Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • Cholangiopathies are a group of rare

    2019-04-30

    Cholangiopathies are a group of rare diseases whose primary or secondary target is the cholangiocyte. The onset and subsequent development processes of cholangiopathies are extremely diverse, with causes that are genetic, neoplastic, immune-mediated, idiopathic, infectious, and toxin- or drug-induced. Cholangiopathies contribute to significant morbidity and mortality and are one of the main causes of liver transplantation in both pediatric and adult patients. In the early stages, cholangiopathies can primarily be characterized by enhanced biliary inflammation and apoptosis that can lead to cholestasis and biliary proliferation. If unmanaged, these hepatic insults can further progress to destruction of cholangiocytes, extensive fibrosis, cirrhosis and possibly cholangiocarcinoma. As previously stated, cholangiocytes begin to proliferate and secrete neuroendocrine factors in response to damage, and this cellular function has been largely characterized during the progression of cholangiopathies. Recently, however, microRNAs (miRNAs) have been recognized as initiators and/or drivers of some cholangiopathies. MiRNAs are short, non-coding RNAs, around 18–23 nucleotides in length, that regulate post-transcriptional gene expression of specific mRNAs. In mammals, miRNAs regulate the expression of approximately 60% of genes. In the nucleus, primary-miRNA (pri-miRNA) is transcribed from DNA by Pol II, and then pri-miRNA is recognized and cleaved by the RNase III endonuclease Drosha to release precursor-miRNA (pre-miRNA). This pre-miRNA (60–90 nucleotides in length) is transported to the purchase NMS-873 in a RAN-GTP-dependent manner via Exportin-5; once in the nucleus it is ultimately processed by another RNase III endonuclease, Dicer, into a miRNA duplex (18–23 nucleotides in length). Next, the miRNA duplex is inserted into the miRNA-associated RNA-induced silencing complex (RISC) and separated into a functional guide strand and a passenger strand. Once in the cytoplasm, the guide strand, or mature miRNA, will recognize and bind to complementary sequences in mRNAs, primarily within the 3′ untranslated region (3′ UTR). This interaction will either result in transcriptional suppression or degradation of the mRNA, depending on binding efficiency. Mature miRNAs play major roles in various cell processes in both physiological and pathological conditions; these include, but are not limited to, proliferation, apoptosis, metabolism, inflammatory response and fibrotic reaction. These effects can be regulated in an autocrine manner or through paracrine signaling by exosome-mediated release of miRNAs. In addition, different types of liver injury can elicit different miRNA secretion patterns and concentrations. Therefore, identifying disease-specific miRNAs could be used as potential diagnostic and therapeutic tools. In this review, we will focus primarily on human studies conducted in the past five years that identify miRNA patterns during cholangiopathies and the possible role that these miRNAs may play during pathogenesis.
    Primary sclerosing cholangitis Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease that primarily affects the biliary epithelium. While PSC is a fairly rare disease, its incidence and prevalence has recently been increasing. PSC primarily affects middle-aged men, but cases have been seen in females as well as pediatric patients. PSC patients typically present with chronic inflammation surrounding the biliary epithelium that eventually leads to bile duct strictures that can obstruct bile flow and lead to hepatic cholestasis. Eventually, this cholestatic injury can induce surrounding resident liver cells to increase liver fibrosis, which can result in cirrhosis. PSC patients are also at a higher risk of developing cholangiocarcinoma (CCA), a highly malignant and devastating disease. Research on the role of miRNAs during PSC pathogenesis has been insufficient. Therefore, the analysis of miRNA expression patterns should become an increased area of interest for the diagnosis of or therapeutic intervention for patients with PSC.