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Publications 2016

Vitamin B12 ameliorates the phenotype of a mouse model of DiGeorge syndrome.

By Lania Gabriella; Colonna Vincenza; Bresciani Alberto; Bisbocci Monica; Francone Alessandra; Altamura Sergio; Baldini Antonio
From Human molecular genetics (2016), 25(20), 4369-4375, Language: English, Database: MEDLINE

Pathological conditions caused by reduced dosage of a gene, such as gene haploinsufficiency, can potentially be reverted by enhancing the expression of the functional allele. In practice, low specificity of therapeutic agents, or their toxicity reduces their clinical applicability. Here, we have used a high throughput screening (HTS) approach to identify molecules capable of increasing the expression of the gene Tbx1, which is involved in one of the most common gene haploinsufficiency syndromes, the 22q11.2 deletion syndrome. Surprisingly, we found that one of the two compounds identified by the HTS is the vitamin B12. Validation in a mouse model demonstrated that vitamin B12 treatment enhances Tbx1 gene expression and partially rescues the haploinsufficiency phenotype. These results lay the basis for preclinical and clinical studies to establish the effectiveness of this drug in the human syndrome.

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Conformational modulation mediated by polyglutamine expansion in CAG repeat expansion disease-associated proteins.

By Verani, Margherita; Bustamante, Maria; Martufi, Paola; Daldin, Manuel; Cariulo, Cristina; Azzollini, Lucia; Fodale, Valentina; Puglisi, Francesca; Weiss, Andreas; MacDonald, Douglas; et al
From Biochemical and Biophysical Research Communications (2016), 478(2), 949-955. Language: English, Database: CAPLUS, DOI:10.1016/j.bbrc.2016.08.057

We have previously reported TR-FRET based immunoassays to detect a conformational change imparted on huntingtin protein by the polyglutamine expansion, which we confirmed using biophys. methodologies. Using these immunoassays, we now report that polyglutamine expansion influences the conformational properties of other polyglutamine disease proteins, exemplified by the androgen receptor (assocd. with spinal bulbar muscular atrophy) and TATA binding protein (assocd. with spinocerebellar ataxia 17). Using artificial constructs bearing short or long polyglutamine expansions or a multimerized, unrelated epitope (mimicking the increase in anti-polyglutamine antibody epitopes present in polyglutamine repeats of increasing length) we confirmed that the conformational TR-FRET based immunoassay detects an intrinsic conformational property of polyglutamine repeats. The TR-FRET based conformational immunoassay may represent a rapid, scalable tool to identify modulators of polyglutamine-mediated conformational change in different proteins assocd. with CAG triplet repeat disorders.

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Discovery and Characterization of Novel Anti-schistosomal Properties of the Anti-anginal Drug, Perhexiline and Its Impact on Schistosoma mansoni Male and Female Reproductive Systems.

By Guidi Alessandra; Lalli Cristiana; Ruberti Giovina; Perlas Emerald; Bolasco Giulia; Nibbio Martina; Monteagudo Edith; Bresciani Alberto
From PLoS neglected tropical diseases (2016), 10(8), e0004928, Language: English, Database: MEDLINE

Schistosomiasis, one of the world’s greatest human neglected tropical diseases, is caused by parasitic trematodes of the genus Schistosoma. A unique feature of schistosome biology is that the induction of sexual maturation as well as the maintenance of the differentiation status of female reproductive organs and egg production, necessary for both disease transmission and pathogenesis, are strictly dependent on the male. The treatment and most control initiatives of schistosomiasis rely today on the long-term application of a single drug, praziquantel (PZQ), mostly by campaigns of mass drug administration. PZQ, while very active on adult parasites, has much lower activity against juvenile worms. Monotherapy also favors the selection of drug resistance and, therefore, new drugs are urgently needed. METHODS AND FINDINGS: Following the screening of a small compound library with an ATP-based luminescent assay on Schistosoma mansoni schistosomula, we here report the identification and characterization of novel antischistosomal properties of the anti-anginal drug perhexiline maleate (PHX). By phenotypic worm survival assays and confocal microscopy studies we show that PHX, in vitro, has a marked lethal effect on all S. mansoni parasite life stages (newly transformed schistosomula, juvenile and adult worms) of the definitive host. We further demonstrate that sub-lethal doses of PHX significantly impair egg production and lipid depletion within the vitellarium of adult female worms. Moreover, we highlighted tegumental damage in adult male worms and remarkable reproductive system alterations in both female and male adult parasites. The in vivo study in S. mansoni-patent mice showed a notable variability of worm burdens in the individual experiments, with an overall minimal schistosomicidal effect upon PHX treatment. The short PHX half-life in mice, together with its very high rodent plasma proteins binding could be the cause of the modest efficacy of PHX in the schistosomiasis murine model. CONCLUSIONS/SIGNIFICANCE: Overall, our data indicate that PHX could represent a promising starting point for novel schistosomicidal drug discovery programmes.

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Crosstalk between mismatch repair and base excision repair in human gastric cancer.

Simonelli V, Leuzzi G, Basile G, D’Errico M, Fortini P, Franchitto A, Viti V, Brown AR, Parlanti E, Pascucci B, Palli D, Giuliani A, Palombo F, Sobol RW, Dogliotti E. (2016)
Oncotarget. 2016 Jun 20;8(49):84827-84840.

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Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs.

By Ontoria, Jesus M.; Paonessa, Giacomo; Ponzi, Simona; Ferrigno, Federica; Nizi, Emanuela; Biancofiore, Ilaria; Malancona, Savina; Graziani, Rita; Roberts, David; Willis, Paul; et al
From ACS Medicinal Chemistry Letters (2016), 7(5), 454-459. Language: English, Database: CAPLUS, DOI:10.1021/acsmedchemlett.5b00468

Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACsThe identification of a new series of P. falciparum growth inhibitors is described. Starting from a series of known human class I HDAC inhibitors a SAR exploration based on growth inhibitory activity in parasite and human cells-based assays led to the identification of compds. with submicromolar inhibition of P. falciparum growth (EC50 < 500 nM) and good selectivity over the activity of human HDAC in cells (up to >50-fold). Inhibition of parasital HDACs as the mechanism of action of this new class of selective growth inhibitors is supported by hyperacetylation studies.

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MK-4101, a Potent Inhibitor of the Hedgehog Pathway, Is Highly Active against Medulloblastoma and Basal Cell Carcinoma.

By Filocamo Gessica; Brunetti Mirko; Colaceci Fabrizio; Sasso Romina; Tanori Mirella; Pasquali Emanuela; Mancuso Mariateresa; Saran Anna; Pazzaglia Simonetta; Alfonsi Romina; et al
From Molecular cancer therapeutics (2016), 15(6), 1177-89, Language: English, Database: MEDLINE

Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1(+/-) mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for the treatment of medulloblastoma and BCC. Results clearly demonstrated a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1(+/-) mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidated the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in tumor cells, showing the maximum inhibitory effect on Gli1 MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF, and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity.

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Use of ‘dilute-and-shoot’ liquid chromatography-high resolution mass spectrometry in preclinical research: application to a DMPK study of perhexiline in mouse plasma.

By Esposito, Simone; Bracacel, Elena; Nibbio, Martina; Speziale, Roberto; Orsatti, Laura; Veneziano, Maria; Monteagudo, Edith; Bonelli, Fabio
From Journal of Pharmaceutical and Biomedical Analysis (2016), 118, 70-80. Language: English, Database: CAPLUS, DOI:10.1016/j.jpba.2015.10.004

This work describes a simple, sensitive and rapid liq. chromatog.-high resoln. mass spectrometry method for the quantitation of perhexiline and the simultaneous detection of perhexiline metabolites in C57bl/6 mice plasma. Only 5 μL of plasma was used for anal. Pretreatment was limited to a 100-fold diln. (‘dil.-and-shoot’). The analyte was detected by high resoln. mass spectrometry (Orbitrap technol.). Three scan events were performed over the entire chromatogram. Targeted single ion monitoring with data dependent acquisition was employed for perhexiline quantitation and confirmation, while full scan was used to perform untargeted detection of perhexiline phase I and phase II circulating metabolites. The calibration curve was linear (r2 = 0.990) ranging from 0.305 ng/mL (LLOQ) to 10000 ng/mL. Matrix effect was limited to 6.1%. The method was applied to a pharmacokinetic study of perhexiline in mouse plasma and the results obtained were compared to a std. sample prepn. method based on protein pptn. and liq. chromatog.-tandem mass spectrometry (MRM mode) detection. The new approach provided comparable results in terms of pharmacokinetics parameters est. with a high sensitivity, addnl. information on perhexiline circulating metabolites and a low consumption of biol. sample. The combination of the ‘dil.-and-shoot’ approach together with HRMS targeted and untargeted detection represents a suitable alternative to classic bioanal. approaches in preclin. research.

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