,gut‐liver axis ,Molecular Medicine ,medicine.symptom ,Steatohepatitis ,business ,Homeostasis ,Fatty Liver, Alcoholic ,Signal Transduction - Abstract
Non‐alcoholic fatty liver disease (NAFLD) and alcohol‐associated liver disease (ALD) represent a spectrum of injury, ranging from simple steatosis to steatohepatitis and cirrhosis. In humans, in fact, fatty changes in the liver, possibly leading to end‐stage disease, were observed after chronic alcohol intake or in conditions of metabolic impairment. In this article, we examined the features and the pro‐inflammatory pathways leading to non‐alcoholic and alcoholic steatohepatitis. The involvement of several events (hits) and multiple inter‐related pathways in the pathogenesis of these diseases suggest that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination treatment towards multiple pro‐inflammatory targets would eventually be required. Gut‐liver crosstalk is involved not only in the impairment of lipid and glucose homoeostasis leading to steatogenesis, but also in the initiation of inflammation and fibrogenesis in both NAFLD and ALD. Modulation of the gut‐liver axis has been suggested as a possible therapeutic approach since gut‐derived components are likely to be involved in both the onset and the progression of liver damage. This review summarizes the translational mechanisms underlying pro‐inflammatory signalling and gut‐liver axis in non‐alcoholic and alcoholic steatohepatitis. With a multitude of people being affected by liver diseases, identification of possible treatments and the elucidation of pathogenic mechanisms are elements of paramount importance.
- Published
- 2020
26. Cholangiocarcinoma: novel therapeutic targets
- Author
-
Domenico Alvaro, Fanyin Meng, Shannon Glaser, Heather Francis, Keisaku Sato, and Gianfranco Alpini
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Clinical Biochemistry ,information science ,Antineoplastic Agents ,Biology ,Article ,Cholangiocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,Drug Development ,parasitic diseases ,Drug Discovery ,microRNA ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,cardiovascular diseases ,Survival rate ,Pharmacology ,Tumor microenvironment ,long non-coding RNA ,fungi ,Treatment options ,Immunotherapy ,medicine.disease ,Long non-coding RNA ,Tree (data structure) ,030104 developmental biology ,Bile Duct Neoplasms ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Mutation ,Disease Progression ,cardiovascular system ,Cancer research ,Molecular Medicine ,immunotherapy ,extracellular vesicles ,Liver cancer ,cholangiocarcinoma ,tumor microenvironment - Abstract
INTRODUCTION: Cholangiocarcinoma (CCA) is a liver cancer derived from the biliary tree with a less than 30% five-year survival rate. Early diagnosis of CCA is challenging and treatment options are limited. Some CCA patients have genetic mutations and several therapeutic drugs or antibodies have been introduced to target abnormally expressed proteins. However, CCA is heterogeneous and patients often present with drug resistance which is attributed to multiple mutations or other factors. Novel approaches and methodologies for CCA treatments are in demand. AREA COVERED: This review summarizes current approaches for CCA treatments leading to the development of novel therapeutic drugs or tools for human CCA patients. A literature search was conducted in PubMed utilizing the combination of the searched term “cholangiocarcinoma” with other keywords such as “miRNA”, “FGFR”, “immunotherapy” or “microenvironment”. Papers published within 2015–2019 were obtained for reading. EXPERT OPINION: Preclinical studies have demonstrated promising therapeutic approaches that target various cells or pathways. Recent studies have revealed that hepatic cells coordinate to promote CCA tumor progression in the tumor microenvironment, which may be a new therapeutic target. Although further studies are required, novel therapeutic tools such as extracellular vesicles could be utilized to manage CCA and its microenvironment.
- Published
- 2020
27. Endothelial dysfunction in pathological processes of chronic liver disease during aging
- Author
-
Ying Wan, Xuedong Li, Elise Slevin, Kelly Harrison, Tian Li, Yudian Zhang, James E. Klaunig, Chaodong Wu, Ashok K. Shetty, X. Charlie Dong, and Fanyin Meng
- Subjects
Liver Cirrhosis ,Aging ,Liver ,Chronic Disease ,Genetics ,Animals ,Humans ,Endothelium, Vascular ,Hypoxia ,Molecular Biology ,Biochemistry ,Biotechnology - Abstract
Aging is associated with gradual changes in liver structure and physiological/pathological functions in hepatic cells including hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). LSECs are specialized hepatic endothelial cells that regulate liver homeostasis. These cells actively impact the hepatic microenvironment as they have fenestrations and a thin morphology to allow substance exchange between circulating blood and the liver tissue. As aging occurs, LSECs have a reduction in both the number and size of fenestrations, which is referred to as pseudocapillarization. This along with the aging of the liver leads to increased oxidative stress, decreased availability of nitric oxide, decreased hepatic blood flow, and increased inflammatory cytokines in LSECs. Vascular aging can also lead to hepatic hypoxia, HSC activation, and liver fibrosis. In this review, we described the basic structure of LSECs, and the effect of LSECs on hepatic inflammation and fibrosis during aging process. We briefly summarized the changes of hepatic microcirculation during liver inflammation, the effect of aging on the clearance function of LSECs, the interactions between LSECs and immunity, hepatocytes or other hepatic nonparenchymal cells, and the therapeutic intervention of liver diseases by targeting LSECs and vascular system. Since LSECs play an important role in the development of liver fibrosis and the changes of LSEC phenotype occur in the early stage of liver fibrosis, the study of LSECs in the fibrotic liver is valuable for the detection of early liver fibrosis and the early intervention of fibrotic response.
- Published
- 2021
28. Irisflorentin suppresses allergic inflammation in mast cells via reducing histamine release and production of pro-inflammatory cytokines
- Author
-
Fanyin Meng and Yunxing Li
- Subjects
Pharmacology ,chemistry.chemical_compound ,chemistry ,business.industry ,Immunology ,Pharmaceutical Science ,Medicine ,business ,Histamine ,Irisflorentin ,Proinflammatory cytokine ,Allergic inflammation - Published
- 2019
29. Hepatitis C Virus Infection and Cholangiocarcinoma
- Author
-
Harshil Dhruv, Scott Celinski, Gianfranco Alpini, Fanyin Meng, Shannon Glaser, and Maria Cristina Navas
- Subjects
0301 basic medicine ,Cirrhosis ,business.industry ,Hepatitis C virus ,fungi ,Hepatitis C ,medicine.disease_cause ,medicine.disease ,digestive system diseases ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,parasitic diseases ,cardiovascular system ,Cancer research ,Medicine ,cardiovascular diseases ,business ,Carcinogenesis ,Liver cancer ,Viral hepatitis ,Oncovirus - Abstract
Hepatitis C virus (HCV) infection is a global public health problem because it is a main cause of liver cirrhosis and hepatocellular carcinoma. This human oncogenic virus is also associated with the development of non-Hodgkin lymphoma and cholangiocarcinoma (CCA). The association between HCV infection and CCA has been examined in a number of epidemiologic studies. However, in vivo and in vitro results demonstrating the oncogenic mechanisms of HCV in CCA development and progression are insufficient. Here, we review the epidemiologic association of HCV and CCA and recent publications of studies of HCV infection of cholangiocytes and CCA cell lines as well as studies of viral infection performed with liver samples obtained from patients. In addition, we also discuss the preliminary results of in vitro assays of HCV protein expression in CCA cell lines. Finally, we discuss the hypothetical role of HCV infection in CCA development by induction of epithelial–mesenchymal transition and up-regulation of hedgehog signaling, and consequently biliary tree inflammation and liver fibrosis. Further studies are required to demonstrate these hypotheses and therefore to elucidate the mechanisms of HCV as a risk factor for CCA.
- Published
- 2019
30. Knockout of α-calcitonin gene-related peptide attenuates cholestatic liver injury by differentially regulating cellular senescence of hepatic stellate cells and cholangiocytes
- Author
-
Tianhao Zhou, Lixian Chen, Paul Baker, Konstantina Kyritsi, Ying Wan, Amelia Sybenga, Shannon Glaser, Gianfranco Alpini, Nan Wu, Chaodong Wu, Fanyin Meng, Heather Francis, Pietro Invernizzi, Julie Venter, Francesca Bernuzzi, Qiaobing Huang, Ludovica Ceci, Wan, Y, Ceci, L, Wu, N, Zhou, T, Chen, L, Venter, J, Francis, H, Bernuzzi, F, Invernizzi, P, Kyritsi, K, Baker, P, Huang, Q, Wu, C, Sybenga, A, Alpini, G, Meng, F, and Glaser, S
- Subjects
Liver Cirrhosis ,Male ,0301 basic medicine ,MAPK/ERK pathway ,Senescence ,MAP Kinase Signaling System ,Calcitonin Gene-Related Peptide ,cholestatic liver diseases ,Cholangitis, Sclerosing ,Cholangiocyte proliferation ,Calcitonin gene-related peptide ,Article ,Cholangiocyte ,Pathology and Forensic Medicine ,03 medical and health sciences ,biliary tract ,cellular senescence ,liver fibrosis ,primary sclerosing cholangitis ,0302 clinical medicine ,MED/12 - GASTROENTEROLOGIA ,Fibrosis ,Hepatic Stellate Cells ,medicine ,Animals ,Humans ,Molecular Biology ,Mice, Knockout ,Liver injury ,integumentary system ,Chemistry ,Cell Biology ,medicine.disease ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,nervous system ,Case-Control Studies ,030220 oncology & carcinogenesis ,Hepatic stellate cell ,Female - Abstract
Background: α-Calcitonin gene-related peptide (α-CGRP) is a 37-amino acid neuropeptide involved in several pathophysiological processes. α-CGRP is involved in the regulation of cholangiocyte proliferation during cholestasis. In this study, we aimed to evaluate if α-CGRP regulates bile duct ligation (BDL)-induced liver fibrosis by using a α-CGRP knockout (α-CGRP−/−) mouse model. Methods: α-CGRP−/− and wild-type (WT) mice were subjected to sham surgery or BDL for 7 days. Then, liver fibrosis and cellular senescence as well as the expression of kinase such as p38 and C-Jun N-terminal protein kinase (JNK) in mitogen-activated protein kinases (MAPK) signaling pathway were evaluated in total liver, together with measurement of cellular senescence in cholangiocytes or hepatic stellate cells (HSCs). Results: There was enhanced hepatic expression of Calca (coding α-CGRP) and the CGRP-receptor components (CRLR, RAMP-1 and RCP) in BDL and in both WT α-CGRP−/− and BDL α-CGRP−/− mice, respectively. Moreover, there was increased CGRP serum levels and hepatic mRNA expression of CALCA and CGRP receptor components in late-stage PSC samples compared to healthy control samples. Depletion of α-CGRP reduced liver injury and fibrosis in BDL mice that was associated with enhanced cellular senescence of hepatic stellate cells and reduced senescence of cholangiocytes as well as decreased activation of p38 and JNK MAPK signaling pathway. Cholangiocyte supernatant from BDL α-CGRP−/− mice inhibited the activation and increased cellular senescence of cultured human HSCs (HHSCs) compared to HHSCs stimulated with BDL cholangiocyte supernatant. Taken together, endogenous α-CGRP promoted BDL-induced cholestatic liver fibrosis through differential changes in senescence of HSCs and cholangiocytes and activation of p38 and JNK signaling. Modulation of α-CGRP/CGRP receptor signaling may be key for the management of biliary senescence and liver fibrosis in cholangiopathies.
- Published
- 2019
31. Preclinical insights into cholangiopathies: disease modeling and emerging therapeutic targets
- Author
-
Lindsey Kennedy, Keisaku Sato, Shannon Glaser, Suthat Liangpunsakul, Gianfranco Alpini, Fanyin Meng, and Heather Francis
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Liver fibrosis ,Cholangitis, Sclerosing ,Clinical Biochemistry ,Disease ,digestive system ,Gastroenterology ,Article ,Cholangiocyte ,Primary sclerosing cholangitis ,03 medical and health sciences ,0302 clinical medicine ,Biliary Atresia ,Biliary atresia ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Pharmacology ,Liver Cirrhosis, Biliary ,business.industry ,Bile duct ,medicine.disease ,digestive system diseases ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Molecular Medicine ,business ,Stem Cell Transplantation - Abstract
INTRODUCTION: The common predominant clinical features of cholangiopathies such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and biliary atresia (BA) are biliary damage/senescence and liver fibrosis. Curative therapies are lacking, and liver transplantation is only option. An understanding of the mechanisms and pathogenesis is needed to develop novel therapies. Previous studies have developed various disease-based research models and have identified candidate therapeutic targets. AREAS COVERED: This review summarizes recent studies performed in preclinical models of cholangiopathies and the current understanding of the pathophysiology representing potential targets for novel therapies. A literature search was conducted in PubMed using the combination of the searched term “cholangiopathies” with one or two keywords including “model”, “cholangiocyte”, “animal”, or “fibrosis”. Papers published within five years were obtained. EXPERT OPINION: Access to appropriate research models is a key challenge in cholangiopathy research; establishing more appropriate models for PBC is an important goal. Several preclinical studies have demonstrated promising results and have led to novel therapeutic approaches, especially for PSC. Further studies on the pathophysiology of PBC and BA are necessary to identify candidate targets. Innovative therapeutic approaches such as stem cell transplantation have been introduced, and those therapies could be applied to PSC, PBC, and BA.
- Published
- 2019
32. Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal‐7 microRNA
- Author
-
Heather Francis, Shannon Glaser, Nan Wu, Demeng Chen, Tianhao Zhou, Sugeily Ramos-Lorenzo, Fanyin Meng, Pietro Invernizzi, Li Huang, Kelly McDaniel, Julie Venter, Gianfranco Alpini, Francesca Bernuzzi, Ludovica Ceci, Chaodong Wu, Keisaku Sato, Mcdaniel, K, Wu, N, Zhou, T, Huan, L, Sato, K, Venter, J, Ceci, L, Chen, D, Ramos-Lorenzo, S, Invernizzi, P, Bernuzzi, F, Wu, C, Francis, H, Glaser, S, Alpini, G, and Meng, F
- Subjects
ductular reaction ,Liver Cirrhosis ,0301 basic medicine ,Cell signaling ,ATP Binding Cassette Transporter, Subfamily B ,liver stem cells ,Cholangitis, Sclerosing ,Liver Stem Cell ,Real-Time Polymerase Chain Reaction ,LIN28 ,Sensitivity and Specificity ,Article ,Cholangiocyte ,Mice ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,MED/12 - GASTROENTEROLOGIA ,Risk Factors ,Fibrosis ,medicine ,Animals ,Humans ,Secretion ,Cells, Cultured ,Mice, Knockout ,Hepatology ,Chemistry ,Stem Cells ,liver fibrosi ,Cell Differentiation ,Primary sclerosing cholangiti ,medicine.disease ,Cell biology ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Hepatocytes ,Hepatic stellate cell ,Female ,030211 gastroenterology & hepatology ,extracellular vesicle ,Stem cell - Abstract
Cholangiopathies are diseases that affect cholangiocytes, the cells lining the biliary tract. Liver stem cells (LSCs) are able to differentiate into all cells of the liver and possibly influence the surrounding liver tissue by secretion of signaling molecules. One way in which cells can interact is through secretion of extracellular vesicles (EVs), which are small membrane-bound vesicles that contain proteins, microRNAs (miRNAs), and cytokines. We evaluated the contents of liver stem cell–derived EVs (LSCEVs), compared their miRNA contents to those of EVs isolated from hepatocytes, and evaluated the downstream targets of these miRNAs. We finally evaluated the crosstalk among LSCs, cholangiocytes, and human hepatic stellate cells (HSCs). We showed that LSCEVs were able to reduce ductular reaction and biliary fibrosis in multidrug resistance protein 2 (MDR2)(−/−) mice. Additionally, we showed that cholangiocyte growth was reduced and HSCs were deactivated in LSCEV-treated mice. Evaluation of LSCEV contents compared with EVs derived from hepatocytes showed a large increase in the miRNA, lethal-7 (let-7). Further evaluation of let-7 in MDR2(−/−) mice and human primary sclerosing cholangitis samples showed reduced levels of let-7 compared with controls. In liver tissues and isolated cholangiocytes, downstream targets of let-7 (identified by ingenuity pathway analysis), Lin28a (Lin28 homolog A), Lin28b (Lin28 homolog B), IL-13 (interleukin 13), NR1H4 (nuclear receptor subfamily 1 group H member 4) and NF-κB (nuclear factor kappa B), are elevated in MDR2(−/−) mice, but treatment with LSCEVs reduced levels of these mediators of ductular reaction and biliary fibrosis through the inhibition of NF-κB and IL-13 signaling pathways. Evaluation of crosstalk using cholangiocyte supernatants from LSCEV-treated cells on cultured HSCs showed that HSCs had reduced levels of fibrosis and increased senescence. CONCLUSION: Our studies indicate that LSCEVs could be a possible treatment for cholangiopathies or could be used for target validation for future therapies.
- Published
- 2019
33. Mo1361: HEPATOCYTE SPECIFIC DELETION OF MICRORNA-34A ALLEVIATES DUCTULAR REACTION AND LIVER FIBROSIS DURING EXPERIMENTAL CHOLESTASIS
- Author
-
Elise Slevin, Ying Wan, Kelly Harrison, Xuedong Li, Tian Li, Sugeily Ramos Lorenzo, Yudian Zhang, Wenjuan Xu, Ashok k. Shetty, Chaodong Wu, James E. Klaunig, Chiung-Kuei Huang, and Fanyin Meng
- Subjects
Hepatology ,Gastroenterology - Published
- 2022
34. Cover page
- Author
-
Linh Pham, Leonardo Baiocchi, Lindsey Kennedy, Keisaku Sato, Vik Meadows, Fanyin Meng, Chiung‐Kuei Huang, Debjyoti Kundu, Tianhao Zhou, Lixian Chen, Gianfranco Alpini, and Heather Francis
- Subjects
Endocrinology - Published
- 2021
35. Mast Cells Promote Nonalcoholic Fatty Liver Disease Phenotypes and Microvesicular Steatosis in Mice Fed a Western Diet
- Author
-
Laura Hargrove, Vik Meadows, Tianhao Zhou, Amelia Sybenga, Debjyoti Kundu, Wasim A. Dar, Burcin Ekser, Jennifer Demieville, Gianfranco Alpini, Ludovica Ceci, Fanyin Meng, Konstantina Kyritsi, Linh Pham, Lindsey Kennedy, Lixian Chen, Heather Francis, and Shannon Glaser
- Subjects
0301 basic medicine ,Senescence ,Adult ,Liver Cirrhosis ,Male ,medicine.medical_specialty ,Adolescent ,Angiogenesis ,Microvesicular Steatosis ,Inflammation ,digestive system ,Article ,03 medical and health sciences ,Mice ,Young Adult ,0302 clinical medicine ,Cholestasis ,Fibrosis ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,Animals ,Humans ,Mast Cells ,Biliary Tract ,Aged ,Aged, 80 and over ,Hepatology ,business.industry ,nutritional and metabolic diseases ,Middle Aged ,medicine.disease ,Aldehyde Oxidoreductases ,digestive system diseases ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Liver ,Diet, Western ,Hepatocytes ,030211 gastroenterology & hepatology ,Female ,medicine.symptom ,Steatosis ,business - Abstract
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is simple steatosis but can develop into nonalcoholic steatohepatitis (NASH), characterized by liver inflammation, fibrosis, and microvesicular steatosis. Mast cells (MCs) infiltrate the liver during cholestasis and promote ductular reaction (DR), biliary senescence, and liver fibrosis. We aimed to determine the effects of MC depletion during NAFLD/NASH. APPROACH AND RESULTS: Wild-type (WT) and Kit(W-sh) (MC-deficient) mice were fed a control diet (CD) or a Western diet (WD) for 16 weeks; select WT and Kit(W-sh) WD mice received tail vein injections of MCs 2 times per week for 2 weeks prior to sacrifice. Human samples were collected from normal, NAFLD, or NASH mice. Cholangiocytes from WT WD mice and human NASH have increased insulin-like growth factor 1 expression that promotes MC migration/activation. Enhanced MC presence was noted in WT WD mice and human NASH, along with increased DR. WT WD mice had significantly increased steatosis, DR/biliary senescence, inflammation, liver fibrosis, and angiogenesis compared to WT CD mice, which was significantly reduced in Kit(W-sh) WD mice. Loss of MCs prominently reduced microvesicular steatosis in zone 1 hepatocytes. MC injection promoted WD-induced biliary and liver damage and specifically up-regulated microvesicular steatosis in zone 1 hepatocytes. Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) expression is reduced in WT WD mice and human NASH but increased in Kit(W-sh) WD mice. MicroRNA 144-3 prime (miR-144-3p) expression was increased in WT WD mice and human NASH but reduced in Kit(W-sh) WD mice and was found to target ALDH1A3. CONCLUSIONS: MCs promote WD-induced biliary and liver damage and may promote microvesicular steatosis development during NAFLD progression to NASH through miR-144-3p/ALDH1A3 signaling. Inhibition of MC activation may be a therapeutic option for NAFLD/NASH treatment. (HEPATOLOGY 2021;74:164–182).
- Published
- 2020
36. Downregulation of p16 Decreases Biliary Damage and Liver Fibrosis in the Mdr2/ Mouse Model of Primary Sclerosing Cholangitis
- Author
-
Shannon Glaser, Lixian Chen, Chaodong Wu, Zhihong Yang, Lindsey Kennedy, Konstantina Kyritsi, Heather Francis, Suthat Liangpunsakul, Debjyoti Kundu, Gianfranco Alpini, Fanyin Meng, Ludovica Ceci, Leonardo Baiocchi, Nan Wu, and Tianhao Zhou
- Subjects
Senescence ,Adult ,Liver Cirrhosis ,Male ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,Cholangitis, Sclerosing ,Intrahepatic bile ducts ,Down-Regulation ,liver ,Cholangiocyte ,Article ,Primary sclerosing cholangitis ,Cell Line ,Mice ,Settore MED/12 ,Downregulation and upregulation ,Sirtuin 1 ,Fibrosis ,Transforming Growth Factor beta ,Internal medicine ,Genetics ,Medicine ,Animals ,Humans ,cholangiocytes ,Biliary Tract ,Molecular Biology ,Cyclin-Dependent Kinase Inhibitor p16 ,miRNA ,biology ,business.industry ,biliary epithelium ,cholangiopathies ,Middle Aged ,medicine.disease ,MicroRNAs ,Endocrinology ,biology.protein ,Female ,Hepatic fibrosis ,business - Abstract
Biliary senescence and hepatic fibrosis are hallmarks of cholangiopathies including primary sclerosing cholangitis (PSC). Senescent cholangiocytes display senescence-associated secretory phenotypes [SASPs, e.g., transforming growth factor-1 (TGF-1)] that further increase biliary senescence (by an autocrine loop) and trigger liver fibrosis by paracrine mechanisms. The aim of this study was to determine the effect of p16 inhibition and role of the TGF-1/microRNA (miR)-34a/sirtuin 1 (SIRT1) axis in biliary damage and liver fibrosis in the Mdr2/ mouse model of PSC. We treated (i) in vivo male wild-type (WT) and Mdr2/ mice with p16 Vivo-Morpholino or controls before measuring biliary mass [intrahepatic bile duct mass (IBDM)] and senescence, biliary SASP levels, and liver fibrosis, and (ii) in vitro intrahepatic murine cholangiocyte lines (IMCLs) with small interfering RNA against p16 before measuring the mRNA expression of proliferation, senescence, and fibrosis markers. p16 and miR-34a increased but SIRT1 decreased in Mdr2/ mice and PSC human liver samples compared to controls. p16 immunoreactivity and biliary senescence and SASP levels increased in Mdr2/ mice but decreased in Mdr2/ mice treated with p16 Vivo-Morpholino. The increase in IBDM and hepatic fibrosis (observed in Mdr2/ mice) returned to normal values in Mdr2/ mice treated with p16 Vivo-Morpholino. TGF-1 immunoreactivity and biliary SASPs levels were higher in Mdr2/ compared to those of WT mice but returned to normal values in Mdr2/ mice treated with p16 Vivo-Morpholino. The expression of fibrosis/senescence markers decreased in cholangiocytes from Mdr2/ mice treated with p16 Vivo-Morpholino (compared to Mdr2/ mice) and in IMCLs (after p16 silencing) compared to controls. Modulation of the TGF-1/miR-34a/SIRT1 axis may be important in the management of PSC phenotypes.
- Published
- 2020
37. The interplay between mast cells, pineal gland, and circadian rhythm: Links between histamine, melatonin, and inflammatory mediators
- Author
-
Linh Pham, Lixian Chen, Vik Meadows, Tianhao Zhou, Lindsey Kennedy, Heather Francis, Debjyoti Kundu, Keisaku Sato, Chiung-Kuei Huang, Fanyin Meng, Gianfranco Alpini, and Leonardo Baiocchi
- Subjects
0301 basic medicine ,circadian rhythm ,Circadian clock ,Inflammation ,mast cells ,melatonin ,Histidine Decarboxylase ,Pineal Gland ,Article ,Melatonin ,03 medical and health sciences ,Pineal gland ,chemistry.chemical_compound ,Settore MED/12 ,0302 clinical medicine ,Endocrinology ,medicine ,clock genes ,Animals ,Humans ,Circadian rhythm ,Interleukin-13 ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Chemistry ,Suprachiasmatic nucleus ,histamine ,Cell biology ,CLOCK ,030104 developmental biology ,medicine.anatomical_structure ,inflammation ,medicine.symptom ,030217 neurology & neurosurgery ,Histamine ,medicine.drug - Abstract
Our daily rhythmicity is controlled by a circadian clock with a specific set of genes located in the suprachiasmatic nucleus in the hypothalamus. Mast cells (MCs) are major effector cells that play a protective role against pathogens and inflammation. MC distribution and activation are associated with the circadian rhythm via two major pathways, IgE/FcεRI- and IL-33/ST2-mediated signaling. Furthermore, there is a robust oscillation between clock genes and MC-specific genes. Melatonin is a hormone derived from the amino acid tryptophan and is produced primarily in the pineal gland near the center of the brain, and histamine is a biologically active amine synthesized from the decarboxylation of the amino acid histidine by the L-histidine decarboxylase enzyme. Melatonin and histamine are previously reported to modulate circadian rhythms by pathways incorporating various modulators in which the nuclear factor-binding near the κ light-chain gene in B cells, NF-κB, is the common key factor. NF-κB interacts with the core clock genes and disrupts the production of pro-inflammatory cytokine mediators such as IL-6, IL-13, and TNF-α. Currently, there has been no study evaluating the interdependence between melatonin and histamine with respect to circadian oscillations in MCs. Accumulating evidence suggests that restoring circadian rhythms in MCs by targeting melatonin and histamine via NF-κB may be promising therapeutic strategy for MC-mediated inflammatory diseases. This review summarizes recent findings for circadian-mediated MC functional roles and activation paradigms, as well as the therapeutic potentials of targeting circadian-mediated melatonin and histamine signaling in MC-dependent inflammatory diseases.
- Published
- 2020
38. Functional Role of the Secretin/Secretin Receptor Signaling During Cholestatic Liver Injury
- Author
-
Paolo Onori, Nan Wu, Eugenio Gaudio, Vik Meadows, Tianhao Zhou, Heather Francis, Lindsey Kennedy, Gianfranco Alpini, Ludovica Ceci, Chaodong Wu, Lixian Chen, Antonio Franchitto, Fanyin Meng, Konstantina Kyritsi, Debjyoti Kundu, Keisaku Sato, Ilaria Lenci, Leonardo Baiocchi, Domenico Alvaro, Burcin Ekser, and Shannon Glaser
- Subjects
dnTGF-βRII ,PBC ,secretin0 ,Epithelium ,Receptors, G-Protein-Coupled ,Secretin ,Settore MED/12 ,fluids and secretions ,PSC ,Bile ,PKA ,CFTR ,Receptor ,Liver injury ,NGF ,Cholestasis ,microRNA ,primary biliary cholangitis ,multidrug resistance 2 (Abcb4) ,primary sclerosing cholangitis ,Liver ,Secretin receptor ,Signal transduction ,cholangiocarcinoma ,Liver pathology ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,dominant-negative transforming growth factor β receptor II ,Functional role ,CCA ,cystic fibrosis transmembrane conductance regulator ,Mdr2 ,miRNA ,nerve growth factor ,protein kinase A ,Sct ,Cellular senescence ,digestive system ,Article ,Receptors, Gastrointestinal Hormone ,Bile Acids and Salts ,medicine ,Animals ,Humans ,Hepatology ,business.industry ,medicine.disease ,digestive system diseases ,Disease Models, Animal ,Chronic Disease ,Cancer research ,Bile Ducts ,business - Abstract
The gastrointestinal peptide, secretin (Sct) is an important homeostatic regulator of pancreatic and liver secretory function. With regard to the liver, discoveries have been made, in the last decades, indicating a key role for the secretin/secretin receptor axis during normal or cholestatic conditions. Since large cholangiocytes are the only cells to express secretin receptor in the liver, research on secretin also expanded our knowledge on biliary epithelia. In this review we examined in detail the role of the secretin/secretin receptor axis, not only on biliary secretion, but also on cholangiocyte proliferation and senescence, as well as in prompting fibrotic processes involving biliary epithelia. Relevant data on human chronic cholestatic liver diseases, such as primary biliary cholangitis or primary sclerosing cholangitis, and obtained in animal models mimicking the diseases or in correlative studies on human are also reported. The aim of this review is to provide an update on the progress regarding the interactions between secretin and the biliary epithelia in normal and pathological conditions, underlining the aspects that suggests modulation of secretin pathway as a possible therapeutic approach for chronic cholestatic human liver disease.
- Published
- 2020
39. Knockout of the Tachykinin Receptor 1 in the Mdr2
- Author
-
Ludovica, Ceci, Heather, Francis, Tianhao, Zhou, Thao, Giang, Zhihong, Yang, Fanyin, Meng, Nan, Wu, Lindsey, Kennedy, Konstantina, Kyritsi, Vik, Meadows, Chaodong, Wu, Suthat, Liangpunsakul, Antonio, Franchitto, Amelia, Sybenga, Burcin, Ekser, Romina, Mancinelli, Paolo, Onori, Eugenio, Gaudio, Shannon, Glaser, and Gianfranco, Alpini
- Subjects
Liver Cirrhosis ,Mice, Knockout ,Disease Models, Animal ,ATP Binding Cassette Transporter, Subfamily B ,Gene Knockdown Techniques ,Cholangitis, Sclerosing ,Animals ,Regular Article ,Bile Ducts ,Receptors, Neurokinin-1 - Abstract
Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated and Mdr2(−/−) (alias Abcb4(−/−)) mice through enhanced transforming growth factor-β1 (TGF-β1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-β1–induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-β1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2(−/−) and NK1R(−/) (alias Tacr1(−/−)) to further address the role of the SP/NK1R axis during chronic cholestasis. In vivo studies were performed in the following 12-week–old male mice: (i) NK1R(−/−); (ii) Mdr2(−/−); and (iii) NK1R(−/−)/Mdr2(−/−) (Tacr1(−/−)/Abcb4(−/−)) and their corresponding wild-type controls. Liver tissues and cholangiocytes were collected, and liver damage, changes in biliary mass/senescence, and inflammation as well as liver fibrosis were evaluated by both immunohistochemistry in liver sections and real-time PCR. miR-31 expression was measured by real-time PCR in isolated cholangiocytes. Decreased ductular reaction, liver fibrosis, biliary senescence, and biliary inflammation were observed in NK1R(−/−)/Mdr2(−/−) mice compared with Mdr2(−/−) mice. Elevated expression of miR-31 was observed in Mdr2(−/−) mice, which was reduced in NK1R(−/−)/Mdr2(−/−) mice. Targeting the SP/NK1R and/or miR-31 may be a potential approach in treating human cholangiopathies, including primary sclerosing cholangitis.
- Published
- 2020
40. Neuroendocrine changes in cholangiocarcinoma growth
- Author
-
Romina Mancinelli, Tianhao Zhou, Fanyin Meng, Lindsey Kennedy, Eugenio Gaudio, Shannon Glaser, Antonio Franchitto, Burcin Ekser, Heather Francis, Keisaku Sato, Paolo Onori, Leonardo Baiocchi, and Gianfranco Alpini
- Subjects
0301 basic medicine ,ductular reaction ,medicine.medical_treatment ,Cholangiocyte proliferation ,information science ,Neuropeptide ,Review ,Malignancy ,neurotransmitters ,03 medical and health sciences ,Settore MED/12 ,0302 clinical medicine ,Mediator ,parasitic diseases ,Humans ,Medicine ,cardiovascular diseases ,Progenitor cell ,cholangiocytes ,Receptor ,lcsh:QH301-705.5 ,liver fibrosis ,hormones ,business.industry ,fungi ,neuropeptides ,General Medicine ,medicine.disease ,3. Good health ,Radiation therapy ,030104 developmental biology ,Bile Duct Neoplasms ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Cancer research ,cardiovascular system ,cholangiocarcinoma ,business ,Hormone - Abstract
Cholangiocarcinoma (CCA) is a highly aggressive malignancy that emerges from the biliary tree. There are three major classes of CCA—intrahepatic, hilar (perihilar), or distal (extrahepatic)—according to the location of tumor development. Although CCA tumors are mainly derived from biliary epithelia (i.e., cholangiocytes), CCA can be originated from other cells, such as hepatic progenitor cells and hepatocytes. This heterogeneity of CCA may be responsible for poor survival rates of patients, limited effects of chemotherapy and radiotherapy, and the lack of treatment options and novel therapies. Previous studies have identified a number of neuroendocrine mediators, such as hormones, neuropeptides, and neurotransmitters, as well as corresponding receptors. The mediator/receptor signaling pathways play a vital role in cholangiocyte proliferation, as well as CCA progression and metastases. Agonists or antagonists for candidate pathways may lead to the development of novel therapies for CCA patients. However, effects of mediators may differ between healthy or cancerous cholangiocytes, or between different subtypes of receptors. This review summarizes current understandings of neuroendocrine mediators and their functional roles in CCA.
- Published
- 2020
41. Melatonin and circadian rhythms in liver diseases: functional roles and potential therapies
- Author
-
Lixian Chen, Nan Wu, Shannon Glaser, Keisaku Sato, Lindsey Kennedy, Antonio Franchitto, Paolo Onori, Fanyin Meng, Tianhao Zhou, Eugenio Gaudio, Gianfranco Alpini, and Heather Francis
- Subjects
0301 basic medicine ,medicine.medical_specialty ,endocrine system ,medicine.disease_cause ,Article ,Melatonin ,03 medical and health sciences ,Pineal gland ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,Animals ,Humans ,Circadian rhythm ,Suprachiasmatic nucleus ,business.industry ,Liver Diseases ,medicine.disease ,circadian rhythms ,clock genes ,liver fibrosis ,liver steatosis ,melatonin ,nonalcoholic fatty liver disease ,reactive oxygen species ,Circadian Rhythm ,CLOCK ,030104 developmental biology ,medicine.anatomical_structure ,Hypothalamus ,business ,030217 neurology & neurosurgery ,Oxidative stress ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress-induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.
- Published
- 2020
42. Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase-A/5-Hydroxytryptamine/5-Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis
- Author
-
David C. Zawieja, Romil Saxena, Tianhao Zhou, Luca Fabris, Heather Francis, Shannon Glaser, Lixian Chen, Nan Wu, Chaodong Wu, April O'Brien, Travis W. Hein, Nicholas J. Skill, Anatoliy A. Gashev, Ludovica Ceci, Fanyin Meng, Konstantina Kyritsi, Gianfranco Alpini, Suthat Liangpunsakul, Pietro Invernizzi, Julie Venter, Kyritsi, K, Chen, L, O'Brien, A, Francis, H, Hein, T, Venter, J, Wu, N, Ceci, L, Zhou, T, Zawieja, D, Gashev, A, Meng, F, Invernizzi, P, Fabris, L, Wu, C, Skill, N, Saxena, R, Liangpunsakul, S, Alpini, G, and Glaser, S
- Subjects
0301 basic medicine ,Liver Cirrhosis ,Male ,medicine.medical_specialty ,Serotonin ,ATP Binding Cassette Transporter, Subfamily B ,Monoamine oxidase ,Cholangitis, Sclerosing ,Tryptophan Hydroxylase ,digestive system ,Article ,Proinflammatory cytokine ,Rats, Sprague-Dawley ,03 medical and health sciences ,Mice ,0302 clinical medicine ,MED/12 - GASTROENTEROLOGIA ,Internal medicine ,Receptor, Serotonin, 5-HT2B ,medicine ,Receptor, Serotonin, 5-HT2C ,Animals ,Humans ,Receptor, Serotonin, 5-HT2A ,cholangiocytes ,Receptor ,serotonin ,cholestasis ,Monoamine Oxidase ,Cell Proliferation ,TPH1 ,Hepatology ,Chemistry ,cholangiopathie ,Tryptophan hydroxylase ,Rats ,030104 developmental biology ,Endocrinology ,Receptors, Serotonin ,Hepatic stellate cell ,Enterochromaffin cell ,030211 gastroenterology & hepatology ,Bile Ducts ,fibrosi - Abstract
BACKGROUND AND AIMS: Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO-A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5-hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile-duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. APPROACH AND RESULTS: While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout (Mdr2(−/−)) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO-A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2(−/−) mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2(−/−) mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2(−/−) mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2(−/−) mice, respectively. 5HT levels increase in Mdr2(−/−) mice and in PSC human patients compared to their controls and decrease in serum of Mdr2(−/−) mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2(−/−) mice. In vitro, cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO-A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls. CONCLUSIONS: Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.
- Published
- 2020
43. Kupffer Cells: Inflammation Pathways and Cell-Cell Interactions in Alcohol-Associated Liver Disease
- Author
-
Elise, Slevin, Leonardo, Baiocchi, Nan, Wu, Burcin, Ekser, Keisaku, Sato, Emily, Lin, Ludovica, Ceci, Lixian, Chen, Sugeily R, Lorenzo, Wenjuan, Xu, Konstantina, Kyritsi, Victoria, Meadows, Tianhao, Zhou, Debiyoti, Kundu, Yuyan, Han, Lindsey, Kennedy, Shannon, Glaser, Heather, Francis, Gianfranco, Alpini, and Fanyin, Meng
- Subjects
Kupffer Cells ,Animal ,Liver Diseases ,Review ,Cell Communication ,Alcoholic ,Disease Models, Animal ,Mice ,Settore MED/12 ,Liver ,Disease Models ,Hepatic Stellate Cells ,Animals ,Humans ,Chemokines ,Reactive Oxygen Species ,Liver Diseases, Alcoholic - Abstract
Chronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease.
- Published
- 2020
44. Knockout of microRNA-21 attenuates alcoholic hepatitis through the VHL/NF-κB signaling pathway in hepatic stellate cells
- Author
-
Li Huang, Chaodong Wu, Fanyin Meng, Heather Francis, Tami Annable, Kelly McDaniel, Gianfranco Alpini, Sugeily Ramos-Lorenzo, Demeng Chen, Nan Wu, Tianhao Zhou, and Shannon Glaser
- Subjects
Liver Cirrhosis ,0301 basic medicine ,Alcoholic liver disease ,Physiology ,medicine.medical_treatment ,Down-Regulation ,Alcoholic hepatitis ,Inflammation ,Mice ,03 medical and health sciences ,Physiology (medical) ,microRNA ,Hepatic Stellate Cells ,medicine ,Animals ,Humans ,Gene silencing ,Cells, Cultured ,Mice, Knockout ,Liver injury ,Hepatology ,Hepatitis, Alcoholic ,business.industry ,Gastroenterology ,medicine.disease ,MicroRNAs ,030104 developmental biology ,Cytokine ,Gene Expression Regulation ,Liver ,Hepatic stellate cell ,Cancer research ,Cytokines ,medicine.symptom ,business ,Research Article ,Signal Transduction - Abstract
microRNA-21 (miRNA) is one of the most abundant miRNAs in chronic liver injuries including alcoholic liver injury. Previous studies have demonstrated that miR-21 plays a role in inflammation in the liver and functions in hepatic stellate cells (HSCs), which reside in the perisinusoidal space between sinusoidal endothelial cells and hepatocytes and regulate sinusoidal circulation. HSCs integrate cytokine-mediated inflammatory responses in the sinusoids and relay them to the liver parenchyma. Here, we showed that the activation of Von Hippel-Lindau (VHL) expression, by miR-21 knockout in vivo and anti-miR-21 or VHL overexpression in vitro, suppressed the production of proinflammatory cytokines, such as interleukin (IL)-6, monocyte chemoattractant protein-1, and IL-1β, in human HSCs during alcoholic liver injury. Sequence and functional analyses confirmed that miR-21 directly targeted the 3′-untranslated region of VHL. Immunofluorescence and real-time PCR analysis revealed that miR-21 depletion blocked NF-κB activation in human HSCs both in cultured HSCs as well as HSCs isolated from alcohol-related liver disease mice liver by laser capture microdissection. We also showed that conditioned medium from anti-miR-21-transfected HSCs suppressed human monocyte-derived THP-1 cell migration. Taken together, our study indicates that depletion of miR-21 may downregulate cytokine production in HSCs and macrophage chemotaxis during alcoholic liver injury and that the targeting of miR-21 may have therapeutic potential for preventing the progression of alcoholic liver diseases. NEW & NOTEWORTHY This study demonstrates that silencing microRNA-21 can inhibit cytokine production and inflammatory responses in human hepatic stellate cells during alcoholic liver injury and that the targeting of microR-21 in hepatic stellate cells may have therapeutic potential for prevention and treatment of alcoholic liver diseases.
- Published
- 2018
45. Biliary epithelium: A neuroendocrine compartment in cholestatic liver disease
- Author
-
Gianfranco Alpini, Laurent Ehrlich, Terry C. Lairmore, Marinda Scrushy, Shannon Glaser, and Fanyin Meng
- Subjects
Liver Cirrhosis ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Sympathetic Nervous System ,Cirrhosis ,Cholangitis ,Article ,Primary sclerosing cholangitis ,Renin-Angiotensin System ,Biliary injury ,03 medical and health sciences ,0302 clinical medicine ,Ductopenia ,Parasympathetic Nervous System ,Transforming Growth Factor beta ,medicine ,Animals ,Humans ,Biliary Tract ,Cell Proliferation ,Melatonin ,Neurotransmitter Agents ,Cholestasis ,Neovascularization, Pathologic ,Hepatology ,business.industry ,Polycystic liver disease ,Neuropeptides ,Gastroenterology ,Epithelial Cells ,medicine.disease ,Neurosecretory Systems ,Arginine Vasopressin ,030104 developmental biology ,Liver ,Hepatic stellate cell ,030211 gastroenterology & hepatology ,Hepatic fibrosis ,business ,Neurohormones - Abstract
Hepatic fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM) that can lead to ductopenia, cirrhosis, and even malignant transformation. In this review, we examine cholestatic liver diseases characterized by extensive biliary fibrosis such as Primary Sclerosing Cholangitis (PSC), Primary Biliary Cholangitis (PBC), Polycystic Liver Disease (PLD), and MDR2(−/−) and BDL mouse models. Following biliary injury, cholangiocytes, the epithelial cells that line the bile ducts, become reactive and adopt a neuroendocrine phenotype in which they secrete and respond to neurohormones and neuropeptides in an autocrine and paracrine fashion. Emerging evidence indicates that cholangiocytes influence and respond to changes in the ECM and stromal cells in the microenvironment. For example, activated myofibroblasts and hepatic stellate cells are major drivers of collagen deposition and biliary fibrosis. Additionally, the liver is richly innervated with adrenergic, cholinergic, and peptidergic fibers that release neurohormones and peptides to maintain homeostasis and can be deranged in disease states. This review summarizes how cholangiocytes interact with their surrounding environment, with particular focus on how autonomic and sensory regulation affects fibrotic pathophysiology.
- Published
- 2018
46. α7-nAChR Knockout Mice Decreases Biliary Hyperplasia and Liver Fibrosis in Cholestatic Bile Duct-Ligated Mice
- Author
-
Tori White, Nan Wu, Laurent Ehrlich, Marinda Scrushy, David E. Dostal, Chad Hall, Gianfranco Alpini, Shannon Glaser, Terry C. Lairmore, Julie Venter, Fanyin Meng, Chaodong Wu, Muhammad Mubarak, April O'Brien, and Lixian Chen
- Subjects
Liver Cirrhosis ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,alpha7 Nicotinic Acetylcholine Receptor ,Intrahepatic bile ducts ,digestive system ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cholestasis ,Transforming Growth Factor beta ,Fibrosis ,Cell Line, Tumor ,Proliferating Cell Nuclear Antigen ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Sirius Red ,Hyperplasia ,Biliary hyperplasia ,Bile duct ,business.industry ,Kupffer cell ,Cholestasis, Extrahepatic ,medicine.disease ,Mice, Inbred C57BL ,Ki-67 Antigen ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Hepatic stellate cell ,Cytokines ,030211 gastroenterology & hepatology ,Bile Ducts ,business - Abstract
α7-nAChR is a nicotinic acetylcholine receptor [specifically expressed on hepatic stellate cells (HSCs), Kupffer cells, and cholangiocytes] that regulates inflammation and apoptosis in the liver. Thus, targeting α7-nAChR may be therapeutic in biliary diseases. Bile duct ligation (BDL) was performed on wild-type (WT) and α7-nAChR−/− mice. We first evaluated the expression of α7-nAChR by immunohistochemistry (IHC) in liver sections. IHC was also performed to assess intrahepatic bile duct mass (IBDM), and Sirius Red staining was performed to quantify the amount of collagen deposition. Immunofluorescence was performed to assess colocalization of α7-nAChR with bile ducts (costained with CK-19) and HSCs (costained with desmin). The mRNA expression of α7-nAChR, Ki-67/PCNA (proliferation), fibrosis genes (TGF-β1, fibronectin-1, Col1α1, and α-SMA), and inflammatory markers (IL-6, IL-1β, and TNF-α) was measured by real-time PCR. Biliary TGF-β1 and hepatic CD68 (Kupffer cell marker) expression was assessed using IHC. α7-nAChR immunoreactivity was observed in both bile ducts and HSCs and increased following BDL. α7-nAChR−/− BDL mice exhibited decreased (i) bile duct mass, liver fibrosis, and inflammation, and (ii) immunoreactivity of TGF-β1 as well as expression of fibrosis genes compared to WT BDL mice. α7-nAChR activation triggers biliary proliferation and liver fibrosis and may be a therapeutic target in managing extrahepatic biliary obstruction.
- Published
- 2018
47. Blocking H1/H2 histamine receptors inhibits damage/fibrosis in Mdr2–/– mice and human cholangiocarcinoma tumorigenesis
- Author
-
Jennifer Demieville, Vik Meadows, Pietro Invernizzi, Francesca Bernuzzi, Heather Francis, Fanyin Meng, Hannah Jones, Steven Smith, Austin Akers, Sharon DeMorrow, Walker Karstens, Laura Hargrove, Gianfranco Alpini, Lindsey Kennedy, Kennedy, L, Hargrove, L, Demieville, J, Karstens, W, Jones, H, Demorrow, S, Meng, F, Invernizzi, P, Bernuzzi, F, Alpini, G, Smith, S, Akers, A, Meadows, V, and Francis, H
- Subjects
Male ,0301 basic medicine ,ATP Binding Cassette Transporter, Subfamily B ,Epithelial-Mesenchymal Transition ,Angiogenesis ,Cholangitis, Sclerosing ,Mepyramine ,Drug Evaluation, Preclinical ,Cholangiocyte proliferation ,Pharmacology ,Article ,Cholangiocarcinoma ,Neovascularization ,Mice ,03 medical and health sciences ,Histamine receptor ,chemistry.chemical_compound ,0302 clinical medicine ,MED/12 - GASTROENTEROLOGIA ,Hepatic Stellate Cells ,medicine ,Animals ,Humans ,Mast Cells ,Mice, Knockout ,Neovascularization, Pathologic ,Hepatology ,Hepatic stellate cell activation ,030104 developmental biology ,Histamine H2 Antagonists ,Liver ,chemistry ,Histamine H1 Antagonists ,Hepatic stellate cell ,030211 gastroenterology & hepatology ,medicine.symptom ,Histamine ,medicine.drug - Abstract
Primary sclerosing cholangitis (PSC) patients are at risk of developing cholangiocarcinoma (CCA). We have shown that (1) histamine increases biliary hyperplasia through H1/H2 histamine receptors (HRs) and (2) histamine levels increase and mast cells (MCs) infiltrate during PSC and CCA. We examined the effects of chronic treatment with H1/H2HR antagonists on PSC and CCA. Wild-type and multidrug-resistant knockout (Mdr2-/- ) mice were treated by osmotic minipumps with saline, mepyramine, or ranitidine (10 mg/kg body weight/day) or a combination of mepyramine/ranitidine for 4 weeks. Liver damage was assessed by hematoxylin and eosin. We evaluated (1) H1/H2HR expression, (2) MC presence, (3) L-histidine decarboxylase/histamine axis, (4) cholangiocyte proliferation/bile duct mass, and (5) fibrosis/hepatic stellate cell activation. Nu/nu mice were implanted with Mz-ChA-1 cells into the hind flanks and treated with saline, mepyramine, or ranitidine. Tumor growth was measured, and (1) H1/H2HR expression, (2) proliferation, (3) MC activation, (4) angiogenesis, and (5) epithelial-mesenchymal transition (EMT) were evaluated. In vitro, human hepatic stellate cells were evaluated for H1HR and H2HR expression. Cultured cholangiocytes and CCA lines were treated with saline, mepyramine, or ranitidine (25 μM) before evaluating proliferation, angiogenesis, EMT, and potential signaling mechanisms. H1/H2HR and MC presence increased in human PSC and CCA. In H1/H2HR antagonist (alone or in combination)-treated Mdr2-/- mice, liver and biliary damage and fibrosis decreased compared to saline treatment. H1/H2HR antagonists decreased tumor growth, serum histamine, angiogenesis, and EMT. In vitro, H1/H2HR blockers reduced biliary proliferation, and CCA cells had decreased proliferation, angiogenesis, EMT, and migration. Conclusion: Inhibition of H1/H2HR reverses PSC-associated damage and decreases CCA growth, angiogenesis, and EMT; because PSC patients are at risk of developing CCA, using HR blockers may be therapeutic for these diseases. (Hepatology 2018).
- Published
- 2018
48. Mechanisms of cholangiocyte responses to injury
- Author
-
Keisaku Sato, Thao Giang, Fanyin Meng, Shannon Glaser, and Gianfranco Alpini
- Subjects
Liver Cirrhosis ,0301 basic medicine ,Cholangiocyte proliferation ,Biology ,Article ,Cholangiocyte ,Receptors, G-Protein-Coupled ,Receptors, Gastrointestinal Hormone ,Primary sclerosing cholangitis ,Secretin ,Extracellular Vesicles ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Molecular Biology ,Cell Proliferation ,Liver injury ,Cholestasis ,Hyperplasia ,Epithelial Cells ,medicine.disease ,MicroRNAs ,030104 developmental biology ,Liver ,Immunology ,Cancer research ,Molecular Medicine ,Secretin receptor ,030211 gastroenterology & hepatology ,Bile Ducts ,Signal transduction ,Homeostasis ,Signal Transduction - Abstract
Cholangiocytes, epithelial cells that line the biliary epithelium, are the primary target cells for cholangiopathies including primary sclerosing cholangitis and primary biliary cholangitis. Quiescent cholangiocytes respond to biliary damage and acquire an activated neuroendocrine phenotype to maintain the homeostasis of the liver. The typical response of cholangiocytes is proliferation leading to bile duct hyperplasia, which is a characteristic of cholestatic liver diseases. Current studies have identified various signaling pathways that are associated with cholangiocyte proliferation/loss and liver fibrosis in cholangiopathies using human samples and rodent models. Although recent studies have demonstrated that extracellular vesicles and microRNAs could be mediators that regulate these messenger/receptor axes, further studies are required to confirm their roles. This review summarizes current studies of biliary response and cholangiocyte proliferation during cholestatic liver injury with particular emphasis on the secretin/secretin receptor axis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
- Published
- 2018
49. Fr407 LIVER SPECIFIC MICRORNA-34A-MEDIATED MACROPHAGE POLARIZATION AND ITS POTENTIAL ROLE IN THE REGULATION OF LIVER FIBROSIS DURING CHOLESTATIC LIVER INJURY
- Author
-
Wenjuan Xu, Chiung-Kuei Huang, Elise Slevin, Ying Wan, and Fanyin Meng
- Subjects
Liver injury ,Hepatology ,business.industry ,MicroRNA 34a ,Liver fibrosis ,Gastroenterology ,medicine ,Cancer research ,Macrophage polarization ,medicine.disease ,business - Published
- 2021
50. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR‐200b down‐regulation
- Author
-
Fanyin Meng, Heather Francis, Eugenio Gaudio, Gianfranco Alpini, Sharon DeMorrow, Yuyan Han, Lindsey Kennedy, Shannon Glaser, Nan Wu, Romina Mancinelli, Tianhao Zhou, Paolo Onori, Francesca Bernuzzi, Pietro Invernizzi, Julie Venter, Antonio Franchitto, Wu, N, Meng, F, Zhou, T, Han, Y, Kennedy, L, Venter, J, Francis, H, Demorrow, S, Onori, P, Invernizzi, P, Bernuzzi, F, Mancinelli, R, Gaudio, E, Franchitto, A, Glaser, S, and Alpini, G
- Subjects
Liver Cirrhosis ,Biliary epithelium ,Cholangiopathy ,Male ,0301 basic medicine ,Pathology ,Fibrosi ,Angiogenesis ,AANAT ,Biochemistry ,angiogenesis ,Fibrosis ,Melatonin ,Biliary hyperplasia ,MicroRNA ,Darkness ,biliary epithelium ,cholangiopathy ,cholestasis ,miRNA ,Angiogenesi ,Cholestasi ,Biotechnology ,medicine.drug ,medicine.medical_specialty ,Liver Cirrhosi ,Cholangitis, Sclerosing ,Angiogenesis Inducing Agent ,Down-Regulation ,Mice, Transgenic ,Primary sclerosing cholangitis ,03 medical and health sciences ,Internal medicine ,Hepatic Stellate Cells ,Genetics ,medicine ,Animals ,Molecular Biology ,Cell Proliferation ,Animal ,business.industry ,Research ,medicine.disease ,Hepatic Stellate Cell ,MicroRNAs ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Hepatic stellate cell ,Angiogenesis Inducing Agents ,Darkne ,business ,Hepatic fibrosis - Abstract
Melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in bile-duct–ligated (BDL) rats; however, no information exists in primary sclerosing cholangitis (PSC). Thus, we aimed to determine the therapeutic effects of prolonged dark therapy or melatonin administration on hepatic fibrosis in the multidrug resistance gene 2–knockout (Mdr2−/−) mouse model of PSC. Melatonin levels, biliary mass, liver fibrosis, angiogenesis and miR-200b expression were evaluated in wild-type and Mdr2−/− mice exposed to darkness or melatonin treatment or in male patients with PSC and healthy controls. Mdr2−/− mice were also treated with miR-200b inhibitor or control before evaluating biliary mass, liver fibrosis, and angiogenesis. After overexpression of arylalkylamine N-acetyltransferase (AANAT; the enzyme regulating melatonin synthesis) or inhibition of miR-200b in cholangiocytes and hepatic stellate cells in vitro, we evaluated angiogenesis and fibrosis gene expression. After exposure to darkness or administration of melatonin, Mdr2−/− mice show elevated serum melatonin levels and inhibition of biliary mass, along with reduction of liver fibrosis and angiogenesis. MicroRNA PCR analysis demonstrated that miR-200b expression increased in Mdr2−/− mice and patients with PSC compared with controls and decreased in Mdr2−/− mice subjected to dark exposure or melatonin treatment. Inhibition of miR-200b in Mdr2−/− ablates biliary proliferation, liver fibrosis, and angiogenesis. In vitro, overexpression of AANAT or inhibition of miR-200b in cholangiocytes and hepatic stellate cells decreased the expression of miR-200b, angiogenesis, and fibrosis genes. Dark therapy or targeting melatonin/miR-200b axis may be important in the management of biliary damage and liver fibrosis in cholangiopathies including PSC.—Wu, N., Meng, F., Zhou, T., Han, Y., Kennedy, L., Venter, J., Francis, H., DeMorrow, S., Onori, P., Invernizzi, P., Bernuzzi, F., Mancinelli, R., Gaudio, E., Franchitto, A., Glaser, S., Alpini G. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation.
- Published
- 2017
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.