Publications by authors named "Maurizio Mattei"

65 Publications

Extensive Histopathological Characterization of Inflamed Bowel in the Dextran Sulfate Sodium Mouse Model with Emphasis on Clinically Relevant Biomarkers and Targets for Drug Development.

Int J Mol Sci 2021 Feb 18;22(4). Epub 2021 Feb 18.

Department of Experimental Medicine, University "Tor Vergata", via Montpellier 1, 00133 Rome, Italy.

This study aims to develop a reliable and reproducible inflammatory bowel disease (IBD) murine model based on a careful spatial-temporal histological characterization. Secondary aims included extensive preclinical studies focused on the in situ expression of clinically relevant biomarkers and targets involved in IBD. C57BL/6 female mice were used to establish the IBD model. Colitis was induced by the oral administration of 2% Dextran Sulfate Sodium (DSS) for 5 days, followed by 2, 4 or 9 days of water. Histological analysis was performed by sectioning the whole colon into rings of 5 mm each. Immunohistochemical analyses were performed for molecular targets of interest for monitoring disease activity, treatment response and predicting outcome. Data reported here allowed us to develop an original scoring method useful as a tool for the histological assessment of preclinical models of DSS-induced IBD. Immunohistochemical data showed a significant increase in TNF-α, α4β7, VEGFRII, GR-1, CD25, CD3 and IL-12p40 expression in DSS mice if compared to controls. No difference was observed for IL-17, IL-23R, IL-36R or F480. Knowledge of the spatial-temporal pattern distribution of the pathological lesions of a well-characterized disease model lays the foundation for the study of the tissue expression of meaningful predictive biomarkers, thereby improving translational success rates of preclinical studies for a personalized management of IBD patients.
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http://dx.doi.org/10.3390/ijms22042028DOI Listing
February 2021

PGE2 released by pancreatic cancer cells undergoing ER stress transfers the stress to DCs impairing their immune function.

Mol Cancer Ther 2021 Feb 25. Epub 2021 Feb 25.

Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata.

This study shows that pancreatic cancer cells undergoing cell death by Valproic Acid (VPA) treatment activated DCs more efficiently than those treated with Trichostatin A (TSA), as demonstrated by CD86 and CD80 surface expression. Surprisingly though, DCs cultured in the presence of supernatant derived from VPA-treated cancer cells showed a reduced allostimulatory capacity and an increased release of IL-10 and IL-8 cytokines in comparison to those exposed to TSA-treated cells culture supernatant. Searching for molecular mechanisms leading to such differences, we found that VPA treatment dysregulated choline metabolism and triggered a stronger ER stress in pancreatic cancer cells than TSA, up-regulating CHOP, and activated COX2, thus promoting the release of prostaglandin (PG) E2. Interestingly, dysfunctional DCs cultured in the presence of VPA-treated cells culture supernatant showed a higher level of intracellular ROS, 4-HNE protein adducts and ER stress, as evidenced by the up-regulation of spliced XBP1 (XBP1s), effects that were reduced when DCs were exposed to supernatant of cancer cells treated with Celecoxib before VPA. Celecoxib indeed prevented PGE2 release, restoring the function of DCs exposed to VPA-treated cells culture supernatant and a similar effect was obtained by silencing XBP1s in DCs treated with VPA-treated cells culture supernatant. These results suggest that PGE2 could be one of the yet unidentified factors able to transfer the stress from cancer cells to DCs, resulting in an impairment of their function.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0699DOI Listing
February 2021

The Salt Tolerance Related Protein (STRP) Mediates Cold Stress Responses and Abscisic Acid Signalling in .

Front Plant Sci 2020 13;11:1251. Epub 2020 Aug 13.

Department of Biology, University of Rome Tor Vergata, Rome, Italy.

Low temperature stress is one of the major causes of crop yield reduction in agriculture. The alteration of gene expression pattern and the accumulation of stress-related proteins are the main strategies activated by plants under this unfavourable condition. Here we characterize the Salt Tolerance Related Protein (STRP). The protein rapidly accumulates under cold treatment, and this effect is not dependent on transcriptional activation of the gene, but on the inhibition of proteasome-mediated degradation. Subcellular localization of STRP was determined by the transient expression of in protoplasts. STRP is localized into the cytosol, nucleus, and associated to the plasma membrane. Under cold stress, the membrane-associated fraction decreases, while in the cytosol and in the nucleus STRP levels strongly increase. STRP has high similarity with WCI16, a wheat Late Embryogenesis Abundant (LEA)-like protein. Despite no canonical LEA motifs in the STRP sequence are present, physicochemical characterization demonstrated that STRP shares common features with LEA proteins, being a high hydrophilic unstructured protein, highly soluble after boiling and with cryoprotectant activity. To clarify the physiological function of STRP, we characterized the phenotype and the response to low temperature stress of the knockout mutant. The mutation causes an equal impairment of plant growth and development both in physiological and cold stress conditions. The mutant is more susceptible to oxidative damage respect to the , showing increased lipid peroxidation and altered membrane integrity. Furthermore, the analysis of Abscisic acid (ABA) effects on protein levels demonstrated that the hormone induces the increase of STRP levels, an effect in part ascribable to its ability to activate expression. ABA treatments showed that the mutant displays an ABA hyposensitive phenotype in terms of seed germination, root development, stomata closure and in the expression of ABA-responsive genes. In conclusion, our results demonstrate that STRP acts as a multifunctional protein in the response mechanisms to low temperature, suggesting a crucial role for this protein in stress perception and in the translation of extracellular stimuli in an intracellular response.
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http://dx.doi.org/10.3389/fpls.2020.01251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438554PMC
August 2020

Immunoprophylaxis pharmacotherapy against canine leishmaniosis: A systematic review and meta-analysis on the efficacy of vaccines approved in European Union.

Vaccine 2020 10 1;38(43):6695-6703. Epub 2020 Sep 1.

Department of Health Sciences, University of Catanzaro "Magna Graecia", Catanzaro, Italy.

Leishmania (L.) infantum is a vector-borne parasite currently endemic in several Southern countries of European Union (EU), and dogs represent the main reservoir and hosts. Data from clinical trials are inconsistent with respect to the efficacy of vaccination against L. infantum infection. Therefore, a quantitative synthesis via pairwise meta-analysis was performed in agreement with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) to increase the strength of evidence and assess the real efficacy profile of vaccines against L. infantum currently approved in EU. Data obtained from 1,394 dogs were extracted from 10 studies. The overall analysis indicated that vaccination is significantly effective in protecting against L. infantum infection (RR 0.40, 95%CI 0.23-0.72; I 70%; P < 0.01 vs. negative controls). The subset analysis performed by excluding the effect modifiers and by considering only the studies that assessed the efficacy of vaccines currently available in EU, indicated that CaniLeish® (RR 0.38, 95%CI 0.20-0.72; I 0%), but not Letifend® (RR 0.43, 95%CI 0.15-1.22; I 37%), significantly protected against L. infantum infection when compared to negative controls (P < 0.05). The number needed to treat analysis showed that 3.77 (95%CI 2.59-6.94) and 10.99 (95%CI 8.28-16.34) dogs had to be treated with CaniLeish® and Letifend®, respectively, to prevent one case of infection compared to negative controls. Vaccination is effective in protecting against the risk L. infantum infection, but further studies are needed to assess whether CaniLeish® and Letifend® are characterized by similar efficacy profile.
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http://dx.doi.org/10.1016/j.vaccine.2020.08.051DOI Listing
October 2020

Chemoenzymatic synthesis of arabinomannan (AM) glycoconjugates as potential vaccines for tuberculosis.

Eur J Med Chem 2020 Oct 15;204:112578. Epub 2020 Jul 15.

Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005, Paris, France; Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry & Chemical Engineering, Hainan Normal University, Haikou 571158, China. Electronic address:

Mycobacteria infection resulting in tuberculosis (TB) is one of the top ten leading causes of death worldwide in 2018, and lipoarabinomannan (LAM) has been confirmed to be the most important antigenic polysaccharide on the TB cell surface. In this study, a convenient synthetic method has been developed for synthesizing three branched oligosaccharides derived from LAM, in which a core building block was prepared by enzymatic hydrolysis in flow chemistry with excellent yield. After several steps of glycosylations, the obtained oligosaccharides were conjugated with recombinant human serum albumin (rHSA) and the ex-vivo ELISA tests were performed using serum obtained from several TB-infected patients, in order to evaluate the affinity of the glycoconjugate products for the human LAM-antibodies. The evaluation results are positive, especially compound 21 that exhibited excellent activity which could be considered as a lead compound for the future development of a new glycoconjugated vaccine against TB.
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http://dx.doi.org/10.1016/j.ejmech.2020.112578DOI Listing
October 2020

Theranostic Designed Near-Infrared Fluorescent Poly (Lactic-co-Glycolic Acid) Nanoparticles and Preliminary Studies with Functionalized VEGF-Nanoparticles.

J Clin Med 2020 Jun 5;9(6). Epub 2020 Jun 5.

Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, Faculty of Medicine and Psychology, "Sapienza" University of Rome, 00189 Roma, Italy.

Poly-lactic-co-glycolic acid nanoparticles (PLGA-NPs) were approved by the Food and Drug Administration (FDA) for drug delivery in cancer. The enhanced permeability and retention (EPR) effect drives their accumulation minimizing the side effects of chemotherapeutics. Our aim was to develop a new theranostic tool for cancer diagnosis and therapy based on PLGA-NPs and to evaluate the added value of vascular endothelial growth factor (VEGF) for enhanced tumor targeting. In vitro and in vivo properties of PLGA-NPs were tested and compared with VEGF-PLGA-NPs. Dynamic light scattering (DLS) was performed to evaluate the particle size, polydispersity index (PDI), and zeta potential of both preparations. Spectroscopy was used to confirm the absorption spectra in the near-infrared (NIR). In vivo, in BALB/c mice bearing a syngeneic tumor in the right thigh, intravenously injected PLGA-NPs showed a high target-to-muscle ratio (4.2 T/M at 24 h post-injection) that increased over time, with a maximum uptake at 72 h and a retention of the NPs up to 240 h. VEGF-PLGA-NPs accumulated in tumors 1.75 times more than PLGA-NPs with a tumor-to-muscle ratio of 7.90 ± 1.61 (versus 4.49 ± 0.54 of PLGA-NPs). Our study highlights the tumor-targeting potential of PLGA-NPs for diagnostic and therapeutic applications. Such NPs can be conjugated with proteins such as VEGF to increase accumulation in tumor lesions.
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http://dx.doi.org/10.3390/jcm9061750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355639PMC
June 2020

Targeting the vascular endothelial growth factor receptor-1 by the monoclonal antibody D16F7 to increase the activity of immune checkpoint inhibitors against cutaneous melanoma.

Pharmacol Res 2020 09 30;159:104957. Epub 2020 May 30.

Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy. Electronic address:

The vascular endothelial growth factor receptor-1 (VEGFR-1) is a membrane receptor for VEGF-A, placenta growth factor (PlGF) and VEGF-B that plays a crucial role in melanoma invasiveness, vasculogenic mimicry and tumor-associated angiogenesis. Furthermore, activation of VEGFR-1 is involved in the mobilization of myeloid progenitors from the bone marrow that infiltrate the tumor. Myeloid-derived suppressor cells and tumor-associated macrophages have been involved in tumor progression and resistance to cancer treatment with immune checkpoint inhibitors (ICIs). We have recently demonstrated that the anti-VEGFR-1 monoclonal antibody (mAb) D16F7 developed in our laboratories is able to inhibit melanoma growth in preclinical in vivo models and to reduce monocyte/macrophage progenitor mobilization and tumor infiltration by myeloid cells. Aim of the study was to investigate whether the anti-VEGFR-1 mAb D16F7 affects the activity of protumoral M2 macrophages in vitro in response to PlGF and inhibits the recruitment of these cells to the melanoma site in vivo. Finally, we tested whether, through its multi-targeted action, D16F7 mAb might increase the efficacy of ICIs against melanoma. The results indicated that VEGFR-1 expression is up-regulated in human activated M2 macrophages compared to activated M1 cells and exposure to the D16F7 mAb decreases in vitro chemotaxis of activated M2 macrophages. In vivo treatment with the anti-VEGFR-1 mAb D16F7 of B6D2F1 mice injected with syngeneic B16F10 melanoma cells resulted in tumor growth inhibition associated with the modification of tumor microenvironment that involves a decrease of melanoma infiltration by M2 macrophages and PD-1+ and FoxP3+ cells. These alterations result in increased M1/M2 and CD8+/FoxP3+ ratios, which favor an antitumor and immunostimulating milieu. Accordingly, D16F7 mAb increased the antitumor activity of the ICIs anti-CTLA-4 and anti-PD-1 mAbs. Overall, these data reinforce the role of VEGFR-1-mediated-signalling as a valid target for reducing tumor infiltration by protumoral macrophages and for improving the efficacy of immunotherapy with ICIs.
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http://dx.doi.org/10.1016/j.phrs.2020.104957DOI Listing
September 2020

Correction: Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue.

Cell Death Dis 2020 Mar 3;11(3):165. Epub 2020 Mar 3.

Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy.

Since online publication of this article, the authors noticed that there was a basic citation error in PubMed citation data. Specifically, the name of the author "Piergiorgio La Rosa" is cited as "Rosa P" in the PubMed citation, when it should be "La Rosa P", "La Rosa" being the surname and "Piergiorgio" the name of the author.
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http://dx.doi.org/10.1038/s41419-020-2347-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054354PMC
March 2020

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue.

Cell Death Dis 2020 01 23;11(1):51. Epub 2020 Jan 23.

Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy.

Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.
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http://dx.doi.org/10.1038/s41419-020-2253-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978516PMC
January 2020

Paternal activation of CB cannabinoid receptor impairs placental and embryonic growth via an epigenetic mechanism.

Sci Rep 2019 11 19;9(1):17034. Epub 2019 Nov 19.

Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.

The cannabinoid receptor type 2 (CB) is the peripheral receptor for cannabinoids, involved in the homeostatic control of several physiological functions. Male mitotic germ cells express a high level of CB, whose activation promotes their differentiation in both in vitro and in vivo experiments, controlling the correct progression of spermatogenesis. However, it remains elusive if CB activation in spermatogonia could affect reproductive success in terms of fertility and healthy pregnancy outcomes. In this study, we explored the effects of male CB activation on sperm number and quality and its influence on next generation health. We show that exposure of male mice to JWH-133, a selective CB agonist, decreased sperm count, impaired placental development and reduced offspring growth. These defects were associated with altered DNA methylation/hydroxymethylation levels at imprinted genes in sperm and conserved in placenta. Our findings reveal that paternal selective activation of CB alters the sperm epigenome and compromises offspring growth. This study demonstrates, for the first time, a new role of CB signaling in male gametes in causing epigenetic alterations that can be transmitted to the next generation by sperm, highlighting potential risks induced by recreational cannabinoid exposure.
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http://dx.doi.org/10.1038/s41598-019-53579-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863860PMC
November 2019

Plasma levels of CRP, neopterin and IP-10 in HIV-infected individuals with and without pulmonary tuberculosis.

J Clin Tuberc Other Mycobact Dis 2019 Aug 5;16:100107. Epub 2019 Jun 5.

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

Introduction: Tuberculosis (TB) is a major cause of morbidity and death worldwide, and disproportionally affects people with HIV. Many cases still remain undiagnosed, and rapid and effective screening strategies are needed to control the TB epidemics. Immunological biomarkers may contribute.

Methods: Plasma samples from healthy individuals (n: 12) and from HIV-infected individuals with (n: 21) and without pulmonary TB (n: 122) were tested for C-reactive protein (CRP), neopterin, and interferon-gamma-inducible protein-10 (IP-10). Increased levels of biomarkers and WHO 4-symptom-screening were compared with the presence of pulmonary TB. Survival status at 12 months was recorded. Associations with CD4 count, BMI, haemoglobin, disease severity, and mortality were analysed.

Results: The plasma levels of the biomarkers were significantly higher in TB-positive (:21) compared to TB-negative (:122) subjects. WHO symptoms, increased neopterin (>10 nmol/L) and CRP (>10 mg/L) showed similar sensitivity and different specificity, with increased CRP showing higher and increased neopterin lower specificity. The three markers were inversely correlated to haemoglobin and to CD4, and CRP levels inversely correlated to BMI. The markers were also significantly higher in individuals with subsequent mortality and in individuals with higher mycobacterial load in sputum according to Xpert results (IP-10 and CRP).

Conclusion: This study showed significant associations of the biomarkers analysed with TB infection and mortality, that could have potential clinical relevance. Biomarker levels may be included in operational research on TB screening and diagnosis.
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http://dx.doi.org/10.1016/j.jctube.2019.100107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830155PMC
August 2019

Identification of microRNAs and relative target genes in Moringa oleifera leaf and callus.

Sci Rep 2019 10 22;9(1):15145. Epub 2019 Oct 22.

Mir-Nat s.r.l., Rome, 00133, Italy.

MicroRNAs, a class of small, non-coding RNAs, play important roles in plant growth, development and stress response by negatively regulating gene expression. Moringa oleifera Lam. plant has many medical and nutritional uses; however, little attention has been dedicated to its potential for the bio production of active compounds. In this study, 431 conserved and 392 novel microRNA families were identified and 9 novel small RNA libraries constructed from leaf, and cold stress treated callus, using high-throughput sequencing technology. Based on the M. oleifera genome, the microRNA repertoire of the seed was re-evaluated. qRT-PCR analysis confirmed the expression pattern of 11 conserved microRNAs in all groups. MicroRNA159 was found to be the most abundant conserved microRNA in leaf and callus, while microRNA393 was most abundantly expressed in the seed. The majority of predicted microRNA target genes were transcriptional factors involved in plant reproduction, growth/development and abiotic/biotic stress response. In conclusion, this is the first comprehensive analysis of microRNAs in M. oleifera leaf and callus which represents an important addition to the existing M. oleifera seed microRNA database and allows for possible exploitation of plant microRNAs induced with abiotic stress, as a tool for bio-enrichment with pharmacologically important phytochemicals.
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http://dx.doi.org/10.1038/s41598-019-51100-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805943PMC
October 2019

Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts.

Commun Biol 2019 21;2:317. Epub 2019 Aug 21.

1Department of Biology, University of Rome Tor Vergata, Rome, Italy.

There is a growing interest in therapeutically targeting the inflammatory response that underlies age-related chronic diseases including obesity and type 2 diabetes. Through integrative small RNA sequencing, we show the presence of conserved plant miR159a and miR156c in dried nuts having high complementarity with the mammalian TNF receptor superfamily member 1a (Tnfrsf1a) transcript. We detected both miR159a and miR156c in exosome-like nut nanovesicles (NVs) and demonstrated that such NVs reduce Tnfrsf1a protein and dampen TNF-α signaling pathway in adipocytes. Synthetic single-stranded microRNAs (ss-miRs) modified with 2'--methyl group function as miR mimics. In plants, this modification naturally occurs on nearly all small RNAs. 2'--methylated ss-miR mimics for miR156c and miR159a decreased Tnfrsf1a protein and inflammatory markers in hypertrophic as well as TNF-α-treated adipocytes and macrophages. miR156c and miR159a mimics effectively suppress inflammation in mice, highlighting a potential role of plant miR-based, single-stranded oligonucleotides in treating inflammatory-associated metabolic diseases.
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http://dx.doi.org/10.1038/s42003-019-0563-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704100PMC
April 2020

Biological acellular pericardial mesh regulated tissue integration and remodeling in a rat model of breast prosthetic implantation.

J Biomed Mater Res B Appl Biomater 2020 02 15;108(2):577-590. Epub 2019 May 15.

Anatomic Pathology, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.

The use of biological meshes has proven beneficial in surgical restriction and periprosthetic capsular contracture following breast prosthetic-reconstruction. Three different types (smooth, texturized, and polyurethane) of silicone round mini prostheses were implanted under rat skin with or without two different bovine acellular pericardial biological meshes (APMs, BioRipar, and Tutomesh). One hundred eighty-six female rats were divided into 12 groups, sacrificed after 3, 6, and 24 weeks and tissue samples investigated by histology and immunohistochemistry. Implantation of both APMs, with or without prostheses, reduced capsular α-SMA expression and CD3 inflammatory cell infiltration, increasing capillary density and cell proliferation, with some differences. In particular, Tutomesh was associated with higher peri-APM CD3 inflammation, prosthetic capsular dermal α-SMA expression and less CD31 vessels and cell proliferation compared with BioRipar. None differences were observed in tissue integration and remodeling following the APM + prostheses implantation; the different prostheses did not influence tissue remodeling. The aim of our study was to investigate if/how the use of different APMs, with peculiar intrinsic characteristics, may influence tissue integration. The structure of APMs critically influenced tissue remodeling after implantation. Further studies are needed to develop new APMs able to optimize tissue integration and neoangiogenesis minimizing periprosthetic inflammation and fibrosis.
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http://dx.doi.org/10.1002/jbm.b.34413DOI Listing
February 2020

Investigation of medicinal plants traditionally used as dietary supplements: A review on .

J Public Health Afr 2018 Dec 21;9(3):841. Epub 2018 Dec 21.

Centro di Servizi Interdipartimentale, Stazione per la Tecnologia Animale, University of Rome 'Tor Vergata', Rome, Italy.

Diet and nutrition are important factors in the promotion and maintenance of good health throughout the entire life course. A plant-based diet may be able to prevent and treat chronic diseases such as diabetes, heart disease and hypertension, obesity, chronic inflammation and cancer. Phytonutrient rich foods are found in traditional African diet which is mostly vegetarian, and most of these food plants are often used for medicinal purposes. This review focuses on a peculiar plant , called the "Miracle Tree", considered to be one of nature's healthiest and most nutritious foods. Countless studies describe the benefits of leaves, pods, seeds and flowers. Its well-documented role in prevention and treatment of chronic diseases is hypothesized here as a result of possible of cross-kingdom regulation by exogenous vegetal microRNAs and synergistic action of plant bioactive components on endogenous human microRNA regulation. The potential health impact of phytocomplexes from African dietary plants within the context of cross-kingdom and endogenous microRNA regulation on health improvement and the overall economic well-being of the continent is estimated to be enormous.
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http://dx.doi.org/10.4081/jphia.2018.841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379786PMC
December 2018

Combined ascorbic acid and T produce better healing compared to bone marrow mesenchymal stem cells in an Achilles tendon injury rat model: a proof of concept study.

J Orthop Surg Res 2019 Feb 18;14(1):54. Epub 2019 Feb 18.

U.O.C. of Immunohaematology and Transfusion Medicine, Laboratory of Stem Cells, Spirito Santo Hospital, Pescara, Italy.

Background: This pilot study aimed to ascertain whether the local application of ascorbic acid (AA), of T, and of rat (r) bone marrow mesenchymal stem cells (BMSCs), alone or in all possible combinations, promoted healing after an Achilles tendon injury in a rat model.

Methods: An Achilles tendon defect was produced in 24 6-8-week-old male inbred Lewis rats. The animals were then randomly divided into eight groups of three rats each. The tendon defect was filled with 50 μL of phosphate-buffered saline (PBS) containing (1) 50 μg/mL AA (AA group), (2) 10 M T (T group), (3) 4 × 10 rBMSCs (rBMSC group), (4) 50 μg/mL AA + 10 M T (AA + T group), (5) 4 × 10 rBMSCs + 50 μg/mL AA (rBMSC + AA group), (6) 4 × 10 rBMSCs + 10 M T (rBMSC + T group), (7) 4 × 10 rBMSCS + 50 μg/mL AA + 10 M T (rBMSC + AA + T group), and (8) PBS only (control group: CTRL). All treatments were administered by local injection immediately after the tendons had been damaged; additionally, AA was injected also on the second and fourth day from the first injection (for groups 1, 4, 5, and 7), and T was injected again every day for 4 days (for groups 2, 4, 6, and 7). At 30 days from initial treatment, tendon samples were harvested, and the quality of tendon repair was evaluated using histological and histomorphological analysis. The structure and morphology of the injured Achilles tendons were evaluated using the modified Svensson, Soslowsky, and Cook score, and the collagen type I and III ratio was calculated.

Results: The group treated with AA combined with T displayed the lowest Svensson, Soslowsky, and Cook total score value of all tissue sections at histopathological examination, with fiber structure close to regular orientation, normal-like tendon vasculature, and no cartilage formation. AA + T also showed the highest collagen I and the lowest collagen III values compared to all other treatments including the CTRL.

Conclusion: There are potential benefits using a combination of AA and T to accelerate tendon healing.
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http://dx.doi.org/10.1186/s13018-019-1098-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380036PMC
February 2019

The impact of ionizing irradiation on liver detoxifying enzymes. A re-investigation.

Cell Death Discov 2019 8;5:66. Epub 2019 Feb 8.

1Department of Chemical Sciences and Technologies, University of Rome "Tor Vergata", Rome, Italy.

By looking at many studies describing the impact of ionizing irradiations in living mice on a few key detoxifying enzymes like catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione transferase, we noted conflicting evidences: almost all papers finalized to demonstrate the protective effects of natural or synthetic drugs against the damage by irradiations, described also a relevant inactivation of these enzymes in the absence of these compounds. Conversely, no inactivation and even enhanced activity has been noted under similar irradiation modality in all studies supporting the "adaptive response". Motivated by these curious discrepancies, we performed irradiation experiments on living mice, explanted mouse livers and liver homogenates observing that, in all conditions the activity of all these enzymes remained almost unchanged except for a slight increase found in explanted livers. Our results put a question about many previous scientific reports in this field.
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http://dx.doi.org/10.1038/s41420-019-0148-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368569PMC
February 2019

Electrochemically Reduced Water Delays Mammary Tumors Growth in Mice and Inhibits Breast Cancer Cells Survival .

Evid Based Complement Alternat Med 2018 26;2018:4753507. Epub 2018 Sep 26.

Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

Electrochemical reduced water (ERW) has been proposed to have beneficial effects on human health due to its rich content of H and the presence of platinum nanoparticles with antioxidant effects. Many studies have demonstrated that ERW scavenging properties are able to reduce the damage caused by oxidative stress in different experimental models. Although few studies have been reported, it has been demonstrated that ERW may display anticancer effects by induction of tumor cells apoptosis and reduction of both angiogenesis and inflammation. In this study, we show that ERW treatment of MCF-7, MDA-MB-453, and mouse (TUBO) breast cancer cells inhibited cell survival in a time-dependent fashion. ERW decreased ErbB2/ expression and impaired pERK1/ERK2 and AKT phosphorylation in breast cancer cells. In addition, ERW treatment induced apoptosis of breast cancer cell lines independently of the status of p53 and ER and PR receptors. Our results showed that ERW treatment of transgenic BALB-T mice delayed the development of mammary tumors compared to the control. In addition, ERW induced a significant prolongation of tumor-free survival and a reduction in tumor multiplicity. Overall, these results suggest a potential beneficial role of ERW in inhibiting cancer cells growth.
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http://dx.doi.org/10.1155/2018/4753507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196883PMC
September 2018

Ecto-Calreticulin is essential for an efficient immunogenic cell death stimulation in mouse melanoma.

Genes Immun 2019 07 4;20(6):509-513. Epub 2018 Oct 4.

Department of Health Science (DISS), University of 'Piemonte Orientale', Novara, Italy.

Skin melanoma remains one of the most aggressive and difficult to treat human malignancy, with an increasing incidence every year. Although surgical resection represents the best therapeutic approach, this is only feasible in cases of early diagnosis. Furthermore, the established malignancy is resistant to all therapeutic strategies employed so far, resulting in an unacceptable patient survival rate. Although the immune-mediated therapeutic approaches, based on anti-PD1 or anti-CTLA4, are very promising and under clinical trial experimentation, they could conceal not yet fully emerged pitfalls such as the development of autoimmune diseases. Therefore, alternative therapeutic approaches are still under investigation, such as the immunogenic cell death (ICD) process. Here we show that the lack of calreticulin translocation onto mouse melanoma cell membrane prevents the stimulation of an effective ICD response in vivo.
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http://dx.doi.org/10.1038/s41435-018-0047-7DOI Listing
July 2019

The RNA binding protein Sam68 controls T helper 1 differentiation and anti-mycobacterial response through modulation of miR-29.

Cell Death Differ 2019 06 26;26(6):1169-1180. Epub 2018 Sep 26.

Laboratory of Neuroembriology, Fondazione Santa Lucia, Rome, Italy.

Polarization of naive T cells into interferon (IFN)-γ-producing T helper 1 (Th1) cells is an essential event in the inflammatory response to pathogens. Herein, we identify the RNA binding protein Sam68 as a specific modulator of Th1 differentiation. Sam68-knockout (ko) naive T cells are strongly defective in IL-12-mediated Th1 polarization and express low levels of T-bet and Eomes. Consequently, Sam68-ko Th1 cells are significantly impaired in IFN-γ production. Moreover, we found that Sam68 is required for the induction of an inflammatory Th1 response during Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection, thus limiting bacterial dissemination in the lungs. Mechanistically, Sam68 directly binds to the microRNA miR-29, a negative regulator of Th1 response, and inhibits its expression during BCG infection. These findings uncover a novel post-transcriptional mechanism required for the Th1-mediated defense against intracellular pathogens and identify a new function for Sam68 in the regulation of the immune response.
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http://dx.doi.org/10.1038/s41418-018-0201-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748099PMC
June 2019

biological fate of poly(vinylalcohol) microbubbles in mice.

Heliyon 2018 Sep 17;4(9):e00770. Epub 2018 Sep 17.

Dipartimento di Scienze e Tecnologie Chimiche, Università degli Studi di Roma "Tor Vergata", via della Ricerca Scientifica 1, 00133 Rome, Italy.

Microbubbles (MBs) are used in clinical practice as vascular ultrasound contrast agents, and are gaining popularity as a platform supporting multimodal imaging and targeted therapy, facilitating drug delivery under ultrasound exposure. Here, we report on the biological impact of newly discovered MBs with promising features as a multimodal theranostic device. The shell of the air-filled MBs is made of the poly(vinyl alcohol) (PVA), a well-established, FDA-approved polymer. Nevertheless, as size, shape and dispersity can significantly impact the biological response of particulate systems, studying their fate after administration is crucial. The safety and the biodistribution of PVA MBs were analysed and by coupling a near infrared (NIR) fluorophore on their shell: MBs accumulated mainly in liver and spleen at 24 hours post-injection with their clearance from the spleen 7 days post-dosing. A possible way of elimination was identified in macrophages ability to engulf MBs both and . One month post-dosing, transmission electron microscopy (TEM) highlighted the lack of relevant defects and the elimination of PVA MBs by Kupffer cells. This study is the first successful attempt to fill the lack of knowledge necessary to bring PVA MBs one step closer to their possible clinical use.
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http://dx.doi.org/10.1016/j.heliyon.2018.e00770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143702PMC
September 2018

PKR and GCN2 stress kinases promote an ER stress-independent eIF2α phosphorylation responsible for calreticulin exposure in melanoma cells.

Oncoimmunology 2018;7(8):e1466765. Epub 2018 May 31.

Department of Epidemiology, National Institute for Infectious Diseases 'L. Spallanzani', Rome, Italy.

The immunogenic cell death (ICD) process represents a novel therapeutic approach to treat tumours, in which cytotoxic compounds promote both cancer cell death and the emission of damage-associated molecular patterns (DAMPs) from dying cells, to activate the immune system against the malignancy. Therefore, we explored the possibility to stimulate the key molecular players with a pivotal role in the execution of the ICD program in melanoma cells. To this aim, we used the pro-ICD agents mitoxantrone and doxorubicin and found that both agents could induce cell death and stimulate the release/exposure of the strictly required DAMPs in melanoma cells: i) calreticulin (CRT) exposure on the cell membrane; ii) ATP secretion; iii) type I IFNs gene up-regulation and iv) HMGB1 secretion, highlighting no interference by oncogenic BRAF. Importantly, although the ER stress-related PERK activation has been linked to CRT externalization, through the phosphorylation of eIF2α, we found that this stress pathway together with PERK were not involved in melanoma cells. Notably, we identified PKR and GCN2 as key mediators of eIF2α phosphorylation, facilitating the translocation of CTR on melanoma cells surface, under pro-ICD drugs stimulation. Therefore, our data indicate that pro-ICD drugs are able to stimulate the production/release of DAMPs in melanoma cells at least in vitro, indicating in this approach a potential new valuable therapeutic strategy to treat human skin melanoma malignancy.
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http://dx.doi.org/10.1080/2162402X.2018.1466765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136861PMC
May 2018

Correction: LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse.

Cell Death Differ 2019 Mar;26(4):779

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

Following publication of their article, the authors reported that the name of the fifth author had been formatted incorrectly in PubMed. Instead of "Rella FD" it should be "Di Rella F".
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http://dx.doi.org/10.1038/s41418-018-0174-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460382PMC
March 2019

Olea europaea small RNA with functional homology to human miR34a in cross-kingdom interaction of anti-tumoral response.

Sci Rep 2018 08 17;8(1):12413. Epub 2018 Aug 17.

Department of Biology, University of Rome "Tor Vergata", Rome, Italy.

Functional foods include compounds with nutritional and health properties. The human diet could play a stronger role in cancer prevention. Only a few studies have described the presence of plant small RNA, in humans who were fed with plant foods, which demonstrated the ability of these molecules to modulate consumer's genes and evidenced the existence of a plant-animal regulation. Through in silico prediction, Olea europaea small RNAs (sRs), which had been previously reported as miRNAs, were identified, each with functional homology to hsa-miR34a. According to this initial funding, we investigated the ability of oeu-sRs to regulate tumorigenesis in human cells. The transfection of these synthetic oeu-sRs reduced the protein expression of hsa-miR34a mRNA targets, increased apoptosis and decreased proliferation in different tumor cells; by contrast, no effect was observed in PBMCs from healthy donors. The introduction of oeu-small RNA in hsa-miR34a-deficient tumor cells restores its function, whereas cells with normal expression of endogenous hsa-miR34a remained unaffected. The natural oeu-small RNAs that were extracted from O. europaea drupes induce the same effects as synthetic sRs. Careful research on the small RNA sequences executed for mapping and annotation in the genome of O. europaea var. Sylvestris and var. Farga led to the hypothesis that RNA fragments with functional homology to human miRNAs could be generated from the degradation of regions of RNA transcripts. These results indicate the possibility of developing novel natural non-toxic drugs that contain active plant-derived tumor-suppressing small RNA with functional homology to hsa-miRNAs and that can support antineoplastic strategies.
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http://dx.doi.org/10.1038/s41598-018-30718-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098056PMC
August 2018

Seroprevalence of Ebola virus infection in Bombali District, Sierra Leone.

J Public Health Afr 2017 Dec 31;8(2):732. Epub 2017 Dec 31.

University of Makeni, Makeni, Sierra Leone.

A serosurvey of anti-Ebola Zaire virus nucleoprotein IgG prevalence was carried out among Ebola virus disease survivors and their Community Contacts in Bombali District, Sierra Leone. Our data suggest that the specie of Ebola virus () responsible of the 2013-2016 epidemic in West Africa may cause mild or asymptomatic infection in a proportion of cases, possibly due to an efficient immune response.
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http://dx.doi.org/10.4081/jphia.2017.732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812302PMC
December 2017

Effect of lipopolysaccharide on the responsiveness of equine bronchial tissue.

Pulm Pharmacol Ther 2018 04 31;49:88-94. Epub 2018 Jan 31.

Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.

Recurrent airway obstruction (RAO) is a main characteristic of horses with severe equine asthma syndrome. The presence of bacterial lipopolysaccharide (LPS) in the airways of horses is thought to play a crucial role in the clinical expression of this disorder. This study pharmacologically characterized the effect of LPS on the responsiveness of equine bronchial tissue. Equine isolated bronchi were incubated overnight with LPS (0.1-100 ng/ml) and then stimulated by electrical field stimulation (EFS). The role of capsaicin sensitive-sensory nerves (capsaicin desensitization treatment), neurokinin-2 (NK) receptors (blocked by GR159897), transient receptor potential vanilloid type 1 receptors (TRPV1; blocked by SB366791), and neurokinin A (NKA) were investigated. Untreated bronchi were used as control tissues. LPS (1 ng/ml) significantly increased the EFS-evoked contractility of equine bronchi compared with control tissues (+742 ± 123 mg; P < 0.001). At higher concentrations LPS induced desensitization to airways hyperresponsiveness (AHR; EC: 5.9 ± 2.6 ng/ml). Capsaicin desensitization and GR159897 significantly prevented AHR induced by LPS at EFS (-197 ± 25%; P < 0.01). SB366791 inhibited AHR at very low EFS frequency (EFS -193 ± 29%; P < 0.01 vs. LPS-treated bronchi). LPS (1 ng/ml) significantly (P < 0.01) increased 3.7 ± 0.7 fold the release of NKA compared with control bronchi. LPS induces biphasic dysfunctional bronchial contractility due to the stimulation of capsaicin sensitive-sensory nerves, increased release of NKA, and activation of NK receptors, whereas TRPV1 receptors appear to play a marginal role in this response. The overnight challenge with low concentrations of LPS represents a suitable model to investigate pharmacological options that may be of value in the treatment of equine RAO.
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http://dx.doi.org/10.1016/j.pupt.2018.01.010DOI Listing
April 2018

Characterization of a new decellularized bovine pericardial biological mesh: Structural and mechanical properties.

J Mech Behav Biomed Mater 2018 02 5;78:420-426. Epub 2017 Dec 5.

Institute of Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.

Implants made from naturally-derived biomaterials, also called biological meshes or biomeshes, typically derive from decellularized extracellular matrix of either animal or human tissue. Biomeshes have many biomedical applications such as ligament repair, bone and cartilage regeneration and soft tissue replacement. Bovine collagen is one of the most widely used and abundantly available xenogenic materials. In particular, bovine pericardium is widely used as extracellular matrix bioprosthetic tissue. The efficiency of a pericardial mesh to function as scaffold depends on the quality of the decellularization protocol used. Moreover, the biomesh mechanical features are critical for a successful surgical repair process, as they must reproduce the biological properties of the autologous tissue. Different methods of physical, chemical, or enzymatic decellularization exist, but no one has proved to be ideal. Therefore, in the present study, we developed a novel decellularization protocol for a bovine pericardium-derived biomesh. We characterized the biomesh obtained by comparing some ultrastructural, physical and mechanical features to a reference commercial biomesh. Quantification revealed that our novel decellularization process removed about 90% of the native pericardial DNA. Microscopic and ultrastructural analysis documented the maintenance of the physiological structure of the pericardial collagen. Moreover, mechanical tests showed that both the extension and resilience of the new biomesh were statistically higher than the commercial control ones. The results presented in this study demonstrate that our protocol is promising in preparing high quality bovine pericardial biomeshes, encouraging further studies to validate its use in tissue engineering and regenerative medicine protocols.
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http://dx.doi.org/10.1016/j.jmbbm.2017.12.003DOI Listing
February 2018

Pharmacological characterization of the interaction between tiotropium and olodaterol administered at 5:5 concentration-ratio in equine bronchi.

COPD 2017 Oct 26;14(5):526-532. Epub 2017 Jul 26.

f Department of Experimental Medicine , University of Campania Luigi Vanvitelli , Naples , Italy.

Equine airways represent a suitable ex vivo model to study the functional impact of pharmacological treatments on human chronic obstructive pulmonary disorders, such as asthma and chronic obstructive pulmonary disease (COPD). We aimed to characterize the pharmacological interaction between the long-acting muscarinic antagonist (LAMA) tiotropium and the long-acting β-agonist (LABA) olodaterol in equine airways. The effect of tiotropium and olodaterol, administered alone and in combination at the ratio of concentrations reproducing ex vivo the concentration-ratio delivered by the currently available fixed-dose combination (FDC) (5:5), was investigated on the cholinergic contractile tone induced by the parasympathetic activation of equine isolated airways. The drug interaction was analysed by using the Bliss Independence and Unified Theory models. Both tiotropium and olodaterol induced a sub-maximal concentration-dependent inhibition of bronchial contractility (E: tiotropium 83.6 ± 14.8%, olodaterol 76.9 ± 17.9%; pEC: tiotropium 8.2 ± 0.5; olodaterol 8.3 ± 0.6). When administered at 5:5 concentration-ratio, tiotropium plus olodaterol completely inhibited the bronchial contractility (E 102.7 ± 8.4%; pEC 9.0 ± 0.7). Strong synergistic interaction was detected for tiotropium/olodaterol combination (combination index 0.011). When administered at low concentrations, the drug mixture elicited up to 94.6 ± 9.5% effect that was 36.0 ± 8.1% greater than the expected additive effect. The results of this study demonstrate that the co-administration of tiotropium plus olodaterol at 5:5 concentration-ratio leads to synergistic inhibition of equine bronchial contractility when compared with either drug administered alone. These findings suggest that the currently available LABA/LABA FDC may be effective in delivering tiotropium/olodaterol combination at equipotency concentrations of each monocomponent into the lung and, thus, inducing synergistic effect in the airways.
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http://dx.doi.org/10.1080/15412555.2017.1344627DOI Listing
October 2017