Prolactin stimulates the proliferation of normal female cholangiocytes by differential regulation of Ca2+-dependent PKC isoforms

<p>Abstract</p> <p>Background</p> <p>Prolactin promotes proliferation of several cells. Prolactin receptor exists as two isoforms: long and short, which activate different transduction pathways including the Ca²⁺-dependent PKC-signaling. No information exists on the role of prolactin in the regulation of the growth of female cholangiocytes. The rationale for using cholangiocytes from female rats is based on the fact that women are preferentially affected by specific cholangiopathies including primary biliary cirrhosis. We propose to evaluate the role and mechanisms of action by which prolactin regulates the growth of female cholangiocytes.</p> <p>Results</p> <p>Normal cholangiocytes express both isoforms (long and short) of prolactin receptors, whose expression increased following BDL. The administration of prolactin to normal female rats increased cholangiocyte proliferation. In purified normal female cholangiocytes, prolactin stimulated cholangiocyte proliferation, which was associated with increased [Ca²⁺]_ilevels and PKCβ-I phosphorylation but decreased PKCα phosphorylation. Administration of an anti-prolactin antibody to BDL female rats decreased cholangiocyte proliferation. Normal female cholangiocytes express and secrete prolactin, which was increased in BDL rats. The data show that prolactin stimulates normal cholangiocyte growth by an autocrine mechanism involving phosphorylation of PKCβ-I and dephosphorylation of PKCα.</p> <p>Conclusion</p> <p>We suggest that in female rats: (i) prolactin has a trophic effect on the growth of normal cholangiocytes by phosphorylation of PKCβ-I and dephosphorylation of PKCα; and (iii) cholangiocytes express and secrete prolactin, which by an autocrine mechanism participate in regulation of cholangiocyte proliferation. Prolactin may be an important therapeutic approach for the management of cholangiopathies affecting female patients.</p

Molecular mechanisms of cholangiocarcinoma

Cholangiocarcinoma (CC), the malignant tumor of the epithelial cells lining the biliary ducts, has undergone a worldwide increase in incidence and mortality. The malignant transformation of the biliary cells originates from a multistep process evolving through chronic inflammation of the biliary tract to CC. In the last few years several advances have been towards understanding and clarifying the molecular mechanisms implicated in the cholangiocarcinogenesis process. However, many pathophysiologic aspects governing the growth of CC are still undefined. The poor prognosis of this tumor underlines the urgent need to codify the underlying molecular mechanisms involved in the growth and progression of CC in order to design effective preventive measures and valid treatment regimens. This review reports on progresses made in the last few years in clarifying the molecular pathways involved in the process of cholangiocarcinogenesis

[Tenofovir and entecavir for chronic hepatitis B infection treatment: a single-center experience]

BACKGROUND AND AIM: The current treatment of chronic hepatitis B infection (CHBV) has achieved several step-ups thanks to the introduction of the new-generation nucleos(t)ide analogs. Entecavir and tenofovir have shown a high genetic resistance barrier and a low rate of side effects. In literature, there are a few studies comparing entecavir and tenofovir in the treatment of CHBV. Thus, we describe the results of our experience in managing CHBV patients with tenofovir vs. entecavir. MATERIALS AND METHODS: We have retrospectively evaluated, from 2007 to date, 20 CHBV patients treated with entecavir and tenofovir. All the patients underwent basal and periodical clinical follow-up, blood tests, virological tests, Fibroscan® test or liver biopsy and also upper abdominal ultrasound examination. Study endpoints were: viral replication inhibition, viral antigens seroconversion and transaminases normalization. Drug-associated side effects were also registered. RESULTS: After 12 weeks of therapy, entecavir and tenofovir lead to HBV-DNA negativization in 44% and 62% of patients, respectively. A case of viral seroconversion for HBeAg and HBsAg was evident in entecavir group, while no cases were registered in tenofovir group. After 12 weeks, 11% of entecavir treated patients and 37% of tenofovir treated patients showed normalization of transaminases. DISCUSSION: Tenofovir seems to exert a better viral replication inhibition (though not statistically significant) and to show transaminases improvement in comparison with entecavir, which, in turn, results more effective in HBeAg/HBsAg seroconversion. Both drugs have a high safety profile in terms of side effects. [Article in Italian

Functional roles of gut bacteria imbalance in cholangiopathies

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, Inflammatio

Gut Microbiota and Alcoholic Liver Disease

The gut-liver axis model has often explained liver disease physiopathology. Among the latter we can mention Non-Alcoholic Liver Steatosis (NAFLD), Liver Steatohepatitis (NASH), liver cirrhosis. In this frame an altered Intestinal Permeability (IP) is the gate for antigenic/toxic substances from gut lumen until target organs such as liver in NAFLD. Altered intestinal permeability was discovered almost forty years ago as consequence of acute and chronic alcohol ingestion. Alcohol Liver Disease (ALD) is a systemic pathology whose beginning and end belong to the intestine. Several recent evidences from the literature show how gut microbiota composition can be altered by alcohol, affects IP and can be modulated by several nonpharmacological and pharmacological agents, becoming the target for ALD treatment. In this review we describe the definition of ALD, gut microbiota composition in healthy and ALD, definition and role of IP in ALD physiopathology and emerging evidences on gut microbiota modulation in ALD treatment from preliminary clinical and non-clinical studies

Postoperative insulin-like growth factor 1 levels reflect the graft's function and predict survival after liver transplantation

Background The reduction of insulin-like growth factor 1 (IGF-1) plasma levels is associated with the degree of liver dysfunction and mortality in cirrhotic patients. However, little research is available on the recovery of the IGF-1 level and its prognostic role after liver transplantation (LT). Methods From April 2010 to May 2011, 31 patients were prospectively enrolled (25/6 M/F; mean age +/- SEM: 55.2 +/- 1.4 years), and IGF-1 serum levels were assessed preoperatively and at 15, 30, 90, 180 and 365 days after transplantation. The influence of the donor and recipient characteristics (age, use of extended criteria donor grafts, D-MELD and incidence of early allograft dysfunction) on hormonal concentration was analyzed. The prognostic role of IGF-1 level on patient survival and its correlation with routine liver function tests were also investigated. Results All patients showed low preoperative IGF-1 levels (mean +/- SEM: 29.5 +/- 2.1), and on postoperative day 15, a significant increase in the IGF-1 plasma level was observed (102.7 +/- 11.7 ng/ml; p65 years) or extended criteria donor grafts. An inverse correlation between IGF-1 and bilirubin serum levels at day 15 (r = -0.3924, p = 0.0320) and 30 (r = -0.3894, p = 0.0368) was found. After multivariate analysis, early (within 15 days) IGF-1 normalization [Exp(b) = 3.913; p = 0.0484] was the only prognostic factor associated with an increased 3-year survival rate. Conclusion IGF-1 postoperative levels are correlated with the graft's quality and reflect liver function. Early IGF-1 recovery is associated with a higher 3-year survival rate after LT

H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

Histamine regulates many functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). As H3R exerts their effects by coupling to Gαi/o proteins reducing adenosine 3′, 5′-monophosphate (cAMP) levels (a key player in the modulation of cholangiocyte hyperplasia/damage), we evaluated the role of H3R in the regulation of biliary growth. We posed the following questions: (1) Do cholangiocytes express H3R? (2) Does in vivo administration of (R)-(α)-(-)-methylhistamine dihydrobromide (RAMH) (H3R agonist), thioperamide maleate (H3R antagonist) or histamine, in the absence/presence of thioperamide maleate, to bile duct ligated (BDL) rats regulate cholangiocyte proliferation? and (3) Does RAMH inhibit cholangiocyte proliferation by downregulation of cAMP-dependent phosphorylation of protein kinase A (PKA)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ets-like gene-1 (Elk-1)? The expression of H3R was evaluated in liver sections by immunohistochemistry and immunofluorescence, and by real-time PCR in cholangiocyte RNA from normal and BDL rats. BDL rats (immediately after BDL) were treated daily with RAMH, thioperamide maleate or histamine in the absence/presence of thioperamide maleate for 1 week. Following in vivo treatment of BDL rats with RAMH for 1 week, and in vitro stimulation of BDL cholangiocytes with RAMH, we evaluated cholangiocyte proliferation, cAMP levels and PKA, ERK1/2 and Elk-1 phosphorylation. Cholangiocytes from normal and BDL rats express H3R. The expression of H3R mRNA increased in BDL compared to normal cholangiocytes. Histamine decreased cholangiocyte growth of BDL rats to a lower extent than that observed in BDL RAMH-treated rats; histamine-induced inhibition of cholangiocyte growth was partly blocked by thioperamide maleate. In BDL rats treated with thioperamide maleate, cholangiocyte hyperplasia was slightly higher than that of BDL rats. In vitro, RAMH inhibited the proliferation of BDL cholangiocytes. RAMH inhibition of cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. Downregulation of cAMP-dependent PKA/ERK1/2/Elk-1 phosphorylation (by activation of H3R) is important in the inhibition of cholangiocyte growth in liver diseases. © 2007 USCAP, Inc All rights reserved