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Dive into the research topics where Liliana Lista is active.

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Featured researches published by Liliana Lista.


Molecular Cancer Therapeutics | 2009

Structure-based design of an urokinase-type plasminogen activator receptor–derived peptide inhibiting cell migration and lung metastasis

Maria Vincenza Carriero; Immacolata Longanesi-Cattani; Katia Bifulco; Ornella Maglio; Liliana Lista; Antonio Barbieri; Giuseppina Votta; Maria Teresa Masucci; Claudio Arra; Renato Franco; Mario De Rosa; Maria Patrizia Stoppelli; Vincenzo Pavone

The urokinase-type plasminogen activator receptor (uPAR) plays a central role in sustaining the malignant phenotype and promoting tumor metastasis. The Ser88-Arg-Ser-Arg-Tyr92 is the minimum chemotactic sequence of uPAR required to induce the same intracellular signaling as its ligand uPA. Here, we describe the generation of new peptide inhibitors of cell migration and invasion derived from SRSRY by a drug design approach. Ac-Arg-Glu-Arg-Phe-NH2 (i.e., RERF), which adopts a turned structure in solution, was selected for its ability to potently prevent SRSRY-directed cell migration. Fluorescein-RERF associates with very high affinity to RBL-2H3 rat basophilic leukemia cells expressing the human formyl peptide receptor (FPR). Accordingly, femtomolar concentrations of RERF prevent agonist-dependent internalization of FPR and inhibit N-formyl-Met-Leu-Phe–dependent migration in a dose-dependent manner. In the absence of FPR, fluorescein-RERF binds to cell surface at picomolar concentrations in an αv integrin–dependent manner. The involvement of vitronectin receptor is further supported by the findings that 100 pmol/L RERF selectively inhibits vitronectin-dependent RBL-2H3 cell migration and prevents SRSRY-triggered uPAR/αv association. Furthermore, RERF reduces the speed of wound closure and the extent of Matrigel invasion by human fibrosarcoma HT1080 cells without affecting cell proliferation. Finally, a 3- to 5-fold reduction of lung metastasis number and size in nude mice following i.v. injection of green fluorescent protein–expressing HT1080 cells in the presence of 3.32 mg/kg RERF is observed. Our findings indicate that RERF effectively prevents malignant cell invasion in vivo with no signs of toxicity and may represent a promising prototype drug for anticancer therapy. [Mol Cancer Ther 2009;8(9):2708–17]


Chemistry: A European Journal | 2012

De Novo Design, Synthesis and Characterisation of MP3, A New Catalytic Four‐Helix Bundle Hemeprotein

Marina Faiella; Ornella Maglio; Flavia Nastri; Angela Lombardi; Liliana Lista; Wilfred R. Hagen; Vincenzo Pavone

A new artificial metalloenzyme, MP3 (MiniPeroxidase 3), designed by combining the excellent structural properties of four-helix bundle protein scaffolds with the activity of natural peroxidases, was synthesised and characterised. This new hemeprotein model was developed by covalently linking the deuteroporphyrin to two peptide chains of different compositions to obtain an asymmetric helix-loop-helix/heme/helix-loop-helix sandwich arrangement, characterised by 1) a His residue on one chain that acts as an axial ligand to the iron ion; 2) a vacant distal site that is able to accommodate exogenous ligands or substrates; and 3) an Arg residue in the distal site that should assist in hydrogen peroxide activation to give an HRP-like catalytic process. MP3 was synthesised and characterised as its iron complex. CD measurements revealed the high helix-forming propensity of the peptide, confirming the appropriateness of the model procedure; UV/Vis, MCD and EPR experiments gave insights into the coordination geometry and the spin state of the metal. Kinetic experiments showed that Fe(III)-MP3 possesses peroxidase-like activity comparable to R38A-hHRP, highlighting the possibility of mimicking the functional features of natural enzymes. The synergistic application of de novo design methods, synthetic procedures, and spectroscopic characterisation, described herein, demonstrates a method by which to implement and optimise catalytic activity for an enzyme mimetic.


Journal of Thrombosis and Haemostasis | 2010

The soluble form of urokinase receptor promotes angiogenesis through its Ser88-Arg-Ser-Arg-Tyr92 chemotactic sequence

Katia Bifulco; Immacolata Longanesi-Cattani; M. Gala; G. Di Carluccio; Maria Teresa Masucci; Vincenzo Pavone; Liliana Lista; Claudio Arra; Maria Patrizia Stoppelli; Maria Vincenza Carriero

Summary.  Background: The urokinase plasminogen activator receptor (u‐PAR) focuses the proteolytic activity of the urokinase plasminogen activator (u‐PA) on the endothelial cell surface, thus promoting angiogenesis in a protease‐dependent manner. The u‐PAR may exist in a glycophosphatidylinositol‐anchored and in a soluble form (soluble u‐PAR [Su‐PAR]), both including the chemotactic Ser88‐Arg‐Ser‐Arg‐Tyr92 internal sequence. Objective: To investigate whether Su‐PAR may trigger endothelial cell signaling leading to new vessel formation through its chemotactic Ser88‐Arg‐Ser‐Arg‐Tyr92 sequence. Methods and Results: In this study, the formation of vascular‐like structures by human umbilical vein endothelial cells was assessed by using a matrigel basement membrane preparation. First, we found that Su‐PAR protein promotes the formation of cord‐like structures, and that this ability is retained by the isolated Ser88‐Arg‐Ser‐Arg‐Tyr92 chemotactic sequence, the maximal effect being reached at 10 nmol L−1 SRSRY peptide (SRSRY). This effect is mediated by the αvβ3 vitronectin receptor, is independent of u‐PA proteolytic activity, and involves the internalization of the G‐protein‐coupled formyl‐peptide receptor in endothelial cells. Furthermore, exposure of human saphenous vein rings to Su‐PAR or SRSRY leads to a remarkable degree of sprouting. Finally, we show that Su‐PAR and SRSRY promote a marked response in angioreactors implanted into the dorsal flank of nude mice, retaining 91% and 66%, respectively, of the angiogenic response generated by a mixture of vascular endothelial growth factor and fibroblast growth factor type 2. Conclusions: Our results show a new protease‐independent activity of Su‐PAR that stimulates in vivo angiogenesis through its Ser88‐Arg‐Ser‐Arg‐Tyr92 chemotactic sequence.


Molecular Cancer Therapeutics | 2014

UPARANT: A Urokinase Receptor–Derived Peptide Inhibitor of VEGF-Driven Angiogenesis with Enhanced Stability and In Vitro and In Vivo Potency

Maria Vincenza Carriero; Katia Bifulco; Michele Minopoli; Liliana Lista; Ornella Maglio; Luigi Mele; Gioconda Di Carluccio; Mario De Rosa; Vincenzo Pavone

This work is based on previous evidence showing that chemotactic sequence of the urokinase receptor (uPAR88-92) drives angiogenesis in vitro and in vivo in a protease-independent manner, and that the peptide Ac-Arg-Glu-Arg-Phe-NH2 (RERF) prevents both uPAR88–92- and VEGF-induced angiogenesis. New N-acetylated and C-amidated peptide analogues containing α-methyl α-amino acids were designed and synthesized to optimize the biochemical properties for therapeutic applications. Among these, Ac-L-Arg-Aib-L-Arg-D-Cα(Me)Phe-NH2, named UPARANT, adopts in solution a turned conformation similar to that found for RERF, is stable to sterilization in 3 mg/mL sealed vials in autoclave for 20 minutes at 120°C, is stable in blood, and displays a long-time resistance to enzymatic proteolysis. UPARANT competes with N-formyl-Met-Leu-Phe (fMLF) for binding to the formyl-peptide receptor, inhibits VEGF-directed endothelial cell migration, and prevents cytoskeletal organization and αvβ3 activation in endothelial cells exposed to VEGF. In vitro, UPARANT inhibits VEGF-dependent tube formation of endothelial cells at a 100× lower concentration than RERF. In vivo, UPARANT reduces to the basal level VEGF-dependent capillary sprouts originating from the host vessels that invaded Matrigel sponges implanted in mice, and completely prevents neovascularization induced by subcorneal implantation of pellets containing VEGF in rabbits. Both excellent stability and potency position UPARANT as a promising new therapeutic agent for the control of diseases fueled by excessive angiogenesis, such as cancer and inflammation. Mol Cancer Ther; 13(5); 1092–104. ©2014 AACR.


Steroids | 2006

Practical one-pot conversion of 17β-estradiol to 10β-hydroxy- (p-quinol) and 10β-chloro-17β-hydroxyestra-1,4-dien-3-one

Liliana Lista; Paola Manini; Alessandra Napolitano; Alessandro Pezzella; Marco d’Ischia

Abstract An efficient one-pot procedure for the preparation of 10β,17β-dihydroxyestra-1,4-dien-3-one (p-quinol, 1, 75%) is reported, involving oxidation of 17β-estradiol with potassium permanganate. Similar treatment of 17β-estradiol with sodium chlorite led to 10β-chloro-17β-hydroxyestra-1,4-dien-3-one (2) in 44% yield along with smaller amounts 4-chloro-10β,17β-dihydroxyestra-1,4-dien-3-one (3), 2,10β-dichloro-17β-hydroxyestra-1,4-dien-3-one (4), and 4,10β-dichloro-17β-hydroxyestra-1,4-dien-3-one (5).


Diabetologia | 2017

Inflammation and N-formyl peptide receptors mediate the angiogenic activity of human vitreous humour in proliferative diabetic retinopathy

Sara Rezzola; Michela Corsini; Paola Chiodelli; Anna Cancarini; Imtiaz M. Nawaz; Daniela Coltrini; Stefania Mitola; Roberto Ronca; Mirella Belleri; Liliana Lista; Dario Rusciano; Mario De Rosa; Vincenzo Pavone; Francesco Semeraro; Marco Presta

Aims/hypothesisAngiogenesis and inflammation characterise proliferative diabetic retinopathy (PDR), a major complication of diabetes mellitus. However, the impact of inflammation on the pathogenesis of PDR neovascularisation has not been elucidated. Here, we assessed the capacity of PDR vitreous fluid to induce pro-angiogenic/proinflammatory responses in endothelium and the contribution of the inflammation-related pattern recognition N-formyl peptide receptors (FPRs) in mediating these responses.MethodsPooled and individual pars plana vitrectomy-derived PDR vitreous fluid (‘PDR vitreous’) samples were assessed in endothelial cell proliferation, motility, sprouting and morphogenesis assays, and for the capacity to induce proinflammatory transcription factor activation, reactive oxygen species production, intercellular junction disruption and leucocyte-adhesion molecule upregulation in these cells. In vivo, the pro-angiogenic/proinflammatory activity of PDR vitreous was tested in murine Matrigel plug and chick embryo chorioallantoic membrane (CAM) assays. Finally, the FPR inhibitors Boc-Phe-Leu-Phe-Leu-Phe (Boc-FLFLF) and Ac-l-Arg-Aib-l-Arg-l-Cα(Me)Phe-NH2 tetrapeptide (UPARANT) were evaluated for their capacity to affect the biological responses elicited by PDR vitreous.ResultsPDR vitreous activates a pro-angiogenic/proinflammatory phenotype in endothelial cells. Accordingly, PDR vitreous triggers a potent angiogenic/inflammatory response in vivo. Notably, the different capacity of individual PDR vitreous samples to induce neovessel formation in the CAM correlates with their ability to recruit infiltrating CD45+ cells. Finally, the FPR inhibitor Boc-FLFLF and the novel FPR antagonist UPARANT inhibit neovessel formation and inflammatory responses triggered by PDR vitreous in the CAM assay.Conclusions/interpretationThis study provides evidence that inflammation mediates the angiogenic activity of PDR vitreous and paves the way for the development of FPR-targeting anti-inflammatory/anti-angiogenic approaches for PDR therapy.


Investigative Ophthalmology & Visual Science | 2016

The Urokinase Receptor-Derived Peptide UPARANT Mitigates Angiogenesis in a Mouse Model of Laser-Induced Choroidal Neovascularization

Maurizio Cammalleri; Massimo Dal Monte; Filippo Locri; Liliana Lista; Monica Aronsson; Anders Kvanta; Dario Rusciano; Mario De Rosa; Vincenzo Pavone; Helder André; Paola Bagnoli

PURPOSE A mouse model of age-related macular degeneration (AMD) was used to investigate the anti-angiogenic and anti-inflammatory role of UPARANT in laser-induced choroidal neovascularization (CNV). METHODS Choroidal neovascularization was induced by laser photocoagulation, and UPARANT was intravitreally injected. Some experiments were also performed after either intravitreal injection of anti-VEGF drugs or systemic administration of UPARANT. Immunohistochemistry using CD31 antibodies was used to evaluate the area of CNV. Evans blue dye extravasation was quantitatively assessed. Transcripts of markers of outer blood retinal barrier were measured by quantitative RT-PCR, also used to evaluate angiogenesis and inflammation markers. Western blot was used to determine levels of transcription factors encoding genes involved in angiogenesis and inflammation. Levels of urokinase-type plasminogen activator (uPA), its receptor (uPAR), and formyl peptide receptors (FPRs) were determined at the transcript and the protein level. RESULTS Intravitreal UPARANT reduced the CNV area and the leakage from the choroid. The uPA/uPAR/FPR system was upregulated in CNV, but was not influenced by UPARANT. UPARANT recovered laser-induced upregulation of transcription factors encoding angiogenic and inflammatory markers. Accordingly, angiogenic and inflammatory factors were also reduced. UPARANT as compared to anti-VEGF drugs displayed similar effects on CNV area. CONCLUSIONS UPARANT mitigates laser-induced CNV by inhibiting angiogenesis and inflammation through an action on transcription factors encoding angiogenesis and inflammatory genes. The finding that UPARANT is effective against CNV may help to establish uPAR and its membrane partners as putative targets in the treatment of AMD.


Investigative Ophthalmology & Visual Science | 2016

Molecular Mechanisms Mediating Antiangiogenic Action of the Urokinase Receptor-Derived Peptide UPARANT in Human Retinal Endothelial Cells

Carla Motta; Gabriella Lupo; Dario Rusciano; Melania Olivieri; Liliana Lista; Mario De Rosa; Vincenzo Pavone; Carmelina Daniela Anfuso

Purpose To investigate the molecular mechanisms of the antiangiogenic activity of UPARANT, an antagonist of the urokinase-type plasminogen activator receptor (uPAR), on primary human retinal endothelial cells (HREC) as a model of in vitro angiogenesis. Methods The antiangiogenic activity of UPARANT was evaluated on endothelial cell migration, invasion, and tube formation. Human REC were further analyzed for viability, transendothelial electrical resistance (TEER), and tight junction (TJ) expression at the protein and mRNA levels. Vascular endothelial growth factor-related signaling molecules were also analyzed by Western and northern blots. Results UPARANT inhibited in a dose-dependent fashion HREC motility, invasion, and tube formation stimulated by VEGF-A, in a range of doses (1-100 nM) that had no effect on cell viability and proliferation. UPARANT also prevented the loss of permeability induced by VEGF-A, restoring normal TEER values and TJ protein expression. At the molecular level, UPARANT inhibited VEGFR-2 and STAT3 phosphorylation, thus decreasing VEGF and hypoxia-inducible factor 1-alpha expression, finally resulting in decreased activation of MEK/ERK, JNK, p38, and AKT signaling proteins. Conclusions These findings indicate that UPARANT exerts its antiangiogenic effects through the inhibition of the downstream signaling activated by angiogenic factors such as VEGF-A.


Investigative Ophthalmology & Visual Science | 2017

The Urokinase Receptor-Derived Peptide UPARANT Recovers Dysfunctional Electroretinogram and Blood–Retinal Barrier Leakage in a Rat Model of Diabetes

Maurizio Cammalleri; Filippo Locri; Stefania Marsili; Massimo Dal Monte; Claudio Pisano; Angelo Mancinelli; Liliana Lista; Dario Rusciano; Mario De Rosa; Vincenzo Pavone; Paola Bagnoli

Purpose The activation of the urokinase-type plasminogen activator and its receptor system is associated with retinal diseases. Among peptide inhibitors of this system, UPARANT acts by preventing the onset of pathologic signs of neovascular ocular diseases. We investigated whether systemic UPARANT may act in a therapeutic regimen by suppressing the retinal damage that characterizes diabetic retinopathy using a rat model of streptozotocin-induced diabetes. Methods In healthy rats, plasma, eye, and retina concentrations of UPARANT were evaluated by mass spectrometry. In rat models of streptozotocin-induced diabetes, the appearance of diabetic retinopathy was assessed by electroretinogram (ERG). UPARANT was then administered at different dosages and daily regimens. ERG recording, Evans blue perfusion, and real-time PCR were used to evaluate UPARANT efficacy. UPARANT safety was also determined. Results UPARANT was found in plasma, eye, and retina soon after its administration and remained detectable after 24 hours. Between the 4th and the 5th week after diabetes onset, UPARANT at 8 mg/kg (daily for 5 days) was effective in recovering dysfunctional ERG. Three-day treatments at 8 mg/kg or a half dose for 5 days were ineffective. ERG recovery lasted approximately 2 weeks. ERG recovery was accompanied by restored blood-retinal barrier integrity and inhibition of inflammatory and angiogenic responses. UPARANT showed a safety profile. Conclusions These data suggest that targeting the urokinase-type plasminogen activator and its receptor system by systemic UPARANT is a potential therapeutic approach for the treatment of early diabetic retinopathy, thus providing a potential alternative approach to delay disease progression in humans.


Biotechnology and Applied Biochemistry | 2015

Branched porphyrins as functional scaffolds for multisite bioconjugation

Mireille Engelen; Angela Lombardi; Rosa Vitale; Liliana Lista; Ornella Maglio; Vincenzo Pavone; Flavia Nastri

Bioconjugation is a rapidly expanding field because of the numerous potential applications of bioconjugate materials. We explored the usefulness of branched porphyrins as rigid scaffolds, bearing multiple sites for bioconjugation. To this end, we first selected the tetrakis(p‐[aminomethyl] phenyl) porphyrin (TAMPP) macrocycle and developed a straightforward synthetic protocol, able to provide the desired tetraphenylporphyrin, carrying four functional amino groups. The partially protection of the amino groups by tert‐butoxy‐carbonyl allowed the selective and specific decoration of the porphyrin with different peptide sequences. To explore the utility of the macrocycle as molecular scaffold for bioconjugation, we selected peptide sequences able to function as thrombin inhibitors. In particular, two peptide sequences, named CS3 and ES7, able to interact, respectively, with the thrombin catalytic site and the fibrinogen recognition exosite, were joined onto the porphyrin macrocycle, providing the multisite‐directed inhibitor CS3–TAMPP–ES7. This multisite inhibitor and its MnIII complex are able to inhibit α‐thrombin‐catalyzed hydrolysis of Tos–Gly–Pro–Arg–nitroanilide with inhibition constants in the micromolar range, as well as the hydrolysis of the natural substrate fibrinogen. The inhibitor is resistant against enzymatic degradation by thrombin and is highly selective. The MnIII complex is capable of interacting with clot‐bound thrombin and partially inhibits clot growth in the presence of fibrinogen. The results herein reported are very promising, suggesting the potential of the newly developed conjugate as new imaging agents for clot detection.

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Vincenzo Pavone

University of Naples Federico II

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Mario De Rosa

Seconda Università degli Studi di Napoli

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Angela Lombardi

University of Naples Federico II

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Ornella Maglio

University of Naples Federico II

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Alessandro Pezzella

University of Naples Federico II

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Flavia Nastri

University of Naples Federico II

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Alessandra Napolitano

University of Naples Federico II

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Marco d'Ischia

University of Naples Federico II

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