Publications by authors named "Luciana Mosca"

53 Publications

Biochemical and Computational Studies of the Interaction between a Glucosamine Derivative, NAPA, and the IKK Kinase.

Int J Mol Sci 2021 02 6;22(4). Epub 2021 Feb 6.

Department of Biochemical Sciences, Sapienza University of Roma, P.le Aldo Moro 5, 00185 Rome, Italy.

The glucosamine derivative 2-(N-Acetyl)-L-phenylalanylamido-2-deoxy-β-D-glucose (NAPA), was shown to inhibit the kinase activity of IKKα, one of the two catalytic subunits of IKK complex, decreasing the inflammatory status in osteoarthritis chondrocytes. In the present work we have investigated the inhibition mechanism of IKKα by NAPA by combining computational simulations, in vitro assays and Mass Spectrometry (MS) technique. The kinase in vitro assay was conducted using a recombinant IKKα and IKKtide, a 20 amino acid peptide substrate derived from IkBα kinase protein and containing the serine residues Ser32 and Ser36. Phosphorylated peptide production was measured by Ultra Performance Liquid Chromatography coupled with Mass Spectrometry (UPLC-MS), and the atomic interaction between IKKα and NAPA has been studied by molecular docking and Molecular Dynamics (MD) approaches. Here we report that NAPA was able to inhibit the IKKα kinase activity with an IC of 0.5 mM, to decrease the K value from 0.337 mM to 0.402 mM and the V from 0.0257 mM·min-1 to 0.0076 mM·min-1. The computational analyses indicate the region between the KD, ULD and SDD domains of IKKα as the optimal binding site explored by NAPA. Biochemical data indicate that there is a non-significant difference between K and K whereas there is a statistically significant difference between the two V values. This evidence, combined with computational results, consistently indicates that the inhibition is non-competitive, and that the NAPA binding site is different than that of ATP or IKKtide.
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http://dx.doi.org/10.3390/ijms22041643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915277PMC
February 2021

Taxanes in cancer treatment: Activity, chemoresistance and its overcoming.

Drug Resist Updat 2021 Jan 9;54:100742. Epub 2021 Jan 9.

Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address:

Since 1984, when paclitaxel was approved by the FDA for the treatment of advanced ovarian carcinoma, taxanes have been widely used as microtubule-targeting antitumor agents. However, their historic classification as antimitotics does not describe all their functions. Indeed, taxanes act in a complex manner, altering multiple cellular oncogenic processes including mitosis, angiogenesis, apoptosis, inflammatory response, and ROS production. On the one hand, identification of the diverse effects of taxanes on oncogenic signaling pathways provides opportunities to apply these cytotoxic drugs in a more rational manner. On the other hand, this may facilitate the development of novel treatment modalities to surmount anticancer drug resistance. In the latter respect, chemoresistance remains a major impediment which limits the efficacy of antitumor chemotherapy. Taxanes have shown impact on key molecular mechanisms including disruption of mitotic spindle, mitosis slippage and inhibition of angiogenesis. Furthermore, there is an emerging contribution of cellular processes including autophagy, oxidative stress, epigenetic alterations and microRNAs deregulation to the acquisition of taxane resistance. Hence, these two lines of findings are currently promoting a more rational and efficacious taxane application as well as development of novel molecular strategies to enhance the efficacy of taxane-based cancer treatment while overcoming drug resistance. This review provides a general and comprehensive picture on the use of taxanes in cancer treatment. In particular, we describe the history of application of taxanes in anticancer therapeutics, the synthesis of the different drugs belonging to this class of cytotoxic compounds, their features and the differences between them. We further dissect the molecular mechanisms of action of taxanes and the molecular basis underlying the onset of taxane resistance. We further delineate the possible modalities to overcome chemoresistance to taxanes, such as increasing drug solubility, delivery and pharmacokinetics, overcoming microtubule alterations or mitotic slippage, inhibiting drug efflux pumps or drug metabolism, targeting redox metabolism, immune response, and other cellular functions.
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http://dx.doi.org/10.1016/j.drup.2020.100742DOI Listing
January 2021

Chemistry and Biochemistry of Sulfur Natural Compounds: Key Intermediates of Metabolism and Redox Biology.

Oxid Med Cell Longev 2020 29;2020:8294158. Epub 2020 Sep 29.

Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, 00185 Rome, Italy.

Sulfur contributes significantly to nature chemical diversity and thanks to its particular features allows fundamental biological reactions that no other element allows. Sulfur natural compounds are utilized by all living beings and depending on the function are distributed in the different kingdoms. It is no coincidence that marine organisms are one of the most important sources of sulfur natural products since most of the inorganic sulfur is metabolized in ocean environments where this element is abundant. Terrestrial organisms such as plants and microorganisms are also able to incorporate sulfur in organic molecules to produce primary metabolites (e.g., methionine, cysteine) and more complex unique chemical structures with diverse biological roles. Animals are not able to fix inorganic sulfur into biomolecules and are completely dependent on preformed organic sulfurous compounds to satisfy their sulfur needs. However, some higher species such as humans are able to build new sulfur-containing chemical entities starting especially from plants' organosulfur precursors. Sulfur metabolism in humans is very complicated and plays a central role in redox biochemistry. The chemical properties, the large number of oxidation states, and the versatile reactivity of the oxygen family chalcogens make sulfur ideal for redox biological reactions and electron transfer processes. This review will explore sulfur metabolism related to redox biochemistry and will describe the various classes of sulfur-containing compounds spread all over the natural kingdoms. We will describe the chemistry and the biochemistry of well-known metabolites and also of the unknown and poorly studied sulfur natural products which are still in search for a biological role.
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http://dx.doi.org/10.1155/2020/8294158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545470PMC
September 2020

Sorcin is an early marker of neurodegeneration, Ca dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases.

Cell Death Dis 2020 10 15;11(10):861. Epub 2020 Oct 15.

Institute of Molecular Biology and Pathology, Italian National Research Council, IBPM-CNR, Rome, Italy.

Dysregulation of calcium signaling is emerging as a key feature in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), and targeting this process may be therapeutically beneficial. Under this perspective, it is important to study proteins that regulate calcium homeostasis in the cell. Sorcin is one of the most expressed calcium-binding proteins in the human brain; its overexpression increases endoplasmic reticulum (ER) calcium concentration and decreases ER stress in the heart and in other cellular types. Sorcin has been hypothesized to be involved in neurodegenerative diseases, since it may counteract the increased cytosolic calcium levels associated with neurodegeneration. In the present work, we show that Sorcin expression levels are strongly increased in cellular, animal, and human models of AD, PD, and HD, vs. normal cells. Sorcin partially colocalizes with RyRs in neurons and microglia cells; functional experiments with microsomes containing high amounts of RyR2 and RyR3, respectively, show that Sorcin is able to regulate these ER calcium channels. The molecular basis of the interaction of Sorcin with RyR2 and RyR3 is demonstrated by SPR. Sorcin also interacts with other ER proteins as SERCA2 and Sigma-1 receptor in a calcium-dependent fashion. We also show that Sorcin regulates ER calcium transients: Sorcin increases the velocity of ER calcium uptake (increasing SERCA activity). The data presented here demonstrate that Sorcin may represent both a novel early marker of neurodegenerative diseases and a response to cellular stress dependent on neurodegeneration.
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http://dx.doi.org/10.1038/s41419-020-03063-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566454PMC
October 2020

GO Nanosheets: Promising Nano Carrier for the S29, 1-(2-Chloro-2-(4-chlorophenyl-ethyl)--(4-fluorobenzyl)-1-pyrazolo[3,4-d] pyrimidin-4-amine, Therapeutic Agent in Neuroblastoma.

Int J Mol Sci 2020 Sep 3;21(17). Epub 2020 Sep 3.

Department of Science and Chemical Technologies, Tor Vergata University of Rome, via della Ricerca Scientifica, 1, 000133 Rome, Italy.

Graphene oxide (GO) derivatives are reported as a valid alternative to conventional carriers of therapeutic agents, because they have a large surface area, an excellent electrical and thermal conductivity and a great capacity for selective binding of drugs and therapeutics, due to the functionalization of their surfaces, edges and sides. In this work GO nanosheets, synthesized by electrochemical exfoliation of graphite (patent N 102015000023739, Tor Vergata University), were investigated as possible carriers of an anticancer drug, the S29, an inhibitor of a cytoplasmic tyrosine kinase (c-SRC) on a neuroblastoma cell line (SK N BE 2 cells). Neuroblastoma is a heterogenous tumor whose characteristics range from spontaneous regression to aggressive phenotypes that are due to different mutations that often occur in SRC family kinases. Inhibitors of tyrosine kinases are currently investigated for their anti-tumoral effects on aggressive neuroblastomas, but their uptake in cells and pharmacokinetics needs to be improved. In this work S29 was stably conjugated with highly water-dispersible GO nanoparticles. S29/GO complex formation was induced by 1h sonication and its stability was analyzed by chromatography coupled with spectrophotometry and mass spectrometry. The synthesized composite (GO-S29) was delivered into SK N BE 2 cells and its effects on cell viability, production of reactive oxygen species (ROS) and migration were studied. The results show that the compound GO-S29 exerts anti-tumoral effects on the neuroblastoma cell line, higher than both GO and S29 do alone and that GO has an additive effect on S29.
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http://dx.doi.org/10.3390/ijms21176430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503945PMC
September 2020

Anthocyanins: A Comprehensive Review of Their Chemical Properties and Health Effects on Cardiovascular and Neurodegenerative Diseases.

Molecules 2020 Aug 21;25(17). Epub 2020 Aug 21.

Laboratory of Histology and Embryology, Institute of Biomedical Sciences Abel Salazar (ICBAS), Rua de Jorge Viterbo Ferreira n°228, 4050-313 Porto, Portugal.

Anthocyanins are a class of water-soluble flavonoids widely present in fruits and vegetables. Dietary sources of anthocyanins include red and purple berries, grapes, apples, plums, cabbage, or foods containing high levels of natural colorants. Cyanidin, delphinidin, malvidin, peonidin, petunidin, and pelargonidin are the six common anthocyanidins. Following consumption, anthocyanin, absorption occurs along the gastrointestinal tract, the distal lower bowel being the place where most of the absorption and metabolism occurs. In the intestine, anthocyanins first undergo extensive microbial catabolism followed by absorption and human phase II metabolism. This produces hybrid microbial-human metabolites which are absorbed and subsequently increase the bioavailability of anthocyanins. Health benefits of anthocyanins have been widely described, especially in the prevention of diseases associated with oxidative stress, such as cardiovascular and neurodegenerative diseases. Furthermore, recent evidence suggests that health-promoting effects attributed to anthocyanins may also be related to modulation of gut microbiota. In this paper we attempt to provide a comprehensive view of the state-of-the-art literature on anthocyanins, summarizing recent findings on their chemistry, biosynthesis, nutritional value and on their effects on human health.
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http://dx.doi.org/10.3390/molecules25173809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504512PMC
August 2020

Green Route for the Isolation and Purification of Hyrdoxytyrosol, Tyrosol, Oleacein and Oleocanthal from Extra Virgin Olive Oil.

Molecules 2020 Aug 11;25(16). Epub 2020 Aug 11.

Department of Biochemical Sciences, "Sapienza" University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.

Extra virgin olive oil (EVOO) phenols represent a significant part of the intake of antioxidants and bioactive compounds in the Mediterranean diet. In particular, hydroxytyrosol (HTyr), tyrosol (Tyr), and the secoiridoids oleacein and oleocanthal play central roles as anti-inflammatory, neuro-protective and anti-cancer agents. These compounds cannot be easily obtained via chemical synthesis, and their isolation and purification from EVOO is cumbersome. Indeed, both processes involve the use of large volumes of organic solvents, hazardous reagents and several chromatographic steps. In this work we propose a novel optimized procedure for the green extraction, isolation and purification of HTyr, Tyr, oleacein and oleocanthal directly from EVOO, by using a Natural Deep Eutectic Solvent (NaDES) as an extracting phase, coupled with preparative high-performance liquid chromatography. This purification method allows the total recovery of the four components as single pure compounds directly from EVOO, in a rapid, economic and ecologically sustainable way, which utilizes biocompatible reagents and strongly limits the use or generation of hazardous substances.
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http://dx.doi.org/10.3390/molecules25163654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464626PMC
August 2020

Blueberry Counteracts BV-2 Microglia Morphological and Functional Switch after LPS Challenge.

Nutrients 2020 Jun 19;12(6). Epub 2020 Jun 19.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100 Latina, Italy.

Microglia, the innate immune cells of the CNS, respond to brain injury by activating and modifying their morphology. Our study arises from the great interest that has been focused on blueberry (BB) for the antioxidant and pharmacological properties displayed by its components. We analyzed the influence of hydroalcoholic BB extract in resting or lipopolysaccharide (LPS)-stimulated microglia BV-2 cells. BB exerted a protective effect against LPS-induced cytotoxicity, as indicated by cell viability. BB was also able to influence the actin cytoskeleton organization, to recover the control phenotype after LPS insult, and also to reduce LPS-driven migration. We evaluated the activity of Rho and Rac1 GTPases, which regulate both actin cytoskeletal organization and migratory capacity. LPS caused an increase in Rac1 activity, which was counteracted by BB extract. Furthermore, we demonstrated that, in the presence of BB, mRNA expression of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α decreased, as did the immunofluorescence signal of iNOS, whereas that of Arg-1 was increased. Taken together, our results show that, during the inflammatory response, BB extract shifts the M1 polarization towards the M2 phenotype through an actin cytoskeletal rearrangement. Based on that, we might consider BB as a nutraceutical with anti-inflammatory activities.
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http://dx.doi.org/10.3390/nu12061830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353350PMC
June 2020

Maternal Immune Activation in Mice Only Partially Recapitulates the Autism Spectrum Disorders Symptomatology.

Neuroscience 2020 10 21;445:109-119. Epub 2020 May 21.

Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.

Prenatal viral/bacterial infections are considered risk factors for autism spectrum disorders (ASD) and rodent models of maternal immune activation (MIA) have been developed and extensively used in preclinical studies. Poly inosinic-cytidylic acid (Poly I:C) was injected in C57BL6/J dams to mimic a viral infection on gestational day 12.5; the experimental design includes 10/12 litters in each treatment group and data were analysed always considering the litter-effect; neonatal (spontaneous motor behaviour and ultrasonic vocalizations) and adult [open field, marble burying, social approach, fear conditioning, prepulse inhibition (PPI)] offspring of both sexes were tested. In vivo magnetic resonance imaging/spectroscopy (MRI-MRS) and high-performance liquid chromatography (HPLC) to quantify both aminoacid and/or neurotransmitter concentration in cortical and striatal regions were also carried out. In both sexes high levels of repetitive motor responses and sensory gating deficits in PPI were the more striking effects of Poly I:C, whereas no alteration of social responses were evidenced. Poly I:C treatment did not affect mean values, but, intriguingly, increased variability in the levels of four aminoacids (aspartate glycine and GABA) selectively in males. As a whole prenatal Poly I:C induced relevant long-term alterations in explorative-stereotyped motor responses and in sensory gating, sparing cognitive and social competences. When systematically assessing differences between male and female siblings within each litter, no significant sex differences were evident except for increased variability of four aminoacid levels in male brains. As a whole, prenatal Poly I:C paradigms appear to be a useful tool to investigate the profound and translationally-relevant effects of developmental immune activation on brain and behavioural development, not necessarily recapitulating the full ASD symptomatology.
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http://dx.doi.org/10.1016/j.neuroscience.2020.05.009DOI Listing
October 2020

One- and Two-Electron Oxidations of β-Amyloid by Carbonate Radical Anion (CO) and Peroxymonocarbonate (HCO): Role of Sulfur in Radical Reactions and Peptide Aggregation.

Molecules 2020 Feb 20;25(4). Epub 2020 Feb 20.

Department of Biochemical Sciences, "Sapienza" University of Rome, 00185 Rome, Italy.

The β-amyloid (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease. The methionine (Met) residue at position 35 in Aβ C-terminal domain is critical for neurotoxicity, aggregation, and free radical formation initiated by the peptide. The role of Met in modulating toxicological properties of Aβ most likely involves an oxidative event at the sulfur atom. We therefore investigated the one- or two-electron oxidation of the Met residue of Aβ fragment and the effect of such oxidation on the behavior of the peptide. Bicarbonate promotes two-electron oxidations mediated by hydrogen peroxide after generation of peroxymonocarbonate (HCO, PMC). The bicarbonate/carbon dioxide pair stimulates one-electron oxidations mediated by carbonate radical anion (CO). PMC efficiently oxidizes thioether sulfur of the Met residue to sulfoxide. Interestingly, such oxidation hampers the tendency of Aβ to aggregate. Conversely, CO causes the one-electron oxidation of methionine residue to sulfur radical cation (MetS). The formation of this transient reactive intermediate during Aβ oxidation may play an important role in the process underlying amyloid neurotoxicity and free radical generation.
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http://dx.doi.org/10.3390/molecules25040961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070857PMC
February 2020

A Probiotic Preparation Hydrolyzes Gliadin and Protects Intestinal Cells from the Toxicity of Pro-Inflammatory Peptides.

Nutrients 2020 Feb 14;12(2). Epub 2020 Feb 14.

Department of Biochemical Sciences, Sapienza University of Roma, 00185 Rome, Italy.

Celiac disease (CD) is an autoimmune enteropathy caused by an intolerance to gluten proteins. It has been hypothesized that probiotic bacteria may exert beneficial effects by modulating inflammatory processes and by sustaining peptide hydrolysis at the intestinal level. This study aims at evaluating the capacity of a probiotic mixture (two different strains of lactobacilli and three of bifidobacteria) to hydrolyze gluten peptides following simulated gastrointestinal digestion of gliadin (PT-gliadin). The capacity of bacterial hydrolysates to counteract the toxic effects of gliadin-derived peptides in Caco-2 cells was also assessed. The protein and peptide mixtures, untreated or proteolyzed with the probiotic preparation, were analyzed before and after each proteolytic step with different techniques (SDS-PAGE, reverse phase HPLC, filtration on different molecular cut-off membranes). These experiments demonstrated that PT-gliadin can be further digested by bacteria into lower molecular weight peptides. PT-gliadin, untreated or digested with the probiotics, was then used to evaluate oxidative stress, IL-6 cytokine production and expression of tight junctions' proteins-such as occludin and zonulin-in Caco-2 cells. PT-gliadin induced IL-6 production and modulation and redistribution of zonulin and occludin, while digestion with the probiotic strains reversed these effects. Our data indicate that this probiotic mixture may exert a protective role in CD.
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http://dx.doi.org/10.3390/nu12020495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071319PMC
February 2020

Gas Chromatographic-Mass Spectrometric Method for the Simultaneous Determination of Resveratrol Isomers and 2,4,6-Trihydroxyphenanthrene in Red Wines Exposed to UV-Light.

J Agric Food Chem 2019 Oct 10;67(42):11752-11757. Epub 2019 Oct 10.

Department of Biochemical Sciences , "Sapienza" University of Rome , p.le A.Moro 5 , 00185 Rome , Italy.

Resveratrol (3,5,4'-trihydroxystilbene) is one of the most abundant polyphenols in red grapes, and red wine represents one of the most important dietary sources of this compound. Although its beneficial properties on human health have been widely investigated over the last 30 years, very little is known about its derivatives. Resveratrol can indeed undergo glycosylation, oligomerization and, upon UV-light exposure, it can isomerize from the -to the -isomer, which can further cyclize to 2,4,6-trihydroxyphenanthrene (THP). Although the effects of THP on human health are not yet known, being a polycyclic aromatic hydrocarbon, it can be potentially harmful. Because no data about THP occurrence in plant food and beverages are available, a simple procedure based on liquid-liquid extraction and gas chromatography-mass spectrometry has been developed and validated for the simultaneous qualitative and quantitative analysis of -resveratrol, -resveratrol, and THP in red wine, before and after UV-light exposure.
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http://dx.doi.org/10.1021/acs.jafc.9b05992DOI Listing
October 2019

Thiotaurine: From Chemical and Biological Properties to Role in HS Signaling.

Adv Exp Med Biol 2019 ;1155:755-771

Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy.

In the last decade thiotaurine, 2-aminoethane thiosulfonate, has been investigated as an inflammatory modulating agent as a result of its ability to release hydrogen sulfide (HS) known to play regulatory roles in inflammation. Thiotaurine can be included in the "taurine family" due to structural similarity to taurine and hypotaurine, and is characterized by the presence of a sulfane sulfur moiety. Thiotaurine can be produced by different pathways, such as the spontaneous transsulfuration between thiocysteine - a persulfide analogue of cysteine - and hypotaurine as well as in vivo from cystine. Moreover, the enzymatic oxidation of cysteamine to hypotaurine and thiotaurine in the presence of inorganic sulfur can occur in animal tissues and last but not least thiotaurine can be generated by the transfer of sulfur from mercaptopyruvate to hypotaurine catalyzed by a sulfurtransferase. Thiotaurine is an effective antioxidant agent as demonstrated by its ability to counteract the damage caused by pro-oxidants in the rat. Recently, we observed the influence of thiotaurine on human neutrophils functional responses. In particular, thiotaurine has been found to prevent human neutrophil spontaneous apoptosis suggesting an alternative or additional role to its antioxidant activity. It is likely that the sulfane sulfur of thiotaurine may modulate neutrophil activation via persulfidation of target proteins. In conclusion, thiotaurine can represent a biologically relevant sulfur donor acting as a biological intermediate in the transport, storage and release of sulfide.
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http://dx.doi.org/10.1007/978-981-13-8023-5_66DOI Listing
September 2019

Insights into the Phytochemistry of the Cuban Endemic Medicinal Plant : Fideloside, a Novel Bioactive 8--glycosyl 2,3-Dihydroflavonol.

Molecules 2019 Aug 6;24(15). Epub 2019 Aug 6.

Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle (Saale), Germany.

(Phyllanthaceae) is an endemic evergreen tropical plant of Cuba that grows in the western part of the island and is used in traditional medicine as an infusion. The aqueous extract of this plant presents a wide range of pharmacological activitiessuch as antimutagenic, antioxidant and antiviral effects. Given the many beneficial effects and the great interest in the development of new pharmacological products from natural sources, the aim of this work was to investigate the phytochemistry of this species and to elucidate the structure of the main bioactive principles. Besides the presence of several known polyphenols, the major constituent was hitherto not described. The chemical structure of this compound, here named Fideloside, was elucidated by means of HR-ESIMS/MS, 1D/2D NMR, FT-IR, and ECD as (2,3)-(-)-3',4',5,7-tetrahydroxydihydroflavonol-8--β-D-glucopyranoside. The compound, as well as the plant aqueous preparations, showed promising bioactive properties, i.e., anti-inflammatory capacity in human explanted monocytes, corroborating future pharmacological use for this new natural C-glycosyl flavanonol.
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http://dx.doi.org/10.3390/molecules24152855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695706PMC
August 2019

Anti-Inflammatory Activity of A Polyphenolic Extract from in In Vitro and In Vivo Models of Alzheimer's Disease.

Int J Mol Sci 2019 Feb 7;20(3). Epub 2019 Feb 7.

Department of Biochemical Sciences, Sapienza University of Rome, 00185 Roma, Italy.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. One of the main features of AD is the increase in amyloid-beta (Aβ) peptide production and aggregation, leading to oxidative stress, neuroinflammation and neurodegeneration. Polyphenols are well known for their antioxidant, anti-inflammatory and neuroprotective effects and have been proposed as possible therapeutic agents against AD. Here, we investigated the effects of a polyphenolic extract of (a plant belonging to the Brassicaceae family) on inflammatory response induced by Aβ. BV2 murine microglia cells treated with both Aβ peptide and extract showed a lower pro-inflammatory (, , ) and a higher anti-inflammatory (, , ) cytokine production compared to cells treated with Aβ only. The activation of the Nrf2-antioxidant response element signaling pathway in treated cells resulted in the upregulation of heme oxygenase-1 mRNA and in an increase of NAD(P)H:quinone oxidoreductase 1 activity. To establish whether the extract is also effective against Aβ-induced neurotoxicity in vivo, we evaluated its effect on the impaired climbing ability of AD Drosophila flies expressing human Aβ. Arabidopsis extract significantly restored the locomotor activity of these flies, thus confirming its neuroprotective effects also in vivo. These results point to a protective effect of the Arabidopsis extract in AD, and prompt its use as a model in studying the impact of complex mixtures derived from plant-based food on neurodegenerative diseases.
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http://dx.doi.org/10.3390/ijms20030708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387160PMC
February 2019

Proline synthesis in developing microspores is required for pollen development and fertility.

BMC Plant Biol 2018 Dec 17;18(1):356. Epub 2018 Dec 17.

Department of Biology and Biotechnology, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.

Background: In many plants, the amino acid proline is strongly accumulated in pollen and disruption of proline synthesis caused abortion of microspore development in Arabidopsis. So far, it was unclear whether local biosynthesis or transport of proline determines the success of fertile pollen development.

Results: We analyzed the expression pattern of the proline biosynthetic genes PYRROLINE-5-CARBOXYLATE SYNTHETASE 1 & 2 (P5CS1 & 2) in Arabidopsis anthers and both isoforms were strongly expressed in developing microspores and pollen grains but only inconsistently in surrounding sporophytic tissues. We introduced in a p5cs1/p5cs1 p5cs2/P5CS2 mutant background an additional copy of P5CS2 under the control of the Cauliflower Mosaic Virus (CaMV) 35S promoter, the tapetum-specific LIPID TRANSFER PROTEIN 12 (Ltp12) promoter or the pollen-specific At5g17340 promoter to determine in which site proline biosynthesis can restore the fertility of proline-deficient microspores. The specificity of these promoters was confirmed by β-glucuronidase (GUS) analysis, and by direct proline measurement in pollen grains and stage-9/10 anthers. Expression of P5CS2 under control of the At5g17340 promoter fully rescued proline content and normal morphology and fertility of mutant pollen. In contrast, expression of P5CS2 driven by either the Ltp12 or CaMV35S promoter caused only partial restoration of pollen development with little effect on pollen fertility.

Conclusions: Overall, our results indicate that proline transport is not able to fulfill the demand of the cells of the male germ line. Pollen development and fertility depend on local proline biosynthesis during late stages of microspore development and in mature pollen grains.
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http://dx.doi.org/10.1186/s12870-018-1571-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296085PMC
December 2018

Poly(ADP-ribosylated) proteins in β-amyloid peptide-stimulated microglial cells.

Biochem Pharmacol 2019 09 9;167:50-57. Epub 2018 Nov 9.

Department of Biochemical Sciences, Sapienza University Roma, Italy. Electronic address:

Amyloid-treated microglia prime and sustain neuroinflammatory processes in the central nervous system activating different signalling pathways inside the cells. Since a key role for PARP-1 has been demonstrated in inflammation and in neurodegeneration, we investigated PARylated proteins in resting and in β-amyloid peptide treated BV2 microglial cells. A total of 1158 proteins were identified by mass spectrometry with 117 specifically modified in the amyloid-treated cells. Intervention of PARylation on the proteome of microglia showed to be widespread in different cellular districts and to affect various cellular pathways, highlighting the role of this dynamic post-translational modification in cellular regulation. Ubiquitination is one of the more enriched pathways, encompassing PARylated proteins like NEDD4, an E3 ubiquitine ligase and USP10, a de-ubiquitinase, both associated with intracellular responses induced by β-amyloid peptide challenge. PARylation of NEDD4 may be involved in the recruiting of this protein to the plasma membrane where it regulates the endocytosis of AMPA receptors, whereas USP10 may be responsible for the increase of p53 levels in amyloid stimulated microglia. Unfolded protein response and Endoplasmic Reticulum Stress pathways, strictly correlated with the Ubiquitination process, also showed enrichment in PARylated proteins. PARylation may thus represent one of the molecular switches responsible for the transition of microglia towards the inflammatory microglia phenotype, a pivotal player in brain diseases including neurodegenerative processes. The establishment of trials with PARP inhibitors to test their efficacy in the containment of neurodegenerative diseases may be envisaged.
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http://dx.doi.org/10.1016/j.bcp.2018.10.026DOI Listing
September 2019

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome.

Transl Neurodegener 2018 6;7:28. Epub 2018 Nov 6.

1Department of Biochemical Sciences, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

Background: Down syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression. Within this context, the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena. By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol (InRapa) that maximizes brain delivery and reduce systemic side effects.

Methods: Ts65Dn mice were administered with InRapa for 12 weeks, starting at 6 months of age demonstrating, at the end of the treatment by radial arms maze and novel object recognition testing, rescued cognition.

Results: The analysis of mTOR signalling, after InRapa, demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR (reduced to physiological levels), which led, through the rescue of autophagy and insulin signalling, to reduced APP levels, APP processing and APP metabolites production, as well as, to reduced tau hyperphosphorylation. In addition, a reduction of oxidative stress markers was also observed.

Discussion: These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis, thus ultimately resulting in improved cognition. Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals.
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http://dx.doi.org/10.1186/s40035-018-0133-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218962PMC
November 2018

Hyaluronan-Based Nanohydrogels for Targeting Intracellular S. Aureus in Human Keratinocytes.

Adv Healthc Mater 2018 06 25;7(12):e1701483. Epub 2018 Apr 25.

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo Moro 5, Rome, 00185, Italy.

Staphylococcus aureus is one of the most significant human pathogens that is frequently isolated in a wide range of superficial and systemic infections. The ability of S. aureus to invade and survive within host cells such as keratinocytes and host immune cells has been increasingly recognized as a potential factor in persistent infections and treatment failures. The incorporation of antibiotics into hyaluronan-cholesterol nanohydrogels represents a novel paradigm in the delivery of therapeutic agents against intracellular bacteria. The work presented herein shows that NHs quickly enter human keratinocytes and accumulate into lysosomes. When used for targeting intracellular S. aureus the antimicrobial activity of loaded levofloxacin is enhanced, possibly changing the antibiotic intracellular fate from cytosol to lysosome. Indeed, gentamicin, an antibiotic that predominantly accumulates in lysosomes, shows significant and equal antibacterial activity when entrapped into NHs. These results strongly suggest that lysosomal formulations may display preferential activity toward intracellular S. aureus, opening new avenues for the use of HA-based NHs for treatment of such skin infections.
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http://dx.doi.org/10.1002/adhm.201701483DOI Listing
June 2018

Erratum to: HPLC Determination of Bioactive Sulfur Compounds, Amino Acids and Biogenic Amines in Biological Specimens.

Adv Exp Med Biol 2017 ;975:E1

Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro, 00185, Rome, Italy.

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http://dx.doi.org/10.1007/978-94-024-1079-2_97DOI Listing
January 2017

Behind Resveratrol Stabilization by Carboxymethylated (1,3/1,6)-β-d-Glucan: Does the Polyphenol Play a Role in Polymer Structural Organization?

Int J Mol Sci 2017 Sep 19;18(9). Epub 2017 Sep 19.

Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, 00185 Rome, Italy.

Resveratrol stability in solution can be improved by combining the polyphenol with carboxymethylated (1,3/1,6)-β-d-glucan (CM-glucan), a carbohydrate polymer widely used in the food and pharmaceutical industries. The present work was undertaken to elucidate the mechanism behind this stabilizing effect. The supramolecular structural, physico-chemical and morphological features of the CM-glucan/resveratrol complex have been studied under different physical and chemical stimuli by means of spectroscopic techniques, microscopy and physical methods such as UV-Visible spectroscopy (UV-Vis), spectrofluorimetry, Circular Dichroism (CD), Infrared spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM). Our experimental data indicate that CM-glucan conformational organized architecture in aqueous solution is enhanced in the presence of resveratrol, suggesting that the polyphenol is able to confer a high degree of order to the polymer by a probable cooperative structural organization that results in a long term stabilization for the polyphenol.
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http://dx.doi.org/10.3390/ijms18092006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618655PMC
September 2017

Carbonate Anion Radical Generated by the Peroxidase Activity of Copper-Zinc Superoxide Dismutase: Scavenging of Radical and Protection of Enzyme by Hypotaurine and Cysteine Sulfinic Acid.

Adv Exp Med Biol 2017;975 Pt 1:551-561

Dipartimento di Scienze Biochimiche, Sapienza Università di Roma, Piazzale Aldo Moro, Rome, Italy.

Copper-zinc superoxide dismutase (SOD) is considered one of the most important mammalian antioxidant defenses and plays a relevant role due to its main function in catalyzing the dismutation of superoxide anion to oxygen and hydrogen peroxide. However, interaction between SOD and HO produced a strong copper-bound oxidant (Cu(II)OH) that seems able to contrast the self-inactivation of the enzyme or oxidize other molecules through its peroxidase activity. The bicarbonate presence enhances the peroxidase activity and produces the carbonate anion radical (CO). CO is a freely diffusible reactive species capable of oxidizing several molecules that are unwieldy to access into the reactive site of the enzyme. Cu(II)OH oxidizes bicarbonate to the CO, which spreads out of the binding site and oxidizes hypotaurine and cysteine sulfinic acid to the respective sulfonates through an efficient reaction. These findings suggest a defense role for sulfinates against the damage caused by CO . The effect of hypotaurine and cysteine sulfinic acid on the CO-mediated oxidation of the peroxidase probe ABTS to ABTS cation radical (ABTS) has been studied. Both sulfinates are able to inhibit the oxidation of ABTS mediated by CO. The effect of hypotaurine and cysteine sulfinic acid against SOD inactivation by HO (~42% protection of enzyme activity) has also been investigated. Interestingly, hypotaurine and cysteine sulfinic acid partially avoid the HO-mediated SOD inactivation, suggesting that the two sulfinates may have access to the SOD reactive site and preserve it by reacting with the copper-bound oxidant. In this way hypotaurine and cysteine sulfinic acid not only intercept CO which could move out from the reactive site and cause oxidative damage, but also prevents the inactivation of SOD.
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http://dx.doi.org/10.1007/978-94-024-1079-2_43DOI Listing
October 2018

HPLC Determination of Bioactive Sulfur Compounds, Amino Acids and Biogenic Amines in Biological Specimens.

Adv Exp Med Biol 2017;975 Pt 1:535-549

Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro, 00185, Rome, Italy.

There is an increasing interest for analytical methods aimed to detect biological sulfur-containing amines, because of their involvement in human diseases and metabolic disorders. This work describes an improved HPLC method for the determination of sulfur containing amino acids and amines from different biological matrices. We optimized a pre-column derivatization procedure using dabsyl chloride, in which dabsylated products can be monitored spectrophotometrically at 460 nm. This method allows the simultaneous analysis of biogenic amines, amino acids and sulfo-amino compounds including carnosine, dopamine, epinephrine, glutathione, cysteine, taurine, lanthionine, and cystathionine in brain specimens, urines, plasma, and cell lysates. Moreover, the method is suitable for the study of physiological and non-physiological derivatives of taurine and glutathione such as hypotaurine, homotaurine, homocysteic acid and S-acetylglutathione. The present method displays good efficiency of derivatization, having the advantage to give rise to stable products compared to other derivatizing agents such as o-phthalaldehyde and dansyl chloride.With this method, we provide a tool to study sulfur cycle from a metabolic point of view in relation to the pattern of biological amino-compounds, allowing researchers to get a complete scenario of organic sulfur and amino metabolism in tissues and cells.
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http://dx.doi.org/10.1007/978-94-024-1079-2_42DOI Listing
October 2018

Studies on Trans-Resveratrol/Carboxymethylated (1,3/1,6)-β-d-Glucan Association for Aerosol Pharmaceutical Applications.

Int J Mol Sci 2017 May 3;18(5). Epub 2017 May 3.

Department of Biochemical Sciences, "Sapienza" University of Rome, Piazzale Aldo Moro, 5, 00185 Roma, Italy.

A resveratrol/carboxymethylated glucan (CM-glucan) combination is known to inhibit rhinovirus replication and expression of inflammatory mediators in nasal epithelia. The aim of this study was to develop an aerosol formulation containing an association of the two molecules which could reach the lower respiratory tract. Mass median aerodynamic diameter (MMAD) of a resveratrol/CM-glucan combination was lower than that shown by resveratrol or CM-glucan alone (2.83 versus 3.28 and 2.96 µm, respectively). The resveratrol/CM-glucan association results in the finest and most monodispersed particles in comparison to the two single components. The association also evidenced lower values for all particle size distribution parameters, suggesting that the pharmacological synergy observed in previous studies may be accompanied by a pharmaceutical one. Moreover, we showed that the CM-glucan matrix did not exert an inhibitory effect on resveratrol nebulization, demonstrating the good suitability of these two molecules in association for simultaneous aerosol volatilization.
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http://dx.doi.org/10.3390/ijms18050967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454880PMC
May 2017

Extra-virgin olive oil phenols block cell cycle progression and modulate chemotherapeutic toxicity in bladder cancer cells.

Oncol Rep 2016 Dec 5;36(6):3095-3104. Epub 2016 Oct 5.

Department of Medical‑Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy.

Epidemiological data indicate that the daily consumption of extra‑virgin olive oil (EVOO), a common dietary habit of the Mediterranean area, lowers the incidence of certain types of cancer, in particular bladder neoplasm. The aim of the present study was to evaluate the antiproliferative activity of polyphenols extracted from EVOO on bladder cancer (BCa), and to clarify the biological mechanisms that trigger cell death. Furthermore, we also evaluated the ability of low doses of extra‑virgin olive oil extract (EVOOE) to modulate the in vitro activity of paclitaxel or mitomycin, two antineoplastic drugs used in the management of different types of cancer. Our results showed that EVOOE significantly inhibited the proliferation and clonogenic ability of T24 and 5637 BCa cells in a dose‑dependent manner. Furthermore, cell cycle analysis after EVOOE treatment showed a marked growth arrest prior to mitosis in the G2/M phase for both cell lines, with the subsequent induction of apoptosis only in the T24 cells. Notably, simultaneous treatment of mitomycin C and EVOOE reduced the drug cytotoxicity due to inhibition of ROS production. Conversely, the co‑treatment of T24 cells with paclitaxel and the polyphenol extract strongly increased the apoptotic cell death at each tested concentration compared to paclitaxel alone. Our results support the epidemiological evidence indicating that olive oil consumption exerts health benefits and may represent a starting point for the development of new anticancer strategies.
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http://dx.doi.org/10.3892/or.2016.5150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112608PMC
December 2016

Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions.

J Alzheimers Dis 2016 08;54(1):307-24

Department of Biochemical Sciences, Sapienza University, Roma, Italy.

Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer's transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer's disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism.
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http://dx.doi.org/10.3233/JAD-151040DOI Listing
August 2016

Evaluation of different extraction methods from pomegranate whole fruit or peels and the antioxidant and antiproliferative activity of the polyphenolic fraction.

Food Chem 2016 Jul 27;202:59-69. Epub 2016 Jan 27.

Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma "La Sapienza", piazzale Aldo Moro, 5 - 00185 Roma, Italy.

Pomegranate is a functional food of great interest, due to its multiple beneficial effects on human health. This fruit is rich in anthocyanins and ellagitannins, which exert a protective role towards degenerative diseases. The aim of the present work was to optimize the extraction procedure, from different parts of the fruit, to obtain extracts enriched in selected polyphenols while retaining biological activity. Whole fruits or peels of pomegranate cultivars, with different geographic origin, were subjected to several extraction methods. The obtained extracts were analyzed for polyphenolic content, evaluated for antioxidant capacity and tested for antiproliferative activity on human bladder cancer T24 cells. Two different extraction procedures, employing ethyl acetate as a solvent, were useful in obtaining extracts enriched in ellagic acid and/or punicalagins. Antioxidative and antiproliferative assays demonstrated that the antioxidant capability is directly related to the phenolic content, whereas the antiproliferative activity is to be mainly attributed to ellagic acid.
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http://dx.doi.org/10.1016/j.foodchem.2016.01.106DOI Listing
July 2016

Resveratrol inhibits rhinovirus replication and expression of inflammatory mediators in nasal epithelia.

Antiviral Res 2015 Nov 19;123:15-21. Epub 2015 Aug 19.

Department of Biochemical Sciences, Sapienza University, I-00185 Rome, Italy.

Human rhinoviruses (HRV), the cause of common colds, are the most frequent precipitants of acute exacerbation of asthma and chronic obstructive pulmonary disease, as well as causes of other serious respiratory diseases. No vaccine or antiviral agents are available for the prevention or treatment of HRV infection. Resveratrol exerts antiviral effect against different DNA and RNA viruses. The antiviral effect of a new resveratrol formulation containing carboxymethylated glucan was analyzed in H1HeLa cell monolayers and ex vivo nasal epithelia infected with HRV-16. Virus yield was evaluated by plaque assay and expression of viral capsid proteins by Western blot. IL-10, IFN-β, IL-6, IL-8 and RANTES levels were evaluated by ELISA assay. ICAM-1 was assessed by Western blot and immunofluorescence. Resveratrol exerted a high, dose-dependent, antiviral activity against HRV-16 replication and reduced virus-induced secretion of IL-6, IL-8 and RANTES to levels similar to that of uninfected nasal epithelia. Basal levels of IL-6 and RANTES were also significantly reduced in uninfected epithelia confirming an anti-inflammatory effect of the compound. HRV-induced expression of ICAM-1 was reversed by resveratrol. Resveratrol may be useful for a therapeutic approach to reduce HRV replication and virus-induced cytokine/chemokine production.
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http://dx.doi.org/10.1016/j.antiviral.2015.08.010DOI Listing
November 2015

Neuroprotective Effect of Brassica oleracea Sprouts Crude Juice in a Cellular Model of Alzheimer's Disease.

Oxid Med Cell Longev 2015 9;2015:781938. Epub 2015 Jun 9.

Department of Biochemical Sciences, Sapienza University, Rome, Italy.

Unlabelled: β-Amyloid peptide (Aβ) aberrant production and aggregation are major factors implicated in the pathogenesis of Alzheimer's disease (AD), causing neuronal death via oxidative stress. Several studies have highlighted the importance of polyphenolic antioxidant compounds in the treatment of AD, but complex food matrices, characterized by a different relative content of these phytochemicals, have been neglected. In the present study, we analyzed the protective effect on SH-SY5Y cells treated with the fragment Aβ 25-35 by two crude juices of broccoli sprouts containing different amounts of phenolic compounds as a result of different growth conditions. Both juices protected against Aβ-induced cytotoxicity and apoptotic cell death as evidenced by cell viability, nuclear chromatin condensation, and apoptotic body formation measurements. These effects were mediated by the modulation of the mitochondrial function and of the HSP70 gene transcription and expression. Furthermore, the juices upregulated the intracellular glutathione content and mRNA levels or activity of antioxidant enzymes such as heme oxygenase-1, thioredoxin, thioredoxin reductase, and

Nad(p)h: quinone oxidoreductase 1 via activation of NF-E2-related factor 2 (Nrf2). Although the effects of the two juices were similar, the juice enriched in phenolic compounds showed a greater efficacy in inducing the activation of the Nrf2 signalling pathway.
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http://dx.doi.org/10.1155/2015/781938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477226PMC
April 2016