A5085467456- Glioma Diagnosis and Treatment
- Cancer, Hypoxia, and Metabolism
- Protein Tyrosine Phosphatases
- Fibroblast Growth Factor Research
- Cancer Cells and Metastasis
- Synthesis and Biological Evaluation
- Liver physiology and pathology
- DNA and Nucleic Acid Chemistry
- Adenosine and Purinergic Signaling
- Carbohydrate Chemistry and Synthesis
- Microtubule and mitosis dynamics
- Chemotherapy-induced cardiotoxicity and mitigation
- Melanoma and MAPK Pathways
- Research on Leishmaniasis Studies
- Biochemical and Molecular Research
- Endoplasmic Reticulum Stress and Disease
- Mosquito-borne diseases and control
- Radiation Therapy and Dosimetry
- Trypanosoma species research and implications
- Pancreatic function and diabetes
- Chronic Lymphocytic Leukemia Research
- Cytomegalovirus and herpesvirus research
- Circular RNAs in diseases
- Enzyme Structure and Function
- Cancer-related molecular mechanisms research
Instituto de Química Médica
2006-2024
Candiolo Cancer Institute
2014-2023
Istituti di Ricovero e Cura a Carattere Scientifico
2014-2023
Lankenau Medical Center
2022
Consejo Superior de Investigaciones Científicas
2008-2014
University of Turin
2012
KU Leuven
2006-2012
University of Brescia
2012
Rega Institute for Medical Research
2006-2012
University of Bari Aldo Moro
2012
The existence of treatment-resistant cancer stem cells contributes to the aggressive phenotype glioblastoma. However, molecular alterations that drive cell proliferation in these tumors remain unknown. In this study, we found expression MET oncogene was associated with neurospheres expressing gene signature mesenchymal and proneural subtypes Met almost absent from classical subtype mutually exclusive amplification EGF receptor (EGFR) gene. Met-positive Met-negative displayed distinct growth...
Glioblastoma (GBM) contains stem-like cells (GSCs) known to be resistant ionizing radiation and thus responsible for therapeutic failure rapidly lethal tumor recurrence. It is that GSC radioresistance relies on efficient activation of the DNA damage response, but mechanisms linking this response with stem status are still unclear. Here, we show MET receptor kinase, a functional marker GSCs, specifically expressed in subset radioresistant GSCs overexpressed human GBM recurring after...
Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), mainly activates prosurvival pathways, including protection from apoptosis. In this work, we investigated cardioprotective mechanisms of Met activation by agonist monoclonal antibodies (mAbs). Cobalt chloride (CoCl2), a chemical mimetic hypoxia, was used to induce cardiac damage in H9c2 cardiomyoblasts, which resulted reduction cell viability (i) caspase-dependent apoptosis and (ii) – surprisingly autophagy. Blocking...
Abstract The inflammatory cytokine Tumor Necrosis Factor Alpha (TNF‐α) is known to trigger invasive growth, a physiological property for tissue healing, turning into hallmark of progression in cancer. However, the response TNF‐α relies on poorly understood molecular mechanisms. We thus investigated whether it involves MET oncogene, which regulates growth program by encoding tyrosine kinase receptor Hepatocyte Growth (HGF). Here we show that pro‐invasive activity requires function, as fully...
ERBB3 overexpression due to miR-205 inactivation confers sensitivity FGF, metabolic activation,
Abstract Melanomas are characterised by accelerated cell proliferation and metabolic reprogramming resulting from the contemporary dysregulation of MAPK pathway, glycolysis tricarboxylic acid (TCA) cycle. Here, we suggest that oncogenic transcription factor EB (TFEB), a key regulator lysosomal biogenesis function, controls melanoma tumour growth through transcriptional programme targeting ERK1/2 activity glucose, glutamine cholesterol metabolism. Mechanistically, TFEB binds negatively...
Doxorubicin anti-cancer therapy is associated with cardiotoxicity, resulting from DNA damage response (DDR). Hepatocyte growth factor (HGF) protects cardiomyocytes injury, but its effective use compromised by low biodistribution. In this study, we have investigated whether the activation of HGF receptor-encoded Met gene-by an agonist monoclonal antibody (mAb) could protect against doxorubicin-induced cardiotoxicity.The mAb (5 mg·kg-1 ) was injected in vivo into C57BL/6J mice, before...
Glioblastoma (GBM) is known as an intractable, highly heterogeneous tumor encompassing multiple subclones, each supported by a distinct glioblastoma stem cell (GSC). The contribution of GSC genetic and transcriptional heterogeneity to subclonal properties debated. In this study, we describe the systematic derivation, propagation, characterization GSCs from single, treatment-naive GBMs (GSC families). tumorigenic potential better correlates with its profile than make-up, classical being...
On the basis of our previous findings that 5'-O-tritylinosine (KIN59) behaves as an allosteric inhibitor angiogenic enzyme thymidine phosphorylase (TPase), we have undertaken synthesis and enzymatic evaluation a novel series nucleoside analogues modified at positions 1, 2, or 6 purine ring 5'-position ribose moiety lead compound KIN59. SAR studies indicate quite large structural variations can be performed on KIN59 without compromising TPase inhibition. Thus, incorporation cyclopropylmethyl...
Thymidine phosphorylase (TPase) is one of the key enzymes involved in pyrimidine nucleoside salvage pathway. However, TPase also stimulates angiogenesis, and its expression correlates well with microvessel density metastasis a variety human tumors. We have shown recently that 5′-<i>O</i>-trityl-inosine (KIN59) allosterically inhibits enzymatic activity. KIN59 TPase-induced angiogenesis chick chorioallantoic membrane (CAM) assay. The trityl group was found to be instrumental preserve both...
5'-O-Tritylinosine (KIN59) is an allosteric inhibitor of the angiogenic enzyme thymidine phosphorylase. Previous observations showed capacity KIN59 to abrogate phosphorylase-induced as well developmental angiogenesis in chicken chorioallantoic membrane (CAM) assay. Here, we show that also inhibits response triggered by fibroblast growth factor-2 (FGF2) but not VEGF CAM Immunohistochemical and reverse transcriptase PCR analyses revealed expression laminin, major proteoglycan basement blood...
The tyrosine kinase receptor encoded by the MET oncogene has been extensively studied. Surprisingly, one extracellular domain, PSI, evolutionary conserved between plexins, semaphorins, and integrins, no established function. PSI sequence contains two CXXC motifs, usually found in protein disulfide isomerases (PDI). Using a scrambled oxidized RNAse enzymatic activity assay vitro, we show, for first time, that domain displays isomerase activity, abolished antibodies. deletion or mutations of...
The Saccharomyces cerevisiae atypical protein kinase Bud32p is a member of the nuclear endopeptidase‐like, kinase, chromatin‐associated/kinase, endopeptidase‐like and other small size (EKC/KEOPS) complex, known to be involved in control transcription telomere homeostasis. Complex subunits (Pcc1p, Pcc2p, Cgi121p, Kae1p) represent, however, subset proteins able interact with Bud32p, suggesting that this may endowed additional roles unrelated its participation EKC/KEOPS complex. In context, we...
Despite the well-established importance of intermolecular cation−π interactions in molecular recognition, intramolecular have been less studied. Here we describe how simultaneous presence an aromatic ring at 5′-position inosine derivative and a positively charged imidazolium purine base drive conformation nucleoside toward very major conformer solution that is stabilized by interaction. Therefore, interaction between ions rings can also be proposed design small molecules where this type...
EndoG, a member of the DNA/RNA non-specific ββα-metal family nucleases, has been demonstrated to be present in many organisms, including Trypanosomatids. This nuclease participates apoptotic program these parasites by migrating from mitochondrion nucleus, where it takes part degradation genomic DNA that characterizes this process. We now demonstrate Leishmania infantum EndoG (LiEndoG) is an endo-exonuclease preferential 5' exonuclease activity on linear DNA. Regardless its role during cell...
Abstract Two series of 5′‐triphenylmethyl (trityl)‐substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes amastigotes. Several these compounds show significant antileishmanial activity, with IC 50 values in the low micromolar range. Among these, 3′‐ O ‐(isoleucylisoleucyl)‐5′‐ ‐(3,3,3‐triphenylpropanoyl)thymidine displays particularly good activity intracellular Assays performed to characterize nature parasite cell death presence...
Previous studies showed that the hepatocyte growth factor (HGF)–Met receptor axis plays long-lasting cardioprotection against doxorubicin anti-cancer therapy. Here, we explored mechanism(s) underlying HGF protective effect. DNA damage was monitored by histone H2AX phosphorylation and apoptosis proteolytic cleavage of caspase 3. In doxorubicin-treated H9c2 cardiomyoblasts, is mediated activation Ras/Raf/Mek/Erk (extracellular signal-regulated kinase 1,2) signaling pathway requires Stat3...
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The efficient microwave-assisted synthesis of 5′-O-trityl inosine derivatives is described. reported protocol allows the protection in significantly higher yields and shorter reaction times than standard thermal conditions. This procedure particularly suitable for modified inosines where 5′-OH sterically hindered (i.e. 8-bromoinosine).
The Hepatocyte growth factor (HGF) and its receptor (MET) promote several physiological activities such as tissue regeneration protection from cell injury of epithelial, endothelial, neuronal muscle cells. therapeutic potential MET activation has been scrutinized in the treatment acute injury, chronic inflammation, renal fibrosis multiple sclerosis (MS), cardiovascular neurodegenerative diseases. On other hand, HGF-MET signaling pathway may be caught by cancer cells turned to work for...
Reaction of 2′,3′-O-isopropylidene inosine with benzyl bromide (1 h, rt) led to the 1,5′-O-dibenzylderivative 4, but by increasing reaction time or temperature, compound 4 is further transformed into 1,7,5′-O-tribenzylinosine derivative 5. Similarly, 7-methyl-1,5′-O-dibenzylderivative 6 has been synthesized from 4. The 1 H-NMR spectra 5 and showed peculiar chemical shifts for geminal protons (H5′ H5″ ribose, CH 2 groups). Preliminary NMR studies have performed, including NOESY experiments...