61 results on '"Mancinelli, Romina"'
Search Results
2. Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies.
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Sanluca, Chiara, Spagnolo, Paolo, Mancinelli, Romina, De Bartolo, Maria Ilenia, Fava, Marina, Maccarrone, Mauro, Carotti, Simone, Gaudio, Eugenio, Leuti, Alessandro, and Vivacqua, Giorgio
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MULTIPLE system atrophy ,PARKINSON'S disease ,LIPID metabolism ,BIOLOGICAL membranes ,SMALL molecules - Abstract
The present review provides a comprehensive examination of the intricate dynamics between α-synuclein, a protein crucially involved in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and multiple system atrophy, and endogenously-produced bioactive lipids, which play a pivotal role in neuroinflammation and neurodegeneration. The interaction of α-synuclein with bioactive lipids is emerging as a critical factor in the development and progression of neurodegenerative and neuroinflammatory diseases, offering new insights into disease mechanisms and novel perspectives in the identification of potential biomarkers and therapeutic targets. We delve into the molecular pathways through which α-synuclein interacts with biological membranes and bioactive lipids, influencing the aggregation of α-synuclein and triggering neuroinflammatory responses, highlighting the potential of bioactive lipids as biomarkers for early disease detection and progression monitoring. Moreover, we explore innovative therapeutic strategies aimed at modulating the interaction between α-synuclein and bioactive lipids, including the development of small molecules and nutritional interventions. Finally, the review addresses the significance of the gut-to-brain axis in mediating the effects of bioactive lipids on α-synuclein pathology and discusses the role of altered gut lipid metabolism and microbiota composition in neuroinflammation and neurodegeneration. The present review aims to underscore the potential of targeting α-synuclein-lipid interactions as a multifaceted approach for the detection and treatment of neurodegenerative and neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Pain in Parkinson's disease: a neuroanatomy-based approach.
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Nardelli, Domiziana, Gambioli, Francesco, Bartolo, Maria Ilenia De, Mancinelli, Romina, Biagioni, Francesca, Carotti, Simone, Falato, Emma, Leodori, Giorgio, Puglisi-Allegra, Stefano, Vivacqua, Giorgio, and Fornai, Francesco
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- 2024
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4. Endoplasmic reticulum stress: A possible connection between intestinal inflammation and neurodegenerative disorders.
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Vivacqua, Giorgio, Mancinelli, Romina, Leone, Stefano, Vaccaro, Rosa, Garro, Ludovica, Carotti, Simone, Ceci, Ludovica, Onori, Paolo, Pannarale, Luigi, Franchitto, Antonio, Gaudio, Eugenio, and Casini, Arianna
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ENDOPLASMIC reticulum ,INFLAMMATORY bowel diseases ,NEURODEGENERATION ,INTESTINES ,INFLAMMATION - Abstract
Background: Different studies have shown the key role of endoplasmic reticulum (ER) stress in autoimmune and chronic inflammatory disorders, as well as in neurodegenerative diseases. ER stress leads to the formation of misfolded proteins which affect the secretion of different cell types that are crucial for the intestinal homeostasis. Purpose: In this review, we discuss the role of ER stress and its involvement in the development of inflammatory bowel diseases, chronic conditions that can cause severe damage of the gastrointestinal tract, focusing on the alteration of Paneth cells and goblet cells (the principal secretory phenotypes of the intestinal epithelial cells). ER stress is also discussed in the context of neurodegenerative diseases, in which protein misfolding represents the signature mechanism. ER stress in the bowel and consequent accumulation of misfolded proteins might represent a bridge between bowel inflammation and neurodegeneration along the gut‐to‐brain axis, affecting intestinal epithelial homeostasis and the equilibrium of the commensal microbiota. Targeting intestinal ER stress could foster future studies for designing new biomarkers and new therapeutic approaches for neurodegenerative disorders. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Inguinoscrotal Hernia, a Possible Cause of Rapidly Developing Fetal Scrotal Mass: Case Report and Literature Update.
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Montironi, Ramona, Giannubilo, Stefano Raffaele, Cappanera, Irene, Battistoni, Giovanna Irene, Mancinelli, Romina, and Ciavattini, Andrea
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RISK assessment ,RARE diseases ,INGUINAL hernia ,FETAL diseases ,HERNIA surgery ,SCROTUM ,DISEASE complications ,FETUS - Abstract
Inguinoscrotal hernia is a common pediatric disease but a rare condition in the fetus. We present a case, from our institution, of fetal inguinoscrotal hernia with possible rapid development. In addition to our case, we present a literature update on fetal inguinoscrotal hernia in order to enhance the ability to recognize it from the other scrotal masses on ultrasound. Antenatal management, differential diagnosis and postnatal management are also discussed. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Expression and role of cocaine-amphetamine regulated transcript (CART) in the proliferation of biliary epithelium.
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Casini, Arianna, Vivacqua, Giorgio, Vaccaro, Rosa, Renzi, Anastasia, Leone, Stefano, Pannarale, Luigi, Franchitto, Antonio, Onori, Paolo, Mancinelli, Romina, and Gaudio, Eugenio
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- 2023
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7. A Combined Panel of Salivary Biomarkers in de novo Parkinson's Disease.
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De Bartolo, Maria Ilenia, Vivacqua, Giorgio, Belvisi, Daniele, Mancinelli, Romina, Fabbrini, Andrea, Manzo, Nicoletta, Costanzo, Matteo, Leodori, Giorgio, Conte, Antonella, Fabbrini, Giovanni, Morini, Sergio, and Berardelli, Alfredo
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PARKINSON'S disease ,HIDRADENITIS suppurativa ,RECEIVER operating characteristic curves ,TUMOR necrosis factors ,ENZYME-linked immunosorbent assay ,MICROTUBULE-associated proteins - Abstract
Objective: To investigate molecular biomarkers of a‐synuclein and tau aggregation, autophagy, and inflammation in the saliva of de novo Parkinson's disease (PD) patients in comparison to healthy subjects (HS), and to correlate molecular data with clinical features of PD patients, in order to establish whether abnormalities of these parameters are associated with specific clusters of de novo PD patients, and their potential diagnostic power in differentiating PD patients from HS. Methods: We measured total and oligomeric a‐synuclein, total‐tau and phosphorylated‐tau, microtubule‐associated protein light chain 3 beta (MAP‐LC3beta), and tumor necrosis factor alpha (TNFalpha) in the saliva of 80 de novo PD patients and 62 HS, using quantitative enzyme‐linked immunosorbent Assay analysis. Results: Oligomeric a‐synuclein, total‐tau, MAP‐LC3beta, and TNFalpha levels resulted significantly higher in patients with respect to HS, while no significant differences were detected for total a‐synuclein or phosphorylated‐tau. Phosphorylated‐tau directly correlated with MAP‐LC3beta, whereas it inversely correlated with TNFalpha in PD patients. An inverse correlation was detected between MAP‐LC3beta and non‐motor symptoms severity. Principal Component Analysis showed that molecular and clinical parameters were independent of each other in de novo PD patients. Receiver operating characteristic curve analysis reported an accurate diagnostic performance of oligomeric a‐synuclein and MAP‐LC3beta. The diagnostic accuracy of total a‐synuclein increased when it was combined with other salivary biomarkers targeting different molecular pathways. Interpretation: Our study proposes a novel biomarker panel using saliva, a non‐invasive biofluid, in de novo PD patients, with implications in understanding the molecular pathways involved in PD pathogenesis and the relevance of different molecular pathways in determining clinical PD subtypes. ANN NEUROL 2023;93:446–459 [ABSTRACT FROM AUTHOR]
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- 2023
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8. The Emerging Role of Ferroptosis in Liver Cancers.
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Casini, Arianna, Leone, Stefano, Vaccaro, Rosa, Vivacqua, Giorgio, Ceci, Ludovica, Pannarale, Luigi, Franchitto, Antonio, Onori, Paolo, Gaudio, Eugenio, and Mancinelli, Romina
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LIVER cancer ,APOPTOSIS ,CANCER cells ,IRON metabolism ,IRON ,REACTIVE oxygen species - Abstract
Liver cancer represents a global health challenge with worldwide growth. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Indeed, approximately 90% of HCC cases have a low survival rate. Moreover, cholangiocarcinoma (CC) is another malignant solid tumor originating from cholangiocytes, the epithelial cells of the biliary system. It is the second-most common primary liver tumor, with an increasing course in morbidity and mortality. Tumor cells always show high metabolic levels, antioxidant modifications, and an increased iron uptake to maintain unlimited growth. In recent years, alterations in iron metabolism have been shown to play an important role in the pathogenesis of HCC. Several findings show that a diet rich in iron can enhance HCC risk. Hence, elevated iron concentration inside the cell may promote the development of HCC. Growing evidence sustains that activating ferroptosis may potentially block the proliferation of HCC cells. Even in CC, it has been shown that ferroptosis plays a crucial role in the treatment of tumors. Several data confirmed the inhibitory effect in cell growth of photodynamic therapy (PDT) that can induce reactive oxygen species (ROS) in CC, leading to an increase in malondialdehyde (MDA) and a decrease in intracellular glutathione (GSH). MDA and GSH depletion/modulation are crucial in inducing ferroptosis, suggesting that PDT may have the potential to induce this kind of cell death through these ways. A selective induction of programmed cell death in cancer cells is one of the main treatments for malignant tumors; thus, ferroptosis may represent a novel therapeutic strategy against HCC and CC. [ABSTRACT FROM AUTHOR]
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- 2022
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9. β-Caryophyllene Counteracts Chemoresistance Induced by Cigarette Smoke in Triple-Negative Breast Cancer MDA-MB-468 Cells.
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Di Sotto, Antonella, Gullì, Marco, Minacori, Marco, Mancinelli, Romina, Garzoli, Stefania, Percaccio, Ester, Incocciati, Alessio, Romaniello, Donatella, Mazzanti, Gabriela, Eufemi, Margherita, and Di Giacomo, Silvia
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TRIPLE-negative breast cancer ,CIGARETTE smoke ,SMOKING ,CANCER cells ,DRUG resistance in cancer cells - Abstract
Exposure to cigarette smoke (CS) has been associated with an increased risk of fatal breast cancers and recurrence, along with chemoresistance and chemotherapy impairment. This strengthens the interest in chemopreventive agents to be exploited both in healthy and oncological subjects to prevent or repair CS damage. In the present study, we evaluated the chemopreventive properties of the natural sesquiterpene β-caryophyllene towards the damage induced by cigarette smoke condensate (CSC) in triple negative breast cancer MDA-MB-468 cells. Particularly, we assessed the ability of the sesquiterpene to interfere with the mechanisms exploited by CSC to promote cell survival and chemoresistance, including genomic instability, cell cycle progress, autophagy/apoptosis, cell migration and related pathways. β-Caryophyllene was found to be able to increase the CSC-induced death of MDA-MB-468 cells, likely triggering oxidative stress, cell cycle arrest and apoptosis; moreover, it hindered cell recovery, autophagy activation and cell migration; at last, a marked inhibition of the signal transducer and activator of transcription 3 (STAT3) activation was highlighted: this could represent a key mechanism of the chemoprevention by β-caryophyllene. Although further studies are required to confirm the in vivo efficacy of β-caryophyllene, the present results suggest a novel strategy to reduce the harmful effect of smoke in cancer patients and to improve the survival expectations in breast cancer women. [ABSTRACT FROM AUTHOR]
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- 2022
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10. Sorafenib Chemosensitization by Caryophyllane Sesquiterpenes in Liver, Biliary, and Pancreatic Cancer Cells: The Role of STAT3/ABC Transporter Axis.
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Di Giacomo, Silvia, Gullì, Marco, Facchinetti, Roberta, Minacori, Marco, Mancinelli, Romina, Percaccio, Ester, Scuderi, Caterina, Eufemi, Margherita, and Di Sotto, Antonella
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PANCREATIC cancer ,SESQUITERPENES ,SORAFENIB ,ATP-binding cassette transporters ,ANTINEOPLASTIC combined chemotherapy protocols ,CELL migration ,SODIUM-glucose cotransporters - Abstract
A combination of anticancer drugs and chemosensitizing agents has been approached as a promising strategy to potentiate chemotherapy and reduce toxicity in aggressive and chemoresistant cancers, like hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and pancreatic ductal adenocarcinoma (PDAC). In the present study, the ability of caryophyllane sesquiterpenes to potentiate sorafenib efficacy was studied in HCC, CCA, and PDAC cell models, focusing on the modulation of STAT3 signaling and ABC transporters; tolerability studies in normal cells were also performed. Results showed that the combination of sorafenib and caryophyllane sesquiterpenes synergized the anticancer drug, especially in pancreatic Bx-PC3 adenocarcinoma cells; a similar trend, although with lower efficacy, was found for the standard ABC transporter inhibitors. Synergistic effects were associated with a modulation of MDR1 (or Pgp) and MRP transporters, both at gene and protein level; moreover, activation of STAT3 cascade and cell migration appeared significantly affected, suggesting that the STAT3/ABC-transporters axis finely regulated efficacy and chemoresistance to sorafenib, thus appearing as a suitable target to overcome drawbacks of sorafenib-based chemotherapy in hepato-biliary-pancreatic cancers. Present findings strengthen the interest in caryophyllane sesquiterpenes as chemosensitizing and chemopreventive agents and contribute to clarifying drug resistance mechanisms in HCC, CCA, and PDAC cancers and to developing possible novel therapeutic strategies. [ABSTRACT FROM AUTHOR]
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- 2022
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11. The Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling.
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Mancinelli, Romina, Ceci, Ludovica, Kennedy, Lindsey, Francis, Heather, Meadows, Vik, Chen, Lixian, Carpino, Guido, Kyritsi, Konstantina, Wu, Nan, Zhou, Tianhao, Sato, Keisaku, Pannarale, Luigi, Glaser, Shannon, Chakraborty, Sanjukta, Alpini, Gianfranco, Gaudio, Eugenio, Onori, Paolo, and Franchitto, Antonio
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HEPATIC fibrosis ,PEPTIDES ,LIVER histology ,CYCLIC adenylic acid ,CALCITONIN ,P16 gene ,CALCITONIN receptors ,LIVER cells - Abstract
Background & aims: Cholangiocytes are the target cells of liver diseases that are characterized by biliary senescence (evidenced by enhanced levels of senescence-associated secretory phenotype, SASP, e.g., TGF-β1), and liver inflammation and fibrosis accompanied by altered bile acid (BA) homeostasis. Taurocholic acid (TC) stimulates biliary hyperplasia by activation of 3′,5′-cyclic cyclic adenosine monophosphate (cAMP) signaling, thereby preventing biliary damage (caused by cholinergic/adrenergic denervation) through enhanced liver angiogenesis. Also: (i) α-calcitonin gene-related peptide (α-CGRP, which activates the calcitonin receptor-like receptor, CRLR), stimulates biliary proliferation/senescence and liver fibrosis by enhanced biliary secretion of SASPs; and (ii) knock-out of α-CGRP reduces these phenotypes by decreased cAMP levels in cholestatic models. We aimed to demonstrate that TC effects on liver phenotypes are dependent on changes in the α-CGRP/CALCRL/cAMP/PKA/ERK1/2/TGF-β1/VEGF axis. Methods: Wild-type and α-CGRP
−/− mice were fed with a control (BAC) or TC diet for 1 or 2 wk. We measured: (i) CGRP levels by both ELISA kits in serum and by qPCR in isolated cholangiocytes (CALCA gene for α-CGRP); (ii) CALCRL immunoreactivity by immunohistochemistry (IHC) in liver sections; (iii) liver histology, intrahepatic biliary mass, biliary senescence (by β-GAL staining and double immunofluorescence (IF) for p16/CK19), and liver fibrosis (by Red Sirius staining and double IF for collagen/CK19 in liver sections), as well as by qPCR for senescence markers in isolated cholangiocytes; and (iv) phosphorylation of PKA/ERK1/2, immunoreactivity of TGF-β1/TGF- βRI and angiogenic factors by IHC/immunofluorescence in liver sections and qPCR in isolated cholangiocytes. We measured changes in BA composition in total liver by liquid chromatography/mass spectrometry. Results: TC feeding increased CALCA expression, biliary damage, and liver inflammation and fibrosis, as well as phenotypes that were associated with enhanced immunoreactivity of the PKA/ERK1/2/TGF-β1/TGF-βRI/VEGF axis compared to BAC-fed mice and phenotypes that were reversed in α-CGRP−/− mice fed TC coupled with changes in hepatic BA composition. Conclusion: Modulation of the TC/ α-CGRP/CALCRL/PKA/ERK1/2/TGF-β1/VEGF axis may be important in the management of cholangiopathies characterized by BA accumulation. [ABSTRACT FROM AUTHOR]- Published
- 2022
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12. Melatonin receptor 1A, but not 1B, knockout decreases biliary damage and liver fibrosis during cholestatic liver injury.
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Wu, Nan, Carpino, Guido, Ceci, Ludovica, Baiocchi, Leonardo, Francis, Heather, Kennedy, Lindsey, Zhou, Tianhao, Chen, Lixian, Sato, Keisaku, Kyritsi, Konstantina, Meadows, Vik, Ekser, Burcin, Franchitto, Antonio, Mancinelli, Romina, Onori, Paolo, Gaudio, Eugenio, Glaser, Shannon, and Alpini, Gianfranco
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- 2022
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13. Distribution of α-synuclein in normal human jejunum and its relations with the chemosensory and neuroendocrine system.
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Casini, Arianna, Mancinelli, Romina, Mammola, Caterina Loredana, Pannarale, Luigi, Chirletti, Piero, Onori, Paolo, and Vaccaro, Rosa
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- 2021
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14. Different iron-handling in inflamed small and large cholangiocytes and in small and large-duct type intrahepatic cholangiocarcinoma.
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Mancinelli, Romina, Cutone, Antimo, Rosa, Luigi, Lepanto, Maria Stefania, Onori, Paolo, Pannarale, Luigi, Franchitto, Antonio, Gaudio, Eugenio, and Valenti, Piera
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- 2020
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15. Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: An In Vitro and In Silico Study.
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Di Sotto, Antonella, Irannejad, Hamid, Eufemi, Margherita, Mancinelli, Romina, Abete, Lorena, Mammola, Caterina Loredana, Altieri, Fabio, Mazzanti, Gabriela, and Di Giacomo, Silvia
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CARYOPHYLLENE ,DOXORUBICIN ,SESQUITERPENES ,P-glycoprotein ,MOLECULAR docking ,DRUG side effects ,ANTINEOPLASTIC agents - Abstract
Doxorubicin represents a valuable choice for different cancers, although the severe side effects occurring at the high effective dose limits its clinical use. In the present study, potential strategies to potentiate low-dose doxorubicin efficacy, including a metronomic schedule, characterized by a short and repeated exposure to the anticancer drug, and the combination with the natural chemosensitizing sesquiterpenes β-caryophyllene and β-caryophyllene oxide, were assessed in human hepatoma HepG2 cells. The involvement of P-glycoprotein (P-gp) in the HepG2–chemosensitization to doxorubicin was evaluated. Also, the direct interaction of caryophyllene sesquiterpenes with P-gp was characterized by molecular docking and dynamic simulation studies. A metronomic schedule allowed us to enhance the low-dose doxorubicin cytotoxicity and the combination with caryophyllane sesquiterpenes further potentiated this effect. Also, an increased intracellular accumulation of doxorubicin and rhodamine 123 induced by caryophyllane sesquiterpenes was found, thus suggesting their interference with P-gp function. A lowered expression of P-gp induced by the combinations, with respect to doxorubicin alone, was observed too. Docking studies found that the binding site of caryophyllane sesquiterpene was next to the ATP binding domain of P-gp and that β-caryophyllene possessed the stronger binding affinity and higher inhibition potential calculated by MM-PBSA. Present findings strengthen our hypothesis about the potential chemosensitizing power of caryophyllane sesquiterpenes and suggest that combining a chemosensitizer and a metronomic schedule can represent a suitable strategy to overcome drawbacks of doxorubicin chemotherapy while exploiting its powerful activity. [ABSTRACT FROM AUTHOR]
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- 2020
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16. Maize polyamine oxidase in the presence of spermine/spermidine induces the apoptosis of LoVo human colon adenocarcinoma cells.
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Ohkubo, Shinji, Mancinelli, Romina, Miglietta, Selenia, Cona, Alessandra, Angelini, Riccardo, Canettieri, Gianluca, Spandidos, Demetrios A., Gaudio, Eugenio, and Agostinelli, Enzo
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- 2019
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17. Role of the Angiogenic Factors in Cholangiocarcinoma.
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Mancinelli, Romina, Mammola, Caterina Loredana, Sferra, Roberta, Pompili, Simona, Vetuschi, Antonella, and Pannarale, Luigi
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VASCULAR endothelial growth factors ,PLACENTAL growth factor ,CHOLANGIOCARCINOMA ,TUMOR markers ,GROWTH factors ,BILE ducts - Abstract
Angiogenesis plays a fundamental role in tumor growth and progression. It is regulated by several growth factors, including vascular endothelial growth factor protein family (VEGF) and its receptors, which are probably the most important factors responsible for the development of new vessels. The VEGF family includes several members: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, placental growth factor (PlGF), and their receptors VEGFR-1, VEGFR-2 and VEGFR-3. Other relevant factors are represented by angiopoietins, thrombospondin-1, and endothelins. However, since the therapeutic benefit associated with VEGF-targeted therapy is really complex, a better understanding of these pathways will lead to future advances in the use of these agents for clinic management of tumors. Here we present a review regarding the role of angiogenic factors in cholangiocarcinoma, which arise from cholangiocytes, the epithelial cells of bile ducts. They are rare and aggressive neoplasms with a poor prognosis and limited treatment options, classified as intrahepatic, perihilar, and distal cholangiocarcinoma based on their anatomical location. Therefore, the identification of specific signaling pathways or new tumor biomarkers is crucial in order to develop more effective anti-angiogenic therapies. [ABSTRACT FROM AUTHOR]
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- 2019
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18. Peribiliary gland damage due to liver transplantation involves peribiliary vascular plexus and vascular endothelial growth factor.
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Franchitto, Antonio, Overi, Diletta, Mancinelli, Romina, Mitterhofer, Anna Paola, Muisean, Paolo, Tinti, Francesca, Umbro, Ilaria, Hübscher, Stefan G., Onori, Paolo, Gaudio, Eugenio, and Carpino, Guido
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- 2019
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19. Epidermal growth factor-like domain multiple 7 (EGFL7): Expression and possible effect on biliary epithelium growth in cholangiocarcinoma.
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Mammola, Caterina L., Vetuschi, Antonella, Pannarale, Luigi, Sferra, Roberta, and Mancinelli, Romina
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- 2018
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20. Differential Redox State Contributes to Sex Disparities in the Response to Influenza Virus Infection in Male and Female Mice.
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Celestino, Ignacio, Checconi, Paola, Amatore, Donatella, De Angelis, Marta, Coluccio, Paolo, Dattilo, Rosanna, Alunni Fegatelli, Danilo, Clemente, Ann Maria, Matarrese, Paola, Torcia, Maria Gabriella, Mancinelli, Romina, Mammola, Caterina Loredana, Garaci, Enrico, Vestri, Anna Rita, Malorni, Walter, Palamara, Anna Teresa, and Nencioni, Lucia
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INFLUENZA viruses ,HOMEOSTASIS ,LABORATORY mice ,PREVENTIVE medicine ,MOUSE diseases - Abstract
Influenza virus replicates intracellularly exploiting several pathways involved in the regulation of host responses. The outcome and the severity of the infection are thus strongly conditioned by multiple host factors, including age, sex, metabolic, and redox conditions of the target cells. Hormones are also important determinants of host immune responses to influenza and are recently proposed in the prophylaxis and treatment. This study shows that female mice are less susceptible than males to mouse-adapted influenza virus (A/PR8/H1N1). Compared with males, PR8-infected females display higher survival rate (+36%), milder clinical disease, and less weight loss. They also have milder histopathological signs, especially free alveolar area is higher than that in males, even if pro-inflammatory cytokine production shows slight differences between sexes; hormone levels, moreover, do not vary significantly with infection in our model. Importantly, viral loads (both in terms of viral M1 RNA copies and tissue culture infectious dose 50%) are lower in PR8-infected females. An analysis of the mechanisms contributing to sex disparities observed during infection reveals that the female animals have higher total antioxidant power in serum and their lungs are characterized by increase in (i) the content and biosynthesis of glutathione, (ii) the expression and activity of antioxidant enzymes (peroxiredoxin 1, catalase, and glutathione peroxidase), and (iii) the expression of the anti-apoptotic protein Bcl-2. By contrast, infected males are characterized by high expression of NADPH oxidase 4 oxidase and phosphorylation of p38 MAPK, both enzymes promoting viral replication. All these factors are critical for cell homeostasis and susceptibility to infection. Reappraisal of the importance of the host cell redox state and sex-related effects may be useful in the attempt to develop more tailored therapeutic interventions in the fight against influenza. [ABSTRACT FROM AUTHOR]
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- 2018
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21. Detection of α-Synuclein in Saliva: The Importance of Preanalytical Assessment.
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Vivacqua, Giorgio, Mancinelli, Romina, Belvisi, Daniele, Suppa, Antonio, and Berardelli, Alfredo
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- 2018
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22. Role of lactoferrin and its receptors on biliary epithelium.
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Mancinelli, Romina, Olivero, Francesca, Carpino, Guido, Overi, Diletta, Rosa, Luigi, Lepanto, Maria Stefania, Cutone, Antimo, Franchitto, Antonio, Alpini, Gianfranco, Onori, Paolo, Valenti, Piera, and Gaudio, Eugenio
- Abstract
Human lactoferrin is an iron-binding glycoprotein present at high concentrations in breast milk and colostrum. It is produced by many exocrine glands and widely distributed in a variety of body fluids. This protein has antimicrobial, immunomodulatory, antioxidant, and anticancer properties. Two important hLf receptors have been identified: LDL receptor related protein (LRP1), a low specificity receptor, and intelectin-1 (ITLN1), a high specificity receptor. No data are present on the role of hLf on the biliary epithelium. Our aims have been to evaluate the expression of Lf and its receptors in human and murine cholangiocytes and its effect on proliferation. Immunohistochemistry and immunofluorescence (IF) were conducted on human healthy and primary biliary cholangitis (PBC) liver samples as well as on liver samples obtained from normal and bile duct ligated (BDL) mice to evaluate the expression of Lf, LRP1 and ITLN1. Cell proliferation in vitro studies were performed on human cholangiocyte cell lines via 3-(4,5-dimetiltiazol-2-il)-2,5-diphenyltetrazolium assay as well as IF to evaluate proliferating cell nuclear antigen (PCNA) expression. Our results show that mouse and human cholangiocytes express Lf, LRP1 and ITLN1, at higher extent in cholangiocytes from BDL and PBC samples. Furthermore, the in vitro addition of bovine Lf (bLf) has a proliferative effect on human cholangiocyte cell line. The results support a proliferative role of hLf on the biliary epithelium; this pro-proliferative effect of hLf and bLf on cholangiocytes could be particularly relevant in human cholangiopathies such as PBC, characterized by cholangiocyte death and ductopenia. [ABSTRACT FROM AUTHOR]
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- 2018
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23. Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases.
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Mancinelli, Romina, Carpino, Guido, Petrungaro, Simonetta, Mammola, Caterina Loredana, Tomaipitinca, Luana, Filippini, Antonio, Facchiano, Antonio, Ziparo, Elio, and Giampietri, Claudia
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- 2017
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24. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation.
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Nan Wu, Fanyin Meng, Tianhao Zhou, Yuyan Han, Kennedy, Lindsey, Venter, Julie, Francis, Heather, DeMorrow, Sharon, Onori, Paolo, Invernizzi, Pietro, Bernuzzi, Francesca, Mancinelli, Romina, Gaudio, Eugenio, Franchitto, Antonio, Glaser, Shannon, and Alpini, Gianfranco
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- 2017
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25. Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2−/− mice by diminishing senescence of cholangiocytes.
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Zhou, Tianhao, Wu, Nan, Meng, Fanyin, Venter, Julie, Giang, Thao K, Francis, Heather, Kyritsi, Konstantina, Wu, Chaodong, Franchitto, Antonio, Alvaro, Domenico, Marzioni, Marco, Onori, Paolo, Mancinelli, Romina, Gaudio, Eugenio, Glaser, Shannon, and Alpini, Gianfranco
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- 2018
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26. Distribution and characterization of α-syn and VIP immunoreactivity in the enteric nervous system of human small intestine.
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Casini, Arianna, Vaccaro, Rosa, Leone, Stefano, Mancini, Patrizia, and Mancinelli, Romina
- Abstract
The article focuses on characterizing the presence and distribution of alpha-synuclein (α-syn) and vasoactive intestinal peptide (VIP) in the normal human jejunum, shedding light on their physiological roles in the enteric nervous system and their potential relevance to neurodegenerative diseases.
- Published
- 2023
27. The emerging role of ferroptosis in course of liver fibrosis.
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Mancinelli, Romina, Ceci, Ludovica, Casini, Arianna, Vaccaro, Rosa, Pannarale, Luigi, Franchitto, Antonio, and Onori, Paolo
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The article focuses on the emerging role of ferroptosis in the progression of liver fibrosis, particularly examining its impact on hepatocytes, Kupffer cells, hepatic stellate cells, and biliary epithelium in experimental rat models of hepatic fibrosis.
- Published
- 2023
28. Abnormal Salivary Total and Oligomeric Alpha-Synuclein in Parkinson’s Disease.
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Vivacqua, Giorgio, Latorre, Anna, Suppa, Antonio, Nardi, Michela, Pietracupa, Sara, Mancinelli, Romina, Fabbrini, Giovanni, Colosimo, Carlo, Gaudio, Eugenio, and Berardelli, Alfredo
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PARKINSON'S disease patients ,PARKINSON'S disease diagnosis ,ALPHA-synuclein ,SALIVA analysis ,COHORT analysis - Abstract
In Parkinson’s disease (PD), alpha-synuclein (a-syn) can be detected in biological fluids including saliva. Although previous studies found reduced a-syn total (a-syn
total ) concentration in saliva of PD patients, no studies have previously examined salivary a-syn oligomers (a-synolig ) concentrations or assessed the correlation between salivary a-syntotal , a-synolig and clinical features in a large cohort of PD patients. Is well known that a-synolig exerts a crucial neurotoxic effect in PD. We collected salivary samples from 60 PD patients and 40 age- and sex-comparable healthy subjects. PD was diagnosed according to the United Kingdom Brain Bank Criteria. Samples of saliva were analyzed by specific anti-a-syn and anti-oligomeric a-syn ELISA kits. A complete clinical evaluation of each patient was performed using MDS-Unified Parkinson's Disease Rating Scale, Beck Depression Inventory, Montreal Cognitive Assessment and Frontal Assessment Battery. Salivary a-syntotal was lower, whereas a-synolig was higher in PD patients than healthy subjects. The a-synolig /a-syntotal ratio was also higher in patients than in healthy subjects. Salivary a-syntotal concentration negatively correlated with that of a-synolig and correlated with several patients’ clinical features. In PD, decreased salivary concentration of a-syntotal may reflect the reduction of a-syn monomers (a-synmon ), as well as the formation of insoluble intracellular inclusions and soluble oligomers. The combined detection of a-syntotal and a-synolig in the saliva might help the early diagnosis of PD. [ABSTRACT FROM AUTHOR]- Published
- 2016
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29. The hepatic effects of melatonin in female cholestatic murine model.
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Mancinelli, Romina, Ceci, Ludovica, Kennedy, Lindsey, Francis, Heather, Glaser, Shannon, Alpini, Gianfranco, Onori, Paolo, and Gaudio, Eugenio
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TIGHT junctions ,MELATONIN ,STAINS & staining (Microscopy) ,HEPATIC fibrosis - Abstract
The article presents a study on hepatic effects of melatonin in female cholestatic murine model. Topics include information on Primary sclerosing cholangitis (PSC) which is a chronic inflammatory disease of the bile duct; how males are more prone to developing PSC compared to females; and role of hepatobiliary junctions in chronic liver diseases.
- Published
- 2022
30. Ischemia reperfusion of the hepatic artery induces the functional damage of large bile ducts by changes in the expression of angiogenic factors.
- Author
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Mancinelli, Romina, Glaser, Shannon, Francis, Heather, Carpino, Guido, Franchitto, Antonio, Vetuschi, Antonella, Sferra, Roberta, Pannarale, Luigi, Venter, Julie, Meng, Fanyin, Alpini, Gianfranco, Onori, Paolo, and Gaudio, Eugenio
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ISCHEMIA ,LIVER transplantation ,CHOLANGIOCARCINOMA ,BILE duct diseases ,GENE expression ,VASCULAR endothelial growth factors ,HEPATIC artery - Abstract
Liver transplantation and cholangiocarcinoma induce biliary dysfunction following ischemia reperfusion (IR). The function of the intrahepatic biliary tree is regulated by both autocrine and paracrine factors. The aim of the study was to demonstrate that IR-induced damage of cholangiocytes is associated with altered expression of biliary angiogenic factors. Normal and bile duct ligation rats underwent 24-h sham or hepatic reperfusion after 30 min of transient occlusion of the hepatic artery (HAIR) or portal vein (PVIR) before collecting liver blocks and cholangiocyte RNA or protein. We evaluated liver histology, biliary apoptosis, proliferation and expression of VEGF-A/C, VEGFR-2/3, Ang-1/2, and Tie-1/2 in liver sections and isolated small and large cholangiocytes. Normal rat intrahepatic cholangiocyte cultures (NRICC) were maintained under standard conditions in normoxic or under a hypoxic atmosphere for 4 h and then transferred to normal conditions for selected times. Subsequently, we measured changes in biliary proliferation and apoptosis and the expression of VEGF-A/C and VEGFR-2/3. In vivo, HAIR (but not PVIR) induced damage of large bile ducts and decreased proliferation and secretin-stimulated cAMP levels. HAIR-induced damage of large bile ducts was associated with increased expression of VEGF-A/C, VEGFR-2/3, Ang-1/2, and Tie-1/2. In vitro, under hypoxic conditions, there was increased apoptosis and reduced proliferation of NRICC concomitant with enhanced expression of VEGFA/ C and VEGFR-2/3. The functional damage of large bile ducts by HAIR and hypoxia is associated with increased expression of angiogenic factors in small cholangiocytes, presumably due to a compensatory mechanism in response to biliary damage. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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31. Vasopressin regulates the growth of the biliary epithelium in polycystic liver disease.
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Mancinelli, Romina, Franchitto, Antonio, Glaser, Shannon, Vetuschi, Antonella, Venter, Julie, Sferra, Roberta, Pannarale, Luigi, Olivero, Francesca, Carpino, Guido, Alpini, Gianfranco, Onori, Paolo, and Gaudio, Eugenio
- Published
- 2016
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32. Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis.
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Yuyan Han, Onori, Paolo, Fanyin Meng, DeMorrow, Sharon, Venter, Julie, Francis, Heather, Franchitto, Antonio, Ray, Debolina, Kennedy, Lindsey, Greene, John, Renzi, Anastasia, Mancinelli, Romina, Gaudio, Eugenio, Glaser, Shannon, and Alpini, Gianfranco
- Subjects
LABORATORY rats ,LIVER diseases ,FIBROSIS ,BILIOUS diseases & biliousness ,BILE ducts - Abstract
Biliary hyperplasia and liver fibrosis are common features in cholestatic liver disease. Melatonin is synthesized by the pineal gland as well as the liver. Melatonin inhibits biliary hyperplasia of bile duct-ligated (BDL) rats. Since melatonin synthesis (by the enzyme serotonin N-acetyltransferase, AANAT) from the pineal gland increases after dark exposure, we hypothesized that biliary hyperplasia and liver fibrosis are diminished by continuous darkness via increased melatonin synthesis from the pineal gland. Normal or BDL rats (immediately after surgery) were housed with light-dark cycles or complete dark for 1 wk before evaluation of 1) the expression of AANAT in the pineal gland and melatonin levels in pineal gland tissue supernatants and serum; 2) biliary proliferation and intrahepatic bile duct mass, liver histology, and serum chemistry; 3) secretin-stimulated ductal secretion (functional index of biliary growth); 4) collagen deposition, liver fibrosis markers in liver sections, total liver, and cholangiocytes; and 5) expression of clock genes in cholangiocytes. In BDL rats exposed to dark there was 1) enhanced AANAT expression/melatonin secretion in pineal gland and melatonin serum levels; 2) improved liver morphology, serum chemistry and decreased biliary proliferation and secretin-stimulated choleresis; and 4) decreased fibrosis and expression of fibrosis markers in liver sections, total liver and cholangiocytes and reduced biliary expression of the clock genes PER1, BMAL1, CLOCK, and Cry1. Thus prolonged dark exposure may be a beneficial noninvasive therapeutic approach for the management of biliary disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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33. Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms.
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DeMorrow, Sharon, Fanyin Meng, Venter, Julie, Leyva-Illades, Dinorah, Francis, Heather, Frampton, Gabriel, Hae Yong Pae, Quinn, Matthew, Onori, Paolo, Glaser, Shannon, McDaniel, Kelly, Mancinelli, Romina, Gaudio, Eugenio, Alpini, Gianfranco, and Franchitto, Antonio
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NEUROPEPTIDE Y ,EPITHELIAL cells ,BILE ducts ,IMMUNOGLOBULINS ,LABORATORY rats ,CELL proliferation ,CELL cycle ,MAMMALS - Abstract
Neuropeptide Y (NPY) exerts its functions through six subtypes of receptors (Y
1 -Y6 ). Biliary homeostasis is regulated by several factors through autocrine/paracrine signaling. NPY inhibits cholangiocarcinoma growth; however, no information exists regarding the autocrine/paracrine role of NPY on biliary hyperplasia during cholestasis. The aims of this study were to determine: 1) the expression of NPY and Y1 -Y5 in cholangiocytes and 2) the paracrine/autocrine effects of NPY on cholangiocyte proliferation. Normal or bile duct ligation (BDL) rats were treated with NPY, neutralizing anti-NPY antibody, or vehicle for 7 days. NPY and NPY receptor (NPYR) expression was assessed in liver sections and isolated cholangiocytes. NPY secretion was assessed in serum and bile from normal and BDL rats, as well as supernatants from normal and BDL cholangiocytes and normal rat cholangiocyte cell line [intrahepatic normal cholangiocyte culture (NRICC)]. We evaluated intrahepatic bile ductal mass (IBDM) in liver sections and proliferation in cholangiocytes. With the use of NRICC, the effects of NPY or anti-NPY antibody on cholangiocyte proliferation were determined. The expression of NPY and all NPYR were increased after BDL. NPY levels were lower in serum and cholangiocyte supernatant from BDL compared with normal rats. NPY secretion from NRICC was detected at both the basolateral and apical domains. Chronic NPY treatment decreased proliferating cellular nuclear antigen (PCNA) expression and IBDM in BDL rats. Administration of anti-NPY antibody to BDL rats increased cholangiocyte proliferation and IBDM. NPY treatment of NRICC decreased PCNA expression and increased the cell cycle arrest, whereas treatment with anti-NPY antibody increased proliferation. Therapies targeting NPY-mediated signaling may prove bene?cial for the treatment of cholangiopathies. [ABSTRACT FROM AUTHOR]- Published
- 2013
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34. GABA induces the differentiation of small into large cholangiocytes by activation of Ca2+/CaMK I-dependent adenylyl cyclase 8.
- Author
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Mancinelli, Romina, Franchitto, Antonio, Glaser, Shannon, Meng, Fanyin, Onori, Paolo, DeMorrow, Sharon, Francis, Heather, Venter, Julie, Carpino, Guido, Baker, Kimberley, Han, Yuyan, Ueno, Yoshiyuki, Gaudio, Eugenio, and Alpini, Gianfranco
- Published
- 2013
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35. Role of follicle-stimulating hormone on biliary cyst growth in autosomal dominant polycystic kidney disease.
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Onori, Paolo, Mancinelli, Romina, Franchitto, Antonio, Carpino, Guido, Renzi, Anastasia, Brozzetti, Stefania, Venter, Julie, Francis, Heather, Glaser, Shannon, Jefferson, Douglas M., Alpini, Gianfranco, and Gaudio, Eugenio
- Subjects
FOLLICLE-stimulating hormone ,POLYCYSTIC kidney disease ,GENETIC disorders ,BILIOUS diseases & biliousness ,IMMUNOHISTOCHEMISTRY ,CYSTS (Pathology) - Abstract
Background Autosomal dominant polycystic kidney disease ( ADPKD) is a common genetic disorder characterized by the progressive development of renal and hepatic cysts. Follicle-stimulating hormone ( FSH) has been demonstrated to be a trophic factor for biliary cells in normal rats and experimental cholestasis induced by bile duct ligation ( BDL). Aims To assess the effect of FSH on cholangiocyte proliferation during ADPKD using both in vivo and in vitro models. Methods Evaluation of FSH receptor ( FSHR), FSH, phospho-extracellular-regulated kinase ( pERK) and c-myc expression in liver fragments from normal patients and patients with ADPKD. In vitro, we studied proliferating cell nuclear antigen ( PCNA) and cAMP levels in a human immortalized, non-malignant cholangiocyte cell line (H69) and in an immortalized cell line obtained from the epithelium lining the hepatic cysts from the patients with ADPKD ( LCDE) with or without transient silencing of the FSH gene. Results Follicle-stimulating hormone is linked to the active proliferation of the cystic wall and to the localization of p-ERK and c-myc. This hormone sustains the biliary growth by activation of the cAMP/ERK signalling pathway. Conclusion These results showed that FSH has an important function in cystic growth acting on the cAMP pathway, demonstrating that it provides a target for medical therapy of hepatic cysts during ADPKD. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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36. Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses of cholangiocytes in rats.
- Author
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Renzi, Anastasia, DeMorrow, Sharon, Onori, Paolo, Carpino, Guido, Mancinelli, Romina, Meng, Fanyin, Venter, Julie, White, Mellanie, Franchitto, Antonio, Francis, Heather, Han, Yuyan, Ueno, Yoshiyuki, Dusio, Giuseppina, Jensen, Kendal J., Greene, John J., Glaser, Shannon, Gaudio, Eugenio, and Alpini, Gianfranco
- Published
- 2013
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37. Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors.
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Renzi, Anastasia, Glaser, Shannon, DeMorrow, Sharon, Mancinelli, Romina, Fanyin Meng, Franchitto, Antonio, Venter, Julie, White, Mellanie, Francis, Heather, Yuyan Han, Alvaro, Domenico, Gaudio, Eugenio, Carpino, Guido, Ueno, Yoshiyuki, Onori, Paolo, and Alpini, Gianfranco
- Subjects
MELATONIN ,HYPERPLASIA ,CHOLESTASIS ,PHOSPHORYLATION ,MITOSIS regulation ,SECRETIN - Abstract
In bile duct-ligated (BDL) rats, large cholangiocytes proliferate by activation of cAMP-dependent signaling. Melatonin, which is secreted from pineal gland as well as extrapineal tissues, regulates cell mitosis by interacting with melatonin receptors (MT1 and MT2) modulating cAMP and clock genes. In the liver, melatonin suppresses oxidative damage and ameliorates fibrosis. No information exists regarding the role of melatonin in the regulation of biliary hyperplasia. We evaluated the mechanisms of action by which melatonin regulates the growth of cholangiocytes. In normal and BDL rats, we determined the hepatic distribution of MT1, MT2, and the clock genes, CLOCK, BMAL1, CRY1, and PER1. Normal and BDL (immediately after BDL) rats were treated in vivo with melatonin before evaluating 1) serum levels of melatonin, bilirubin, and transaminases; 2) intrahepatic bile duct mass (IBDM) in liver sections; and 3) the expression of MT1 and MT2, clock genes, and PKA phosphorylation. In vitro, large cholangiocytes were stimulated with melatonin in the absence/presence of luzindole (MT1/MT2 antagonist) and 4-phenyl-2-propionamidotetralin (MT2 antagonist) before evaluating cell proliferation, cAMP levels, and PKA phosphorylation. Cholangiocytes express MT1 and MT2, CLOCK, BMAL1, CRY1, and PER1 that were all upregulated following BDL. Administration of melatonin to BDL rats decreased IBDM, serum bilirubin and transaminases levels, the expression of all clock genes, cAMP levels, and PKA phosphorylation in cholangiocytes. In vitro, melatonin decreased the proliferation, cAMP levels, and PKA phosphorylation, decreases that were blocked by luzindole. Melatonin may be important in the management of biliary hyperplasia in human cholangiopathies. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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- View/download PDF
38. Activation of alpha.
- Author
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Alpini, Gianfranco, Franchitto, Antonio, DeMorrow, Sharon, Onori, Paolo, Gaudio, Eugenio, Wise, Candace, Francis, Heather, Venter, Julie, Kopriva, Shelley, Mancinelli, Romina, Carpino, Guido, Stagnitti, Franco, Ueno, Yoshiyuki, Han, Yuyan, Meng, Fanyin, and Glaser, Shannon
- Published
- 2011
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39. Knockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligation.
- Author
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Glaser, Shannon, Lam, Ian P., Franchitto, Antonio, Gaudio, Eugenio, Onori, Paolo, Chow, Billy K., Wise, Candace, Kopriva, Shelley, Venter, Julie, White, Mellanie, Ueno, Yoshiyuki, Dostal, David, Carpino, Guido, Mancinelli, Romina, Butler, Wendy, Chiasson, Valorie, DeMorrow, Sharon, Francis, Heather, and Alpini, Gianfranco
- Published
- 2010
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- View/download PDF
40. Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF-κB and induction of apoptosis.
- Author
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Onori, Paolo, DeMorrow, Sharon, Gaudio, Eugenio, Franchitto, Antonio, Mancinelli, Romina, Venter, Julie, Kopriva, Shelley, Ueno, Yoshiyuki, Alvaro, Domenico, Savage, Jennifer, Alpini, Gianfranco, and Francis, Heather
- Published
- 2009
- Full Text
- View/download PDF
41. Endothelin inhibits cholangiocarcinoma growth by a decrease in the vascular endothelial growth factor expression.
- Author
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Fava, Giammarco, DeMorrow, Sharon, Gaudio, Eugenio, Franchitto, Antonio, Onori, Paolo, Carpino, Guido, Glaser, Shannon, Francis, Heather, Coufal, Monique, Marucci, Luca, Alvaro, Domenico, Marzioni, Marco, Horst, Trenton, Mancinelli, Romina, Benedetti, Antonio, and Alpini, Gianfranco
- Subjects
ENDOTHELINS ,CHOLANGIOCARCINOMA ,VASCULAR endothelium ,SECRETIN ,TUMORS - Abstract
Background: Endothelins (ET-1, ET-2, ET-3) are peptides with vasoactive properties interacting with ET
A and ETB receptors. ET-1 inhibits secretin-stimulated ductal secretion (hallmark of cholangiocyte growth) of cholestatic rats by interaction with ET receptors. Aim: The aims of the studies were to evaluate (i) the effect of ET-1 on cholangiocarcinoma growth in Mz-ChA-1 cells and nude mice and (ii) whether ET-1 regulation of cholangiocarcinoma growth is associated with changes in the expression of vascular endothelial growth factor-A (VEGF-A), VEGF-C, VEGF receptor-2 (VEGFR-2) and VEGFR-3. Methods: We determined the expression of ETA and ETB receptors on normal and malignant (Mz-ChA-1) cholangiocytes and human cholangiocarcinoma tissue and the effect of ET-1 on the proliferation and expression of VEGF-A, VEGF-C (regulators of tumour angiogenesis) and its receptors, VEGFR-2 and VEGFR-3, in Mz-ChA-1 cells. In vivo, Mz-ChA-1 cells were injected into the flanks of athymic mice and injections of ET-1 or saline into the tumours were performed daily. The effect of ET-1 on tumour size, cell proliferation, apoptosis, collagen quantity and the expression of VEGF-A and VEGF-C and VEGFR-2 and VEGFR-3 were measured after 73 days. Results: Higher expression of ETA and ETB was observed in malignant compared with normal cholangiocytes. ET-1 inhibited proliferation and VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression of Mz-ChA-1 cells. Chronic ET-1 treatment decreased tumour volume, tumour cell proliferation and VEGF-A and VEGF-C expression but increased apoptosis and collagen tissue deposition compared with controls. Conclusions: Modulation of VEGF-A and VEGF-C (by ET-1) may be important for managing cholangiocarcinoma growth. [ABSTRACT FROM AUTHOR]- Published
- 2009
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42. Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1.
- Author
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Mancinelli, Romina, Onori, Paolo, Gaudio, Eugenio, DeMorrow, Sharon, Franchitto, Antonio, Francis, Heather, Glaser, Shannon, Carpino, Guido, Venter, Julie, Alvaro, Domenico, Kopriva, Shelley, White, Mellanie, Kossie, Ashley, Savage, Jennifer, and Alpini, Gianfranco
- Subjects
FOLLICLE-stimulating hormone ,CELL proliferation ,PHOSPHORYLATION ,AUTOCRINE mechanisms ,IMMUNOGLOBULINS ,GASTROINTESTINAL hormones - Abstract
Sex hormones regulate cholangiocyte hyperplasia in bile duct-ligated (BDL) rats. We studied whether follicle-stimulating homione (FSH) regulates cholangiocyte proliferation. FSH receptor (FSHR) and FSH expression was evaluated in liver sections, purified cholangiocytes, and cholangiocyte cultures (NRICC). In vivo, normal female and male rats were treated with FSH or immediately after BDL with antide (a gonadotropin-releasing hormone antagonist blocking FSH secretion) or a neutralizing FSH antibody for 1 wk. We evaluated 1) cholangiocyte proliferation in sections and cholangiocytes and 2) changes in secretin-stimulated cAMP (functional index of cholangiocyte growth) levels, and ERK 1/2 and Elk-1 phosphorylation. NRICC were stimulated with FSH before evaluation of proliferation, cAMP/IP
3 levels, and ERK 1/2 and Elk-1 phosphorylation. To determine whether FSH regulates cholangiocyte proliferation by an autocrine mechanism, we evaluated the effects of 1) cholangiocyte supernatant (containing FSH) on NRICC proliferation and 2) FSH silencing in NRICC before measuring proliferation and ERK1/2 and Elk-1 phosphorylation. Cholangiocytes and NRICC express FSHR and FSH and secrete FSH. In vivo administration of FSH to normal rats increased, whereas administration of antide and anti-FSH antibody to BDL rats decreased 1) ductal mass and 2) secretin-stimulated cAMP levels, proliferation, and ERK1/2 and Elk-1 phbsphorylation in cholangiocytes compared with controls. In NRICC, FSH increased cholangiocyte proliferation, cAMP levels, and ERK1/2 and Elk-1 phosphorylation. The supematant of cholangiocytes increased NRICC proliferation, inhibited by preincubation with anti-FSH antibody. Silencing of FSH gene decreases cholangiocyte proliferation and ERK1/2 and Elk-1 phosphorylation. Modulation of cholangiocyte FSH expression may be important for the management of cholangiopathies. [ABSTRACT FROM AUTHOR]- Published
- 2009
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43. Morphological and immunohistochemical changes in the enteric nervous system of normal and inflamed intestine.
- Author
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Casini, Arianna, Vaccaro, Rosa, Leone, Stefano, Onori, Paolo, and Mancinelli, Romina
- Subjects
ENTERIC nervous system ,SUBMUCOUS plexus ,AUTONOMIC nervous system ,INTESTINES ,GASTROINTESTINAL system ,NEURAL crest - Abstract
The article presents a study which explores the morphological and immunohistochemical changes in the enteric nervous system of normal and inflamed intestine. It mentions that study investigate and characterize the changes between normal and inflamed intestine through the morphology of the myenteric plexus using various histological techniques.
- Published
- 2022
44. The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway.
- Author
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DeMorrow, Sharon, Francis, Heather, Gaudio, Eugenio, Venter, Julie, Franchitto, Antonio, Kopriva, Shelley, Onori, Paolo, Mancinelli, Romina, Frampton, Gabriel, Coufal, Monique, Mitchell, Brett, Vaculin, Bradley, and Alpini, Gianfranco
- Subjects
CHOLANGIOCARCINOMA ,PROGNOSIS ,PROTEIN kinases ,FOCAL adhesion kinase ,CELL proliferation - Abstract
Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options. The noncanonical Wnt pathway is mediated predominantly by Wnt 5a, which activates a Ca2~-dependent pathway involving protein kinase C, or a Ca2~-independent pathway involving the orphan receptor Ror2 and subsequent activation of Jun NH2-terminal kinase (iNK). This pathway is associated with growth-suppressing effects in numerous cell types. We have shown that anandamide decreases cholangiocarci- noma growth in vitro. Therefore, we determined the effects of anandamide on cholangiocarcinoma tumor growth in vivo using a xenograft model and evaluated the effects of anandamide on the noncanonical Wnt signaling pathways. Chronic administration of anandamide decreased tumor growth and was associated with increased Wnt 5a expression in vitro and in vivo. Treatment of cholangiocarcinoma cells with recombinant Wnt 5a decreased cell proliferation in vitro. Neither anandamide nor Wnt 5a affected intracellular calcium release, but both increased the JNK phosphorylation. Stable knockdown of Wnt 5a or Ror2 expression in cholangiocarcinoma cells abolished the effects of anandamide on cell proliferation and JNK activation. Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment. The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
45. Progesterone stimulates the proliferation of female and male cholangiocytes via autocrine/paracrine mechanisms.
- Author
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Glaser, Shannon, Demorrow, Sharon, Francis, Heather, Ueno, Yoshiyuki, Gaudio, Eugenio, Vaculin, Shelley, Venter, Julie, Franchitto, Antonio, Onori, Paolo, Vaculin, Bradley, Marzioni, Marco, Wise, Candace, Pilanthananond, Metaneeya, Savage, Jennifer, Pierce, Lisa, Mancinelli, Romina, and Alpini, Gianfranco
- Subjects
PROGESTERONE ,AUTOCRINE mechanisms ,PARACRINE mechanisms ,NEUROENDOCRINE cells ,LIVER diseases ,CHOLESTASIS - Abstract
During cholestatic liver diseases, cholangiocytes express neuroendocrine phenotypes and respond to a number of hormones and neuropeptides by paracrine and autocrine mechanisms. We examined whether the neuroendocrine hormone progesterone is produced by and targeted to cholangiocytes, thereby regulating biliary proliferation during cholestasis. Nuclear (PR-A and PR-B) and membrane (PRGMC1, PRGMC2, and mPRa) progesterone receptor expression was evaluated in liver sections and cholangiocytes from normal and bile duct ligation (BDL) rats, and NRC cells (normal rat cholangiocyte line). In vivo, normal rats were chronically treated with progesterone for 1 wk, or immediately after BDL, rats were treated with a neutralizing progesterone antibody for 1 wk. Cholangiocyte growth was measured by evaluating the number of bile ducts in liver sections. The expression of the progesterone synthesis pathway was evaluated in liver sections, cholangiocytes and NRC. Progesterone secretion was evaluated in supernatants from normal and BDL cholangiocytes and NRC. In vitro, NRC were stimulated with progesterone and cholangiocyte supernatants in the presence or absence of antiprogesterone antibody. Aminoglutethimide was used to block progesterone synthesis. Cholangiocytes and NRC express the PR-B nuclear receptor and PRGMC1, PRGMC2, and mPRα. In vivo, progesterone increased the number of bile ducts of normal rats, whereas antiprogesterone antibody inhibited cholangiocyte growth stimulated by BDL. Normal and BDL cholangiocytes expressed the biosynthetic pathway for and secrete progesterone. In vitro, 1) progesterone increased NRC proliferation; 2) cholangiocyte supernatants increased NRC proliferation, which was partially inhibited by preincubation with antiprogesterone; and 3) inhibition of progesterone steroidogenesis prevented NRC proliferation. In conclusion, progesterone may be an important autocrine/paracrine regulator of cholangiocyte proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
46. Placental CoQ_{10} levels in HELLP syndrome.
- Author
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Giannubilo, Stefano R., Tranquilli, Andrea L., Santolini, Cristina, Principi, Federica, Mancinelli, Romina, and Littarru, Gian Paolo
- Subjects
OXIDATIVE stress ,PREECLAMPSIA ,UBIQUINONES ,LIQUID nitrogen ,BLOOD vessels ,PLACENTA ,COENZYMES - Abstract
Oxidative stress is considered a key factor in HELLP syndrome, a severe complication of preeclampsia in pregnancy. In the present study we analysed the content of Coenzyme Q_{10} (CoQ_{10}), a fundamental component of the mitochondrial respiratory chain and recognized lipophilic antioxidant, in placentas from women affected by HELLP syndrome and compared them with the relative controls. Twenty-eight patients with HELLP syndrome and twenty-eight age-matched healthy pregnant controls were enrolled. Two aliquots of placental tissue were taken immediately after delivery and placed into liquid nitrogen. Thawed samples were homogenised by Ultra-Turrax; total protein and CoQ_{10} concentration were thereafter analysed. CoQ_{10} concentration was 0.162 ± 0.07μg/mg protein in HELLP syndrome versus 0.87 ± 0.003μg/mg protein in controls, the difference being highly significant. A positive correlation, within the placentas from HELLP, was found between the weight of the new-born and CoQ_{10}/protein ratio. A significant positive correlation was also present between CoQ_{10}/protein ratio and Apgar at 1st and 5th minute as well as between CoQ_{10}/protein ratio and the median cerebral artery pulsatility index. The increase in placental CoQ_{10} in this syndrome might derive from a compensatory mechanism in a situation of increased oxidative stress. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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- View/download PDF
47. Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3/Ca2+ and cAMP-dependent signaling mechanisms.
- Author
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Francis, Heather L, DeMorrow, Sharon, Franchitto, Antonio, Venter, Julie K, Mancinelli, Romina A, White, Mellanie A, Meng, Fanyin, Ueno, Yoshiyuki, Carpino, Guido, Renzi, Anastasia, Baker, Kimberly K, Shine, Hannah E, Francis, Taylor C, Gaudio, Eugenio, Alpini, Gianfranco D, and Onori, Paolo
- Published
- 2012
- Full Text
- View/download PDF
48. Morphological and functional heterogeneity of the mouse intrahepatic biliary epithelium.
- Author
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Glaser, Shannon S, Gaudio, Eugenio, Rao, Arundhati, Pierce, Lisa M, Onori, Paolo, Franchitto, Antonio, Francis, Heather L, Dostal, David E, Venter, Julie K, DeMorrow, Sharon, Mancinelli, Romina, Carpino, Guido, Alvaro, Domenico, Kopriva, Shelley E, Savage, Jennifer M, and Alpini, Gianfranco D
- Published
- 2009
- Full Text
- View/download PDF
49. Impaired TFEB-dependent autophagy leads to higher anti-apoptotic c-Flip protein levels in cancer cells.
- Author
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de Franchis, Valerio, Petrungaro, Simonetta, Mandolini, Enrico, Mancinelli, Romina, and Giampietri, Claudia
- Subjects
AUTOPHAGY ,PROTEIN expression ,CELL determination ,LIVER cells ,PROTEOLYSIS ,CANCER cells - Abstract
The role of autophagy in cancer cells is largely debated. Experimental data suggest an impairment of autophagy during the initial steps of cancer development while an increase of autophagy in established tumors. In the present work we analyzed autophagy involvement in a human cholangiocarcinoma cell line (HuCCT1) vs a normal cholangiocyte cell line (H69). By comparing these experimental models we highlighted a strong difference in the expression level and subcellular localization of Transcription Factor EB (TFEB), previously shown as a master protein in driving autophagy (E Zhao and MJ Czaja, 2012) as well as in inducing liver cell commitment toward cholangiocyte lineage (Pastore N et al. 2020). More in detail we found higher TFEB nuclear localization in healthy H69 than in HuCCT1, correlating with the higher level of autophagy flux observed in H69 cells, evaluated through LC3II and p62 analyses. We therefore hypothesized that TFEB trafficking in the nucleus might be pivotal to control cholangiocyte cell differentiation status and autophagy, thus representing a possible player in counteracting cholangiocarcinoma growth. We also analyzed GSK-3beta and c-Flip proteins expression since GSK-3beta inhibition has been previously shown to promote degradation of the anti-apoptotic protein c-Flip (Na Zhang et al., 2018) via autophagy. Remarkably we found higher levels of c-Flip and higher activity of GSK-3beta in HuCCT1 as compared to H69 cells. We thus speculate that a fine autophagy control via TFEB may be involved in apoptosis modulation through c-Flip degradation in cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2021
50. Characterization of α-synuclein (α-syn) in normal human jejunum and its correlations with the neuroendocrine system.
- Author
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Casini, Arianna, Mammola, Caterina Loredana, Mancinelli, Romina, Onori, Paolo, and Vaccaro, Rosa
- Subjects
NEUROENDOCRINE system ,ENTERIC nervous system ,NERVE growth factor ,ALPHA-synuclein ,CYTOSKELETAL proteins ,JEJUNUM ,NEURAL transmission - Abstract
Alpha-synuclein (a-syn) is a presynaptic neuronal protein and its structural alterations play an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease (PD) (1). It has been originally described in the brain and aggregated α-syn has also been found in the peripheral nerves including the enteric nervous system (ENS) of PD patients (2). ENS is a network of neurons and glia found in the gut wall which controls gastrointestinal function independently from the central nervous system. Moreover, two types of epithelial cells are crucial in the creation of an interface between the lumen and the ENS: they are the tuft cells and the enterochromaffin cells (EECs) (3-4). In addition, the abundant enteric glial cells (EGCs) in the intestinal mucosa play a key role in controlling the intestinal epithelial barrier (5). Our aim has been to localize and characterize the presence of α-syn in the normal human jejunum wall. Surgical specimens of proximal jejunum wall were collected from patients submitted to pancreaticoduodenectomy and intestinal sections underwent immunohistochemical procedure using monoclonal antibody for α-syn. α-Syn has been found both at the level of ENS and the epithelial cells. To characterize α-syn immunoreactive epithelial cells we used markers as choline acetyltransferase (ChAT), useful to the identification of tuft cells (3). Then, we evaluated the co-presence of α-syn with 5-hydroxytryptamine (5-HT), expressed in EECs (4). Finally, we used the low-affinity nerve growth factor receptor (p75NTR), to detect peripheral EGCs. The presence of α-syn has been demonstrated in EECs but not in the tuft cells. Additionally, p75NTR has been highlighted in EGCs of the mucosal layer, and co-localized with α-syn in EECs but not in ChAT-positive cells. These findings suggest that α-syn could play a crucial role in synaptic transmission of the ENS and may contribute to maintain the integrity of the epithelial barrier of the small intestine through EECs. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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