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RUOLO DELLA MELATONINA E DEL PATHWAY SU CUI ESSA AGISCE NELLA REGOLAZIONE DELLA CRESCITA DELL’EPITELIO BILIARE SIA IN CONDIZIONI SPERIMENTALI CHE NELLE COLANGIOPATIE UMANE E NEL COLANGIOCARCINOMA
Full text linkCholangiocytes are ephitilial cells which line the biliary tree and that in normal condition are mitotically quiescient. Under experimental conditions, such as bile duct ligation (BDL) or in some human cholangiopathies (eg, primary biliary cirrhosis-PBC) cholangiocytes undergo a marked proliferation. A number of factors including Vascular endothelial growth factor (VEGF) and Follicle-stimulating hormone (FSH) regulate biliary tree growth. Melatonin is secreted by the pineal gland and other tissues where it acts as a local regulator of growth, as in the gastrointestinal tract. Melatonin exerts its effects through two membrane receptors (MT1 and MT2) and is synthesized from tryptophan by four enzymes: tryptophan-hydroxylase (TPH), aromatic-amino acid decarboxylase (AADC), serotonin N-acetyltransferase (AANAT) and acetilserotonin- O-methyltransferase (ASMT). Melatonin acts by modulating the expression of Clock genes in the pineal gland. In the liver melatonin reduces oxidative damage. Little information exists about the effects of melatonin on biliary epithelium, therefore the aim of this study was to evaluate the role of melatonin in the regulation of proliferation of biliary epithelium. To this end, we used normal and BDL rats treated or not with: i) melatonin, ii) Arilalkilamina-N-acetyltransferase (AANAT) mistatch and iii) AANAT Vivo Morpholino for 7days and iiii) nude mice injected with the cholangiocarcinoma cell line (Mz-Cha-1) treated or not with melatonin. On liver samples of the experimental models we evaluated: i) the expression of melatonin, the melatonin receptors (MT1 and MT2) and Clock genes, cholangiocytes proliferation and apoptosis, ii) basal and secretin Cyclic adenosine monophosphate (cAMP) levels and Protein Chinase A (PKA) phosphorylation. In addition, we evaluated the expression of melatonin, its receptors and AANAT also in fragments of normal human liver, cholangiocarcioma and PBC. In vitro, large mouse cholangiocytes (LMC), normal human cholangiocytes (H69) and cholangiocarcinoma cell line (Mz-Cha-1) were treated with melatonin 10-11 M for 48h, plus or minus Luzindole (MT1 antagonist) or cis-4-Phenyl-2-propionamidotetralin(4P-PDOT) (MT1 and MT2 antagonist); Finally, we evaluated the effects of AANAT overexpression in LMC and in Mz-Cha-1 on proliferation, apoptosis and cAMP pathway. The results obtained showed that: cholangiocytes expess AANAT, melatonin and its receptors MT1 and MT2 and Clock genes. Chronic administration of melatonin in vivo decreased cholangiocytes proliferation after BDL, and the down-regulation of AANAT in Normal and BDL AANAT Morpholino treated rats increased proliferation. In vitro, melatonin decreased LMC proliferation, decreased which is blocked by Luzindole but not by (4P-PDOT). Overexpression of AANAT in LMC decreased cholangiocytes proliferation, and the intracellular cAMP levels. The expression of AANAT and melatonin decreased in cholangiocarcinoma, instead increased is the expression of MT1 and MT2. In nude mice injected with CCA cell lines the tumor decreased after treatment with melatonin. Overexpression of AANAT in Mz-Cha-1 decreased proliferation and increased apoptosis. In PBC the expression of AANAT, melatonin and its receptors increased if compared to normal. Based on the results obtained, we can say that melatonin plays an important role in the regulation of cholangiocytes proliferation during cholestatic liver diseases and cholangiocarcinoma
Expression of brain derivated neurotrophic factor and of its receptors: TrKB and p75NT in normal and bile duct ligated rat liver
Full text linkCholangiocytes are the cells lining the biliary tree from canals of Hering to larger bile ducts. By morphology, they are divided in small and large cholangiocytes, which result heterogeneous at functional and proliferative levels. Proliferating cholangiocytes acquire a neuroendocrine phenotype, modulated by several factors including neurotrophins. Brain Derivated Neurotrophic Factor (BDNF) is a neurotrophin expressed in the nervous system and also in different types of epithelial and progenitor cells. The aim of the present study is to detect the expression of BDNF and of its two receptors (TrKB and p75NT, or p75NTR) in normal and bile duct ligated (BDL) rat livers. In normal and BDL livers, BDNF and its receptors are expressed by small and large cholangiocytes and by hepatic progenitors cells. In cholangiocytes, the expression of BDNF and of its receptors changes after different BDL timing. After one or two weeks of BDL, both BDNF and TrKB and p75NT receptors are highly expressed, while after BDL for three weeks BDNF expression is drastically reduced and p75NT receptor prevails on TrKB. The expression of BDNF and of its receptors correlates with the proliferation rate of biliary tree during BDL. Indeed, after one or two weeks of BDL, proliferation prevails on apoptosis, whereas after BDL for three weeks, apoptosis prevails on proliferation. Our morphological results strongly suggest that BDNF plays a role in the remodeling of biliary tree during cholestasis and that it may be involved in the pathophysiology of cholestasic liver diseases.Cholangiocytes are the cells lining the biliary tree from canals of Hering to larger bile ducts. By morphology, they are divided in small and large cholangiocytes, which result heterogeneous at functional and proliferative levels. Proliferating cholangiocytes acquire a neuroendocrine phenotype, modulated by several factors including neurotrophins. Brain Derivated Neurotrophic Factor (BDNF) is a neurotrophin expressed in the nervous system and also in different types of epithelial and progenitor cells. The aim of the present study is to detect the expression of BDNF and of its two receptors (TrKB and p75NT, or p75NTR) in normal and bile duct ligated (BDL) rat livers. In normal and BDL livers, BDNF and its receptors are expressed by small and large cholangiocytes and by hepatic progenitors cells. In cholangiocytes, the expression of BDNF and of its receptors changes after different BDL timing. After one or two weeks of BDL, both BDNF and TrKB and p75NT receptors are highly expressed, wh
Role of hepatic progenitor cells in nonalcoholic fatty liver disease development: Cellular cross-talks and molecular networks
No full textNonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases ranging from simple fatty liver to nonalcoholic steatohepatitis, (NASH) which may progress to cirrhosis and hepatocellular carcinoma. NASH has been independently correlated with atherosclerosis progression and cardiovascular risk. NASH development is characterized by intricate interactions between resident and recruited cells that enable liver damage progression. The increasing general agreement is that the cross-talk between hepatocytes, hepatic stellate cells (HSCs) and macrophages in NAFLD has a main role in the derangement of lipid homeostasis, insulin resistance, danger recognition, immune tolerance response and fibrogenesis. Moreover, several evidences have suggested that hepatic stem/progenitor cell (HPCs) activation is a component of the adaptive response of the liver to oxidative stress in NAFLD. HPC activation determines the appearance of a ductular reaction. In NASH, ductular reaction is independently correlated with progressive portal fibrosis raising the possibility of a periportal fibrogenetic pathway for fibrogenesis that is parallel to the deposition of subsinusoidal collagen in zone 3 by HSCs. Recent evidences indicated that adipokines, a class of circulating factors, have a key role in the cross-talk among HSCs, HPCs and liver macrophages. This review will be focused on cellular cross-talk and the relative molecular networks which are at the base of NASH progression and fibrosis
Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology
Full text linkCholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA).
During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases
Inhibition of the liver expression of arylalkylamine N-acetyltransferase increases the expression of angiogenic factors in cholangiocytes
No full textReduction of biliary serotonin N-acetyltransferase (AANAT) expression and melatonin administration/secretion in cholangiocytes increases biliary proliferation and the expression of SR, CFTR and Cl(-)/HCO3 (-) AE2. The balance between biliary proliferation/damage is regulated by several autocrine neuroendocrine factors including vascular endothelial growth factor-A/C (VEGF-A/C). VEGFs are secreted by several epithelia, where they modulate cell growth by autocrine and paracrine mechanisms. No data exists regarding the effect of AANAT modulation on the expressions of VEGFs by cholangiocytes. In this study, we evaluated the effect of local modulation of biliary AANAT expression on the cholangiocytes synthesis of VEGF-A/C. The decrease in AANAT expression and subsequent lower melatonin secretion by cholangiocytes was associated with increased expression of VEGF-A/C. Overexpression of AANAT in cholangiocyte lines decreased the expression of VEGF-A/C. Modulation of melatonin synthesis may affect the expression of VEGF-A/C by cholangiocytes and may modulate the hepatic microvascularization through the regulation of VEGF-A/C expression regulating biliary functions
IMMUNOLOCALIZATION OF COCAINE-AMPHETAMINE REGULATED TRANSCRIPT (CART) IN BILIARY EPITHELIUM
No full textCholangiocytes proliferation can be modulated by several neuroendocrine factors (1). The peptide cocaine-amphetamine-regulated transcript (CART) has various physiological functions and is widely expressed in many organs (2). CART increases the survival of hippocampal neurons by up-regulating Brain Derived Neurotrophic Factor (BDNF) (3). Recent study has detected the expression of BDNF and of its two receptors (TrKB and p75NT) in cholangiocytes of rat liver and their involvement in proliferation rate of biliary tree (4). Aim of this study is to investigate the expression of CART in the rat biliary epithelium. Male Wistar rats were divided into normal (n=6) and BDL (n=6) group. All rats were sacrificed after 1 week. Liver samples from both BDL and normal group were collected to perform light microscopy and immunohistochemistry for CART, CK19 (cytokeratin-19) and PCNA (proliferating cell nuclear antigen). Our results show an increased expression of CART together with the growth of intrahepatic bile ductal mass (IBDM) and of cholangiocytes proliferation in BDL. CART may be implicated in the remodeling of biliary epithelium during cholestasis through key mediators of cell survival and proliferation, as well as through BDNF activated pathways
Expression of vascular endothelial growth factors and their receptors by hepatic progenitor cells in human liver diseases
No full textHepatic stem/progenitor cells (HPCs) are stem cells residing in the most peripheral branches of the biliary tree; these cells are able to differentiate towards mature hepatocyte or mature cholangiocyte; moreover in normal conditions, they are mostly quiescent cells. HPC activation has been involved in the progression of chronic parenchymal diseases (chronic viral hepatitis) and chronic biliary diseases (such as Primary Biliary Cirrhosis: PBC) and in the occurrence of intrahepatic cholangiocarcinoma. The HPCs participate in the repair of liver damage either through the replacement of dead cells or by driving fundamental repair processes, including fibrosis and angiogenesis. Little information exists regarding the expression of VEGF by HPC in the course of liver non-malignant pathologies. In this study, we evaluated: (I) the presence of HPCs in PBC and HCV-related Cirrhosis (HCV-C) samples, and (II) the expression of VEGFs and VEGF-Rs in PBC and HCV-C samples. Our results showed (I) PBC samples presented a more extensive expansion of HPC population in comparison with those of HCV-C samples; (II) PBC samples showed a more extensive angiogenesis if compared to HCV-C; and (III) PBC samples were characterized by an increased expression of VEGF-A and VEGF-C if compared to HCV-C and the number of HPCs expressing VEGFs was correlated with the extension of ductular reaction and angiogenesis. The role of VEGFs in the expansion of HPC niche could have important implication in the management of fibrogenic processes and carcinogenesis
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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