Browsing by Subject "Cholangiocytes"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Concise Review: Functional Roles and Therapeutic Potentials of Long Non-coding RNAs in Cholangiopathies
    (Frontiers Media, 2020-02) Sato, Keisaku; Glaser, Shannon; Francis, Heather; Alpini, Gianfranco; Medicine, School of Medicine
    Long non-coding RNAs (lncRNAs) are RNAs with lengths exceeding 200 nucleotides that are not translated into proteins. It is well-known that small non-coding RNAs, such as microRNAs (miRNAs), regulate gene expression and play an important role in cholangiopathies. Recent studies have demonstrated that lncRNAs may also play a key role in the pathophysiology of cholangiopathies. Patients with cholangiopathies often develop cholangiocarcinoma (CCA), which is cholangiocyte-derived cancer, in the later stage. Cholangiocytes are a primary target of therapies for cholangiopathies and CCA development. Previous studies have demonstrated that expression levels of lncRNAs are altered in the liver of cholangiopathies or CCA tissues. Some lncRNAs regulate gene expression by inhibiting functions of miRNAs leading to diseased liver conditions or CCA progression, suggesting that lncRNAs could be a novel therapeutic target for those disorders. This review summarizes current understandings of functional roles of lncRNAs in cholangiopathies and seek their potentials for novel therapies.
  • Thumbnail Image
    Item
    Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?
    (MDPI, 2021-07-04) Baiocchi, Leonardo; Lenci, Ilaria; Milana, Martina; Kennedy, Lindsey; Sato, Keisaku; Zhang, Wenjun; Ekser, Burcin; Ceci, Ludovica; Meadows, Vik; Glaser, Shannon; Alpini, Gianfranco; Francis, Heather; Medicine, School of Medicine
    Cholangiocarcinoma is a lethal disease with scarce response to current systemic therapy. The rare occurrence and large heterogeneity of this cancer, together with poor knowledge of its molecular mechanisms, are elements contributing to the difficulties in finding an appropriate cure. Cholangiocytes (and their cellular precursors) are considered the liver component giving rise to cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli employing the cAMP/PKA system for the translation of messages in the intracellular space. For instance, in physiological conditions, stimulation of the secretin receptor determines an increase of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes' injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific pieces of evidence link cAMP signaling system to cholangiocytes' proliferation, the possible changes of this pathway during cancer growth also seem relevant. In this review, we summarize the current findings regarding the cAMP pathway and its role in biliary normal and neoplastic cell proliferation. Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed.
  • Thumbnail Image
    Item
    Downregulation of p16 Decreases Biliary Damage and Liver Fibrosis in the Mdr2 / Mouse Model of Primary Sclerosing Cholangitis
    (Cognizant Communication Corporation, 2020-11) Kyritsi, Konstantina; Francis, Heather; Zhou, Tianhao; Ceci, Ludovica; Wu, Nan; Yang, Zhihong; Meng, Fanyin; Chen, Lixian; Baiocchi, Leonardo; Kundu, Debjyoti; Kennedy, Lindsey; Liangpunsakul, Suthat; Wu, Chaodong; Glaser, Shannon; Alpini, Gianfranco; Medicine, School of Medicine
    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.
  • Thumbnail Image
    Item
    Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease
    (MDPI, 2021-08-12) Zhou, Tianhao; Kundu, Debjyoti; Robles-Linares, Jonathan; Meadows, Vik; Sato, Keisaku; Baiocchi, Leonardo; Ekser, Burcin; Glaser, Shannon; Alpini, Gianfranco; Francis, Heather; Kennedy, Lindsey; Medicine, School of Medicine
    Fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), are global health disparities, particularly in the United States, as a result of cultural eating habits and lifestyle. Pathological studies on NAFLD have been mostly focused on hepatocytes and other inflammatory cell types; however, the impact of other biliary epithelial cells (i.e., cholangiocytes) in the promotion of NAFLD is growing. This review article will discuss how cholestatic injury and cholangiocyte activity/ductular reaction influence NAFLD progression. Furthermore, this review will provide informative details regarding the fundamental properties of cholangiocytes and bile acid signaling that can influence NAFLD. Lastly, studies relating to the pathogenesis of NAFLD, cholangiopathies, and ductular reaction will be analyzed to help gain insight for potential therapies.
  • Thumbnail Image
    Item
    Neuroendocrine Changes in Cholangiocarcinoma Growth
    (MDPI, 2020-02-13) Sato, Keisaku; Francis, Heather; Zhou, Tianhao; Meng, Fanyin; Kennedy, Lindsey; Ekser, Burcin; Baiocchi, Leonardo; Onori, Paolo; Mancinelli, Romina; Gaudio, Eugenio; Franchitto, Antonio; Glaser, Shannon; Alpini, Gianfranco; Medicine, School of Medicine
    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.