Publications by authors named "Simona Dinicola"

35 Publications

Altered Ovarian Inositol Ratios May Account for Pathological Steroidogenesis in PCOS.

Int J Mol Sci 2020 Sep 28;21(19). Epub 2020 Sep 28.

Department of Experimental Medicine, Sapienza University of Rome, Systems Biology Group Lab, 00161 Rome, Italy.

The presence of abnormal ovarian ratios of myo-inositol (MI) to D-chiro-inositol (DCI) is a recurrent feature in PCOS. Available evidence suggests that MI and DCI may modulate steroid biosynthesis, likely in an opposite manner. Specifically, MI seems to induce estrogen production, while DCI has a role in the synthesis of androgens. Elevated insulin levels, generally associated with PCOS, alter the physiological MI/DCI ratio, increasing MI-to-DCI conversion through activation of a specific epimerase enzyme. DCI directly increases testosterone biosynthesis in thecal cells and reduces its conversion to estradiol by downregulating aromatase enzyme in granulosa cells. This manuscript reviews the literature that supports the connection between altered MI/DCI ratios and pathological steroidogenesis observed in PCOS women. Furthermore, it discusses the application of inositol-based treatment protocols in managing PCOS symptoms and improving the quality of patients' life.
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http://dx.doi.org/10.3390/ijms21197157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582282PMC
September 2020

c-Src Recruitment is Involved in c-MET-Mediated Malignant Behaviour of NT2D1 Non-Seminoma Cells.

Int J Mol Sci 2019 Jan 14;20(2). Epub 2019 Jan 14.

Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, "Sapienza" University of Rome, 00161 Rome, Italy.

c-MET pathway over-activation is the signature of malignancy acquisition or chemotherapy resistance of many cancers. We recently demonstrated that type II Testicular Germ Cell Tumours (TGCTs) express c-MET receptor. In particular, we elucidated that the non-seminoma lesions express c-MET protein at higher level, compared with the seminoma ones. In line with this observation, NTERA-2 clone D1 (NT2D1) non-seminoma cells increase their proliferation, migration and invasion in response to Hepatocyte Growth Factor (HGF). One of the well-known adaptor-proteins belonging to c-MET signaling cascade is c-Src. Activation of c-Src is related to the increase of aggressiveness of many cancers. For this reason, we focused on the role of c-Src in c-MET-triggered and HGF-dependent NT2D1 cell activities. In the present paper, we have elucidated that this adaptor-protein is involved in HGF-dependent NT2D1 cell proliferation, migration and invasion, since Src inhibitor-1 administration abrogates these responses. Despite these biological evidences western blot analyses have not revealed the increase of c-Src activation because of HGF administration. However, notably, immunofluorescence analyses revealed that cytoplasmic and membrane-associated localization of c-Src shifted to the nuclear compartment after HGF stimulation. These results shed new light in the modality of HGF-dependent c-Src recruitment, and put the basis for novel investigations on the relationship between c-Src, and TGCT aggressiveness.
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http://dx.doi.org/10.3390/ijms20020320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358843PMC
January 2019

Increase in motility and invasiveness of MCF7 cancer cells induced by nicotine is abolished by melatonin through inhibition of ERK phosphorylation.

J Pineal Res 2018 May 8;64(4):e12467. Epub 2018 Mar 8.

Systems Biology Group, Rome, Italy.

Through activation of the ERK pathway, nicotine, in both normal MCF-10A and low-malignant breast cancer cells (MCF7), promotes increased motility and invasiveness. Melatonin antagonizes both these effects by inhibiting almost completely ERK phosphorylation. As melatonin has no effect on nonstimulated cells, it is likely that melatonin can counteract ERK activation only downstream of nicotine-induced activation. This finding suggests that melatonin hampers ERK phosphorylation presumably by targeting a still unknown intermediate factor that connects nicotine stimulation to ERK phosphorylation. Furthermore, downstream of ERK activation, melatonin significantly reduces fascin and calpain activation while restoring normal vinculin levels. Melatonin also counteracts nicotine effects by reshaping the overall cytoskeleton architecture and abolishing invasive membrane protrusion. In addition, melatonin decreases nicotine-dependent ROCK1/ROCK2 activation, thus further inhibiting cell contractility and motility. Melatonin actions are most likely attributable to ERK inhibition, although melatonin could display other ERK-independent effects, namely through a direct modulation of additional molecular and structural factors, including coronin, cofilin, and cytoskeleton components.
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http://dx.doi.org/10.1111/jpi.12467DOI Listing
May 2018

Nicotine increases colon cancer cell migration and invasion through epithelial to mesenchymal transition (EMT): COX-2 involvement.

J Cell Physiol 2018 06 15;233(6):4935-4948. Epub 2018 Jan 15.

Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy.

Cigarette smoking is a recognized risk factor for colon cancer and nicotine, the principal active component of tobacco, plays a pivotal role in increasing colon cancer cell growth and survival. The aim of this study was to determine the effect of nicotine on cellular Caco-2 and HCT-8 migration and invasion, focusing on epithelial to mesenchymal transition (EMT) induction, and COX-2 pathway involvement. In both these cell lines, treatment with nicotine increased COX-2 expression and the release of its enzymatic product PGE . Moreover, nicotine-stimulated cells showed increased migratory and invasive behavior, mesenchymal markers up-regulation and epithelial markers down-regulation, nuclear translocation of the β-catenin, increase of MMP-2 and MMP-9 activity, and enhanced NF-κB expression. Noticeably, all these effects are largely mediated by COX-2 activity, as simultaneous treatment of both cell lines with nicotine and NS-398, a selective COX-2 inhibitor, greatly reduced the number of migrating and invading cells and reverted nicotine-induced EMT. These findings emphasize that nicotine triggers EMT, leading hence to increased migration and invasiveness of colon cancer cells. Thereby, the use of COX-2 inhibitor drugs might likely counteract nicotine-mediated EMT effects on colon cancer development and progression.
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http://dx.doi.org/10.1002/jcp.26323DOI Listing
June 2018

Systems Biology Approach and Mathematical Modeling for Analyzing Phase-Space Switch During Epithelial-Mesenchymal Transition.

Methods Mol Biol 2018 ;1702:95-123

Department of Experimental Medicine, Systems Biology Group Lab, Sapienza University of Rome, Rome, Italy.

In this report, we aim at presenting a viable strategy for the study of Epithelial-Mesenchymal Transition (EMT) and its opposite Mesenchymal-Epithelial Transition (MET) by means of a Systems Biology approach combined with a suitable Mathematical Modeling analysis. Precisely, it is shown how the presence of a metastable state, that is identified at a mesoscopic level of description, is crucial for making possible the appearance of a phase transition mechanism in the framework of fast-slow dynamics for Ordinary Differential Equations (ODEs).
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http://dx.doi.org/10.1007/978-1-4939-7456-6_7DOI Listing
July 2018

Nutritional and Acquired Deficiencies in Inositol Bioavailability. Correlations with Metabolic Disorders.

Int J Mol Sci 2017 Oct 20;18(10). Epub 2017 Oct 20.

Department of Experimental Medicine, Systems Biology Group, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy.

Communities eating a western-like diet, rich in fat, sugar and significantly deprived of fibers, share a relevant increased risk of both metabolic and cancerous diseases. Even more remarkable is that a low-fiber diet lacks some key components-as phytates and inositols-for which a mechanistic link has been clearly established in the pathogenesis of both cancer and metabolic illness. Reduced bioavailability of inositol in living organisms could arise from reduced food supply or from metabolism deregulation. Inositol deregulation has been found in a number of conditions mechanistically and epidemiologically associated to high-glucose diets or altered glucose metabolism. Indeed, high glucose levels hinder inositol availability by increasing its degradation and by inhibiting both myo-Ins biosynthesis and absorption. These underappreciated mechanisms may likely account for acquired, metabolic deficiency in inositol bioavailability.
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http://dx.doi.org/10.3390/ijms18102187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666868PMC
October 2017

Alpha-Lipoic Acid Downregulates IL-1β and IL-6 by DNA Hypermethylation in SK-N-BE Neuroblastoma Cells.

Antioxidants (Basel) 2017 Sep 26;6(4). Epub 2017 Sep 26.

Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via Antonio Scarpa 16, 00161 Rome, Italy.

Alpha-lipoic acid (ALA) is a pleiotropic molecule with antioxidant and anti-inflammatory properties, of which the effects are exerted through the modulation of NF-kB. This nuclear factor, in fact, modulates different inflammatory cytokines, including IL-1b and IL-6, in different tissues and cell types. We recently showed that IL-1b and IL-6 DNA methylation is modulated in the brain of Alzheimer's disease patients, and that IL-1b expression is associated to DNA methylation in the brain of patients with tuberous sclerosis complex. These results prompted us to ask whether ALA-induced repression of IL-1b and IL-6 was dependent on DNA methylation. Therefore, we profiled DNA methylation in the 5'-flanking region of the two aforementioned genes in SK-N-BE human neuroblastoma cells cultured in presence of ALA 0.5 mM. Our experimental data pointed out that the two promoters are hypermethylated in cells supplemented with ALA, both at CpG and non-CpG sites. Moreover, the observed hypermethylation is associated with decreased mRNA expression and decreased cytokine release. These results reinforce previous findings indicating that IL-1b and IL-6 undergo DNA methylation-dependent modulation in neural models and pave the road to study the epigenetic mechanisms triggered by ALA.
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http://dx.doi.org/10.3390/antiox6040074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745484PMC
September 2017

Modulation of both Insulin Resistance and Cancer Growth by Inositol.

Curr Pharm Des 2017 ;23(34):5200-5210

Department of Surgery "Pietro Valdoni", Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy.

Insulin resistance indicates a deregulated set of biochemical pathways and physiological functions involved in the pathogenesis of a number of diseases, including type 2 diabetes and cancer. Conversely, a number of synthetic and natural insulin sensitizers, including inositol, have been recognized to exert both anti-diabetic as well as anti-cancer properties. Inositol participates in insulin transduction signaling, and deregulated inositol metabolism has been ascertained in several conditions associated with insulin resistance. Two distinct inositolphosphoglycans released upon insulin stimulation act as insulin-mimetic by counteracting hyperinsulinemia, hyperglycemia and their metabolic complications. Additionally, inositol may directly interfere with both glucose metabolism and carcinogenesis by modulating a number of critical processes downstream of insulin stimulation, including anti-oxidant defenses, oxidative glucose metabolism and endocrine modulation. A selected cluster of biochemical factors (PI3K/Akt, PDH and AMPK-related pathways), that are presently considered putative targets for anticancer treatments, are also specifically modulated by inositol or its derivatives. What is more, studies on inositol mechanism of action paved the way in understanding that both insulin resistance and cancer share a few perturbed, critical biochemical pathways. Asides from the basic investigations, preliminary studies in vivo demonstrated the beneficial effect of inositol in fostering glucose homeostasis as well as in antagonizing cancer growth. Thereby, inositol fulfills the requirement to target both insulin resistance and cancer, and its clinical usefulness deserves to be adequately addressed by specific, randomized trials.
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http://dx.doi.org/10.2174/1381612823666170830123634DOI Listing
April 2019

Simulated microgravity triggers epithelial mesenchymal transition in human keratinocytes.

Sci Rep 2017 04 3;7(1):538. Epub 2017 Apr 3.

Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.

The microgravitational environment is known to affect the cellular behaviour inducing modulation of gene expression and enzymatic activities, epigenetic modifications and alterations of the structural organization. Simulated microgravity, obtained in the laboratory setting through the use of a Random Positioning Machine (RPM), represents a well recognized and useful tool for the experimental studies of the cellular adaptations and molecular changes in response to weightlessness. Short exposure of cultured human keratinocytes to the RPM microgravity influences the cellular circadian clock oscillation. Therefore, here we searched for changes on the regenerative ability and response to tissue damage of human epidermal cells through the analysis of the effects of the simulated microgravity on the re-epithelialization phase of the repair and wound healing process. Combining morphological, biochemical and molecular approaches, we found that the simulated microgravity exposure of human keratinocytes promotes a migratory behavior and triggers the epithelial-mesenchymal transition (EMT) through expression of the typical EMT transcription factors and markers, such as Snail1, Snail2 and ZEB2, metalloproteases, mesenchymal adhesion molecules and cytoskeletal components.
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http://dx.doi.org/10.1038/s41598-017-00602-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428850PMC
April 2017

Broad Spectrum Anticancer Activity of Myo-Inositol and Inositol Hexakisphosphate.

Int J Endocrinol 2016 4;2016:5616807. Epub 2016 Oct 4.

Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy; Azienda Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy.

Inositols (myo-inositol and inositol hexakisphosphate) exert a wide range of critical activities in both physiological and pathological settings. Deregulated inositol metabolism has been recorded in a number of diseases, including cancer, where inositol modulates different critical pathways. Inositols inhibit pRB phosphorylation, fostering the pRB/E2F complexes formation and blocking progression along the cell cycle. Inositols reduce PI3K levels, thus counteracting the activation of the PKC/RAS/ERK pathway downstream of PI3K activation. Upstream of that pathway, inositols disrupt the ligand interaction between FGF and its receptor as well as with the EGF-transduction processes involving IGF-II receptor and AP-1 complexes. Additionally, Akt activation is severely impaired upon inositol addition. Downregulation of both Akt and ERK leads consequently to NF-kB inhibition and reduced expression of inflammatory markers (COX-2 and PGE2). Remarkably, inositol-induced downregulation of presenilin-1 interferes with the epithelial-mesenchymal transition and reduces Wnt-activation, -catenin translocation, Notch-1, N-cadherin, and SNAI1 release. Inositols interfere also with the cytoskeleton by upregulating Focal Adhesion Kinase and E-cadherin and decreasing Fascin and Cofilin, two main components of pseudopodia, leading hence to invasiveness impairment. This effect is reinforced by the inositol-induced inhibition on metalloproteinases and ROCK1/2 release. Overall, these effects enable inositols to remodel the cytoskeleton architecture.
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http://dx.doi.org/10.1155/2016/5616807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067332PMC
October 2016

Pharmacodynamics and pharmacokinetics of inositol(s) in health and disease.

Expert Opin Drug Metab Toxicol 2016 Oct 14;12(10):1181-96. Epub 2016 Jul 14.

g Department of Psychology, Section of Neuroscience , Sapienza University of Rome , Rome , Italy.

Introduction: Inositol and its derivatives comprise a huge field of biology. Myo-inositol is not only a prominent component of membrane-incorporated phosphatidylinositol, but participates in its free form, with its isomers or its phosphate derivatives, to a multitude of cellular processes, including ion channel permeability, metabolic homeostasis, mRNA export and translation, cytoskeleton remodeling, stress response.

Areas Covered: Bioavailability, safety, uptake and metabolism of inositol is discussed emphasizing the complexity of interconnected pathways leading to phosphoinositides, inositol phosphates and more complex molecules, like glycosyl-phosphatidylinositols.

Expert Opinion: Besides being a structural element, myo-inositol exerts unexpected functions, mostly unknown. However, several reports indicate that inositol plays a key role during phenotypic transitions and developmental phases. Furthermore, dysfunctions in the regulation of inositol metabolism have been implicated in several chronic diseases. Clinical trials using inositol in pharmacological doses provide amazing results in the management of gynecological diseases, respiratory stress syndrome, Alzheimer's disease, metabolic syndrome, and cancer, for which conventional treatments are disappointing. However, despite the widespread studies carried out to identify inositol-based effects, no comprehensive understanding of inositol-based mechanisms has been achieved. An integrated metabolomics-genomic study to identify the cellular fate of therapeutically administered myo-inositol and its genomic/enzymatic targets is urgently warranted.
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http://dx.doi.org/10.1080/17425255.2016.1206887DOI Listing
October 2016

Inositol induces mesenchymal-epithelial reversion in breast cancer cells through cytoskeleton rearrangement.

Exp Cell Res 2016 07 26;345(1):37-50. Epub 2016 May 26.

Department of Experimental Medicine, Sapienza University of Rome, Systems Biology Group Lab, viale Regina Elena 324, 00161 Rome, Italy. Electronic address:

Inositol displays multi-targeted effects on many biochemical pathways involved in epithelial-mesenchymal transition (EMT). As Akt activation is inhibited by inositol, we investigated if such effect could hamper EMT in MDA-MB-231 breast cancer cells. In cancer cells treated with pharmacological doses of inositol E-cadherin was increased, β-catenin was redistributed behind cell membrane, and metalloproteinase-9 was significantly reduced, while motility and invading capacity were severely inhibited. Those changes were associated with a significant down-regulation of PI3K/Akt activity, leading to a decrease in downstream signaling effectors: NF-kB, COX-2, and SNAI1. Inositol-mediated inhibition of PS1 leads to lowered Notch 1 release, thus contributing in decreasing SNAI1 levels. Overall, these data indicated that inositol inhibits the principal molecular pathway supporting EMT. Similar results were obtained in ZR-75, a highly metastatic breast cancer line. These findings are coupled with significant changes on cytoskeleton. Inositol slowed-down vimentin expression in cells placed behind the wound-healing edge and stabilized cortical F-actin. Moreover, lamellipodia and filopodia, two specific membrane extensions enabling cell migration and invasiveness, were no longer detectable after inositol addiction. Additionally, fascin and cofilin, two mandatory required components for F-actin assembling within cell protrusions, were highly reduced. These data suggest that inositol may induce an EMT reversion in breast cancer cells, suppressing motility and invasiveness through cytoskeleton modifications.
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http://dx.doi.org/10.1016/j.yexcr.2016.05.007DOI Listing
July 2016

Does myo-inositol effect on PCOS follicles involve cytoskeleton regulation?

Med Hypotheses 2016 Jun 4;91:1-5. Epub 2016 Apr 4.

Department of Psychology, Section of Neuroscience, Sapienza University of Rome, Via dei Marsi 78, 00185 Rome, Italy.

Inositol metabolism is severely impaired in follicles obtained from cystic ovaries, leading to deregulated insulin transduction and steroid synthesis. On the contrary, inositol administration to women suffering from polycystic ovary syndrome (PCOS) has been proven to efficiently counteract most of the clinical hallmarks displayed by PCOS patients, including insulin resistance, hyperandrogenism and oligo-amenorrhea. We have recently observed that myo-inositol induces significant changes in cytoskeletal architecture of breast cancer cells, by modulating different biochemical pathways, eventually modulating the epithelial-mesenchymal transition. We hypothesize that inositol and its monophosphate derivatives, besides their effects on insulin transduction, may efficiently revert histological and functional features of cystic ovary by inducing cytoskeleton rearrangements. We propose an experimental model that could address not only whether inositol modulates cytoskeleton dynamics in both normal and cystic ovary cells, but also whether this effect may interfere with ovarian steroidogenesis. A more compelling understanding of the mechanisms of action of inositol (and its derivatives) would greatly improve its therapeutic utilization, by conferring to current treatments a well-grounded scientific rationale.
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http://dx.doi.org/10.1016/j.mehy.2016.03.014DOI Listing
June 2016

A Randomized Pilot Study of Inositol in Association with Betaine and Boswellia in the Management of Mastalgia and Benign Breast Lump in Premenopausal Women.

Breast Cancer (Auckl) 2016 20;10:37-43. Epub 2016 Apr 20.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.; Systems Biology Group Lab, Sapienza University of Rome, Rome, Italy.

Benign mammary lumps and mastalgia are the most common breast disorders; yet, there is no clear-cut consensus about the best strategy for their treatment. We hypothesized that a combination, including boswellic acid, betaine, and myoinositol, would be beneficial in breast disorders by exerting a pleiotropic effect on multiple pathways. Indeed, myoinositol has already been proven to modulate some factors involved in the genesis of breast diseases, such as fibrosis and metabolic and endocrine cues. In our study, 76 women were randomly assigned to either the experimental or the placebo arm. After six months of treatment, statistically significant differences between the two groups were recorded for pain relief (56% vs 17%) and breast density reduction (60% vs 9%). Furthermore, benign breast mass dimension showed a reduction in the experimental group (40% vs 16%). The combination of boswellic acid, betaine, and myoinositol has been demonstrated to be effective in the treatment of breast pain and radiologically and histologically confirmed benign breast mass and in the reduction of breast density, one of the pivotal risk factors for the development of breast cancer, without any side effects.
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http://dx.doi.org/10.4137/BCBCR.S38408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839963PMC
April 2016

Paradoxical E-cadherin increase in 5FU-resistant colon cancer is unaffected during mesenchymal-epithelial reversion induced by γ-secretase inhibition.

Life Sci 2016 Jan 30;145:174-83. Epub 2015 Dec 30.

Department of Experimental Medicine, Sapienza University of Rome, Systems Biology Group Lab, viale Regina Elena 324, 00161 Rome, Italy; Systems Biology Group Lab, Sapienza University of Rome, Rome, Italy. Electronic address:

Aim: Presenilin-1 (PS1), the main component of γ-secretase activity support a key role during Epithelial-Mesenchymal Transition (EMT) and chemoresistance acquisition by triggering a complex sequence of molecular events, including E-cadherin down-regulation. However, we hypothesize that EMT and chemoresistance should be deemed separate processes in HCT-8 colon cancer cells.

Main Methods: HCT-8 and HCT-8FUres invasion was evaluated by trans-well assay. uPA activity was detected by zymography. Prostaglandin E2 levels were quantified using an ELISA kit. E-cadherin FL and CTF2, PS1, Notch1, Cyclin D1, COX2, SNAI1 and α-SMA expression were determined using Western blot technique. β-Catenin localization was observed by confocal microscopy. Cell apoptosis was evaluated by cytofluorimetric assay, and measurement of caspase-3 and cl-PARP. γ-Secretase activity was inhibited by DAPT, a γ-secretase inhibitor.

Key Findings: Chemoresistant HCT-8 underwent EMT that can be efficiently reversed by inhibiting PS1 activity, leading thus to a normalization of mostly of the pivotal features showed by the invasive cancer phenotype. Indeed, we observed decreased SNAI1 and Notch 1 activation, altogether with reduced E-cadherin cleavage. Concomitantly, resistant HCT-8 invasiveness was almost completely abolished. However, such reversion was not followed by any increase in apoptotic rate, not by changes in E-cadherin levels. Indeed, despite HCT-8FUres underwent an undeniable EMT, full-length E-cadherin levels were found remarkably higher than those observed in wild HCT-8.

Significance: High E-cadherin concentration in presence of enhanced γ-secretase activity is incontestably a paradoxically result, highlighting that E-cadherin loss is not a pre-requisite for EMT. Additionally, EMT and chemoresistance acquisition in HCT-8 should be considered as distinct processes.
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http://dx.doi.org/10.1016/j.lfs.2015.12.048DOI Listing
January 2016

Multiwalled carbon nanotube buckypaper induces cell cycle arrest and apoptosis in human leukemia cell lines through modulation of AKT and MAPK signaling pathways.

Toxicol In Vitro 2015 Oct 18;29(7):1298-308. Epub 2015 May 18.

Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy; Azienda Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy. Electronic address:

MWCNT buckypaper (BP) shows physico-chemical and mechanical properties that make it potentially useful as a substrate in nano-bio interface research including in tissue engineering. When used as a scaffold material, BP comes into contact with host cells and surrounding tissues; therefore it is critical to determine its biocompatibility and interaction with living systems. The aim of this study was to investigate BP effects on cell growth, apoptosis and reactive oxygen species (ROS) production in three human leukemia cell lines HL-60, U-937 and K-562. BP was able to induce both the reduction of cell proliferation, associated with an arrest in G0/G1 phase of cell cycle and the increase of apoptosis in leukemic cell lines, thus exerting both cytostatic and cytotoxic effects. The growth inhibitory effect was likely mediated by the decrease of cyclins D, E, A, B1 levels and CDK4 expression; meanwhile, the apoptotic effect, not mediated by ROS production, was presumably due to the combined action of the survival and pro-apoptotic AKT and MAPK signal transduction pathways. These results raised the issue of biocompatibility of MWCNT BP for the creation of carbon nanotubes based scaffolds to utilize as prostheses in tissue engineering.
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http://dx.doi.org/10.1016/j.tiv.2015.05.006DOI Listing
October 2015

Phenotypic switch induced by simulated microgravity on MDA-MB-231 breast cancer cells.

Biomed Res Int 2014 18;2014:652434. Epub 2014 Aug 18.

Department of Experimental Medicine, "Sapienza" University of Rome, Systems Biology Group, Viale Regina Elena 324, Via A. Scarpa 14, 00161 Rome, Italy.

Microgravity exerts dramatic effects on cell morphology and functions, by disrupting cytoskeleton and adhesion structures, as well as by interfering with biochemical pathways and gene expression. Impairment of cells behavior has both practical and theoretical significance, given that investigations of mechanisms involved in microgravity-mediated effects may shed light on how biophysical constraints cooperate in shaping complex living systems. By exposing breast cancer MDA-MB-231 cells to simulated microgravity (~0.001 g), we observed the emergence of two morphological phenotypes, characterized by distinct membrane fractal values, surface area, and roundness. Moreover, the two phenotypes display different aggregation profiles and adherent behavior on the substrate. These morphological differences are mirrored by the concomitant dramatic functional changes in cell processes (proliferation and apoptosis) and signaling pathways (ERK, AKT, and Survivin). Furthermore, cytoskeleton undergoes a dramatic reorganization, eventually leading to a very different configuration between the two populations. These findings could be considered adaptive and reversible features, given that, by culturing microgravity-exposed cells into a normal gravity field, cells are enabled to recover their original phenotype. Overall these data outline the fundamental role gravity plays in shaping form and function in living systems.
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http://dx.doi.org/10.1155/2014/652434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151603PMC
April 2015

Soft gel capsules improve melatonin's bioavailability in humans.

Expert Opin Drug Metab Toxicol 2014 Sep 21;10(9):1193-8. Epub 2014 Jul 21.

Sapienza University of Rome, Department of Surgery P. Valdoni , via A. Scarpa 14, 00166 Rome , Italy.

Objective: Oral bioavailability is one of the most important properties in drug design and development. A poor oral bioavailability can result in low efficacy and unpredictable response to a drug. Several dosages of melatonin have been used for various investigations to clarify its bioavailability in humans. Aiming to search for a pharmaceutical form, which is better absorbed, the pharmacokinetic (PK) profile of the new manufactured melatonin soft gelatin (soft gel) capsule form has been evaluated and compared with the commercially available melatonin powder.

Research Design And Methods: A total of 60 healthy volunteers received 1, 3 mg of melatonin powder and 1 mg of melatonin in soft gel capsules. PK profiles were obtained by analysis of melatonin plasma concentration, and the respective melatonin bioavailability was compared.

Results: Melatonin soft gel capsule form showed similar PK parameters compared with the highest doses of melatonin in powder form, but its bioavailability was improved.

Conclusions: Soft gel capsules improved the bioavailability of melatonin in humans even when administered dose was reduced. Considering the number of conditions in which melatonin supplementation is recommended, this evidence could support a broader use of melatonin in clinical practice.
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http://dx.doi.org/10.1517/17425255.2014.943183DOI Listing
September 2014

The rationale of the myo-inositol and D-chiro-inositol combined treatment for polycystic ovary syndrome.

J Clin Pharmacol 2014 Oct 18;54(10):1079-92. Epub 2014 Jul 18.

Dept of Experimental Medicine, Systems Biology Group, University La Sapienza, Roma, Italy.

PCOS is one of the most common endocrine disorders affecting women and it is characterized by a combination of hyper-androgenism, chronic anovulation, and insulin resistance. While a significant progress has recently been made in the diagnosis for PCOS, the optimal infertility treatment remains to be determined. Two inositol isomers, myo-inositol (MI) and D-chiro-inositol (DCI) have been proven to be effective in PCOS treatment, by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome. However, DCI alone, mostly when it is administered at high dosage, negatively affects oocyte quality, whereas the association MI/DCI, in a combination reproducing the plasma physiological ratio (40:1), represents a promising alternative in achieving better clinical results, by counteracting PCOS at both systemic and ovary level.
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http://dx.doi.org/10.1002/jcph.362DOI Listing
October 2014

Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells.

J Pineal Res 2014 Aug 10;57(1):120-9. Epub 2014 Jul 10.

Department of Surgery "P. Valdoni", "Sapienza" University of Rome, Rome, Italy.

Compelling evidence demonstrated that melatonin increases p53 activity in cancer cells. p53 undergoes acetylation to be stabilized and activated for driving cells destined for apoptosis/growth inhibition. Over-expression of p300 induces p53 acetylation, leading to cell growth arrest by increasing p21 expression. In turn, p53 activation is mainly regulated in the nucleus by MDM2. MDM2 also acts as E3 ubiquitin ligase, promoting the proteasome-dependent p53 degradation. MDM2 entry into the nucleus is finely tuned by two different modulations: the ribosomal protein L11, acts by sequestering MDM2 in the cytosol, whereas the PI3K-AkT-dependent MDM2 phosphorylation is mandatory for MDM2 translocation across the nuclear membrane. In addition, MDM2-dependent targeting of p53 is regulated in a nonlinear fashion by MDM2/MDMX interplay. Melatonin induces both cell growth inhibition and apoptosis in MCF7 breast cancer cells. We previously reported that this effect is associated with reduced MDM2 levels and increased p53 activity. Herein, we demonstrated that melatonin drastically down-regulates MDM2 gene expression and inhibits MDM2 shuttling into the nucleus, given that melatonin increases L11 and inhibits Akt-PI3K-dependent MDM2 phosphorylation. Melatonin induces a 3-fold increase in both MDMX and p300 levels, decreasing simultaneously Sirt1, a specific inhibitor of p300 activity. Consequently, melatonin-treated cells display significantly higher values of both p53 and acetylated p53. Thus, a 15-fold increase in p21 levels was observed in melatonin-treated cancer cells. Our results provide evidence that melatonin enhances p53 acetylation by modulating the MDM2/MDMX/p300 pathway, disclosing new insights for understanding its anticancer effect.
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http://dx.doi.org/10.1111/jpi.12150DOI Listing
August 2014

MMP7 expression in colorectal tumours of different stages.

In Vivo 2014 Jan-Feb;28(1):105-10

Via Borea 3, Guidonia Montecelio (RM), 00012, Italy. Mob: +39 3289592236,

Background/aim: Matrix metalloproteinases (MMPs) are involved in cancer biology. Expression of MMP7 (matrilysin) in colorectal cancer is associated with metastatic disease even though it is expressed in most tumour states. In the present study, our purpose was to analyze MMP7 in bowel and lymph nodes of different tumour stages and to evaluate its expression as a cancer biomarker.

Patients And Methods: 28 patients surgically-treated for benign and malignant colorectal tumours were recruited and analyzed for MMP7 in tumoural tissue, lymph nodes and serum by histology, immunohistochemistry, ELISA and western blotting.

Results: Immunohistochemistry showed prevalent expression of MMP7 in advanced cancer. A significant increase (p<0.001) was evident in serum of stage III/IV cancers compared to both adenomas and non-metastatic disease. MMP7 was increased in cancer tissues with prevalence in stage I/II. Lymph nodes presented a significant increase of MMP7 (p<0.05 adenoma vs. stage I/II and p<0.001 vs. stage III/IV).

Conclusion: MMP7 increases with dysplasia and cancer disease stage in tumour tissue as well as in the regional lymph nodes. It may be used as a complement in investigating suspected locally advanced cancer.
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September 2014

Microenvironment promotes tumor cell reprogramming in human breast cancer cell lines.

PLoS One 2013 30;8(12):e83770. Epub 2013 Dec 30.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy ; Italian Space Agency (ASI), Rome, Italy.

The microenvironment drives mammary gland development and function, and may influence significantly both malignant behavior and cell growth of mammary cancer cells. By restoring context, and forcing cells to properly interpret native signals from the microenvironment, the cancer cell aberrant behavior can be quelled, and organization re-established. In order to restore functional and morphological differentiation, human mammary MCF-7 and MDA-MB-231 cancer cells were allowed to grow in a culture medium filled with a 10% of the albumen (EW, Egg White) from unfertilized chicken egg. That unique microenvironment behaves akin a 3D culture and induces MCF-7 cells to produce acini and branching duct-like structures, distinctive of mammary gland differentiation. EW-treated MDA-MB-231 cells developed buds of acini and duct-like structures. Both MCF-7 and MDA-MB-231 cells produced β-casein, a key milk component. Furthermore, E-cadherin expression was reactivated in MDA-MB-231 cells, as a consequence of the increased cdh1 expression; meanwhile β-catenin - a key cytoskeleton component - was displaced behind the inner cell membrane. Such modification hinders the epithelial-mesenchymal transition in MDA-MB-231 cells. This differentiating pathway is supported by the contemporary down-regulation of canonical pluripotency markers (Klf4, Nanog). Given that egg-conditioned medium behaves as a 3D-medium, it is likely that cancer phenotype reversion could be ascribed to the changed interactions between cells and their microenvironment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083770PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875474PMC
August 2014

Shape in migration: quantitative image analysis of migrating chemoresistant HCT-8 colon cancer cells.

Cell Adh Migr 2013 Sep-Oct;7(5):450-9. Epub 2013 Oct 22.

Department of Experimental Medicine; "Sapienza" University of Rome; Roma, Italy.

Unsuccessful cytotoxic anticancer treatments may contribute to tumor morphologic instability and consequent tissue invasion, promoting the selection of a more malignant phenotype. Indeed, morphological changes have been demonstrated to be more pronounced in strongly vs. weakly metastatic cells. By means of normalized bending energy, we have previously quantitatively defined the link between cell shape modifications and the acquisition of a more malignant phenotype by 5-FU-resistant colon cancer cells (HCT-8FUres). Such changes were significantly correlated with an increase in motility speed. Herein, we propose a method to quantitatively analyze the shape of wild and chemoresistant HCT-8 migration front cells during wound healing assay. We evaluated the reliability of parameters (area/perimeter ratio [A/p], circularity, roundness, fractal dimension, and solidity) in describing the biological behavior of the two cell lines, enabling hence in distinguishing the chemoresistant line from the other one. We found solidity index the parameter that better described the difference between chemoresistant and wild cells. Moreover, solidity is able to capture the differences between chemoresistant and wild cells at each time point of the migration process. Indeed, motility speed was found to be inversely correlated with solidity, a quantitative index of cell deformability. Deformability is an outstanding hallmark of the process leading to metastatic spread; consequently, solidity may be considered a marker of acquired metastatic property.
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http://dx.doi.org/10.4161/cam.26765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903690PMC
September 2014

TCam-2 seminoma cells exposed to egg-derived microenvironment modify their shape, adhesive pattern and migratory behaviour: a molecular and morphometric analysis.

PLoS One 2013 1;8(10):e76192. Epub 2013 Oct 1.

Department of Anatomy, Histology, Forensic Medicine and Orthopedics - Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.

Seminoma is one of the most common Testicular Germ Cell Tumours that originates during embryonic development due to an alteration of the local niche that in turn results in a delayed or blocked differentiation of Primordial Germ Cells. The block of differentiation is actually a common way to develop cancer disease as postulated by the "embryonic rest theory of cancer". In agreement with this theory different studies have demonstrated that embryonic cues display the capacity of reprogramming aggressive cancer cells towards a less aggressive phenotype. Herein we investigate the ability of a culture medium added with 10% egg albumen (EW, Egg White) to modulate seminoma cell phenotype and behaviour, by ensuring a proper set of morphogenetic signals. We chose to use the TCam-2 seminoma cell line that has been established as the only available cell line, obtained from a primary testicular seminoma. EW is able to: 1) modify TCam-2 cell spreading rate and cell-substrate adhesion without affecting proliferation and survival indexes; 2) modulate TCam-2 actin distribution pattern increasing cortical localization of actin filaments; 3) increase TCam-2 cell-cell junction capability; 4) decrease both chemo-sensitive and collective TCam-2 migratory behaviour. According to these observations morphometric fractal analysis revealed the ability of EW to increase Circularity and Solidity parameters and, consequently, to decrease Fractal dimension. Prompted by these observations we hypothesize that EW treatment could rescue, at least in part, the neoplastic-metastatic behaviour of seminoma cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076192PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788130PMC
July 2014

Nicotine increases survival in human colon cancer cells treated with chemotherapeutic drugs.

Toxicol In Vitro 2013 Dec 2;27(8):2256-63. Epub 2013 Oct 2.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, Piazza Sassari 3, 00161 Rome, Italy; Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via Antonio Scarpa 14, 00161 Rome, Italy.

Cigarette smoking is implicated in the development of colon cancer. Furthermore, nicotine increases cell proliferation and inhibits apoptosis through α7-nicotinic acetylcholine receptor (α7-nAChR) activation in human colon carcinoma cells. An open issue is whether nicotine interfere with colorectal cancer pharmacological treatment, by inhibiting drug-mediated apoptosis. To assess this hypothesis, we evaluated nicotine effect on Caco-2 and HCT-8 colon cancer cells, treated with 5-Fluorouracil (5-FU) and Camptothecin (CPT), chemotherapeutics commonly utilized as adjuvant treatment of colon cancer. Nicotine decreased anti-proliferative and pro-apoptotic effects exerted by chemotherapeutics on both cell lines. These effects partially reverted by exposure to α-bungarotoxin (α-BTX), an inhibitor of α7-nAChR. Nicotine addition to Caco-2 and HCT-8, treated with 5-FU or CPT, decreased the cleavage of substrate of caspase 3 and 7, poly-ADP-ribose polymerase (PARP). Moreover, P-ERK/ERK ratio was modified by nicotine addition to 5-FU and CPT treated cells in an opposite manner. However, when co-administrating PD98059, an ERK phosphorylation inhibitor, an increased apoptosis was observed. In Caco-2 and HCT-8 nicotine reverted 5-FU and CPT apoptotic effects through AKT phosphorylation, as demonstrated by apoptotic increase in presence of LY294002, an AKT phosphorylation inhibitor. Nicotine interfered with colorectal cancer pharmacological treatment in vitro by inhibiting apoptosis induced by chemotherapeutic drugs. Nicotine anti-apoptotic effects were exerted through ERK and AKT pathway activation.
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http://dx.doi.org/10.1016/j.tiv.2013.09.020DOI Listing
December 2013

Grape seed extract suppresses MDA-MB231 breast cancer cell migration and invasion.

Eur J Nutr 2014 11;53(2):421-31. Epub 2013 Jun 11.

Department of Clinical and Molecular Medicine, La Sapienza University, Piazza Sassari 3, 00161, Rome, Italy.

Background And Aim: Breast cancer remains a leading cause of mortality among women. In metastasis, cascade migration of cancer cells and invasion of extracellular matrix (ECM) represent critical steps. Urokinase-type plasminogen activator (uPA), as well as metalloproteinases MMP-2 and MMP-9, strongly contribute to ECM remodelling, thus becoming associated with tumour migration and invasion. In addition, the high expression of cytoskeletal (CSK) proteins, as fascin, has been correlated with clinically aggressive metastatic tumours, and CSK proteins are thought to affect the migration of cancer cells. Consumption of fruits and vegetables, characterized by high procyanidin content, has been associated to a reduced mortality for breast cancer. Therefore, we investigated the biological effect of grape seed extract (GSE) on the highly metastatic MDA-MB231 breast cancer cell line, focusing on studying GSE ability in inhibiting two main metastatic processes, i.e., cell migration and invasion.

Methods: After MDA-MB231 breast cancer cells stimulated with GSE migration and invasion were evaluated by means of trans-well assays and uPA as well as MMPs activity was detected by gelatin zymography. Fascin, β-catenin and nuclear factor-κB (NF-κB) expression were determined using western blot technique. β-Catenin localization was observed by confocal microscopy.

Results: We observed that high concentrations of GSE inhibited cell proliferation and apoptosis. Conversely, low GSE concentration decreased cell migration and invasion, likely by hampering β-catenin expression and localization, fascin and NF-κB expression, as well as by decreasing the activity of uPA, MMP-2 and MMP-9.

Conclusions: These results make GSE a powerful candidate for developing preventive agents against cancer metastasis.
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http://dx.doi.org/10.1007/s00394-013-0542-6DOI Listing
October 2014

Grape seed extract triggers apoptosis in Caco-2 human colon cancer cells through reactive oxygen species and calcium increase: extracellular signal-regulated kinase involvement.

Br J Nutr 2013 Sep 25;110(5):797-809. Epub 2013 Feb 25.

Department of Clinical and Molecular Medicine, Piazza Sassari 3, La Sapienza University, 00161 Rome, Italy.

Grape seed extract (GSE) from Italia, Palieri and Red Globe cultivars inhibits cell growth and induces apoptosis in Caco-2 human colon cancer cells in a dose-dependent manner. In order to investigate the mechanism(s) supporting the apoptotic process, we analysed reactive oxygen species (ROS) production, intracellular Ca2+ handling and extracellular signal-regulated kinase (ERK) activation. Upon exposure to GSE, ROS and intracellular Ca2+ levels increased in Caco-2 cells, concomitantly with ERK inactivation. As ERK activity is thought to be essential for promoting survival pathways, inhibition of this kinase is likely to play a relevant role in GSE-mediated anticancer effects. Indeed, pretreatment with N-acetyl cysteine, a ROS scavenger, reversed GSE-induced apoptosis, and promoted ERK phosphorylation. This effect was strengthened by ethylene glycol tetraacetic acid-mediated inhibition of extracellular Ca2+ influx. ROS and Ca2+ influx inhibition, in turn, increased ERK phosphorylation, and hence almost entirely suppressed GSE-mediated apoptosis. These data suggested that GSE triggers a previously unrecognised ERK-based mechanism, involving both ROS production and intracellular Ca2+ increase, eventually leading to apoptosis in cancer cells.
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http://dx.doi.org/10.1017/S0007114512006095DOI Listing
September 2013

Nicotine stimulates proliferation and inhibits apoptosis in colon cancer cell lines through activation of survival pathways.

J Surg Res 2012 Nov 10;178(1):233-41. Epub 2012 Mar 10.

Department of Surgery Pietro Valdoni, Sapienza University of Rome, Rome, Italy.

Background: Colorectal cancer is one of the leading causes of cancer-related death throughout the world, and the risk to develop this malignant disease seems to be associated with long-term cigarette smoking. Nicotine, one of the major components of cigarette smoking, can stimulate cell proliferation and suppress apoptosis both in normal cells and in several human cancer cell lines derived from various organs. However, although nicotine appears to have a role in stimulating cell proliferation of colon cancer cells, there is no information on its role in inhibiting apoptosis in these cells.

Materials And Methods: Human colorectal cancer cell lines Caco-2 and HCT-8 were treated with 1 μM nicotine alone or in combination with 1 μM α-BTX in complete or in serum free medium. Cell proliferation and apoptosis were determined by cell count performed with a cell counter and by cytofluorimetric assay respectively. PI3K/Akt and PKC/ERK1/2 pathways, survivin, and P-Bcl2 (Ser70) were investigated by Western blot analysis.

Results: Nicotine induced an increase in cell proliferation and a decrease of apoptosis in Caco-2 and HCT-8 cells. Both cell growth and apoptosis appear to be mediated by α7-nicotinic acetylcholine receptors, since treatment with α-Bungarotoxin inhibited these processes. Nicotine induced a statistically significant increase in the expression of PI3K and in P-Akt/Akt ratio as well as in the expression of PKC, ERK1/2, survivin, and P-Bcl2 (Ser70) in both cell lines.

Conclusions: Nicotine, contained in cigarette smoking, could participate in colon cancer development and progression by stimulating cell proliferation and suppressing physiological apoptosis.
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http://dx.doi.org/10.1016/j.jss.2011.12.029DOI Listing
November 2012

Antiproliferative and apoptotic effects triggered by Grape Seed Extract (GSE) versus epigallocatechin and procyanidins on colon cancer cell lines.

Int J Mol Sci 2012 10;13(1):651-64. Epub 2012 Jan 10.

Department of Experimental Medicine, "La Sapienza" University, Viale Regina Elena 324, Rome 00161, Italy; E-Mails: (S.D.); (S.P.); (E.L.).

Grape seed extract has been proven to exert anticancer effects on different tumors. These effects are mainly ascribed to catechin and procyanidin content. Analytical studies demonstrated that grape seed extract composition is complex and it is likely other components could exert biological activities. Using cell count and flow cytometry assays, we evaluated the cytostatic and apoptotic effects produced by three different grape seed extracts from Italia, Palieri and Red Globe cultivars, on Caco2 and HCT-8 colon cancer cells. These effects were compared to those induced by epigallocatechin and procyanidins, alone or in association, on the same cell lines. All the extracts induced growth inhibition and apoptosis in Caco2 and HCT-8 cells, along the intrinsic apoptotic pathway. On both cell lines, growth inhibition induced by Italia and Palieri grape seed extracts was significantly higher than that it has been recorded with epigallocatechin, procyanidins and their association. In Caco2 cells, the extract from Red Globe cultivar was less effective in inducing growth inhibition than procyanidins alone and in association with epigallocatechin, whereas, in HCT-8 cells, only the association of epigallocatechin and procyanidins triggers a significant proliferation decrease. On both cell lines, apoptosis induced by Italia, Palieri and Red Globe grape seed extracts was considerably higher than has been recorded with epigallocatechin, procyanidins and their association. These data support the hypothesis by which other compounds, present in the grape seed extracts, are likely to enhance the anticancer effects.
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http://dx.doi.org/10.3390/ijms13010651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269711PMC
February 2015

Dose-dependent effect of rosuvastatin in the regulation of metalloproteinase expression.

Ann Vasc Surg 2011 Aug 28;25(6):823-9. Epub 2011 May 28.

Department of Surgery Pietro Valdoni, University of Rome Sapienza, Rome, Italy.

Background: The importance of rosuvastatin at therapeutic dosage in regulating the release, activity, protein level, and expression of matrix metalloproteinases (MMP)-2 and MMP-9 was investigated.

Methods: Human umbilical artery smooth muscle cells were stimulated, in vitro, in a serum-free medium with rosuvastatin at various concentrations (2, 4, 7, and 10 ng/mL, which correspond to the maximal plasma concentration observed in healthy men after a daily oral intake of 5, 10, 20, and 40 mg, respectively). The release of MMP-2 and MMP-9 in the conditioned medium was assessed by enzyme-linked immunosorbent assay and confirmed by Western blot, the activity and expression were determined by zymography and polymerase chain reaction, respectively.

Results: Human umbilical artery smooth muscle cells stimulated with rosuvastatin at 7 and 10 ng/mL had a significant lower release, activity, protein level, and expression of MMP-2 and MMP-9, when compared with those stimulated at 2 and 4 ng/mL (MMP-2 =p < 0.0001 and p < 0.0001, respectively; MMP-9 =p < 0.0001 and p < 0.0001, respectively).

Conclusion: The effects of rosuvastatin in reducing MMP-2 and MMP-9, which might stabilize the atherosclerotic plaques, are dose-dependent.
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http://dx.doi.org/10.1016/j.avsg.2011.03.008DOI Listing
August 2011