Publications by authors named "Anna Malfitano"

67 Publications

Cytokine storm syndrome in a young patient with cystic fibrosis.

Pediatr Pulmonol 2021 Oct 22;56(10):3435-3437. Epub 2021 Jul 22.

Cystic Fibrosis Regional Reference Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

We report the case of a patient with cystic fibrosis (CF) presenting with a full-blown cytokine storm syndrome probably triggered by infection. This condition is rare and the diagnosis can be particularly difficult in patients with a complex chronic disease such as CF. However, timely recognition and appropriate treatment in the early stages are key to avoiding a potentially fatal course.
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http://dx.doi.org/10.1002/ppul.25579DOI Listing
October 2021

Self-assembly of bio-inspired heterochiral peptides.

Bioorg Chem 2021 Sep 30;114:105047. Epub 2021 May 30.

Department of Pharmacy, University of Naples "Federico II", Italy. Electronic address:

Peptide hydrogels, deriving from natural protein fragments, present unique advantages as compatibility and low cost of production that allow their wide application in different fields as wound healing, cell delivery and tissue regeneration. To engineer new biomaterials, the change of the chirality of single amino acids demonstrated a powerful approach to modulate the self-assembly mechanism. Recently we unveiled that a small stretch spanning residues 268-273 in the C-terminal domain (CTD) of Nucleophosmin 1 (NPM1) is an amyloid sequence. Herein, we performed a systematic D-scan of this sequence and analyzed the structural properties of obtained peptides. The conformational and kinetic features of self-aggregates and the morphologies of derived microstructures were investigated by means of different biophysical techniques, as well as the compatibility of hydrogels was evaluated in HeLa cells. All the investigated hexapeptides formed hydrogels even if they exhibited different conformational intermediates during aggregation, and they structural featured are finely tuned by introduced chiralities.
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http://dx.doi.org/10.1016/j.bioorg.2021.105047DOI Listing
September 2021

Conformational consequences of NPM1 rare mutations: An aggregation perspective in Acute Myeloid Leukemia.

Bioorg Chem 2021 08 18;113:104997. Epub 2021 May 18.

Department of Pharmacy, University of Naples "Federico II", 80134 Naples, Italy. Electronic address:

Often proteins association is a physiological process used by cells to regulate their growth and to adapt to different stress conditions, including mutations. In the case of a subtype of Acute Myeloid Leukemia (AML), mutations of nucleophosmin 1 (NPM1) protein cause its aberrant cytoplasmatic mislocalization (NPMc+). We recently pointed out an amyloidogenic propensity of protein regions including the most common mutations of NPMc+ located in the C-terminal domain (CTD): they were able to form, in vitro, amyloid cytotoxic aggregates with fibrillar morphology. Herein, we analyzed the conformational characteristics of several peptides including rare AML mutations of NPMc+. By means of different spectroscopic, microscopic and cellular assays we evaluated the importance of amino acid composition, among rare AML mutations, to determine amyloidogenic propensity. This study could add a piece of knowledge to the structural consequences of mutations in cytoplasmatic NPM1c+.
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http://dx.doi.org/10.1016/j.bioorg.2021.104997DOI Listing
August 2021

A Comparative Study of the Effects of Platinum (II) Complexes on β-Amyloid Aggregation: Potential Neurodrug Applications.

Int J Mol Sci 2021 Mar 16;22(6). Epub 2021 Mar 16.

Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.

Herein the effects of three platinum complexes, namely (-4-2)-(2,2'-bipyridine)dichloridoplatinum(II), Pt-bpy, (-4-2)-dichlorido(1,10-phenanthroline) platinum(II), Pt-phen, and (-4-2)-chlorido(2,2':6',2''-terpyridine)platinum(II) chloride, Pt-terpy, on the aggregation of an amyloid model system derived from the C-terminal domain of Aβ peptide (Aβ) were investigated. Thioflavin T (ThT) binding assays revealed the ability of Pt(II) compounds to repress amyloid aggregation in a dose-dependent way, whereas the ability of Aβ peptide to interfere with ligand field of metal complexes was analyzed through UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. Spectroscopic data provided micromolar EC values and allowed to assess that the observed inhibition of amyloid aggregation is due to the formation of adducts between Aβ peptide and complexes upon the release of labile ligands as chloride and that they can explore different modes of coordination toward Aβ with respect to the entire Aβ polypeptide. In addition, conformational studies through circular dichroism (CD) spectroscopy suggested that Pt-terpy induces soluble β-structures of monomeric Aβ, thus limiting self-recognition. Noticeably, Pt-terpy demonstrated the ability to reduce the cytotoxicity of amyloid peptide in human SH-SY5Y neuroblastoma cells. Presented data corroborate the hypothesis to enlarge the application field of already known metal-based agents to neurodegenerative diseases, as potential neurodrugs.
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http://dx.doi.org/10.3390/ijms22063015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998721PMC
March 2021

Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of the Oncolytic Virus in Malignant Mesothelioma Cell Lines.

Int J Mol Sci 2020 Oct 4;21(19). Epub 2020 Oct 4.

Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.

Malignant mesothelioma (MM) is a very aggressive asbestos-related cancer, for which no therapy proves to be effective. We have recently shown that the oncolytic adenovirus had antitumor effects in MM cell lines and murine xenografts. Previous studies demonstrated that -induced host cell cycle checkpoint deregulation and consequent DNA lesions associated with the virus efficacy. However, the cellular DNA damage response (DDR) can counteract this virus action. Therefore, we assessed whether AZD1775, an inhibitor of the G2/M DNA damage checkpoint kinase WEE1, could enhance MM cell sensitivity to . Through cell viability assays, we found that AZD1775 synergized with selectively in MM cell lines and increased -induced cell death, which showed hallmarks of apoptosis (annexinV-positivity, caspase-dependency, BCL-XL decrease, chromatin condensation). Predictably, and/or AZD1775 activated the DDR, as indicated by increased levels of three main DDR players: phosphorylated histone H2AX (γ-H2AX), phospho-replication protein A (RPA)32, phospho-checkpoint kinase 1 (CHK1). also increased inactive Tyr-15-phosphorylated cyclin-dependent kinase 1 (CDK1), a key WEE1 substrate, which is indicative of G2/M checkpoint activation. This increase in phospho-CDK1 was effectively suppressed by AZD1775, thus suggesting that this compound could, indeed, abrogate the -induced DNA damage checkpoint in MM cells. Overall, our data suggest that the -AZD1775 combination could be a feasible strategy against MM.
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http://dx.doi.org/10.3390/ijms21197333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582744PMC
October 2020

Proteostasis unbalance of nucleophosmin 1 in Acute Myeloid Leukemia: An aggregomic perspective.

Int J Biol Macromol 2020 Dec 2;164:3501-3507. Epub 2020 Sep 2.

Department of Pharmacy, University of Naples "Federico II", 80134, Italy. Electronic address:

The role exerted by the nucleus in the regulation of proteostasis in both health and disease is recognized of outmost importance, even though not fully understood. Many recent investigations are focused on its ability to modulate and coordinate protein quality control machineries in mammalian cells. Nucleophosmin 1 (NPM1) is one of the most abundant nucleolar proteins and its gene is mutated in ~30% of Acute Myeloid Leukemia (AML) patients. Mutations are localized in the C-terminal domain of the protein and cause cytoplasmatically delocalized and possibly aggregated forms of NPM1 (NPM1c+). Therapeutic interventions targeted on NPM1c+ are in demand and, to this end, deeper knowledge of NPM1c+ behavior in the blasts' cytosol is required. Here by means of complementary biophysical techniques we compared the conformational and aggregative behavior of the entire C-terminal domains of NPM1wt and type A NPM1c+ (bearing the most common mutation). Overall data show that only Cterm_mutA is able to form amyloid-like assemblies with fibrillar morphology and that the oligomers are toxic in human neuroblastoma SHSY cells. This study adds a novel piece of knowledge to the comprehension of the molecular roles exerted by cytoplasmatic NPM1c+ and suggests the exploitation of the amyloidogenic propensity of NPM1c+ as a new strategy for targeting AML with NPM1 mutations.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.08.248DOI Listing
December 2020

Tumor-Associated Macrophage Status in Cancer Treatment.

Cancers (Basel) 2020 Jul 21;12(7). Epub 2020 Jul 21.

Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy.

Tumor-associated macrophages (TAMs) represent the most abundant innate immune cells in tumors. TAMs, exhibiting anti-inflammatory phenotype, are key players in cancer progression, metastasis and resistance to therapy. A high TAM infiltration is generally associated with poor prognosis, but macrophages are highly plastic cells that can adopt either proinflammatory/antitumor or anti-inflammatory/protumor features in response to tumor microenvironment stimuli. In the context of cancer therapy, many anticancer therapeutics, apart from their direct effect on tumor cells, display different effects on TAM activation status and density. In this review, we aim to evaluate the indirect effects of anticancer therapies in the modulation of TAM phenotypes and pro/antitumor activity.
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http://dx.doi.org/10.3390/cancers12071987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409350PMC
July 2020

Virotherapy: From single agents to combinatorial treatments.

Biochem Pharmacol 2020 07 21;177:113986. Epub 2020 Apr 21.

Dipartimento di Scienze Mediche Traslazionali, Università Federico II Napoli, Italy. Electronic address:

Virotherpay is emerging as a promising strategy against cancer, and three oncolytic viruses (OVs) have gained approval in different countries for the treatment of several cancer types. Beyond the capability to selectively infect, replicate and lyse cancer cells, OVs act through a multitude of events, including modification of the tumour micro/macro-environment as well as a complex modulation of the anti-tumour immune response by activation of danger signals and immunogenic cell death pathways. Most OVs show limited effects, depending on the viral platform and the interactions with the host. OVs used as monotherapy only in a minority of patients elicited a full response. Better outcomes were obtained using OVs in combination with other treatments, such as immune therapy or chemotherapy, suggesting that the full potential of OVs can be unleashed in combination with other treatment modalities. Here, we report the main described combination of OVs with conventional chemotherapeutic agents: platinum salts, mitotic inhibitors, anthracyclines and other antibiotics, anti-metabolites, alkylating agents and topoisomerase inhibitors. Additionally, our work provides an overview of OV combination with targeted therapies: histone deacetylase inhibitors, kinase inhibitors, monoclonal antibodies, inhibitors of DNA repair, inhibitors of the proteasome complex and statins that demonstrated enhanced OV anti-neoplastic activity. Although further studies are required to assess the best combinations to translate the results in the clinic, it is clear that combined therapies, acting with complementary mechanisms of action might be useful to target cancer lesions resistant to currently available treatments.
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http://dx.doi.org/10.1016/j.bcp.2020.113986DOI Listing
July 2020

Reply to Comment on "Malfitano, A.M. et al. Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer" 2019, , 1532.

Cancers (Basel) 2020 Jan 23;12(2). Epub 2020 Jan 23.

Dipartimento di Scienze Mediche Traslazionali, Università Federico II Napoli, URT "Genomic of Diabetes" of Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research (CNR), 80131 Naples, Italy.

Our work is focused on the future clinical use of oncolytic viruses (OVs) for the treatment of aggressive thyroid carcinomas. Therefore, we provide a brief description of the overall use of OVs in the clinic. Rigvir is among the few OVs that have already been used for the treatment of patients, and studies describing its effects have been briefly commented and cited in our text [1]. [...].
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http://dx.doi.org/10.3390/cancers12020281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073196PMC
January 2020

G-Quadruplex Binders Induce Immunogenic Cell Death Markers in Aggressive Breast Cancer Cells.

Cancers (Basel) 2019 Nov 15;11(11). Epub 2019 Nov 15.

Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy.

Background: DNA G-quadruplex (G4) structures represent potential anti-cancer targets. In this study, we compared the effect of two G4-targeting compounds, C066-3108 and the gold standard BRACO-19.

Methods: In breast and prostate cancer cells, cytotoxicity induced by both molecules was measured by a sulforhodamine B assay. In breast cancer cells, cycle, apoptosis, the formation of G4 structures, calreticulin and high mobility group box 1 (HMGB1), as well as T cell activation, were analyzed by flow cytometry and adenosine triphosphate (ATP) by luminescence.

Results: Both ligands inhibited cell survival and induced DNA damage. In MCF-7 cells, G4 ligands increased the subG0/G1 phase of the cell cycle inducing apoptosis and reduced intracellular ATP. In untreated MCF-7 cells, we observed a slight presence of G4 structures associated with the G2/M phase. In MDA-MB231 cells, G4 ligands decreased the G1 and enhanced the G2/M phase. We observed a decrease of intracellular ATP, calreticulin cell surface exposure and an increase of HMGB1, accompanied by T cell activation. Both compounds induced G4 structure formation in the subG0/G1 phase.

Conclusions: Our data report similar effects for both compounds and the first evidence that G4 ligands induce the release of danger signals associated with immunogenic cell death and induction of T cell activation.
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http://dx.doi.org/10.3390/cancers11111797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895816PMC
November 2019

Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer.

Cancers (Basel) 2019 Oct 10;11(10). Epub 2019 Oct 10.

Dipartimento di Scienze Mediche Traslazionali, Università Federico II Napoli, URT "Genomic of Diabetes" of Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research (CNR), 80131 Naples, Italy.

Virotherapy is a novel cancer treatment based on oncolytic viruses (OVs), which selectively infect and lyse cancer cells, without harming normal cells or tissues. Several viruses, either naturally occurring or developed through genetic engineering, are currently under investigation in clinical studies. Emerging reports suggesting the immune-stimulatory property of OVs against tumor cells further support the clinical use of OVs for the treatment of lesions lacking effective therapies. Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), have a poor prognosis and limited treatment options. Therefore, several groups investigated the therapeutic potential of OVs in PDTC/ATC models producing experimental data sustaining the potential clinical efficacy of OVs in these cancer models. Moreover, the presence of an immunosuppressive microenvironment further supports the potential use of OVs in ATC. In this review, we present the results of the studies evaluating the efficacy of OVs alone or in combination with other treatment options. In particular, their potential therapeutic combination with multiple kinases inhibitors (MKIs) or immune checkpoint inhibitors are discussed.
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http://dx.doi.org/10.3390/cancers11101532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826611PMC
October 2019

The Oncolytic Virus 922-947 Triggers Immunogenic Cell Death in Mesothelioma and Reduces Xenograft Growth.

Front Oncol 2019 12;9:564. Epub 2019 Jul 12.

Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori IRCCS, Fondazione G. Pascale, Naples, Italy.

Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with asbestos exposure that urgently requires effective therapeutic strategies. Current treatments are unable to increase significantly patient survival, which is often limited to <1 year from diagnosis. Virotherapy, based on the use of oncolytic viruses that exert anti-cancer effects by direct cell lysis and through the induction of anti-tumor immune response, represents an alternative therapeutic option for rare tumors with limited life expectancy. In this study, we propose the use of the adenovirus 922-947, engineered to allow selective replication in cancer cells, to counteract MPM. We performed a thorough preclinical assessment of 922-947 effects in a set of MPM cell lines and xenografts. Cytotoxicity of 922-947 alone and in combination assays was evaluated by sulforhodamine B assay. Cell cycle, calreticulin expression, and high mobility group box protein 1 (HMGB1) secretion were determined by flow cytometry, whereas ATP content was determined by a luminescence-based bioassay. The modulation of angiogenic factors in MPM-infected cells was evaluated through ELISA. We found that 922-947 infection exhibits cytotoxic effects in MPM cell lines, affecting cell viability, cell cycle progression, and regulating main hallmarks of immunogenic cell death inducing calreticulin surface exposure, HMGB1 and ATP release. Our results also suggest that 922-947 may affect angiogenic signals by regulation of VEGF-A and IL-8 secretion. Furthermore, 922-947 shows anti-tumor efficacy in murine xenograft models reducing tumor growth and enhancing survival. Finally, the combination with cisplatin potentiated the cytotoxic effect of 922-947. Overall our data identify virotherapy, based on the use of 922-947, as a new possible therapeutic strategy against MPM, which could be used alone, in combination with standard chemotherapy drugs, as shown here, or other approaches also aimed at enhancing the antitumoral immune response elicited by the virus.
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http://dx.doi.org/10.3389/fonc.2019.00564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639422PMC
July 2019

Platinum(II) , Complexes Inhibit the Aggregation of Amyloid Model Systems.

Int J Mol Sci 2019 Feb 14;20(4). Epub 2019 Feb 14.

Department of Pharmacy, University of Naples Federico II, Napoli 80134, Italy.

Platinum(II) complexes with different cinnamic acid derivatives as ligands were investigated for their ability to inhibit the aggregation process of amyloid systems derived from Aβ, Yeast Prion Protein Sup35p and the C-terminal domain of nucleophosmin 1. Thioflavin T binding assays and circular dichroism data indicate that these compounds strongly inhibit the aggregation of investigated peptides exhibiting IC values in the micromolar range. MS analysis confirms the formation of adducts between peptides and Pt(II) complexes that are also able to reduce amyloid cytotoxicity in human SH-SY5Y neuroblastoma cells. Overall data suggests that bidentate ligands based on β-hydroxy dithiocinnamic esters can be used to develop platinum or platinoid compounds with anti-amyloid aggregation properties.
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http://dx.doi.org/10.3390/ijms20040829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413125PMC
February 2019

Structural insights into amyloid structures of the C-terminal region of nucleophosmin 1 in type A mutation of acute myeloid leukemia.

Biochim Biophys Acta Proteins Proteom 2019 06 30;1867(6):637-644. Epub 2019 Jan 30.

Department of Pharmacy, University of Naples "Federico II", Italy. Electronic address:

Acute myeloid leukemia (AML) is a clinically and a molecularly heterogeneous disease characterized by the accumulation of undifferentiated and uncontrolled proliferation of hematopoietic progenitor cells. The sub-group named "AML with gene mutations" includes mutations in nucleophosmin (NPM1) assumed as a distinct leukemic entity. NPM1 is an abundant multifunctional protein belonging to the nucleoplasmin family of nuclear chaperones. AML mutated protein is translocated into the cytoplasm (NPM1c+) retaining all functional domains except the loss of a unique NoLs (nucleolar localization signal) at the C-term domain (CTD) and the subsequent disruption of a three helix bundle as tertiary structure. The oligomeric state of NPM1 is of outmost importance for its biological roles and our previous studies linked an aggregation propensity of distinct regions of CTD to leukomogenic potentials of AML mutations. Here we investigated a polypeptide spanning the third and second helices of the bundle of type A mutated CTD. By a combination of several techniques, we ascertained the amyloid character of the aggregates and of fibrils resulting from a self-recognition mechanism. Further amyloid assemblies resulted cytoxic in MTT assay strengthening a new idea of a therapeutic strategy in AML consisting in the self-degradation of mutated NPM1.
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http://dx.doi.org/10.1016/j.bbapap.2019.01.010DOI Listing
June 2019

Nucleophosmin-1 regions associated with acute myeloid leukemia interact differently with lipid membranes.

Biochim Biophys Acta Gen Subj 2018 Apr 10;1862(4):967-978. Epub 2018 Jan 10.

Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.bbagen.2018.01.005DOI Listing
April 2018

Immuno-Modulatory and Anti-Inflammatory Effects of Dihydrogracilin A, a Terpene Derived from the Marine Sponge Dendrilla membranosa.

Int J Mol Sci 2017 Jul 28;18(8). Epub 2017 Jul 28.

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.

We assessed the immunomodulatory and anti-inflammatory effects of 9,11-dihydrogracilin A (DHG), a molecule derived from the Antarctic marine sponge . We used in vitro and in vivo approaches to establish DHG properties. Human peripheral blood mononuclear cells (PBMC) and human keratinocytes cell line (HaCaT cells) were used as in vitro system, whereas a model of murine cutaneous irritation was adopted for in vivo studies. We observed that DHG reduces dose dependently the proliferative response and viability of mitogen stimulated PBMC. In addition, DHG induces apoptosis as revealed by AnnexinV staining and downregulates the phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), signal transducer and activator of transcription (STAT) and extracellular signal-regulated kinase (ERK) at late time points. These effects were accompanied by down-regulation of interleukin 6 (IL-6) production, slight decrease of IL-10 and no inhibition of tumor necrosis factor-alpha (TNF-α) secretion. To assess potential properties of DHG in epidermal inflammation we used HaCaT cells; this compound reduces cell growth, viability and migration. Finally, we adopted for the in vivo study the croton oil-induced ear dermatitis murine model of inflammation. Of note, topical use of DHG significantly decreased mouse ear edema. These results suggest that DHG exerts anti-inflammatory effects and its anti-edema activity in vivo strongly supports its potential therapeutic application in inflammatory cutaneous diseases.
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http://dx.doi.org/10.3390/ijms18081643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578033PMC
July 2017

Characterization of linear mimetic peptides of Interleukin-22 from dissection of protein interfaces.

Biochimie 2017 Jul 4;138:106-115. Epub 2017 May 4.

Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134, Naples, Italy. Electronic address:

Interleukin-22 (IL-22) belongs to the family of IL-10 cytokines and is involved in a wide number of human diseases, including inflammatory disorders and cancer pathology. The ligand-receptor complex IL-22/IL-22R plays a key role in several pathways especially in the regulation and resolution of immune responses. The identification of novel compounds able to modulate IL-22/IL-22R complex could open the route to new therapeutic strategies in multiple human diseases. In this study, we designed and characterized IL-22 derived peptides at protein interface regions: several sequences revealed able to interfere with the protein complex with IC in the micromolar range as evaluated through Surface Plasmon Resonance (SPR) experiments. Their conformational characterization was carried out through Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopies, shedding new light into the features of IL-22 fragments and on structural determinants of IL-22/IL-22R1 recognition. Finally, several peptides were tested on human keratinocyte cultures for evaluating their ability to mimic the activation of molecular pathways downstream to IL-22R in response to IL-22 binding.
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http://dx.doi.org/10.1016/j.biochi.2017.05.002DOI Listing
July 2017

Cannabidiol: State of the art and new challenges for therapeutic applications.

Pharmacol Ther 2017 Jul 22;175:133-150. Epub 2017 Feb 22.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Italy; Corporea, Fondazione Idis-Città della Scienza, Naples, Italy. Electronic address:

Over the past years, several lines of evidence support a therapeutic potential of Cannabis derivatives and in particular phytocannabinoids. Δ-THC and cannabidiol (CBD) are the most abundant phytocannabinoids in Cannabis plants and therapeutic application for both compounds have been suggested. However, CBD is recently emerging as a therapeutic agent in numerous pathological conditions since devoid of the psychoactive side effects exhibited instead by Δ-THC. In this review, we highlight the pharmacological activities of CBD, its cannabinoid receptor-dependent and -independent action, its biological effects focusing on immunomodulation, angiogenetic properties, and modulation of neuronal and cardiovascular function. Furthermore, the therapeutic potential of cannabidiol is also highlighted, in particular in nuerological diseases and cancer.
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http://dx.doi.org/10.1016/j.pharmthera.2017.02.041DOI Listing
July 2017

Immunomodulatory properties of 1,2-dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxamide derivative VL15.

Biochimie 2017 Apr 20;135:173-180. Epub 2017 Feb 20.

Dipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126, Pisa, Italy. Electronic address:

1,2-Dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxamide derivative VL15 has been recently developed as a selective cannabinoid CB2 receptor compound. Given the high selectivity of this compound at the cannabinoid CB2 receptor and the well-known protective function of this receptor in neurological disorders with autoimmune component like multiple sclerosis, we assessed the immunomodulatory properties of VL15. We assessed on activated peripheral blood mononuclear cells), proliferation and viability, cell cycle progression and measured activation markers and the expression of phosphorylated proteins. We found that VL15 reduces PBMC proliferation slightly affecting cell vitality, blocks the cell cycle progression and down-regulates the levels of T cell activation markers as well as the expression of phosphorylated proteins, NF-kB, IKKαβ, IKBα, ERK and Akt. VL15 was also used in drug-permeability assays on Caco-2 cell line to evaluate its oral bioavailability and on MDCKII-hMDR1 cell lines to estimate its propensity to cross the blood-brain barrier by passive diffusion, in order to potentially maintain its efficiency on the infiltrating auto-reactive lymphocytes in the central nervous system. In these models, VL15 showed high intestinal absorption and good blood-brain barrier penetration. Our findings suggest that VL15, by controlling the immune response, might find potential application as orally administered drug in pathologies like multiple sclerosis.
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http://dx.doi.org/10.1016/j.biochi.2017.02.009DOI Listing
April 2017

Editorial (Thematic Issue: From Old Cannabinoids to Emerging New Synthetic Derivatives with Potential Therapeutic Application in Neurological Disorders).

Authors:
Anna M Malfitano

Recent Pat CNS Drug Discov 2016 ;10(2):75

Dep. of Medicine and Surgery, University of Salerno, Italy.

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http://dx.doi.org/10.2174/157488981002160919201100DOI Listing
September 2018

Endocannabinoid System in Neurological Disorders.

Recent Pat CNS Drug Discov 2016 ;10(2):90-112

Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, Baronissi, 84081 Salerno, Italy and Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 84084 Fisciano (Salerno)- Italy.

Background: Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others.

Methods: In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies.

Results: Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis. Current treatments ameliorate the symptoms but are not curative. Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration. To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions.

Conclusion: Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases.
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http://dx.doi.org/10.2174/1574889810999160719105433DOI Listing
July 2017

Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders.

Recent Pat CNS Drug Discov 2016 Jun 19. Epub 2016 Jun 19.

Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, Baronissi, 84081 Salerno, Italy.

Agents acting via cannabinoid receptors have been widely developed; starting from the chemical structure of phytocannabinoids isolated from cannabis sativa plant, specific and selective compounds of these receptors have been produced ranging from partial to full agonists and /or antagonists endowed with different potency. The enhanced interest on developing such classes of drugs is due to the beneficial properties widely reported by both anecdotal reports and scientific studies describing the potential medicinal use of cannabinoids and their derivatives in numerous pathological conditions in both in vitro and in vivo models. The use of these drugs has been found to be of benefit in a wide number of neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases, just to mention some. In particular, being the cannabinoid CB1 receptor a central receptor expressed by neurons of the central nervous system, the attention for the treatment of neurological diseases has been mainly focused on compounds acting via this receptor, however some of these compounds has been showed to act by alternative pathways in some cases unrelated to CB1 receptors. Nonetheless, endocannabinoids are potent regulators of the synaptic function in the central nervous system and their levels are modulated in neurological diseases. In this study, we focused on endocannabinoid mechanism of action in neuronal signaling and on cannabimimetic drug potential application in neurological disorders. Finally, novel patents on cannabis-based drugs with applicability in central nervous system disorders are highlighted, to suggest future potential therapeutic utility of derivatives of this ancient plant.
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June 2016

Cannabinoids and Neuro-Inflammation: Regulation of Brain Immune Response.

Recent Pat CNS Drug Discov 2016 ;10(2):178-203

Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, Baronissi, 84081 Salerno, Italy and Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 84084 Fisciano (Salerno)- Italy.

Background: Cannabinoid receptors are involved in the neuro-pathogenic mechanisms of inflammatory conditions of the central nervous system and their expression can be modulated during diseases.

Methods: In this manuscript we highlight the function of cannabinoid receptors, their signalling and expression at peripheral and central levels in order to understand their implication in neuro-inflammation and review the effects of cannabinoids in neuro-inflammatory disorders.

Results: Brain inflammatory processes are characterized by infiltration of numerous types of cells: both peripheral and brain resident immune cells and other neuronal cells. The disruption of the blood brain barrier favours cell infiltration in the central nervous system with consequent neuronal damage, a common event in many neuro-inflammatory diseases. Cannabinoids affect brain adaptive and immune response, regulate inflammatory mediators and can exert a role in blood brain barrier damage prevention.

Conclusion: Various patents describe the beneficial properties of cannabinoids in numerous neurodegenerative diseases with inflammatory components and overall effects support the therapeutic application of cannabinoids.
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http://dx.doi.org/10.2174/1574889810666160620103725DOI Listing
July 2017

Molecular signaling involving intrinsically disordered proteins in prostate cancer.

Asian J Androl 2016 Sep-Oct;18(5):673-81

Department of Pharmacy, Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples "Federico II", 80134 Naples, Italy.

Investigations on cellular protein interaction networks (PINs) reveal that proteins that constitute hubs in a PIN are notably enriched in Intrinsically Disordered Proteins (IDPs) compared to proteins that constitute edges, highlighting the role of IDPs in signaling pathways. Most IDPs rapidly undergo disorder-to-order transitions upon binding to their biological targets to perform their function. Conformational dynamics enables IDPs to be versatile and to interact with a broad range of interactors under normal physiological conditions where their expression is tightly modulated. IDPs are involved in many cellular processes such as cellular signaling, transcriptional regulation, and splicing; thus, their high-specificity/low-affinity interactions play crucial roles in many human diseases including cancer. Prostate cancer (PCa) is one of the leading causes of cancer-related mortality in men worldwide. Therefore, identifying molecular mechanisms of the oncogenic signaling pathways that are involved in prostate carcinogenesis is crucial. In this review, we focus on the aspects of cellular pathways leading to PCa in which IDPs exert a primary role.
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http://dx.doi.org/10.4103/1008-682X.181817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000787PMC
March 2017

Phytocannabinoids and Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders.

Recent Pat CNS Drug Discov 2016 ;10(2):157-177

Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, Baronissi, 84081 Salerno, Italy and Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 84084 Fisciano (Salerno)- Italy.

Background: Starting from the chemical structure of phytocannabinoids, isolated from Cannabis sativa plant, research groups designed numerous cannabimimetic drugs. These compounds according to their activities can be partial, full agonists and antagonists of cannabinoid receptors. Anecdotal reports and scientific studies described beneficial properties of cannabinoids and their derivatives in several pathological conditions like neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases.

Methods: In this study, starting from the endocannabinoid mechanism of action in neuronal signaling, we highlight and discuss potential application and recent patents of cannabimimetic drugs in neurological disorders.

Results: The cannabinoid CB1 receptor was considered particularly interesting for therapeutic approaches in neurological diseases, because primarily expressed by neurons of the central nervous system. In many experimental models, these drugs act via this receptor, however, CB1 receptor independent mechanisms have been also described. Furthermore, endogenous ligands of cannabinoid receptors, the endocannabinoids, are potent modulators of the synaptic function in the brain. In neurological diseases, numerous studies reported modulation of the levels of endocannabinoids according to the phase of the disease and its progression.

Conclusions: Finally, although the study of the mechanisms of action of these compounds is still unsolved, many reports and patents strongly suggest therapeutic potential of these compounds in neurological diseases.
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July 2017

Immuno-Modulatory Properties of a Quinolin-2-(1H)-on-3-Carboxamide Derivative: Relevance in Multiple Sclerosis.

Recent Pat CNS Drug Discov 2016 ;10(2):113-121

Background: We have recently released the structure of a class of quinolin-2-(1H)-on-3-carboxamide derivatives and among them; the drug A2 has the highest CB2 receptor selectivity.

Objective: In this work we assessed the immuno-modulatory properties of A2 in lymphocytes isolated from peripheral blood of multiple sclerosis patients and healthy donors.

Methods: Cell proliferative response was measured by 3H-thymidine incorporation, cell viability and apoptosis by trypan blue, annexin V staining and western blot. Cell activation was investigated by flow cytometry and molecular pathways by western blot.

Results: A2 exerted anti-proliferative effects with down-regulation of TNF-α, IL-10 and Rantes in both cell types. No relevant changes were observed in cell viability between the two cell types. In cells from healthy subjects, A2 did not induce apoptosis, inhibited the cell cycle and similarly down-regulated in CD4+T cells the markers CD69, CD25, CD49d and CD54. Indeed, A2 also inhibited the phosphorylation of Akt, NF-kB, IKKα/β, ERK and blocked the expression of Cox-2 and CB2 receptor. Published patents also describe CB2 receptor agonists like purine derivatives. Differently, in cells from patients, A2 did not affect CD49d, while potently blocked CD54 expression. A2 inhibitory effects of Akt and Cox-2 expression were confirmed, whereas unchanged level of the CB2 receptor was observed in these cells.

Conclusion: We reported similar effects of A2 in both cell types; however, a different mechanism of action might be suggested in cells from patients concerning cell activation and CB2 receptor expression. Overall, these data suggest an anti-inflammatory profile of A2 with potential implication in multiple sclerosis.
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http://dx.doi.org/10.2174/1574889810666160421121726DOI Listing
July 2017

Breast adiponcosis: a call for further research.

Endocrine 2017 Jan 4;55(1):326-327. Epub 2016 Jan 4.

Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, Baronissi, 84081, Salerno, Italy.

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http://dx.doi.org/10.1007/s12020-015-0839-8DOI Listing
January 2017

Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients' cells.

Oncotarget 2015 Jun;6(17):15464-81

Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.

Herein we show that a majority of human brain tumor samples and cell lines over-expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas. Functional studies, using U251MG glioma cells and primary tumor cell lines derived from glioma patients expressing different levels of CB1, highlighted SR141716 efficacy in inducing apoptosis via G1 phase stasis and block of TGF-β1 secretion through a mechanism that involves STAT3 inhibition. According to the multivariate role of STAT3 in the immune escape too, interestingly SR141716 lead also to the functional and selective expression of MICA/B on the surface of responsive malignant glioma cells, but not on NHA. This makes SR141716 treated-glioma cells potent targets for allogeneic NK cell-mediated recognition through a NKG2D restricted mechanism, thus priming them for NK cell antitumor reactivity. These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558164PMC
http://dx.doi.org/10.18632/oncotarget.3895DOI Listing
June 2015

New quinolone- and 1,8-naphthyridine-3-carboxamides as selective CB2 receptor agonists with anticancer and immuno-modulatory activity.

Eur J Med Chem 2015 Jun 24;97:10-8. Epub 2015 Apr 24.

Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.

Several recent studies suggest that selective CB2 receptor agonists may represent a valid pharmacological approach in the treatment of various diseases due to the absence of relevant psychoactive side effect. In this study, we synthesized and tested a series of new quinoline-2(1H)-one- and 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine derivatives characterized by a 4-methylcyclohexylamido substituent in position 3 of the heterocyclic nucleus with high CB2 receptor affinity and selectivity. Two compounds showing the best binding and selectivity profile behaved as a full agonist and a partial agonist at the CB2 receptor and induced a concentration-dependent decrease of cell viability on LNCaP, a prostatic cancer cell line expressing CB2 receptor. Moreover considering that the CB2 receptor is mainly expressed in cells and organs of the immune system, the same compounds were studied for their potential immune-modulatory and anti-inflammatory effects in activated lymphocytes isolated from healthy controls and multiple sclerosis (MS) patients.
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http://dx.doi.org/10.1016/j.ejmech.2015.04.034DOI Listing
June 2015

Comment on "the negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia.".

Haematologica 2015 Mar;100(3):e118-9

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, Fisciano, Salerno, Italy

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http://dx.doi.org/10.3324/haematol.2014.122168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349294PMC
March 2015
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