Browsing by Author "O’Brien, April"

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    FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2-/- Mouse Model of Primary Sclerosing Cholangitis
    (Wolters Kluwer, 2022) O’Brien, April; Zhou, Tianhao; White, Tori; Medford, Abigail; Chen, Lixian; Kyritsi, Konstantina; Wu, Nan; Childs, Jonathan; Stiles, Danaleigh; Ceci, Ludovica; Chakraborty, Sanjukta; Ekser, Burcin; Baiocchi, Leonardo; Carpino, Guido; Gaudio, Eugenio; Wu, Chaodong; Kennedy, Lindsey; Francis, Heather; Alpini, Gianfranco; Glaser, Shannon; Medicine, School of Medicine
    Fibroblast growth factor 1 (FGF1) belongs to a family of growth factors involved in cellular growth and division. MicroRNA 16 (miR-16) is a regulator of gene expression, which is dysregulated during liver injury and insult. However, the role of FGF1 in the progression of biliary proliferation, senescence, fibrosis, inflammation, angiogenesis, and its potential interaction with miR-16, are unknown. In vivo studies were performed in male bile duct-ligated (BDL, 12-week-old) mice, multidrug resistance 2 knockout (Mdr2-/-) mice (10-week-old), and their corresponding controls, treated with recombinant human FGF1 (rhFGF1), fibroblast growth factor receptor (FGFR) antagonist (AZD4547), or anti-FGF1 monoclonal antibody (mAb). In vitro, the human cholangiocyte cell line (H69) and human hepatic stellate cells (HSCs) were used to determine the expression of proliferation, fibrosis, angiogenesis, and inflammatory genes following rhFGF1 treatment. PSC patient and control livers were used to evaluate FGF1 and miR-16 expression. Intrahepatic bile duct mass (IBDM), along with hepatic fibrosis and inflammation, increased in BDL mice treated with rhFGF1, with a corresponding decrease in miR-16, while treatment with AZD4547 or anti-FGF1 mAb decreased hepatic fibrosis, IBDM, and inflammation in BDL and Mdr2-/- mice. In vitro, H69 and HSCs treated with rhFGF1 had increased expression of proliferation, fibrosis, and inflammatory markers. PSC samples also showed increased FGF1 and FGFRs with corresponding decreases in miR-16 compared with healthy controls. Conclusion: Our study demonstrates that suppression of FGF1 and miR-16 signaling decreases the presence of hepatic fibrosis, biliary proliferation, inflammation, senescence, and angiogenesis. Targeting the FGF1 and miR-16 axis may provide therapeutic options in treating cholangiopathies such as PSC.
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    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
    (Wiley, 2020-03) Kyritsi, Konstantina; Chen, Lixian; O’Brien, April; Francis, Heather; Hein, Travis W.; Venter, Julie; Wu, Nan; Ceci, Ludovica; Zhou, Tianhao; Zawieja, David; Gashev, Anatoliy A.; Meng, Fanyin; Invernizzi, Pietro; Fabris, Luca; Wu, Chaodong; Skill, Nicholas J.; Saxena, Romil; Liangpunsakul, Suthat; Alpini, Gianfranco; Glaser, Shannon S.; Medicine, School of Medicine
    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.
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    Role of Non-Coding RNAs in the Progression of Liver Cancer: Evidence from Experimental Models
    (MDPI, 2019-10-25) O’Brien, April; Zhou, Tianhao; Tan, Christopher; Alpini, Gianfranco; Glaser, Shannon; Medicine, School of Medicine
    Liver cancer is a devastating cancer that ranges from relatively rare (around 2% of all cancers in the United States) to commonplace (up to 50% of cancers in underdeveloped countries). Depending upon the stage of pathogenesis, prognosis, or functional liver tissue present, transplantation or partial hepatectomy may be the only available treatment option. However, due to the rise in metabolic syndrome and the increasing demand for livers, patients often wait months or years for available organs. Due to this shortage, doctors must have other treatment options available. One promising area of cancer research lies in understanding the role of regulatory non-coding RNAs (ncRNAs) as oncogenic drivers and potential targets for prospective therapies. While the role of these ncRNAs was not initially clear, many of them have since been recognized to function as important players in the regulation of gene expression, epigenetic modification, and signal transduction in both normal and cancer cell cycles. Dysregulation of these different ncRNA subtypes has been implicated in the pathogenesis and progression of many major cancers including hepatocellular carcinoma. This review summarizes current findings on the roles noncoding RNAs play in the progression of liver cancer and the various animal models used in current research to elucidate those data.
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    The Role of Lymphatics in Cholestasis: A Comprehensive Review
    (Thieme, 2020) O’Brien, April; Gasheva, Olga; Alpini, Gianfranco; Zawieja, David; Gashev, Anatoliy; Glaser, Shannon; Medicine, School of Medicine
    Cholestatic liver disease affects millions of people worldwide and stems from a plethora of causes such as immune dysfunction, genetics, cancerous growths, and lifestyle choices. While not considered a classical lymphatic organ, the liver plays a vital role in the lymph system producing up to half of the body’s lymph per day. The lymphatic system is critical to the health of an organism with its networks of vessels that provide drainage for lymphatic fluid and routes for surveilling immune cells. Cholestasis results in an increase of inflammatory cytokines, growth factors, and inflammatory infiltrate. Left unchecked, further disease progression will include collagen deposition which impedes both the hepatic and lymphatic ducts, eventually resulting in an increase in hepatic decompensation, increasing portal pressures, and accumulation of fluid within the abdominal cavity (ascites). Despite the documented interplay between these vital systems, little is known about the effect of liver disease on the lymph system and its biological response. This review looks at the current cholestatic literature from the perspective of the lymphatic system and summarizes what is known about the role of the lymph system in liver pathogenesis during hepatic injury and remodeling, immune-modulating events, or variations in interstitial pressures.
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    Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma
    (MDPI, 2021-11-09) Roy, Sukanya; Kumaravel, Subhashree; Banerjee, Priyanka; White, Tori K.; O’Brien, April; Seelig, Catherine; Chauhan, Rahul; Ekser, Burcin; Bayless, Kayla J.; Alpini, Gianfranco; Glaser, Shannon S.; Chakraborty, Sanjukta; Surgery, School of Medicine
    Cholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis.