Publications by authors named "Eugenio Gaudio"

265 Publications

Prolonged Chronic Consumption of a High Fat with Sucrose Diet Alters the Morphology of the Small Intestine.

Int J Mol Sci 2021 Jul 6;22(14). Epub 2021 Jul 6.

Department of Biotechnological and Applied Sciences, University of L'Aquila, 67100 L'Aquila, Italy.

(1) The high-fat diet (HFD) of western countries has dramatic effect on the health of several organs, including the digestive tract, leading to the accumulation of fats that can also trigger a chronic inflammatory process, such as that which occurs in non-alcohol steatohepatitis. The effects of a HFD on the small intestine, the organ involved in the absorption of this class of nutrients, are still poorly investigated. (2) To address this aspect, we administered a combined HFD with sucrose (HFD w/Suc, fat: 58% Kcal) regimen (18 months) to mice and investigated the morphological and molecular changes that occurred in the wall of proximal tract of the small intestine compared to the intestine of mice fed with a standard diet (SD) (fat: 18% Kcal). (3) We found an accumulation of lipid droplets in the mucosa of HFD w/Suc-fed mice that led to a disarrangement of mucosa architecture. Furthermore, we assessed the expression of several key players involved in lipid metabolism and inflammation, such as perilipin, leptin, leptin receptor, PI3K, p-mTOR, p-Akt, and TNF-α. All these molecules were increased in HFD mice compared to the SD group. We also evaluated anti-inflammatory molecules like adiponectin, adiponectin receptor, and PPAR-γ, and observed their significant reduction in the HFD w/Suc group compared to the control. Our data are in line with the knowledge that improper eating habits present a primary harmful assault on the bowel and the entire body's health. (4) These results represent a promising starting point for future studies, helping to better understand the complex and not fully elucidated spectrum of intestinal alterations induced by the overconsumption of fat.
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http://dx.doi.org/10.3390/ijms22147280DOI Listing
July 2021

c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability.

Cell Death Dis 2021 Jul 8;12(7):686. Epub 2021 Jul 8.

Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome, Italy.

c-FLIP (cellular FLICE-like inhibitory protein) protein is mostly known as an apoptosis modulator. However, increasing data underline that c-FLIP plays multiple roles in cellular homoeostasis, influencing differently the same pathways depending on its expression level and isoform predominance. Few and controversial data are available regarding c-FLIP function in autophagy. Here we show that autophagic flux is less effective in c-FLIP-/- than in WT MEFs (mouse embryonic fibroblasts). Indeed, we show that the absence of c-FLIP compromises the expression levels of pivotal factors in the generation of autophagosomes. In line with the role of c-FLIP as a scaffold protein, we found that c-FLIP interacts with Beclin-1 (BECN1: coiled-coil, moesin-like BCL2-interacting protein), which is required for autophagosome nucleation. By a combination of bioinformatics tools and biochemistry assays, we demonstrate that c-FLIP interaction with Beclin-1 is important to prevent Beclin-1 ubiquitination and degradation through the proteasomal pathway. Taken together, our data describe a novel molecular mechanism through which c-FLIP positively regulates autophagy, by enhancing Beclin-1 protein stability.
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http://dx.doi.org/10.1038/s41419-021-03957-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266807PMC
July 2021

The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity.

Int J Mol Sci 2021 Jun 5;22(11). Epub 2021 Jun 5.

Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy.

In nonalcoholic steatohepatitis animal models, an increased lipid droplet size in hepatocytes is associated with fibrogenesis. Hepatocytes with large droplet (Ld-MaS) or small droplet (Sd-MaS) macrovesicular steatosis may coexist in the human liver, but the factors associated with the predominance of one type over the other, including hepatic fibrogenic capacity, are unknown. In pre-ischemic liver biopsies from 225 consecutive liver transplant donors, we retrospectively counted hepatocytes with Ld-MaS and Sd-MaS and defined the predominant type of steatosis as involving ≥50% of steatotic hepatocytes. We analyzed a donor Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism, hepatic expression of proteins involved in lipid metabolism by RT-PCR, hepatic stellate cell (HSC) activation by α-SMA immunohistochemistry and, one year after transplantation, histological progression of fibrosis due to Hepatitis C Virus (HCV) recurrence. Seventy-four livers had no steatosis, and there were 98 and 53 with predominant Ld-MaS and Sd-MaS, respectively. In linear regression models, adjusted for many donor variables, the percentage of steatotic hepatocytes affected by Ld-MaS was inversely associated with hepatic expression of Insulin Induced Gene 1 (INSIG-1) and Niemann-Pick C1-Like 1 gene (NPC1L1) and directly with donor PNPLA3 variant M, HSC activation and progression of post-transplant fibrosis. In humans, Ld-MaS formation by hepatocytes is associated with abnormal PNPLA3-mediated lipolysis, downregulation of both the intracellular cholesterol sensor and cholesterol reabsorption from bile and increased hepatic fibrogenesis.
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http://dx.doi.org/10.3390/ijms22116100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200978PMC
June 2021

The Italian law on body donation: A position paper of the Italian College of Anatomists.

Ann Anat 2021 Nov 15;238:151761. Epub 2021 Jun 15.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.

In Italy, recent legislation (Law No. 10/2020) has tuned regulations concerning the donation of one's postmortem body and tissues for study, training, and scientific research purposes. This study discusses several specific issues to optimise the applicability and effectiveness of such an important, novel regulatory setting. Critical issues arise concerning the learners, the type of training and teaching activities that can be planned, the position of academic anatomy institutes, the role of family members in the donation process, the time frame of the donation process, the eligibility of partial donation, or the simultaneous donation of organs and tissues to patients awaiting transplantation. In particular, a universal time limit for donations (i.e., one year) makes it impossible to plan the long-term use of specific body parts, which could be effectively preserved for the advanced teaching and training of medical students and surgeons. The abovementioned conditions lead to the limited use of corpses, thus resulting in the inefficiency of the whole system of body donation. Overall, the donors' scope for the donation of their body could be best honoured by a more flexible and tuneable approach that can be used on a case-by-case basis. Furthermore, it is deemed necessary to closely monitor the events scheduled for corpses in public nonacademic institutions or private enterprises. This paper presents useful insights from Italian anatomists with the hope of providing inspiration for drafting the regulations. In conclusion, this paper focuses on the critical issues derived from the recently introduced Italian law on the donation and use of the body after death and provides suggestions to lawmakers for future implementations.
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http://dx.doi.org/10.1016/j.aanat.2021.151761DOI Listing
November 2021

Publisher Correction: HMGA1-pseudogene7 transgenic mice develop B cell lymphomas.

Sci Rep 2021 Jun 11;11(1):12741. Epub 2021 Jun 11.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

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http://dx.doi.org/10.1038/s41598-021-92173-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196011PMC
June 2021

Molecular Landscape and Therapeutic Strategies in Cholangiocarcinoma: An Integrated Translational Approach towards Precision Medicine.

Int J Mol Sci 2021 May 25;22(11). Epub 2021 May 25.

Medical-Surgical and Biotechnologies Sciences, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, 04100 Latina, Italy.

Cholangiocarcinomas (CCAs) are heterogeneous biliary tract malignancies with dismal prognosis, mainly due to tumor aggressiveness, late diagnosis, and poor response to current therapeutic options. High-throughput technologies have been used as a fundamental tool in unveiling CCA molecular landscape, and several molecular classifications have been proposed, leading to various targeted therapy trials. In this review, we aim to analyze the critical issues concerning the status of precision medicine in CCA, discussing molecular signatures and clusters, related to both anatomical classification and different etiopathogenesis, and the latest therapeutic strategies. Furthermore, we propose an integrated approach comprising the CCA molecular mechanism, pathobiology, clinical and histological findings, and treatment perspectives for the ultimate purpose of improving the methods of patient allocations in clinical trials and the response to personalized therapies.
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http://dx.doi.org/10.3390/ijms22115613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199244PMC
May 2021

Study of the antilymphoma activity of pracinostat reveals different sensitivities of DLBCL cells to HDAC inhibitors.

Blood Adv 2021 05;5(10):2467-2480

Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Bellinzona, Switzerland.

Histone deacetylase inhibitors (HDACis) are antitumor agents with distinct efficacy in hematologic tumors. Pracinostat is a pan-HDACi with promising early clinical activity. However, similar to other HDACis, its activity as a single agent is limited. Diffuse large B-cell lymphoma (DLBCL) includes distinct molecular subsets or metabolically defined subtypes that rely in different ways on the B-cell receptor signaling pathway, oxidative phosphorylation, and glycolysis for their survival. The antitumor activity of pracinostat has not been determined in lymphomas. We performed preclinical in vitro activity screening of 60 lymphoma cell lines that included 25 DLBCLs. DLBCL cells belonging to distinct metabolic subtypes were treated with HDACis for 6 hours or 14 days followed by transcriptional profiling. DLBCL xenograft models enabled assessment of the in vivo antilymphoma activity of pracinostat. Combination treatments with pracinostat plus 10 other antilymphoma agents were performed. Western blot was used to assess acetylation levels of histone and nonhistone proteins after HDACi treatment. Robust antiproliferative activity was observed across all lymphoma histotypes represented. Focusing on DLBCL, we identified a low-sensitivity subset that almost exclusively consists of the oxidative phosphorylation (OxPhos)-DLBCL metabolic subtype. OxPhos-DLBCL cells also showed poorer sensitivity to other HDACis, including vorinostat. Transcriptomic analysis revealed fewer modulated transcripts but an enrichment of antioxidant pathway genes after HDACi treatment of OxPhos-DLBCLs compared with high-sensitivity B-cell receptor (BCR)-DLBCLs. Pharmacologic inhibition of antioxidant production rescued sensitivity of OxPhos-DLBCLs to pracinostat whereas BCR-DLBCLs were unaffected. Our study provides novel insights into the antilymphoma activity of pracinostat and identifies a differential response of DLBCL metabolic subtypes to HDACis.
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http://dx.doi.org/10.1182/bloodadvances.2020003566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152508PMC
May 2021

Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma.

Oncogene 2021 Jun 6;40(22):3799-3814. Epub 2021 May 6.

Core Research Laboratory - Institute for Cancer Research and Prevention (ISPRO), Florence, Italy.

Despite the development of new targeted and immune therapies, the prognosis of metastatic melanoma remains bleak. Therefore, it is critical to better understand the mechanisms controlling advanced melanoma to develop more effective treatment regimens. Hedgehog/GLI (HH/GLI) signaling inhibitors targeting the central pathway transducer Smoothened (SMO) have shown to be clinical efficacious in skin cancer; however, several mechanisms of non-canonical HH/GLI pathway activation limit their efficacy. Here, we identify a novel SOX2-BRD4 transcriptional complex driving the expression of GLI1, the final effector of the HH/GLI pathway, providing a novel mechanism of non-canonical SMO-independent activation of HH/GLI signaling in melanoma. Consistently, we find a positive correlation between the expression of GLI1 and SOX2 in human melanoma samples and cell lines. Further, we show that combined targeting of canonical HH/GLI pathway with the SMO inhibitor MRT-92 and of the SOX2-BRD4 complex using a potent Proteolysis Targeted Chimeras (PROTACs)-derived BRD4 degrader (MZ1), yields a synergistic anti-proliferative effect in melanoma cells independently of their BRAF, NRAS, and NF1 mutational status, with complete abrogation of GLI1 expression. Combination of MRT-92 and MZ1 strongly potentiates the antitumor effect of either drug as single agents in an orthotopic melanoma model. Together, our data provide evidence of a novel mechanism of non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex, and describe the efficacy of a new combinatorial treatment for a subset of melanomas with an active SOX2-BRD4-GLI1 axis.
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http://dx.doi.org/10.1038/s41388-021-01783-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175236PMC
June 2021

The Charming World of the Extracellular Matrix: A Dynamic and Protective Network of the Intestinal Wall.

Front Med (Lausanne) 2021 16;8:610189. Epub 2021 Apr 16.

Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.

The intestinal extracellular matrix (ECM) represents a complex network of proteins that not only forms a support structure for resident cells but also interacts closely with them by modulating their phenotypes and functions. More than 300 molecules have been identified, each of them with unique biochemical properties and exclusive biological functions. ECM components not only provide a scaffold for the tissue but also afford tensile strength and limit overstretch of the organ. The ECM holds water, ensures suitable hydration of the tissue, and participates in a selective barrier to the external environment. ECM-to-cells interaction is crucial for morphogenesis and cell differentiation, proliferation, and apoptosis. The ECM is a dynamic and multifunctional structure. The ECM is constantly renewed and remodeled by coordinated action among ECM-producing cells, degrading enzymes, and their specific inhibitors. During this process, several growth factors are released in the ECM, and they, in turn, modulate the deposition of new ECM. In this review, we describe the main components and functions of intestinal ECM and we discuss their role in maintaining the structure and function of the intestinal barrier. Achieving complete knowledge of the ECM world is an important goal to understand the mechanisms leading to the onset and the progression of several intestinal diseases related to alterations in ECM remodeling.
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http://dx.doi.org/10.3389/fmed.2021.610189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085262PMC
April 2021

Accuracy of Transient Elastography in Assessing Fibrosis at Diagnosis in Naïve Patients With Primary Biliary Cholangitis: A Dual Cut-Off Approach.

Hepatology 2021 Mar 16. Epub 2021 Mar 16.

Studiosa Senior, University of Padua, Padua, Italy.

Background And Aims: Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Noninvasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis (AF) at disease presentation in PBC.

Approach And Results: We collected data from 167 consecutive treatment-naïve PBC patients who underwent liver biopsy (LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to the Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for AF (Ludwig stage ≥III). Effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. The derivation cohort consisted of 126 patients with valid LSM and LB; VCTE identified patients with AF with an AUROC of 0.89. LSM cutoffs ≤6.5 and >11.0 kPa enabled to exclude and confirm, respectively, AF (negative predictive value [NPV] = 0.94; positive predictive value [PPV] = 0.89; error rate = 5.6%). These values were externally validated in an independent cohort of 91 PBC patients (NPV = 0.93; PPV = 0.89; error rate = 8.6%). Multivariable analysis found that the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry.

Conclusions: In a multicenter study of treatment-naïve PBC patients, we identified two cutoffs (LSM ≤6.5 and >11.0 kPa) able to discriminate at diagnosis the absence or presence, respectively, of AF in PBC patients, with external validation. In patients with LSM between these two cutoffs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.
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http://dx.doi.org/10.1002/hep.31810DOI Listing
March 2021

Anti-tumor Effect of Oleic Acid in Hepatocellular Carcinoma Cell Lines Autophagy Reduction.

Front Cell Dev Biol 2021 5;9:629182. Epub 2021 Feb 5.

Department of Anatomical, Histological, Forensic Medicine, and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy.

Oleic acid (OA) is a component of the olive oil. Beneficial health effects of olive oil are well-known, such as protection against liver steatosis and against some cancer types. In the present study, we focused on OA effects in hepatocellular carcinoma (HCC), investigating responses to OA treatment (50-300 μM) in HCC cell lines (Hep3B and Huh7.5) and in a healthy liver-derived human cell line (THLE-2). Upon OA administration higher lipid accumulation, perilipin-2 increase, and autophagy reduction were observed in HCC cells as compared to healthy cells. OA in the presence of 10% FBS significantly reduced viability of HCC cell lines at 300 μM through Alamar Blue staining evaluation, and reduced cyclin D1 expression in a dose-dependent manner while it was ineffective on healthy hepatocytes. Furthermore, OA increased cell death by about 30%, inducing apoptosis and necrosis in HCC cells but not in healthy hepatocytes at 300 μM dosage. Moreover, OA induced senescence in Hep3B, reduced P-ERK in both HCC cell lines and significantly inhibited the antiapoptotic proteins c-Flip and Bcl-2 in HCC cells but not in healthy hepatocytes. All these results led us to conclude that different cell death processes occur in these two HCC cell lines upon OA treatment. Furthermore, 300 μM OA significantly reduced the migration and invasion of both HCC cell lines, while it has no effects on healthy cells. Finally, we investigated autophagy role in OA-dependent effects by using the autophagy inducer torin-1. Combined OA/torin-1 treatment reduced lipid accumulation and cell death as compared to single OA treatment. We therefore concluded that OA effects in HCC cells lines are, at least, in part dependent on OA-induced autophagy reduction. In conclusion, we report for the first time an autophagy dependent relevant anti-cancer effect of OA in human hepatocellular carcinoma cell lines.
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http://dx.doi.org/10.3389/fcell.2021.629182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892977PMC
February 2021

Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells.

Sci Rep 2021 Jan 28;11(1):2557. Epub 2021 Jan 28.

Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with marked resistance to chemotherapeutics without therapies. The tumour microenvironment of iCCA is enriched of Cancer-Stem-Cells expressing Epithelial-to-Mesenchymal Transition (EMT) traits, being these features associated with aggressiveness and drug resistance. Treatment with the anti-diabetic drug Metformin, has been recently associated with reduced incidence of iCCA. We aimed to evaluate the anti-cancerogenic effects of Metformin in vitro and in vivo on primary cultures of human iCCA. Our results showed that Metformin inhibited cell proliferation and induced dose- and time-dependent apoptosis of iCCA. The migration and invasion of iCCA cells in an extracellular bio-matrix was also significantly reduced upon treatments. Metformin increased the AMPK and FOXO3 and induced phosphorylation of activating FOXO3 in iCCA cells. After 12 days of treatment, a marked decrease of mesenchymal and EMT genes and an increase of epithelial genes were observed. After 2 months of treatment, in order to simulate chronic administration, Cytokeratin-19 positive cells constituted the majority of cell cultures paralleled by decreased Vimentin protein expression. Subcutaneous injection of iCCA cells previously treated with Metformin, in Balb/c-nude mice failed to induce tumour development. In conclusion, Metformin reverts the mesenchymal and EMT traits in iCCA by activating AMPK-FOXO3 related pathways suggesting it might have therapeutic implications.
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http://dx.doi.org/10.1038/s41598-021-81172-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844056PMC
January 2021

Understanding the mechanism of action of pyrrolo[3,2-]quinoxaline-derivatives as kinase inhibitors.

RSC Med Chem 2020 Jun 19;11(6):665-675. Epub 2020 May 19.

Department of Chemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 , Zürich , Switzerland . Email: ; ; Tel: (+41) 446353945.

The X-ray structure of the catalytic domain of the EphA3 tyrosine kinase in complex with a previously reported type II inhibitor was used to design two novel quinoxaline derivatives, inspired by kinase inhibitors that have reached clinical development. These two new compounds were characterized by an array of cell-based assays and gene expression profiling experiments. A global chemical proteomics approach was used to generate the drug-protein interaction profile, which suggested suitable therapeutic indications. Both inhibitors, studied in the context of angiogenesis and in a relevant lymphoma model, showed high efficacy in the control of tumor size.
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http://dx.doi.org/10.1039/d0md00049cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557569PMC
June 2020

Cholangiocarcinoma: bridging the translational gap from preclinical to clinical development and implications for future therapy.

Expert Opin Investig Drugs 2021 Apr 8;30(4):365-375. Epub 2020 Dec 8.

Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA.

: Cholangiocarcinoma (CCA) is a devastating liver tumor with a poor prognosis. While less than 50% of the patients with CCA may benefit from surgical resection, the rest undergoes chemotherapy with disappointing results (mean survival <2 years). Alternative pharmacological treatments are needed to improve the outcomes in patients with CCA.: In this review, we discuss CCA-related (1) experimental systems used in preclinical studies; (2) pharmacological targets identified by genetic analysis; (3) results obtained in preliminary trials in human with their pros and cons; and (4) possible targeting of endocrinal modulation. A PubMed bibliographic search matching the term 'cholangiocarcinoma' with 'experimental model', 'preclinical model', 'genetic target', 'targeted therapy', 'clinical trial', or 'translational research' was conducted and manuscripts published between 2010 and 2020 were retrieved for reading and reviewing.: Several factors contribute to the translational gap between bench research and clinical practice in CCA. The tumor heterogeneity, lack of a preclinical model recapitulating the different features of CCA, and difficult patient enrollment in clinical trials are elements to consider for basic and clinical research in CCA. Establishment of international networks formed by experts in the field of CCA may improve future research and its translational findings on patients.
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http://dx.doi.org/10.1080/13543784.2021.1854725DOI Listing
April 2021

Vav1 Sustains the In Vitro Differentiation of Normal and Tumor Precursors to Insulin Producing Cells Induced by all-Trans Retinoic Acid (ATRA).

Stem Cell Rev Rep 2021 Apr 9;17(2):673-684. Epub 2020 Nov 9.

Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Fossato di Mortara, 70, 44121, Ferrara, Italy.

All-trans retinoic acid (ATRA) promotes the development and the function of insulin producing cells and induces partial differentiation of pancreatic tumor cells. A number of evidences clearly indicate that the ATRA mediated signaling may have a substantial role in therapeutic approaches based on restoration of functional β-cells. Among the proteins up-regulated by ATRA, Vav1 is involved in maturation and function of haematopoietic cells and is essential for retinoids induced differentiation of tumor promyelocytes. The presence of Vav1 in solid tissues, including pancreas, is considered ectopic and no role in the differentiation of human epithelial cells has so far been described. We demonstrated here that Vav1 sustains the maturation to β-cells of the normal precursors human Biliary Tree Stem/progenitor Cells (hBTSCs) induced by a differentiation medium containing ATRA and that, in the mature normal pancreas, insulin-producing cells express variable levels of Vav1. Using pancreatic ductal adenocarcinoma (PDAC)-derived cells, we also revealed that the ATRA induced up-modulation of Vav1 is essential for the retinoid-induced trans-differentiation of neoplastic cells into insulin producing cells. The results of this study identify Vav1 as crucial molecule in ATRA induced maturation of insulin producing cells and suggest this protein as a marker for new strategies ended to restore functional β-cells. Graphical abstract.
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http://dx.doi.org/10.1007/s12015-020-10074-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036226PMC
April 2021

Different iron-handling in inflamed small and large cholangiocytes and in small and large-duct type intrahepatic cholangiocarcinoma.

Eur J Histochem 2020 Oct 19;64(4). Epub 2020 Oct 19.

Department of Public Health and Infectious Diseases, Sapienza University of Rome.

Cholangiocarcinoma (CCA) represents the second most common primary hepatic malignancy and originates from the neoplastic transformation of the biliary cells. The intrahepatic subtype includes two morpho-molecular forms: large-duct type intrahepatic CCA (iCCA) and small-duct type iCCA. Iron is fundamental for the cellular processes, contributing in tumor development and progression. The aim of this study was to evaluate iron uptake, storage, and efflux proteins in both lipopolysaccharide-inflamed small and large cholangiocytes as well as in different iCCA subtypes. Our results show that, despite an increase in interleukin-6 production by both small and large cholangiocytes, ferroportin (Fpn) was decreased only in small cholangiocytes, whereas transferrin receptor-1 (TfR1) and ferritin (Ftn) did not show any change. Differently from in vitro models, Fpn expression was increased in malignant cholangiocytes of small-duct type iCCA in comparison to large-duct type iCCA and peritumoral tissues. TfR1, Ftn and hepcidin were enhanced, even if at different extent, in both malignant cholangiocytes in comparison to the surrounding samples. Lactoferrin was higher in large-duct type iCCA in respect to small-duct type iCCA and peritumoral tissues. These findings show a different iron handling by inflamed small and large cholangiocytes, and small and large-duct type iCCA. The difference in iron homeostasis by the iCCA subtypes may have implications for the tumor management.
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http://dx.doi.org/10.4081/ejh.2020.3156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586138PMC
October 2020

Targeting CD205 with the antibody drug conjugate MEN1309/OBT076 is an active new therapeutic strategy in lymphoma models.

Haematologica 2020 11 1;105(11):2584-2591. Epub 2020 Nov 1.

Università della Svizzera italiana, Istituto Oncologico di Ricerca, Bellinzona, Switzerland.

Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematological cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class antibody drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leukemias and multiple myeloma by immunohistochemistry on tissue microarrays. Anti-tumor activity of MEN1309/OBT076 as single agent was then shown across 42 B-cell lymphoma cell lines with a median IC50 of 200 pM and induction of apoptosis in 25/42 (59.5%) of the cases. The activity appeared highly correlated with its target expression. After in vivo validation as the single agent, the antibody drug conjugate synergized with the BCL2 inhibitor venetoclax, and the anti-CD20 monoclonal antibody rituximab. The first-in-class antibody drug targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti-tumor activity in lymphoma, warranting further investigations as a single agent and in combination.
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http://dx.doi.org/10.3324/haematol.2019.227215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604571PMC
November 2020

Pyrrolo[2',3':3,4]cyclohepta[1,2-][1,2]oxazoles, a New Class of Antimitotic Agents Active against Multiple Malignant Cell Types.

J Med Chem 2020 10 11;63(20):12023-12042. Epub 2020 Oct 11.

Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.

A new class of pyrrolo[2',3':3,4]cyclohepta[1,2-][1,2]oxazoles was synthesized for the treatment of hyperproliferative pathologies, including neoplasms. The new compounds were screened in the 60 human cancer cell lines of the NCI drug screen and showed potent activity with GI values reaching the nanomolar level, with mean graph midpoints of 0.08-0.41 μM. All compounds were further tested on six lymphoma cell lines, and eight showed potent growth inhibitory effects with IC values lower than 500 nM. Mechanism of action studies showed the ability of the new [1,2]oxazoles to arrest cells in the G2/M phase in a concentration dependent manner and to induce apoptosis through the mitochondrial pathway. The most active compounds inhibited tubulin polymerization, with IC values of 1.9-8.2 μM, and appeared to bind to the colchicine site. The G2/M arrest was accompanied by apoptosis, mitochondrial depolarization, generation of reactive oxygen species, and PARP cleavage.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901646PMC
October 2020

Distinct EpCAM-Positive Stem Cell Niches Are Engaged in Chronic and Neoplastic Liver Diseases.

Front Med (Lausanne) 2020 2;7:479. Epub 2020 Sep 2.

Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy.

In normal human livers, EpCAM cells are mostly restricted in two distinct niches, which are (i) the bile ductules and (ii) the mucous glands present inside the wall of large intrahepatic bile ducts (the so-called peribiliary glands). These EpCAM cell niches have been proven to harbor stem/progenitor cells with great importance in liver and biliary tree regeneration and in the pathophysiology of human diseases. The EpCAM progenitor cells within bile ductules are engaged in driving regenerative processes in chronic diseases affecting hepatocytes or interlobular bile ducts. The EpCAM population within peribiliary glands is activated when regenerative needs are finalized to repair large intra- or extra-hepatic bile ducts affected by chronic pathologies, including primary sclerosing cholangitis and ischemia-induced cholangiopathies after orthotopic liver transplantation. Finally, the presence of distinct EpCAM cell populations may explain the histological and molecular heterogeneity characterizing cholangiocarcinoma, based on the concept of multiple candidate cells of origin. This review aimed to describe the precise anatomical distribution of EpCAM populations within the liver and the biliary tree and to discuss their contribution in the pathophysiology of human liver diseases, as well as their potential role in regenerative medicine of the liver.
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http://dx.doi.org/10.3389/fmed.2020.00479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492539PMC
September 2020

DCLK1, a Putative Stem Cell Marker in Human Cholangiocarcinoma.

Hepatology 2021 01;73(1):144-159

Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

Background And Aims: Cholangiocarcinoma (CCA) is a very aggressive cancer showing the presence of high cancer stem cells (CSCs). Doublecortin-like kinase1 (DCLK1) has been demonstrated as a CSC marker in different gastroenterological solid tumors. Our aim was to evaluate in vitro the expression and the biological function of DCLK1 in intrahepatic CCA (iCCA) and perihilar CCA (pCCA).

Approach And Results: Specimens surgically resected of human CCA were enzymatically digested, submitted to immunosorting for specific CSC markers (LGR5 [leucine-rich repeat-containing G protein-coupled receptor], CD [clusters of differentiation] 90, EpCAM [epithelial cell adhesion molecule], CD133, and CD13), and primary cell cultures were prepared. DCLK1 expression was analyzed in CCA cell cultures by real-time quantitative PCR, western blot, and immunofluorescence. Functional studies have been performed by evaluating the effects of selective DCLK1 inhibitor (LRRK2-IN-1) on cell proliferation (MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay, cell population doubling time), apoptosis, and colony formation capacity. DCLK1 was investigated in situ by immunohistochemistry and real-time quantitative PCR. DCLK1 serum concentration was analyzed by enzyme-linked immunosorbent assay. We describe DCLK1 in CCA with an increased gene and protein DCLK1 expression in pCCA and in iCCA cells compared with unsorted cells. LRRK2-IN-1 showed an anti-proliferative effect in a dose-dependent manner. LRRK2-IN-1 markedly impaired cell proliferation, induced apoptosis, and decreased colony formation capacity and colony size in both iCCA and pCCA compared with the untreated cells. In situ analysis confirmed that DCLK1 is present only in tumors, and not in healthy tissue. Interestingly, DCLK1 was detected in the human serum samples of patients with iCCA (high), pCCA (high), HCC (low), and cirrhosis (low), but it was almost undetectable in healthy controls.

Conclusions: DCLK1 characterizes a specific CSC subpopulation of iCCA and pCCA , and its inhibition exerts anti-neoplastic effects in primary CCA cell cultures. Human DCLK1 serum might represent a serum biomarker for the early CCA diagnosis.
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http://dx.doi.org/10.1002/hep.31571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243252PMC
January 2021

Antitumor activity of the dual BET and CBP/EP300 inhibitor NEO2734.

Blood Adv 2020 09;4(17):4124-4135

Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland.

Bromodomain and extra-terminal domain (BET) proteins, cyclic adenosine monophosphate response element-binding protein (CBP), and the E1A-binding protein of p300 (EP300) are important players in histone acetylation. Preclinical evidence supports the notion that small molecules targeting these proteins individually or in combination can elicit antitumor activity. Here, we characterize the antitumor activity of the pan BET/CBP/EP300 inhibitor NEO2734 and provide insights into its mechanism of action through bromodomain-binding assays, in vitro and in vivo treatments of cancer cell lines, immunoblotting, and transcriptome analyses. In a panel of 60 models derived from different tumor types, NEO2734 exhibited antiproliferative activity in multiple cell lines, with the most potent activity observed in hematologic and prostate cancers. Focusing on lymphoma cell lines, NEO2374 exhibited a pattern of response and transcriptional changes similar to lymphoma cells exposed to either BET or CBP/EP300 inhibitors alone. However, NEO2734 was more potent than single-agent BET or CBP/EP300 inhibitors alone. In conclusion, NEO2734 is a novel antitumor compound that shows preferential activity in lymphomas, leukemias, and prostate cancers.
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http://dx.doi.org/10.1182/bloodadvances.2020001879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479962PMC
September 2020

Knockout of the Tachykinin Receptor 1 in the Mdr2 (Abcb4) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis.

Am J Pathol 2020 11 23;190(11):2251-2266. Epub 2020 Jul 23.

Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana. Electronic address:

Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated and Mdr2 (alias Abcb4) mice through enhanced transforming growth factor-β1 (TGF-β1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-β1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-β1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2 and NK1R (alias Tacr1) to further address the role of the SP/NK1R axis during chronic cholestasis. In vivo studies were performed in the following 12-week-old male mice: (i) NK1R; (ii) Mdr2; and (iii) NK1R/Mdr2 (Tacr1/Abcb4) and their corresponding wild-type controls. Liver tissues and cholangiocytes were collected, and liver damage, changes in biliary mass/senescence, and inflammation as well as liver fibrosis were evaluated by both immunohistochemistry in liver sections and real-time PCR. miR-31 expression was measured by real-time PCR in isolated cholangiocytes. Decreased ductular reaction, liver fibrosis, biliary senescence, and biliary inflammation were observed in NK1R/Mdr2 mice compared with Mdr2 mice. Elevated expression of miR-31 was observed in Mdr2 mice, which was reduced in NK1R/Mdr2 mice. Targeting the SP/NK1R and/or miR-31 may be a potential approach in treating human cholangiopathies, including primary sclerosing cholangitis.
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http://dx.doi.org/10.1016/j.ajpath.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592721PMC
November 2020

Nutrition education in medical schools (NEMS). An ESPEN position paper.

Clin Nutr 2020 09 3;39(9):2938-2939. Epub 2020 Jul 3.

Department of Gastroenterology and Nutritional Support, Hopital Erasme and Institut Bordet, Free University of Brussels, Brussels, Belgium.

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http://dx.doi.org/10.1016/j.clnu.2020.06.031DOI Listing
September 2020

Cholangiocarcinoma 2020: the next horizon in mechanisms and management.

Nat Rev Gastroenterol Hepatol 2020 09 30;17(9):557-588. Epub 2020 Jun 30.

National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain.

Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
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http://dx.doi.org/10.1038/s41575-020-0310-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447603PMC
September 2020

Immobilization quality and cardiopulmonary effects of etorphine alone compared with etorphine-azaperone in blesbok (Damaliscus pygargus phillipsi).

Vet Anaesth Analg 2020 Jul 1;47(4):528-536. Epub 2020 Apr 1.

Department of Animal Medicine Production and Health, University of Padova, Padova, Italy.

Objective: To evaluate the immobilization quality and cardiopulmonary effects of etorphine alone compared with etorphine-azaperone in blesbok (Damaliscus pygargus phillipsi).

Study Design: Blinded, randomized, crossover design.

Animals: A total of 12 boma-habituated female blesbok weighing [mean ± standard deviation (SD)] 57.5 ± 2.5 kg.

Methods: Each animal was administered etorphine (0.09 mg kg) or etorphine-azaperone (0.09 mg kg; 0.35 mg kg) intramuscularly with 1-week intertreatment washout period. Time to first sign of altered state of consciousness and immobilization time were recorded. Physiological variables were recorded, arterial blood samples were taken during a 40-minute immobilization period, and naltrexone (mean ± SD: 1.83 ± 0.06 mg kg) was intravenously administered. Recovery times were documented, and induction, immobilization and recovery were subjectively scored. Statistical analyses were performed; p < 0.05 was significant.

Results: No difference was observed in time to first sign, immobilization time and recovery times between treatments. Time to head up was longer with etorphine-azaperone (0.5 ± 0.2 versus 0.4 ± 0.2 minutes; p = 0.015). Etorphine caused higher arterial blood pressures (mean: 131 ± 17 versus 110 ± 11 mmHg, p < 0.0001), pH, rectal temperature and arterial oxygen partial pressure (59.2 ± 7.7 versus 42.2 ± 9.8 mmHg), but lower heart (p = 0.002) and respiratory rates (p = 0.01). Etorphine-azaperone combination led to greater impairment of ventilatory function, with higher end-tidal carbon dioxide (p < 0.0001) and arterial partial pressure of carbon dioxide (58.0 ± 4.5 versus 48.1 ± 5.1 mmHg). Immobilization quality was greater with etorphine-azaperone than with etorphine alone (median scores: 4 versus 3; p < 0.0001).

Conclusions And Clinical Relevance: Both treatments provided satisfactory immobilization of blesbok; however, in addition to a deeper level of immobilization, etorphine-azaperone caused greater ventilatory impairment. Oxygen supplementation is recommended with both treatments.
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http://dx.doi.org/10.1016/j.vaa.2019.10.012DOI Listing
July 2020

Multi-Targeting Bioactive Compounds Extracted from Essential Oils as Kinase Inhibitors.

Molecules 2020 May 6;25(9). Epub 2020 May 6.

Dipartimento di Scienze della Salute, Università "Magna Græcia" di Catanzaro, Campus Universitario "S. Venuta", Viale Europa, Loc. Germaneto, 88100 Catanzaro, Italy.

Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features.
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http://dx.doi.org/10.3390/molecules25092174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249159PMC
May 2020

Viral Hepatitis and Iron Dysregulation: Molecular Pathways and the Role of Lactoferrin.

Molecules 2020 Apr 24;25(8). Epub 2020 Apr 24.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy.

The liver is a frontline immune site specifically designed to check and detect potential pathogens from the bloodstream to maintain a general state of immune hyporesponsiveness. One of the main functions of the liver is the regulation of iron homeostasis. The liver detects changes in systemic iron requirements and can regulate its concentration. Pathological states lead to the dysregulation of iron homeostasis which, in turn, can promote infectious and inflammatory processes. In this context, hepatic viruses deviate hepatocytes' iron metabolism in order to better replicate. Indeed, some viruses are able to alter the expression of iron-related proteins or exploit host receptors to enter inside host cells. Lactoferrin (Lf), a multifunctional iron-binding glycoprotein belonging to the innate immunity, is endowed with potent antiviral activity, mainly related to its ability to block viral entry into host cells by interacting with viral and/or cell surface receptors. Moreover, Lf can act as an iron scavenger by both direct iron-chelation or the modulation of the main iron-related proteins. In this review, the complex interplay between viral hepatitis, iron homeostasis, and inflammation as well as the role of Lf are outlined.
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http://dx.doi.org/10.3390/molecules25081997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221917PMC
April 2020

HMGA1-pseudogene7 transgenic mice develop B cell lymphomas.

Sci Rep 2020 04 27;10(1):7057. Epub 2020 Apr 27.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

We have recently identified and characterized two pseudogenes (HMGA1P6 and HMGA1P7) of the HMGA1 gene, which has a critical role in malignant cell transformation and cancer progression. HMGA1P6 and HMGAP17 act as microRNA decoy for HMGA1 and other cancer-related genes upregulating their protein levels. We have previously shown that they are upregulated in several human carcinomas, and their expression positively correlates with a poor prognosis and an advanced cancer stage. To evaluate in vivo oncogenic activity of HMGA1 pseudogenes, we have generated a HMGA1P7 transgenic mouse line overexpressing this pseudogene. By a mean age of 12 months, about 50% of the transgenic mice developed splenomegaly and accumulation of lymphoid cells in several body compartments. For these mice FACS and immunohistochemical analyses suggested the diagnosis of B-cell lymphoma that was further supported by clonality analyses and RNA expression profile of the pathological tissues of the HMGA1P7 transgenic tissues. Therefore, these results clearly demonstrate the oncogenic activity of HMGA1 pseudogenes in vivo.
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http://dx.doi.org/10.1038/s41598-020-62974-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184748PMC
April 2020

Long-term abuse of a high-carbohydrate diet is as harmful as a high-fat diet for development and progression of liver injury in a mouse model of NAFLD/NASH.

Nutrition 2020 Jul - Aug;75-76:110782. Epub 2020 Mar 5.

Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Italy.

Objectives: Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease globally. It is caused by a complex network of factors, including diet. The hallmark of NAFLD is the benign accumulation of triacylglycerols, however, this condition may worsen into non-alcoholic steatohepatitis (NASH), a more severe form associated with inflammation and fibrosis. Currently, no therapies are available, and diet modifications are the only strategy. Although there is increasing evidence emerging about how an abuse of carbohydrates could be involved in the progression of liver injury, a comprehensive understanding of the damage induced by an enriched carbohydrate diet is still far from complete. The aim of this study was to investigate and compare the effects of a low-fat/high-carbohydrate diet (LF-HCD) with high-fat (HFD) and standard (SD) diets in a nutritional mouse model of NAFLD/NASH.

Methods: Histologic, real-time polymerase chain reaction, and immunohistochemical evaluations were performed.

Results: The results showed that the prolonged abuse of both LF-HCDs and HFDs induced a significant increase in hepatic steatosis, inflammation, and fibrosis scores compared with SD. At the same time, both LF-HCDs and HFDs led to significant increases in the expression of the molecules involved in the progression of NAFLD that we assessed (perilipin, CD68, TGF-β1, CTGF, leptin, leptin receptor, and α-SMA).

Conclusions: The present study highlighted that the simple substitution of fats with carbohydrates is not a proper strategy to prevent or mitigate the progression of NAFLD/NASH. Further studies are required to define the best nutritional strategy to prevent NAFLD and its related metabolic syndrome.
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http://dx.doi.org/10.1016/j.nut.2020.110782DOI Listing
June 2021
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