92 results on '"Straino, S"'
Search Results
2. Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors
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Minetti, G C, Colussi, C, Adami, R, Serra, C, Mozzetta, C, Parente, V, Fortuni, S, Straino, S, Sampaolesi, M, Di Padova, M, Illi, B, Gallinari, P, Steinkuhler, C, Capogrossi, M C, Sartorelli, V, Bottinelli, R, Gaetano, C, and Puri, P L
- Abstract
Author(s): G C Minetti [1, 9]; C Colussi [2, 9]; R Adami [3, 9]; C Serra [1, 4]; C Mozzetta [1]; V Parente [3]; S Fortuni [1]; S Straino [2]; [...]
- Published
- 2006
- Full Text
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3. Cyclo-oxygenase-2 (COX-2) inhibition reduces apoptosis in acute myocardial infarction
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Abbate, A., Limana, F., Capogrossi, M. C., Santini, D., Biondi-Zoccai, G. G. L., Scarpa, S., Germani, A., Straino, S., Severino, A., Vasaturo, F., Campioni, M., Liuzzo, G., Crea, F., Vetrovec, G. W., Biasucci, L. M., and Baldi, A.
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- 2006
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4. Multiple effects of High Mobility Group Box 1 in skeletal muscle regeneration
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DE MORI R, STRAINO S, DI CARLO A, MANGONI A, POMPILIO G, PALUMBO R, BIANCHI M, CAPOGROSSI MC, GERMANI A, DE MORI, R, Straino, S, DI CARLO, A, Mangoni, A, Pompilio, G, Palumbo, R, Bianchi, M, Capogrossi, Mc, and Germani, A
- Published
- 2007
5. Improvement of cardiac function with parecoxib, a cyclo-oxigenase-2 inhibitor in a rat model of ischemic heart failure
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ABBATE A, SALLOUM FN, OCKAILI RA, FOWLER III AA, BIONDI ZOCCAI GGL, STRAINO S, LIPINSKI MJ, CREA F, BIASUCCI LM, VETROVEC GW, KUKREJA RC, BALDI, Alfonso, Abbate, A, Salloum, Fn, Ockaili, Ra, FOWLER III, Aa, BIONDI ZOCCAI, Ggl, Straino, S, Lipinski, Mj, Baldi, Alfonso, Crea, F, Biasucci, Lm, Vetrovec, Gw, and Kukreja, Rc
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- 2007
6. Ex vivo acidic preconditioning enhances bone marrow ckit+ cell therapeutic potential via increased CXCR4 expression
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Cencioni, C, Melchionna, R, Straino, S, Romani, M, Cappuzzello, C, Annese, V, Wu, J, Pompilio, G, Santoni, A, Gaetano, C, Napolitano, M, Capogrossi, M, Capogrossi, M., CAPPUZZELLO, CLAUDIA, Cencioni, C, Melchionna, R, Straino, S, Romani, M, Cappuzzello, C, Annese, V, Wu, J, Pompilio, G, Santoni, A, Gaetano, C, Napolitano, M, Capogrossi, M, Capogrossi, M., and CAPPUZZELLO, CLAUDIA
- Abstract
Aims The chemokine receptor CXCR4 modulates endothelial progenitor cell migration, homing, and differentiation, and plays a key role in cardiovascular regeneration. Here we examined the effect of ex vivo acidic preconditioning (AP) on CXCR4 expression and on the regenerative potential of mouse bone marrow (BM) ckit+ cells. Methods and results Acidic preconditioning was achieved by exposing BM ckit+ cells to hypercarbic acidosis (pH 7.0) for 24 h; control cells were kept at pH 7.4. Acidic preconditioning enhanced CXCR4 and stromal cell-derived factor 1 (SDF-1) mRNA levels, as well as CXCR4 phosphorylation. Acidic preconditioning ability to modulate CXCR4 expression depended on cytosolic calcium [Ca2+]i mobilization and on nitric oxide (NO), as determined by [Ca2+]i buffering with BAPTA, and by treatment with the NO donor (DETA/NO) and the NO synthase inhibitor (L-NAME). Further, AP increased SDF-1-driven chemotaxis, transendothelial migration, and differentiation toward the endothelial lineage in vitro. In a mouse model of hindlimb ischaemia, control and AP ckit+ cells were transplanted into the ischaemic muscle; AP cells accelerated blood flow recovery, increased capillary, and arteriole number as well as the number of regenerating muscle fibres vs. control. These effects were abolished by treating AP cells with L-NAME. Conclusion Acidic preconditioning represents a novel strategy to enhance BM ckit+ cell therapeutic potential via NO-dependent increase in CXCR4 expression. © The Author 2013.
- Published
- 2013
7. Detrimental effect of class-selective histone deacetylase inhibitors during tissue regeneration following hindlimb ischemia
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Spallotta, F, Tardivo, S, Nanni, Simona, Rosati, Jd, Straino, S, Mai, A, Valente, S, Capogrossi, Mc, Farsetti, A, Martone, J, Bozzoni, I, Pontecorvi, Alfredo, Gaetano, C, Colussi, C., Nanni, Simona (ORCID:0000-0002-3320-1584), Pontecorvi, Alfredo (ORCID:0000-0003-0570-6865), Spallotta, F, Tardivo, S, Nanni, Simona, Rosati, Jd, Straino, S, Mai, A, Valente, S, Capogrossi, Mc, Farsetti, A, Martone, J, Bozzoni, I, Pontecorvi, Alfredo, Gaetano, C, Colussi, C., Nanni, Simona (ORCID:0000-0002-3320-1584), and Pontecorvi, Alfredo (ORCID:0000-0003-0570-6865)
- Abstract
Histone deacetylase inhibitors (DIs) are promising drugs for the treatment of several pathologies including ischemic and failing heart where they demonstrated efficacy. However, adverse side effects and cardiotoxicity have also been reported. Remarkably, no information is available about the effect of DIs during tissue regeneration following acute peripheral ischemia. In this study, mice made ischemic by femoral artery excision were injected with the DIs MS275 and MC1568, selective for class I and IIa histone deacetylases (HDACs), respectively. In untreated mice, soon after damage, class IIa HDAC phosphorylation and nuclear export occurred, paralleled by dystrophin and neuronal nitric-oxide synthase (nNOS) down-regulation and decreased protein phosphatase 2A activity. Between 14 and 21 days after ischemia, dystrophin and nNOS levels recovered, and class IIa HDACs relocalized to the nucleus. In this condition, the MC1568 compound increased the number of newly formed muscle fibers but delayed their terminal differentiation, whereas MS275 abolished the early onset of the regeneration process determining atrophy and fibrosis. The selective DIs had differential effects on the vascular compartment: MC1568 increased arteriogenesis whereas MS275 inhibited it. Capillarogenesis did not change. Chromatin immunoprecipitations revealed that class IIa HDAC complexes bind promoters of proliferation-associated genes and of class I HDAC1 and 2, highlighting a hierarchical control between class II and I HDACs during tissue regeneration. Our findings indicate that class-selective DIs interfere with normal mouse ischemic hindlimb regeneration and suggest that their use could be limited by alteration of the regeneration process in peripheral ischemic tissues.
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- 2013
8. A nitric oxide-dependent cross-talk between class I and III histone deacetylases accelerates skin repair
- Author
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Spallotta, F, Cencioni, C, Straino, S, Nanni, Simona, Rosati, J, Artuso, S, Manni, I, Colussi, C, Piaggio, G, Martelli, F, Valente, S, Mai, A, Capogrossi, Mc, Farsetti, A, Gaetano, C., Nanni, Simona (ORCID:0000-0002-3320-1584), Spallotta, F, Cencioni, C, Straino, S, Nanni, Simona, Rosati, J, Artuso, S, Manni, I, Colussi, C, Piaggio, G, Martelli, F, Valente, S, Mai, A, Capogrossi, Mc, Farsetti, A, Gaetano, C., and Nanni, Simona (ORCID:0000-0002-3320-1584)
- Abstract
In a mouse model of skin repair we found that the class I-IIa histone deacetylase inhibitor trichostatin A accelerated tissue regeneration. Unexpectedly, this effect was suppressed by Sirtinol, a class III histone deacetylase (HDAC) (sirtuin)-selective inhibitor. The role of sirtuins (SIRTs) was then investigated by using resveratrol and a novel SIRT1-2-3 activator, the MC2562 compound we synthesized recently. Both resveratrol and MC2562 were effective in accelerating wound repair. The local administration of natural or synthetic SIRT activators, in fact, significantly accelerated skin regeneration by increasing keratinocyte proliferation. In vitro experiments revealed that the activation of SIRTs stimulated keratinocyte proliferation via endothelial NO synthase phosphorylation and NO production. In this condition, the class I member HDAC2 was found S-nitrosylated on cysteine, a post-transduction modification associated with loss of activity and DNA binding capacity. After deacetylase inhibitor or SIRT activator treatment, ChIP showed, in fact, a significant HDAC2 detachment from the promoter region of insulin growth factor I (IGF-I), fibroblast growth factor 10 (FGF-10), and Epithelial Growth Factor (EGF), which may be the final recipients and effectors of the SIRT-NO-HDAC signaling cascade. Consistently, the effect of SIRT activators was reduced in the presence of NG-nitro-L-arginine methyl ester (L-NAME), a general inhibitor of NO synthesis. In conclusion, the NO-dependent cross-talk among class III and I histone deacetylases suggests an unprecedented signaling pathway important for skin repair.
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- 2013
9. Angiogenic impairment of the vascular endothelium: a novel mechanism and potential therapeutic target in muscular dystrophy
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Palladino, Mariangela, Gatto, Ilaria, Neri, Valentina, Straino, S, Smith, Rc, Silver, M, Gaetani, Eleonora, Marcantoni, Margherita, Giarretta, Igor, Stigliano, Egidio, Capogrossi, M, Hlatky, L, Landolfi, Raffaele, Pola, Roberto, Gaetani, Eleonora (ORCID:0000-0002-7808-1491), Giarretta, Igor (ORCID:0000-0001-5380-0843), Landolfi, Raffaele (ORCID:0000-0002-7913-8576), Pola, Roberto (ORCID:0000-0001-5224-2931), Palladino, Mariangela, Gatto, Ilaria, Neri, Valentina, Straino, S, Smith, Rc, Silver, M, Gaetani, Eleonora, Marcantoni, Margherita, Giarretta, Igor, Stigliano, Egidio, Capogrossi, M, Hlatky, L, Landolfi, Raffaele, Pola, Roberto, Gaetani, Eleonora (ORCID:0000-0002-7808-1491), Giarretta, Igor (ORCID:0000-0001-5380-0843), Landolfi, Raffaele (ORCID:0000-0002-7913-8576), and Pola, Roberto (ORCID:0000-0001-5224-2931)
- Abstract
Dystrophin, the missing or defective protein in Duchenne muscular dystrophy, is expressed not only in muscle cells but also in vascular endothelial cells (ECs). In this study, we assessed the effects of dystrophin deficiency on the angiogenic capacities of ECs.
- Published
- 2013
10. Proteomic profile of differentially expressed plasma proteins from dystrophic mice and following suberoylanilide hydroxamic acid treatment
- Author
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Colussi, C, Banfi, C, Brioschi, M, Tremoli, E, Straino, S, Spallotta, F, Mai, A, Rotili, D, Capogrossi, M, Gaetano, C, Mai, Antonello, Rotili, Dante, Capogrossi, M C, Gaetano, Carlo, Colussi, C, Banfi, C, Brioschi, M, Tremoli, E, Straino, S, Spallotta, F, Mai, A, Rotili, D, Capogrossi, M, Gaetano, C, Mai, Antonello, Rotili, Dante, Capogrossi, M C, and Gaetano, Carlo
- Abstract
Purpose: Histone Deacetylase Inhibitors (DI) ameliorates dystrophic muscle regeneration restoring muscular strength in the mdx mouse model of Duchenne muscular dystrophy (DMD). The further development of these compounds as drugs for DMD treatment is currently hampered by the lack of knowledge about DIs effect in large dystrophic animal models and that of suitable biomarkers to monitor their efficacy. Experimental design: In this study we applied proteomic analysis to identify differentially expressed proteins present in plasma samples from mdx mice treated with the Suberoylanilide hydroxamic acid (SAHA) and relative normal controls (WT). Results: Several differentially expressed proteins were identified between untreated wild type and mdx mice. Among these, fibrinogen, epidermal growth factor 2 receptor, major urinary protein and glutathione peroxidase 3 (GPX3) were constitutively up-regulated in mdx, while complement C3, complement C6, gelsolin, leukaemia inhibitory factor receptor (LIFr), and alpha 2 macroglobulin were down-regulated compared to WT mice. SAHA determined the normalization of LIFr and GPX3 protein level while apoliprotein E was de novo up-regulated in comparison to vehicle-treated mdx mice. Conclusions and clinical relevance: Collectively, these data unravel potential serological disease biomarkers of mdx that could be useful to monitor muscular dystrophy response to DI treatment.
- Published
- 2010
11. GMP-based CD133(+) cells isolation maintains progenitor angiogenic properties and enhances standardization in cardiovascular cell therapy
- Author
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Gaipa, G, Tilenni, M, Straino, S, Burba, I, Zaccagnini, G, Belotti, D, Biagi, E, Valentini, M, Perseghin, P, Parma, M, Di Campli, C, Biondi, A, Capogrossi, M, Pompilio, G, Pesce, M, BIAGI, ETTORE, BIONDI, ANDREA, Capogrossi, MC, Pesce, M., Gaipa, G, Tilenni, M, Straino, S, Burba, I, Zaccagnini, G, Belotti, D, Biagi, E, Valentini, M, Perseghin, P, Parma, M, Di Campli, C, Biondi, A, Capogrossi, M, Pompilio, G, Pesce, M, BIAGI, ETTORE, BIONDI, ANDREA, Capogrossi, MC, and Pesce, M.
- Abstract
The aim of the present study was to develop and validate a good manufacturing practice (GMP) compliant procedure for the preparation of bone marrow (BM) derived CD133 + cells for cardiovascular repair. Starting from available laboratory protocols to purify CD133 + cells from human cord blood, we implemented these procedures in a GMP facility and applied quality control conditions defining purity, microbiological safety and vitality of CD133 + cells. Validation of CD133 + cells isolation and release process were performed according to a two-step experimental program comprising release quality checking (step 1) as well as 'proofs of principle' of their phenotypic integrity and biological function (step 2). This testing program was accomplished using in vitro culture assays and in vivo testing in an immunosuppressed mouse model of hindlimb ischemia. These criteria and procedures were successfully applied to GMP production of CD133 + cells from the BM for an ongoing clinical trial of autologous stem cells administration into patients with ischemic cardiomyopathy. Our results show that GMP implementation of currently available protocols for CD133 + cells selection is feasible and reproducible, and enables the production of cells having a full biological potential according to the most recent quality requirements by European Regulatory Agencies.
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- 2010
12. Nitric oxide determines mesodermic differentiation of mouse embryonic stem cells by activating class IIa histone deacetylases: potential therapeutic implications in a mouse model of hindlimb ischemia
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Spallotta, F, Rosati, J, Straino, S, Nanni, Simona, Grasselli, A, Ambrosino, V, Rotili, D, Valente, S, Farsetti, A, Mai, A, Capogrossi, Mc, Gaetano, C, Illi, B., Nanni, Simona (ORCID:0000-0002-3320-1584), Spallotta, F, Rosati, J, Straino, S, Nanni, Simona, Grasselli, A, Ambrosino, V, Rotili, D, Valente, S, Farsetti, A, Mai, A, Capogrossi, Mc, Gaetano, C, Illi, B., and Nanni, Simona (ORCID:0000-0002-3320-1584)
- Abstract
In human endothelial cells, nitric oxide (NO) results in class IIa histone deacetylases (HDACs) activation and marked histone deacetylation. It is unknown whether similar epigenetic events occur in embryonic stem cells (ESC) exposed to NO and how this treatment could influence ESC therapeutic potential during tissue regeneration.This study reports that the NO-dependent class IIa HDACs subcellular localization and activity decreases the global acetylation level of H3 histones in ESC and that this phenomenon is associated with the inhibition of Oct4, Nanog, and KLF4 expression. Further, a NO-induced formation of macromolecular complexes including HDAC3, 4, 7, and protein phosphatase 2A (PP2A) have been detected. These processes correlated with the expression of the mesodermal-specific protein brachyury (Bry) and the appearance of several vascular and skeletal muscle differentiation markers. These events were abolished by the class IIa-specific inhibitor MC1568 and by HDAC4 or HDAC7 short interfering RNA (siRNA). The ability of NO to induce mesodermic/cardiovascular gene expression prompted us to evaluate the regenerative potential of these cells in a mouse model of hindlimb ischemia. We found that NO-treated ESCs injected into the cardiac left ventricle selectively localized in the ischemic hindlimb and contributed to the regeneration of muscular and vascular structures. These findings establish a key role for NO and class IIa HDACs modulation in ESC mesodermal commitment and enhanced regenerative potential in vivo.
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- 2010
13. Proteomic profile of differentially expressed plasma proteins from dystrophic mice and following suberoylanilide hydroxamic acid treatment
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Colussi, C., primary, Banfi, C., additional, Brioschi, M., additional, Tremoli, E., additional, Straino, S., additional, Spallotta, F., additional, Mai, Antonello, additional, Rotili, Dante, additional, Capogrossi, M. C., additional, and Gaetano, Carlo, additional
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- 2009
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14. Proteomic profile of differentially expressed plasma proteins from dystrophic mice and following suberoylanilide hydroxamic acid treatment.
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Colussi, C., Banfi, C., Brioschi, M., Tremoli, E., Straino, S., Spallotta, F., Mai, Antonello, Rotili, Dante, Capogrossi, M. C., and Gaetano, Carlo
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- 2010
- Full Text
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15. Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction.
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Abbate A, Salloum FN, Vecile E, Das A, Hoke NN, Straino S, Biondi-Zoccai GGL, Houser J, Qureshi IZ, Ownby ED, Gustini E, Biasucci LM, Severino A, Capogrossi MC, Vetrovec GW, Crea F, Baldi A, Kukreja RC, and Dobrina A
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- 2008
16. Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia.
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Emanueli, C, Minasi, A, Zacheo, A, Chao, J, Chao, L, Salis, M B, Straino, S, Tozzi, M G, Smith, R, Gaspa, L, Bianchini, G, Stillo, F, Capogrossi, M C, and Madeddu, P
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- 2001
17. Myoendothelial differentiation of umbilical cord blood CD34 + cells in ischemic tissues
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Orlandi, A., Iachininoto, M.G., De Falco, E., Torella, A.R., Straino, S., Capogrossi, M.C., Pompilio, G., and Pesce, M.
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- 2004
- Full Text
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18. Estrogen stimulates angiogenesis in normoperfused skeletal muscle in rabbits - Response
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Gowdak, L. H. W., Poliakova, L., Wang, X. T., Lakatta, E. G., Talan, M., Fishbein, K. W., Spencer, R. G. S., Kovesdi, I., Zacheo, A., Palumbo, R., Straino, S., Emanueli, C., Massimiliano M. Marrocco-Trischitta, Capogrossi, M. C., and Anversa, P.
19. Adenovirus-mediated VEGF(121) gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia
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Gowdak, L. H. W., Poliakova, L., Wang, X. T., Kovesdi, I., Fishbein, K. W., Zacheo, A., Palumbo, R., Straino, S., Emanueli, C., Massimiliano M. Marrocco-Trischitta, Lakatta, E. G., Anversa, P., Spencer, R. G. S., Talan, M., and Capogrossi, M. C.
20. Erratum: Adenovirus-mediated human tissue kallikrein gene delivery inhibits neontima formation induced by interruption of blood flow in mice (Arteriosclerosis, Thrombosis, and Vascular Biology (June 2000) (1459-1466))
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Costanza Emanueli, Salis, M. B., Chao, J., Chao, L., Agata, J., Lin, K. -F, Munao, A., Straino, S., Minasi, A., Capogrossi, M. C., and Madeddu, P.
21. Dilated and failing cardiomyopathy in bradykinin B-2 receptor knockout mice
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Emanueli, C., Maestri, R., Corradi, D., Marchione, R., Minasi, A., MARIA GRAZIA TOZZI, Salis, M. B., Straino, S., Capogrossi, M. C., Olivetti, G., and Madeddu, P.
22. Identification of protein disulfide isomerase as a cardiomyocyte survival factor in ischemic cardiomyopathy
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Luigi M. Biasucci, Maddalena Piro, Ulrike Herbrand, Pasquale Mellone, Nina Schmidt, Gabriele Toietta, Feliciano Baldi, Maurizio C. Capogrossi, Rossana Bussani, Giovanna Liuzzo, Furio Silvestri, Stefania Straino, Mara Campioni, Stilla Frede, Michael Ehrmann, Filippo Crea, Alfonso Baldi, Joachim Fandrey, Anna Severino, Fadi N Salloum, Antonio Abbate, Florinda Feroce, Giuliana Di Rocco, Severino, A, Campioni, M, Straino, S, Salloum, Fn, Schmidt, N, Herbrand, U, Frede, S, Toietta, G, DI ROCCO, G, Bussani, Rossana, Silvestri, Furio, Piro, M, Liuzzo, G, Biasucci, Lm, Mellone, P, Feroce, F, Capogrossi, M, Baldi, F, Fandrey, J, Ehrmann, M, Crea, F, Abbate, A, Baldi, A., Severino, A., Campioni, M., Straino, S., Salloum, F., Schmidt, N., Herbrand, U., Frede, S., Toietta, G., DI ROCCO, G., Bussani, R., Silvestri, F., Piro, M., Liuzzo, G., Biasucci, L., Mellone, P., Feroce, F., Capogrossi, G., Baldi, F., Fandrey, J., Ehrmann, M., Crea, F., Abbate, A., and Baldi, Alfonso
- Subjects
Male ,medicine.medical_specialty ,HL1-cells ,Ischemia ,Cardiomyopathy ,Cell Culture Techniques ,Myocardial Infarction ,Protein Disulfide-Isomerases ,PDI ,Apoptosis ,Mice ,Gene expression ,medicine ,Animals ,Humans ,Myocytes, Cardiac ,RNA, Messenger ,Protein disulfide-isomerase ,Aged ,Aged, 80 and over ,Ischemic cardiomyopathy ,Ventricular Remodeling ,business.industry ,Transfection ,Middle Aged ,medicine.disease ,Cell Hypoxia ,Surgery ,Cell biology ,Mice, Inbred C57BL ,Unfolded protein response ,Female ,Cardiology and Cardiovascular Medicine ,business ,Biologie - Abstract
Objectives: The aim of the study was to analyze the molecular mechanisms activated during postinfarction remodeling in human hearts. Background: The molecular mechanisms of initial response to ischemic insult in the heart and the pathways involved in compensation and remodeling are still largely unknown. Methods: Up-regulation or down-regulation of gene expression in the human viable peri-infarct (vs. remote) myocardial region was investigated by complementary deoxyribonucleic acid array technology and confirmed at a single-gene/protein level with reverse transcriptase polymerase chain reaction and immunohistochemistry. An in vitro model of cardiomyocyte hypoxia in HL1 cells was used to validate anti-apoptotic effects of the candidate gene/protein and to assess the associated downstream cascade. Finally, a mouse model of myocardial infarction was used to test the in vivo effects of exogenous transfection with the candidate gene/protein. Results: Protein disulfide isomerase (PDI), a member of the unfolded protein response, is 3-fold up-regulated in the viable peri-infarct myocardial region, and in a postmortem model, its expression is significantly inversely correlated with apoptotic rate and with presence of heart failure (HF) and biventricular dilatation. Induced PDI expression in HL1 cells conferred protection from hypoxia-induced apoptosis. Adenoviral-mediated PDI gene transfer to the mouse heart resulted in 2.5-fold smaller infarct size, significantly reduced cardiomyocyte apoptosis in the peri-infarct region, and smaller left ventricular end-diastolic diameter versus mice treated with a transgene-null adenoviral vector. Conclusions: These results suggest that PDI promotes survival after ischemic damage and that zinc-superoxide dismutase is one of the PDI molecular targets. Pharmacological modulation of this pathway might prove useful for future prevention and treatment of HF. © 2007 American College of Cardiology Foundation.
- Published
- 2007
23. Additive Manufacturing of Multi‐Scale Porous Soft Tissue Implants That Encourage Vascularization and Tissue Ingrowth
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Stefania Straino, Ruth E. Levey, Monica Salamone, James J. Prendergast, Liam Burke, Eoin D. O'Cearbhaill, Carmelo Bruno, Fergal Coulter, Kevin M. Moerman, Aoife Lowery, Ryan Paetzold, Stefano Deotti, Michael G. Monaghan, Brian S. Coulter, Gabriella Bellavia, Eimear B. Dolan, Rachel Beatty, Scott T. Robinson, Peter Dockery, Francesca Cianfarani, Garry P. Duffy, Giulio Ghersi, O'Cearbhaill, Eoin D [0000-0002-4666-5863], Apollo - University of Cambridge Repository, Coulter F.B., Levey R.E., Robinson S.T., Dolan E.B., Deotti S., Monaghan M., Dockery P., Coulter B.S., Burke L.P., Lowery A.J., Beatty R., Paetzold R., Prendergast J.J., Bellavia G., Straino S., Cianfarani F., Salamone M., Bruno C.M., Moerman K.M., Ghersi G., Duffy G.P., and O'Cearbhaill E.D.
- Subjects
Materials science ,Swine ,soft tissue implants ,medical grade silicone ,Silicones ,Biomedical Engineering ,Tissue integration ,Pharmaceutical Science ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Biomaterials ,Medical grade silicone ,chemistry.chemical_compound ,Silicone ,Settore BIO/10 - Biochimica ,Materials Testing ,Animals ,Humans ,Porosity ,Implant failure ,Soft tissue ,Prostheses and Implants ,medical device coatings ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,chemistry ,device-tissue interaction ,Implant ,0210 nano-technology ,additive manufacturing ,Tissue ingrowth ,Biomedical engineering - Abstract
Medical devices, such as silicone-based prostheses designed for soft tissue implantation, often induce a suboptimal foreign-body response which results in a hardened avascular fibrotic capsule around the device, often leading to patient discomfort or implant failure. Here, it is proposed that additive manufacturing techniques can be used to deposit durable coatings with multiscale porosity on soft tissue implant surfaces to promote optimal tissue integration. Specifically, the “liquid rope coil effect”, is exploited via direct ink writing, to create a controlled macro open-pore architecture, including over highly curved surfaces, while adapting atomizing spray deposition of a silicone ink to create a microporous texture. The potential to tailor the degree of tissue integration and vascularization using these fabrication techniques is demonstrated through subdermal and submuscular implantation studies in rodent and porcine models respectively, illustrating the implant coating's potential applications in both traditional soft tissue prosthetics and active drug-eluting devices.
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- 2021
24. Ex vivo acidic preconditioning enhances bone marrow ckit+ cell therapeutic potential via increased CXCR4 expression
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Marta Romani, Chiara Cencioni, Joseph C. Wu, Roberta Melchionna, Maurizio C. Capogrossi, Angela Santoni, Monica Napolitano, Valentina Annese, Stefania Straino, Giulio Pompilio, Claudia Cappuzzello, Carlo Gaetano, Cencioni, C, Melchionna, R, Straino, S, Romani, M, Cappuzzello, C, Annese, V, Wu, J, Pompilio, G, Santoni, A, Gaetano, C, Napolitano, M, and Capogrossi, M
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Male ,Receptors, CXCR4 ,Stromal cell ,Cellular differentiation ,Bone Marrow Cells ,Preconditioning ,Endothelial progenitor cell ,Cell therapy ,Mice ,Basic Science ,Ischemia ,Medicine ,Animals ,Regeneration ,Nitric Oxide Donors ,Cell migration ,Ischemic Preconditioning ,Egtazic Acid ,Chelating Agents ,Bone Marrow Transplantation ,Cell Proliferation ,Endothelial Cell ,Chelating Agent ,business.industry ,Cell growth ,Animal ,Endothelial Cells ,Cell Differentiation ,Nitric Oxide Donor ,Hydrogen-Ion Concentration ,Hypoxia-Inducible Factor 1, alpha Subunit ,Chemokine CXCL12 ,Cell biology ,Hindlimb ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Chemokine ,Immunology ,Ischemic preconditioning ,Bone Marrow Cell ,Bone marrow ,Hindlimb ischaemia ,Chemokines ,business ,Cardiology and Cardiovascular Medicine ,Ex vivo - Abstract
Aims The chemokine receptor CXCR4 modulates endothelial progenitor cell migration, homing, and differentiation, and plays a key role in cardiovascular regeneration. Here we examined the effect of ex vivo acidic preconditioning (AP) on CXCR4 expression and on the regenerative potential of mouse bone marrow (BM) ckit+ cells. Methods and results Acidic preconditioning was achieved by exposing BM ckit+ cells to hypercarbic acidosis (pH 7.0) for 24 h; control cells were kept at pH 7.4. Acidic preconditioning enhanced CXCR4 and stromal cell-derived factor 1 (SDF-1) mRNA levels, as well as CXCR4 phosphorylation. Acidic preconditioning ability to modulate CXCR4 expression depended on cytosolic calcium [Ca2+]i mobilization and on nitric oxide (NO), as determined by [Ca2+]i buffering with BAPTA, and by treatment with the NO donor (DETA/NO) and the NO synthase inhibitor (L-NAME). Further, AP increased SDF-1-driven chemotaxis, transendothelial migration, and differentiation toward the endothelial lineage in vitro. In a mouse model of hindlimb ischaemia, control and AP ckit+ cells were transplanted into the ischaemic muscle; AP cells accelerated blood flow recovery, increased capillary, and arteriole number as well as the number of regenerating muscle fibres vs. control. These effects were abolished by treating AP cells with L-NAME. Conclusion Acidic preconditioning represents a novel strategy to enhance BM ckit+ cell therapeutic potential via NO-dependent increase in CXCR4 expression. © The Author 2013.
- Published
- 2013
25. Combined Therapy with Sonic Hedgehog Gene Transfer and Bone Marrow-Derived Endothelial Progenitor Cells Enhances Angiogenesis and Myogenesis in the Ischemic Skeletal Muscle
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Enrico Pola, Maurizio C. Capogrossi, Mariangela Palladino, Eleonora Gaetani, Roberto Pola, Valentina Neri, Ilaria Gatto, Roy C. Smith, Stefania Straino, Giuseppe Leone, Lynn Hlatky, Egidio Stigliano, Palladino, M, Gatto, I, Neri, V, Stigliano, E, Smith, R, Pola, E, Straino, S, Gaetani, E, Capogrossi, M, Leone, G, Hlatky, L, and Pola, R
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Male ,animal structures ,Physiology ,Angiogenesis ,Genetic enhancement ,Ischemia ,Neovascularization, Physiologic ,Bone Marrow Cells ,Biology ,Muscle Development ,Shh ,Mice ,angiogenesis ,medicine ,Animals ,Regeneration ,Hedgehog Proteins ,myogenesi ,Sonic hedgehog ,Progenitor cell ,Muscle, Skeletal ,Bone Marrow Transplantation ,endothelial progenitor cells ,Myogenesis ,Regeneration (biology) ,Settore MED/09 - MEDICINA INTERNA ,angiogenesi ,Endothelial Cells ,Genetic Therapy ,medicine.disease ,Hindlimb ,Mice, Inbred C57BL ,medicine.anatomical_structure ,embryonic structures ,cardiovascular system ,biology.protein ,Cancer research ,Bone marrow ,myogenesis ,Cardiology and Cardiovascular Medicine ,circulatory and respiratory physiology - Abstract
We have previously demonstrated that sonic hedgehog (Shh) gene transfer improves angiogenesis in the setting of ischemia by upregulating the expression of multiple growth factors and enhancing the incorporation of endogenous bone marrow (BM)-derived endothelial progenitor cells (EPCs). In this study, we hypothesized that combined therapy with Shh gene transfer and BM-derived EPCs is more effective than Shh gene therapy alone in an experimental model of peripheral limb ischemia. We used old mice, which have a significantly reduced angiogenic response to ischemia, and compared the ability of Shh gene transfer, exogenous EPCs, or both to improve regeneration after ischemia. We found a significantly higher capillary density in the Shh + EPC-treated muscles compared to the other experimental groups. We also found that Shh gene transfer increases the incorporation and survival of transplanted EPCs. Finally, we found a significantly higher number of regenerating myofibers in the ischemic muscles of mice receiving combined treatment with Shh and BM-derived EPCs. In summary, the combination of Shh gene transfer and BM-derived EPCs more effectively promotes angiogenesis and muscle regeneration than each treatment individually and merits further investigation for its potential beneficial effects in ischemic diseases.
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- 2012
26. Nε-lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart
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Ezio Musso, Stefano Rossi, Cristina Chimenti, Angela Nebbioso, Francesco Spallotta, Maurizio C. Capogrossi, Gianluca Sbardella, Sabrina Castellano, Stefania Straino, Antonello Mai, Donatella Stilli, Carlo Gaetano, Jessica Rosati, Claudia Colussi, Emilio Macchi, Andrea Frustaci, Roberta Berni, Lucia Altucci, Colussi, C, Rosati, J, Straino, S, Spallotta, F, Berni, R, Stilli, D, Rossi, S, Musso, E, Macchi, E, Mai, A, Sbardella, G, Castellano, S, Chimenti, C, Frustaci, A, Nebbioso, Angela, Altucci, Lucia, Capogrossi, Mc, and Gaetano, C.
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Connexin ,Protein acetylation ,Hydroxamic Acids ,Mice ,MDX mice ,Muscular dystrophy ,Epigenetics ,Animals ,Immunoprecipitation ,Duchenne cardiomyopathy ,Myocytes, Cardiac ,p300-CBP Transcription Factors ,Histone Acetyltransferases ,acetylation ,Vorinostat ,Multidisciplinary ,Connexin-43 ,biology ,Lysine ,Gap junction ,Gap Junctions ,muscular dystrophy | protein acetylation ,Biological Sciences ,HDAC3 ,Molecular biology ,Anacardic Acids ,Muscular Dystrophy, Duchenne ,Histone ,Microscopy, Fluorescence ,PCAF ,Acetylation ,Connexin 43 ,Mice, Inbred mdx ,cardiovascular system ,biology.protein ,sense organs ,Histone deacetylase ,Cardiomyopathies - Abstract
Wanting to explore the epigenetic basis of Duchenne cardiomyopathy, we found that global histone acetylase activity was abnormally elevated and the acetylase P300/CBP-associated factor (PCAF) coimmunoprecipitated with connexin 43 (Cx43), which was N ε -lysine acetylated and lateralized in mdx heart. This observation was paralleled by Cx43 dissociation from N -cadherin and zonula occludens 1, whereas pp60-c-Src association was unaltered. In vivo treatment of mdx with the pan-histone acetylase inhibitor anacardic acid significantly reduced Cx43 N ε -lysine acetylation and restored its association to GAP junctions (GJs) at intercalated discs. Noteworthy, in normal as well as mdx mice, the class IIa histone deacetylases 4 and 5 constitutively colocalized with Cx43 either at GJs or in the lateralized compartments. The class I histone deacetylase 3 was also part of the complex. Treatment of normal controls with the histone deacetylase pan-inhibitor suberoylanilide hydroxamic acid (MC1568) or the class IIa-selective inhibitor 3-{4-[3-(3-fluorophenyl)-3-oxo-1-propen-1-yl]-1-methyl-1H-pyrrol-2-yl}-N-hydroxy-2-propenamide (MC1568) determined Cx43 hyperacetylation, dissociation from GJs, and distribution along the long axis of ventricular cardiomyocytes. Consistently, the histone acetylase activator pentadecylidenemalonate 1b (SPV106) hyperacetylated cardiac proteins, including Cx43, which assumed a lateralized position that partly reproduced the dystrophic phenotype. In the presence of suberoylanilide hydroxamic acid, cell to cell permeability was significantly diminished, which is in agreement with a Cx43 close conformation in the consequence of hyperacetylation. Additional experiments, performed with Cx43 acetylation mutants, revealed, for the acetylated form of the molecule, a significant reduction in plasma membrane localization and a tendency to nuclear accumulation. These results suggest that Cx43 N ε -lysine acetylation may have physiopathological consequences for cell to cell coupling and cardiac function.
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- 2011
27. GMP-based CD133(+) cells isolation maintains progenitor angiogenic properties and enhances standardization in cardiovascular cell therapy
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Marco Valentini, Giuseppe Gaipa, Maurizio C. Capogrossi, Andrea Biondi, Ettore Biagi, Maurizio Pesce, Germana Zaccagnini, Ilaria Burba, Cristiana Di Campli, Manuela Tilenni, Stefania Straino, Paolo Perseghin, Giulio Pompilio, Matteo Parma, Daniela Belotti, Gaipa, G, Tilenni, M, Straino, S, Burba, I, Zaccagnini, G, Belotti, D, Biagi, E, Valentini, M, Perseghin, P, Parma, M, Di Campli, C, Biondi, A, Capogrossi, M, Pompilio, G, and Pesce, M
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Quality Control ,Cell Survival ,Cellular differentiation ,Myocardial Ischemia ,Neovascularization, Physiologic ,Cell Separation ,Biology ,Pharmacology ,Cell therapy ,angiogenesis ,Mice ,In vivo ,Antigens, CD ,Ischemia ,Validation ,medicine ,Animals ,Humans ,Good manufacturing practice ,AC133 Antigen ,CD133 ,Cell Proliferation ,Glycoproteins ,Stem Cells ,GMP ,Hematopoietic stem cell ,Cell Differentiation ,Cell Biology ,Original Articles ,Reference Standards ,Fetal Blood ,Vascular Endothelial Growth Factor Receptor-2 ,Hindlimb ,Angiogenesi ,medicine.anatomical_structure ,Phenotype ,Cardiovascular Diseases ,Cord blood ,Immunology ,Molecular Medicine ,Bone marrow ,Stem cell ,Peptides ,Stem Cell Transplantation - Abstract
The aim of the present study was to develop and validate a good manufacturing practice (GMP) compliant procedure for the preparation of bone marrow (BM) derived CD133(+) cells for cardiovascular repair. Starting from available laboratory protocols to purify CD133(+) cells from human cord blood, we implemented these procedures in a GMP facility and applied quality control conditions defining purity, microbiological safety and vitality of CD133(+) cells. Validation of CD133(+) cells isolation and release process were performed according to a two-step experimental program comprising release quality checking (step 1) as well as 'proofs of principle' of their phenotypic integrity and biological function (step 2). This testing program was accomplished using in vitro culture assays and in vivo testing in an immunosuppressed mouse model of hindlimb ischemia. These criteria and procedures were successfully applied to GMP production of CD133(+) cells from the BM for an ongoing clinical trial of autologous stem cells administration into patients with ischemic cardiomyopathy. Our results show that GMP implementation of currently available protocols for CD133(+) cells selection is feasible and reproducible, and enables the production of cells having a full biological potential according to the most recent quality requirements by European Regulatory Agencies.
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- 2010
28. Proteomic profile of differentially expressed plasma proteins from dystrophic mice and following suberoylanilide hydroxamic acid treatment
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Antonello Mai, Maura Brioschi, Claudia Colussi, Dante Rotili, Stefania Straino, Elena Tremoli, Carlo Gaetano, Francesco Spallotta, Cristina Banfi, M.C. Capogrossi, Colussi, C, Banfi, C, Brioschi, M, Tremoli, E, Straino, S, Spallotta, F, Mai, A, Rotili, D, Capogrossi, M, and Gaetano, C
- Subjects
Duchenne muscular dystrophy ,musculoskeletal diseases ,Proteomics ,mdx mouse ,GPX3 ,Proteome ,Clinical Biochemistry ,Molecular Sequence Data ,duchenne muscular dystrophy ,histone deacetylase inhibitors ,plasma proteome ,Leukemia inhibitory factor receptor ,Biology ,Hydroxamic Acids ,Mice ,Epidermal growth factor ,Histone deacetylase Inhibitor ,medicine ,Animals ,Amino Acid Sequence ,Muscular dystrophy ,Vorinostat ,Dose-Response Relationship, Drug ,Reproducibility of Results ,Blood Proteins ,medicine.disease ,Blood proteins ,Molecular biology ,Muscular Dystrophy, Duchenne ,Plasma proteome ,Gene Expression Regulation ,Gelsolin - Abstract
Purpose: Histone Deacetylase Inhibitors (DI) ameliorates dystrophic muscle regeneration restoring muscular strength in the mdx mouse model of Duchenne muscular dystrophy (DMD). The further development of these compounds as drugs for DMD treatment is currently hampered by the lack of knowledge about DIs effect in large dystrophic animal models and that of suitable biomarkers to monitor their efficacy. Experimental design: In this study we applied proteomic analysis to identify differentially expressed proteins present in plasma samples from mdx mice treated with the Suberoylanilide hydroxamic acid (SAHA) and relative normal controls (WT). Results: Several differentially expressed proteins were identified between untreated wild type and mdx mice. Among these, fibrinogen, epidermal growth factor 2 receptor, major urinary protein and glutathione peroxidase 3 (GPX3) were constitutively up-regulated in mdx, while complement C3, complement C6, gelsolin, leukaemia inhibitory factor receptor (LIFr), and alpha 2 macroglobulin were down-regulated compared to WT mice. SAHA determined the normalization of LIFr and GPX3 protein level while apoliprotein E was de novo up-regulated in comparison to vehicle-treated mdx mice. Conclusions and clinical relevance: Collectively, these data unravel potential serological disease biomarkers of mdx that could be useful to monitor muscular dystrophy response to DI treatment.
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- 2009
29. Altered SDF-1-mediated differentiation of bone marrow-derived endothelial progenitor cells in diabetes mellitus
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Elena De Falco, Roberto Rizzi, Chiara Cencioni, Guido Melillo, Anna Rita Torella, Luca Di Vito, Stefania Straino, Daniele Avitabile, Giulio Pompilio, Pierangela Totta, Maurizio Pesce, Daniele Porcelli, Francesco Spallotta, Monica Napolitano, Maurizio C. Capogrossi, Antonella Zacheo, De Falco, E, Avitabile, D, Totta, Pierangela, Straino, S, Spallotta, F, Cencioni, C, Torella, Ar, Rizzi, R, Porcelli, D, Zacheo, A, Di Vito, L, Pompilio, G, Napolitano, M, Melillo, G, Capogrossi, Mc, and Pesce, M.
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Male ,medicine.medical_specialty ,Chemokine ,Stromal cell ,endothelium ,Cellular differentiation ,Bone Marrow Cells ,Cell Separation ,Endothelial progenitor cell ,Diabetes Mellitus, Experimental ,SDF-1 ,Mice ,Ischemia ,stem cells ,Internal medicine ,medicine ,Animals ,Progenitor cell ,PI3K/AKT ,diabetes ,biology ,chemokine ,Endothelial Cells ,Skeletal muscle ,Cell Differentiation ,Cell Biology ,Chemokine CXCL12 ,Tissue Remodeling/Regeneration ,stem cell ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,diabetes mellitus ,biology.protein ,Molecular Medicine ,diabetes, endothelium, stem cells ,Bone marrow ,Stem cell ,Proto-Oncogene Proteins c-akt - Abstract
In diabetic patients and animal models of diabetes mellitus (DM), circulating endothelial progenitor cell (EPC) number is lower than in normoglycaemic conditions and EPC angiogenic properties are inhibited. Stromal cell derived factor-1 (SDF-1) plays a key role in bone marrow (BM) c-kit(+) stem cell mobilization into peripheral blood (PB), recruitment from PB into ischemic tissues and differentiation into endothelial cells. The aim of the present study was to examine the effect of DM in vivo and in vitro, on murine BM-derived c-kit(+) cells and on their response to SDF-1. Acute hindlimb ischemia was induced in streptozotocin-treated DM and control mice; circulating c-kit(+) cells exhibited a rapid increase followed by a return to control levels which was significantly faster in DM than in control mice. CXCR4 expression by BM c-kit(+) cells as well as SDF-1 protein levels in the plasma and in the skeletal muscle, both before and after the induction of ischemia, were similar between normoglycaemic and DM mice. However, BM-derived c-kit(+) cells from DM mice exhibited an impaired differentiation towards the endothelial phenotype in response to SDF-1; this effect was associated with diminished protein kinase phosphorylation. Interestingly, SDF-1 ability to induce differentiation of c-kit(+) cells from DM mice was restored when cells were cultured under normoglycaemic conditions whereas c-kit(+) cells from normoglycaemic mice failed to differentiate in response to SDF-1 when they were cultured in hyperglycaemic conditions. These results show that DM diminishes circulating c-kit(+) cell number following hindlimb ischemia and inhibits SDF-1-mediated AKT phosphorylation and differentiation towards the endothelial phenotype of BM-derived c-kit(+) cells.
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- 2009
30. HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment
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Barbara Illi, Carmela Dell'Aversana, Stefania Straino, Annalisa Antonini, Chiara Mozzetta, Gianluca Ragone, Giulia Piaggio, Paola Gallinari, Claudia Colussi, Lucia Altucci, Maurizio C. Capogrossi, Emilio Clementi, Mario Pescatori, Pier Lorenzo Puri, Germana Zaccagnini, Carlo Gaetano, Christian Steinkühler, Jessica Rosati, Antonello Mai, Aymone Gurtner, Fabio Martelli, Giulia Minetti, Colussi, C, Mozzetta, C, Gurtner, A, Illi, B, Rosati, J, Straino, S, Ragone, G, Pescatori, M, Zaccagnini, G, Antonini, A, Minetti, G, Martelli, F, Piaggio, G, Gallinari, P, Steinkulher, C, Clementi, E, Dell'Aversana, C, Altucci, Lucia, Mai, A, Capogrossi, Mc, Puri, Pl, and Gaetano, C.
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musculoskeletal diseases ,Satellite Cells, Skeletal Muscle ,Nitrogen ,Pyridines ,Duchenne muscular dystrophy ,Histone Deacetylase 2 ,Nitric Oxide ,Endothelial NOS ,Histone Deacetylases ,Epigenesis, Genetic ,Myoblasts ,Mice ,HDAC ,In vivo ,medicine ,Animals ,Enzyme Inhibitors ,RNA, Small Interfering ,Muscular dystrophy ,skeletal muscle ,Muscle, Skeletal ,Cells, Cultured ,Distrophy ,Multidisciplinary ,biology ,Histone deacetylase 2 ,epigenetic ,Biological Sciences ,Muscular Dystrophy, Animal ,medicine.disease ,Molecular biology ,Histone Deacetylase Inhibitors ,Mice, Inbred C57BL ,Muscular Dystrophy, Duchenne ,Repressor Proteins ,Benzamides ,Mice, Inbred mdx ,Cancer research ,biology.protein ,Histone deacetylase ,Dystrophin ,Deacetylase activity - Abstract
The overlapping histological and biochemical features underlying the beneficial effect of deacetylase inhibitors and NO donors in dystrophic muscles suggest an unanticipated molecular link among dystrophin, NO signaling, and the histone deacetylases (HDACs). Higher global deacetylase activity and selective increased expression of the class I histone deacetylase HDAC2 were detected in muscles of dystrophin-deficient MDX mice. In vitro and in vivo siRNA-mediated down-regulation of HDAC2 in dystrophic muscles was sufficient to replicate the morphological and functional benefits observed with deacetylase inhibitors and NO donors. We found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation. These data reveal a special contribution of HDAC2 in the pathogenesis of Duchenne muscular dystrophy and indicate that HDAC2 inhibition by NO-dependent S-nitrosylation is important for the therapeutic response to NO donors in MDX mice. They also define a common target for independent pharmacological interventions in the treatment of Duchenne muscular dystrophy.
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- 2008
31. Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction
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Giuseppe Biondi-Zoccai, Edoardo Gustini, Rakesh C. Kukreja, George W. Vetrovec, Stefania Straino, Evan D. Ownby, Anna Severino, Anindita Das, Nicholas N Hoke, Ian Z Qureshi, Fadi N Salloum, Antonio Abbate, Jon-Erik Houser, Maurizio C. Capogrossi, Aldo Dobrina, Luigi M. Biasucci, Filippo Crea, Alfonso Baldi, Elena Vecile, Abbate, A, Salloum, Fn, Vecile, E, Das, A, Hoke, Nn, Straino, S, BIONDI ZOCCAI, Gg, Houser, Je, Qureshi, Iz, Ownby, Ed, Gustini, E, Biasucci, Lm, Severino, A, Capogrossi, Mc, Vetrovec, Gw, Crea, F, Baldi, A, Kukreja, Rc, Dobrina, Aldo, BIONDI ZOCCAI, Ggl, Baldi, Alfonso, and Dobrina, A.
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medicine.drug_class ,Ischemia ,Myocardial Infarction ,Myocardial Ischemia ,Heart failure ,Apoptosis ,Mice, Inbred Strains ,Pharmacology ,Mice ,Physiology (medical) ,medicine ,Animals ,Myocytes, Cardiac ,Myocardial infarction ,Rats, Wistar ,Cytokine ,apoptosis ,cytokine ,heart failure ,ischemia ,pharmacology ,remodeling ,Anakinra ,business.industry ,Antagonist ,Apoptosi ,Interleukin ,medicine.disease ,Receptor antagonist ,Caspase Inhibitors ,Remodeling ,Rats ,Interleuchina1Ra ,Disease Models, Animal ,Interleukin 1 Receptor Antagonist Protein ,Interleukin 1 receptor antagonist ,Miocardiociti ,Anesthesia ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Background— Experimental interleukin-1 receptor antagonist gene overexpression has shown that interleukin-1 receptor antagonist is cardioprotective during global cardiac ischemia. The aim of the present study was to test the impact of an exogenous recombinant human interleukin-1 receptor antagonist (anakinra) in experimental acute myocardial infarction. Methods and Results— Two animal studies were conducted: one of immediate anakinra administration during ischemia in the mouse and one of delayed anakinra administration 24 hours after ischemia in the rat. Seventy-eight Institute of Cancer Research mice and 20 Wistar rats underwent surgical coronary artery ligation (or sham operation) and were treated with either anakinra 1 mg/kg or NaCl 0.9% (saline). Treatment was administered during surgery and then daily for 6 doses in the mice and starting on day 2 daily for 5 doses in the rats. Twenty-eight mice underwent infarct size assessment 24 hours after surgery, 6 saline-treated mice and 22 mice treated with increasing doses of anakinra (1 mg/kg [n=6], 10 mg/kg [n=6], and 100 mg/kg [n=10]); 6 mice were euthanized at 7 days for protein expression analysis. The remaining animals underwent transthoracic echocardiography before surgery and 7 days later just before death. Cardiomyocyte apoptosis was measured in the peri-infarct regions. The antiapoptotic effect of anakinra was tested in a primary rat cardiomyocyte culture during simulated ischemia and in vitro on caspase-1 and -9 activities. At 7 days, 15 of the 16 mice (94%) treated with anakinra were alive versus 11 of the 20 mice (55%) treated with saline ( P =0.013). No differences in infarct size at 24 hours compared with saline were observed with the 1- and 10-mg/kg doses, whereas a 13% reduction in infarct size was found with the 100-mg/kg dose ( P =0.015). Treatment with anakinra was associated with a significant reduction in cardiomyocyte apoptosis in both the immediate and delayed treatment groups (3.1±0.2% versus 0.5±0.3% [ P P Conclusions— Administration of anakinra within 24 hours of acute myocardial infarction significantly ameliorates the remodeling process by inhibiting cardiomyocyte apoptosis in 2 different experimental animal models of AMI. This may open the door for using anakinra to prevent postischemic cardiac remodeling and heart failure.
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- 2008
32. Protective effects of parecoxib, a cyclo-oxygenase-2 inhibitor, in postinfarction remodeling in the rat
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Pasquale Mellone, Maddalena Piro, George W. Vetrovec, Luigi M. Biasucci, Ramzi A Ockaili, Antonio Abbate, Giuseppe Biondi-Zoccai, Rakesh C. Kukreja, Anna Severino, Ian Z Qureshi, Maurizio C. Capogrossi, Filippo Crea, Alfonso Baldi, Stefania Straino, Anindita Das, Fadi N Salloum, Straino, S, Salloum, Fn, Baldi, Alfonso, Ockaili, Ra, Piro, M, Das, A, Qureshi, Iz, Biasucci, Lm, Capogrossi, Mc, BIONDI ZOCCAI, Gg, Severino, A, Mellone, P, Crea, F, Vetrovec, Gw, Kukreja, Rc, and Abbate, A.
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Male ,medicine.medical_specialty ,Urology ,Ischemia ,Myocardial Infarction ,Hemodynamics ,acute myocardial infarction ,heart failure ,Apoptosis ,ischemia ,cyclo-oxygenase-2 ,Left coronary artery ,Parecoxib ,medicine.artery ,medicine ,Animals ,Myocardial infarction ,Rats, Wistar ,Ventricular remodeling ,Pharmacology ,Cyclooxygenase 2 Inhibitors ,Ventricular Remodeling ,business.industry ,Myocardium ,Heart ,Isoxazoles ,Organ Size ,medicine.disease ,Survival Analysis ,Rats ,Arterioles ,medicine.anatomical_structure ,Ventricle ,Echocardiography ,Anesthesia ,Heart failure ,Cytokines ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
OBJECTIVE: Selective cyclo-oxygenase-2 (COX-2) inhibitors have been shown to preserve hemodynamic performance in experimental models of acute myocardial infarction (AMI) in rodents. The impact of COX-2 inhibition on apoptosis, vascular density, and postinfarction remodeling has not yet been fully characterized. The aim of the present study was to evaluate the effects of parecoxib, a selective COX-2 inhibitor, in an experimental AMI model in the rat. METHODS: Twenty-four male Wistar rats (10 weeks of age, weighing 350-500 g) underwent surgical left coronary artery ligation. Four animals died within 24 hours. Starting on day 2, 10 rats received parecoxib (0.75 mg/kg intraperitoneal) daily for 5 days and the remaining 10 received NaCl-0.9%. Animals underwent transthoracic echocardiography before surgery and 7 days later for the measurement of end-diastolic and end-systolic diameter and wall thickness; thereafter, animals were sacrificed and histological analysis was performed to evaluate cardiomyocyte apoptosis and small arteriolar density. Data are expressed as mean and standard error. RESULTS: Three saline-treated (30%) and zero parecoxib-treated animals died before day 7. Compared with saline-treated animals, rats treated with parecoxib had a smaller end-diastolic diameter (6.3 ± 0.1 vs. 7.0 ± 0.1 mm, P = 0.018) and end-systolic diameter (2.7 ± 0.1 vs. 3.9 ± 0.1 mm, P = 0.027), and had a greater fractional shortening (57 ± 1 vs. 45 ± 2%, P = 0.050). Systolic thickness in the anterior (infarct) wall was also significantly greater in the parecoxib-treated animals (3.2 ± 0.1 vs. 2.7 ± 0.1 mm, P = 0.008), while the posterior wall was not significantly affected (P = 0.08). Aneurysmal dilatation of the left ventricle was more frequent in saline-treated versus parecoxib-treated animals (43 vs. 0%, P = 0.025). Parecoxib treatment was associated with lower apoptotic rates (1.0 ± 0.2 vs. 4.0 ± 0.4%, P < 0.001) and preservation of arteriolar density (20 ± 5 vs. 8 ± 2 mm/mm, P = 0.018) in the peri-infarct area, without differences in circulating interleukin-1β, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma levels. CONCLUSION: Administration of parecoxib significantly ameliorates the remodeling process after AMI, possibly through prevention of apoptosis and preservation of myocardial vascularity. These findings aid in the understanding of the role of COX-2 in ischemic damage and remodeling. © 2007 Lippincott Williams & Wilkins, Inc.
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- 2007
33. Cyclo-oxygenase-2 (COX-2) inhibition reduces apoptosis in acute myocardial infarction
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Luigi M. Biasucci, M.C. Capogrossi, Giuseppe Biondi-Zoccai, A. Germani, Susanna Scarpa, Mara Campioni, George W. Vetrovec, Daniele Santini, F. Limana, Stefania Straino, Antonio Abbate, Alfonso Baldi, Anna Severino, F Crea, Giovanna Liuzzo, Fortunata Vasaturo, Abbate, A, Limana, F, Caporossi, Mc, Santini, D, BIONDI ZOCCAI, Ggl, Scarpa, S, Germani, A, Straino, S, Severino, A, Vasaturo, F, Campioni, M, Liuzzo, G, Crea, F, Vetrovec, Gw, Biasucci, Lm, and Baldi, Alfonso
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Male ,Cancer Research ,medicine.medical_specialty ,COX2-inhibitor ,Clinical Biochemistry ,Pharmaceutical Science ,Apoptosis ,Mice ,Internal medicine ,Animals ,Medicine ,Cyclo oxygenase 2 ,Cyclo-oxygenase ,Pharmacology ,Pathologic anatomy ,Cyclooxygenase 2 Inhibitors ,business.industry ,Biochemistry (medical) ,Remodelling ,Apoptosi ,Cell Biology ,Mice, Inbred C57BL ,Disease Models, Animal ,Myocardial infarction ,Cyclooxygenase 2 ,Cardiology ,Vascular pathology ,business ,Humanities - Abstract
Department of Medicine, Virginia Commonwealth University, Richmond, VA USA A. Abbate (A. Abbate, G. W. Vetrovec); Institute of Cardiology, Catholic University, Rome, Italy (G. G. L. Biondi-Zoccai, A. Severino, M. Campioni, G. Liuzzo, F. Crea, L. M. Biasucci); Department of Vascular Pathology, Istituto Dermopatico Immacolata, Rome, Italy (F. Limana, M. C. Capogrossi, S. Straino); Section of Oncology, Campus Bio-Medico University, Rome, Italy (D. Santini); Department of Experimental Medicine and of Pathology, Universita degli Studi “La Sapienza”, Rome, Italy (S. Scarpa, F. Vasaturo); Centro Cardiologico Fondazione Monzino, Milano, Italy (A. Germani); Department of Biochemistry and Biophysics “F. Cedrangolo”, Section of Pathologic Anatomy, Second University of Naples, Naples, Italy (A. Baldi)
- Published
- 2006
34. Myoendothelial differentiation of umbilical cord blood CD34+ cells in ischemic tissues
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Orlandi, A., Iachininoto, M.G., De Falco, E., Torella, A.R., Straino, S., Capogrossi, M.C., Pompilio, G., and Pesce, M.
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- 2004
- Full Text
- View/download PDF
35. Towards a Whole Sample Imaging Approach Using Diffusion Tensor Imaging to Examine the Foreign Body Response to Explanted Medical Devices.
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Levey RE, Tornifoglio B, Stone AJ, Kerskens C, Robinson ST, Coulter FB, Bagnall R, O'Connor R, Dolan EB, Dockery P, Bellavia G, Straino S, Cianfarani F, Johnson P, O'Cearbhaill E, Lally C, and Duffy GP
- Abstract
Analysing the composition and organisation of the fibrous capsule formed as a result of the Foreign Body Response (FBR) to medical devices, is imperative for medical device improvement and biocompatibility. Typically, analysis is performed using histological techniques which often involve random sampling strategies. This method is excellent for acquiring representative values but can miss the unique spatial distribution of features in 3D, especially when analysing devices used in large animal studies. To overcome this limitation, we demonstrate a non-destructive method for high-resolution large sample imaging of the fibrous capsule surrounding human-sized implanted devices using diffusion tensor imaging (DTI). In this study we analyse the fibrous capsule surrounding two unique macroencapsulation devices that have been implanted in a porcine model for 21 days. DTI is used for 3D visualisation of the microstructural organisation and validated using the standard means of fibrous capsule investigation; histological analysis and qualitative micro computed tomography (microCT) and scanning electron microscopy (SEM) imaging. DTI demonstrated the ability to distinguish microstructural differences in the fibrous capsules surrounding two macroencapsulation devices made from different materials and with different surface topographies. DTI-derived metrics yielded insight into the microstructural organisation of both capsules which was corroborated by microCT, SEM and histology. The non-invasive characterisation of the integration of implants in the body has the potential to positively influence analysis methods in pre-clinical studies and accelerate the clinical translation of novel implantable devices.
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- 2022
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36. Additive Manufacturing of Multi-Scale Porous Soft Tissue Implants That Encourage Vascularization and Tissue Ingrowth.
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Coulter FB, Levey RE, Robinson ST, Dolan EB, Deotti S, Monaghan M, Dockery P, Coulter BS, Burke LP, Lowery AJ, Beatty R, Paetzold R, Prendergast JJ, Bellavia G, Straino S, Cianfarani F, Salamone M, Bruno CM, Moerman KM, Ghersi G, Duffy GP, and O'Cearbhaill ED
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- Animals, Humans, Materials Testing, Porosity, Swine, Prostheses and Implants, Silicones
- Abstract
Medical devices, such as silicone-based prostheses designed for soft tissue implantation, often induce a suboptimal foreign-body response which results in a hardened avascular fibrotic capsule around the device, often leading to patient discomfort or implant failure. Here, it is proposed that additive manufacturing techniques can be used to deposit durable coatings with multiscale porosity on soft tissue implant surfaces to promote optimal tissue integration. Specifically, the "liquid rope coil effect", is exploited via direct ink writing, to create a controlled macro open-pore architecture, including over highly curved surfaces, while adapting atomizing spray deposition of a silicone ink to create a microporous texture. The potential to tailor the degree of tissue integration and vascularization using these fabrication techniques is demonstrated through subdermal and submuscular implantation studies in rodent and porcine models respectively, illustrating the implant coating's potential applications in both traditional soft tissue prosthetics and active drug-eluting devices., (© 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)
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- 2021
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37. Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models.
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Duffy GP, Robinson ST, O'Connor R, Wylie R, Mauerhofer C, Bellavia G, Straino S, Cianfarani F, Mendez K, Beatty R, Levey R, O'Sullivan J, McDonough L, Kelly H, Roche ET, and Dolan EB
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- Animals, Humans, Models, Animal, Polymers, Prostheses and Implants, Hydrogels, Regenerative Medicine
- Abstract
Regenerative medicine approaches, specifically stem cell technologies, have demonstrated significant potential to treat a diverse array of pathologies. However, such approaches have resulted in a modest clinical benefit, which may be attributed to poor cell retention/survival at the disease site. A delivery system that facilitates regional and repeated delivery to target tissues can provide enhanced clinical efficacy of cell therapies when localized delivery of high doses of cells is required. In this study, a new regenerative reservoir platform (Regenervoir) is described for use in large animal models, with relevance to cardiac, abdominal, and soft tissue pathologies. Regenervoir incorporates multiple novel design features essential for clinical translation, with a focus on scalability, mechanism of delivery, fixation to target tissue, and filling/refilling with a therapeutic cargo, and is demonstrated in an array of clinical applications that are easily translated to human studies. Regenervoir consists of a porous reservoir fabricated from a single material, a flexible thermoplastic polymer, capable of delivering cargo via fill lines to target tissues. A radiopaque shear thinning hydrogel can be delivered to the therapy reservoir and multiple fixation methods (laparoscopic tacks and cyanoacrylate bioadhesive) can be used to secure Regenervoir to target tissues through a minimally invasive approach., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2020
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38. A bioresorbable biomaterial carrier and passive stabilization device to improve heart function post-myocardial infarction.
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Dolan EB, Hofmann B, de Vaal MH, Bellavia G, Straino S, Kovarova L, Pravda M, Velebny V, Daro D, Braun N, Monahan DS, Levey RE, O'Neill H, Hinderer S, Greensmith R, Monaghan MG, Schenke-Layland K, Dockery P, Murphy BP, Kelly HM, Wildhirt S, and Duffy GP
- Subjects
- Adipose Tissue cytology, Animals, Biocompatible Materials, Cell Movement drug effects, Cell- and Tissue-Based Therapy methods, Equipment Design, Female, Humans, Hyaluronic Acid, Hydrogels chemistry, Hydrogels pharmacology, Mesenchymal Stem Cell Transplantation, Myocardial Infarction physiopathology, Pericardium, Swine, Viscosity, Absorbable Implants, Cell- and Tissue-Based Therapy instrumentation, Hydrogels administration & dosage, Mesenchymal Stem Cells drug effects, Myocardial Infarction therapy
- Abstract
The limited regenerative capacity of the heart after a myocardial infarct results in remodeling processes that can progress to congestive heart failure (CHF). Several strategies including mechanical stabilization of the weakened myocardium and regenerative approaches (specifically stem cell technologies) have evolved which aim to prevent CHF. However, their final performance remains limited motivating the need for an advanced strategy with enhanced efficacy and reduced deleterious effects. An epicardial carrier device enabling a targeted application of a biomaterial-based therapy to the infarcted ventricle wall could potentially overcome the therapy and application related issues. Such a device could play a synergistic role in heart regeneration, including the provision of mechanical support to the remodeling heart wall, as well as providing a suitable environment for in situ stem cell delivery potentially promoting heart regeneration. In this study, we have developed a novel, single-stage concept to support the weakened myocardial region post-MI by applying an elastic, biodegradable patch (SPREADS) via a minimal-invasive, closed chest intervention to the epicardial heart surface. We show a significant increase in %LVEF 14 days post-treatment when GS (clinical gold standard treatment) was compared to GS + SPREADS + Gel with and without cells (p ≤ 0.001). Furthermore, we did not find a significant difference in infarct quality or blood vessel density between any of the groups which suggests that neither infarct quality nor vascularization is the mechanism of action of SPREADS. The SPREADS device could potentially be used to deliver a range of new or previously developed biomaterial hydrogels, a remarkable potential to overcome the translational hurdles associated with hydrogel delivery to the heart., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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39. Advanced Material Catheter (AMCath), a minimally invasive endocardial catheter for the delivery of fast-gelling covalently cross-linked hyaluronic acid hydrogels.
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Dolan EB, Kovarova L, O'Neill H, Pravda M, Sulakova R, Scigalkova I, Velebny V, Daro D, Braun N, Cooney GM, Bellavia G, Straino S, Cavanagh BL, Flanagan A, Kelly HM, Duffy GP, and Murphy BP
- Subjects
- Animals, Cell Line, Cells, Immobilized cytology, Cells, Immobilized transplantation, Cross-Linking Reagents administration & dosage, Equipment Design, Humans, Injections, Myocardial Infarction therapy, Stem Cell Transplantation, Stem Cells cytology, Swine, Biocompatible Materials administration & dosage, Cardiac Catheters, Drug Delivery Systems instrumentation, Hyaluronic Acid administration & dosage, Hydrogels administration & dosage
- Abstract
Injectable hydrogels that aim to mechanically stabilise the weakened left ventricle wall to restore cardiac function or to deliver stem cells in cardiac regenerative therapy have shown promising data. However, the clinical translation of hydrogel-based therapies has been limited due to difficulties injecting them through catheters. We have engineered a novel catheter, Advanced Materials Catheter (AMCath), that overcomes translational hurdles associated with delivering fast-gelling covalently cross-linked hyaluronic acid hydrogels to the myocardium. We developed an experimental technique to measure the force required to inject such hydrogels and determined the mechanical/viscoelastic properties of the resulting hydrogels. The preliminary in vivo feasibility of delivering fast-gelling hydrogels through AMCath was demonstrated by accessing the porcine left ventricle and showing that the hydrogel was retained in the myocardium post-injection (three 200 μL injections delivered, 192, 204 and 183 μL measured). However, the mechanical properties of the hydrogels were reduced by passage through AMCath (≤20.62% reduction). We have also shown AMCath can be used to deliver cardiopoietic adipose-derived stem cell-loaded hydrogels without compromising the viability (80% viability) of the cells in vitro. Therefore, we show that hydrogel/catheter compatibility issues can be overcome as we have demonstrated the minimally invasive delivery of a fast-gelling covalently cross-linked hydrogel to the beating myocardium.
- Published
- 2018
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40. Cyclophilin A modulates bone marrow-derived CD117(+) cells and enhances ischemia-induced angiogenesis via the SDF-1/CXCR4 axis.
- Author
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Perrucci GL, Straino S, Corlianò M, Scopece A, Napolitano M, Berk BC, Lombardi F, Pompilio G, Capogrossi MC, and Nigro P
- Subjects
- Animals, Bone Marrow Cells drug effects, Cell Adhesion drug effects, Cell Movement drug effects, Cell Proliferation drug effects, Cells, Cultured, Chemokine CXCL12 metabolism, Cyclophilin A pharmacology, Disease Models, Animal, Hindlimb drug effects, Humans, Ischemia metabolism, Mice, Mice, Inbred C57BL, Receptors, CXCR4 metabolism, Signal Transduction drug effects, Cyclophilin A administration & dosage, Hindlimb blood supply, Ischemia drug therapy, Neovascularization, Physiologic drug effects, Proto-Oncogene Proteins c-kit metabolism
- Abstract
Background: Critical limb ischemia (CLI) is a major health problem with no adequate treatment. Since CLI is characterized by insufficient tissue vascularization, efforts have focused on the discovery of novel angiogenic factors. Cyclophilin A (CyPA) is an immunophilin that has been shown to promote angiogenesis in vitro and to enhance bone marrow (BM) cell mobilization in vivo. However, its potential as an angiogenic factor in CLI is still unknown. Thus, this study aimed to evaluate whether CyPA might induce neo-angiogenesis in ischemic tissues., Methods and Results: Wild-type C57Bl/6j mice underwent acute hind-limb ischemia (HLI) and received a single intramuscular administration of recombinant CyPA or saline. Limb perfusion, capillary density and arteriole number in adductor muscles were significantly increased after CyPA treatment. Interestingly, BM-derived CD117(+) cell recruitment was significantly higher in ischemic adductor tissue of mice treated with CyPA versus saline. Therefore, the effect of CyPA on isolated BM-derived CD117(+) cells in vitro was evaluated. Low concentrations of CyPA stimulated CD117(+) cell proliferation while high concentrations promoted cell death. Moreover, CyPA enhanced CD117(+) cell adhesion and migration in a dose-dependent manner. Mechanistic studies revealed that CyPA up-regulated CXCR4 in CD117(+) cells and in adductor muscles after ischemia. Additionally, SDF-1/CXCR4 axis inhibition by the CXCR4 antagonist AMD3100 decreased CyPA-mediated CD117(+) cell recruitment in the ischemic limb., Conclusion: CyPA induces neo-angiogenesis by recruiting BM-derived CD117(+) cell into ischemic tissues, at least in part, through SDF-1/CXCR4 axis., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)
- Published
- 2016
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41. Characterization of the Pall Celeris system as a point-of-care device for therapeutic angiogenesis.
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Spaltro G, Straino S, Gambini E, Bassetti B, Persico L, Zoli S, Zanobini M, Capogrossi MC, Spirito R, Quarti C, and Pompilio G
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- Animals, Blood Component Removal, Cell Differentiation, Cell Movement, Cell Separation methods, Chemokine CXCL12 metabolism, Disease Models, Animal, Endothelial Cells cytology, Filtration, Flow Cytometry, Hindlimb blood supply, Humans, Leukocytes immunology, Mice, Reperfusion, Vascular Endothelial Growth Factor A metabolism, Ischemia therapy, Neovascularization, Physiologic, Peripheral Arterial Disease therapy, Point-of-Care Systems
- Abstract
Background Aims: The Pall Celeris system is a filtration-based point-of-care device designed to obtain a high concentrate of peripheral blood total nucleated cells (PB-TNCs). We have characterized the Pall Celeris-derived TNCs for their in vitro and in vivo angiogenic potency., Methods: PB-TNCs isolated from healthy donors were characterized through the use of flow cytometry and functional assays, aiming to assess migratory capacity, ability to form capillary-like structures, endothelial trans-differentiation and paracrine factor secretion. In a hind limb ischemia mouse model, we evaluated perfusion immediately and 7 days after surgery, along with capillary, arteriole and regenerative fiber density and local bio-distribution., Results: Human PB-TNCs isolated by use of the Pall Celeris filtration system were shown to secrete a panel of angiogenic factors and migrate in response to vascular endothelial growth factor and stromal-derived factor-1 stimuli. Moreover, after injection in a mouse model of hind limb ischemia, PB-TNCs induced neovascularization by increasing capillary, arteriole and regenerative fiber numbers, with human cells detected in murine tissue up to 7 days after ischemia., Conclusions: The Pall Celeris system may represent a novel, effective and reliable point-of-care device to obtain a PB-derived cell product with adequate potency for therapeutic angiogenesis., (Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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42. Angiogenic impairment of the vascular endothelium: a novel mechanism and potential therapeutic target in muscular dystrophy.
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Palladino M, Gatto I, Neri V, Straino S, Smith RC, Silver M, Gaetani E, Marcantoni M, Giarretta I, Stigliano E, Capogrossi M, Hlatky L, Landolfi R, and Pola R
- Subjects
- Animals, Apoptosis, Aspirin pharmacology, Carcinoma, Lewis Lung blood supply, Carcinoma, Lewis Lung metabolism, Carcinoma, Lewis Lung pathology, Caveolin 1 metabolism, Cell Movement, Cell Proliferation, Cells, Cultured, Cellular Senescence, Coculture Techniques, Corneal Neovascularization metabolism, Corneal Neovascularization pathology, Corneal Neovascularization physiopathology, Cyclic GMP metabolism, Disease Models, Animal, Dystrophin genetics, Endothelial Cells drug effects, Endothelial Cells pathology, Endothelium, Vascular drug effects, Endothelium, Vascular pathology, Endothelium, Vascular physiopathology, Ischemia metabolism, Ischemia pathology, Ischemia physiopathology, Mice, Mice, Inbred mdx, Muscular Dystrophy, Duchenne drug therapy, Muscular Dystrophy, Duchenne genetics, Muscular Dystrophy, Duchenne pathology, Muscular Dystrophy, Duchenne physiopathology, Mutation, Myoblasts, Skeletal metabolism, Myoblasts, Skeletal pathology, Neovascularization, Pathologic, Nitric Oxide metabolism, Nitric Oxide Synthase Type III metabolism, Time Factors, Dystrophin metabolism, Endothelial Cells metabolism, Endothelium, Vascular metabolism, Muscular Dystrophy, Duchenne metabolism, Neovascularization, Physiologic drug effects
- Abstract
Objective: Dystrophin, the missing or defective protein in Duchenne muscular dystrophy, is expressed not only in muscle cells but also in vascular endothelial cells (ECs). In this study, we assessed the effects of dystrophin deficiency on the angiogenic capacities of ECs., Approach and Results: We isolated vascular ECs from mdx mice, the murine equivalent of Duchenne muscular dystrophy in humans, and wild-type controls, and we found that mdx-derived ECs have impaired angiogenic properties, in terms of migration, proliferation, and tube formation. They also undergo increased apoptosis in vitro compared with wild-type cells and have increased senescence-associated β-galactosidase activity. Mdx-derived ECs also display reduced ability to support myoblast proliferation when cocultured with satellite cell-derived primary myoblasts. These endothelial defects are mirrored by systemic impairment of angiogenesis in vivo, both on induction of ischemia, stimulation with growth factors in the corneal model and matrigel plug assays, and tumor growth. We also found that dystrophin forms a complex with endothelial NO synthase and caveolin-1 in ECs, and that NO production and cGMP formation are compromised in ECs isolated from mdx mice. Interestingly, treatment with aspirin enhances production of both cGMP and NO in dystrophic ECs, whereas low-dose aspirin improves the dystrophic phenotype of mdx mice in vivo, in terms of resistance to physical exercise, muscle fiber permeability, and capillary density., Conclusions: These findings demonstrate that impaired angiogenesis is a novel player and potential therapeutic target in Duchenne muscular dystrophy.
- Published
- 2013
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43. Enhancement of lysine acetylation accelerates wound repair.
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Spallotta F, Cencioni C, Straino S, Sbardella G, Castellano S, Capogrossi MC, Martelli F, and Gaetano C
- Abstract
In physiopathological conditions, such as diabetes, wound healing is significantly compromised and chronic complications, including ulcers, may occur. In a mouse model of skin repair, we recently reported that wound treatment with Sirtuin activators and class I HDAC inhibitors induced keratinocyte proliferation and enhanced healing via a nitric oxide (NO) dependent mechanism. We observed an increase in total protein acetylation in the wound area, as determined by acetylation of α-tubulin and histone H3 Lysine 9. We reasoned that this process activated cell function as well as regulated gene expression to foster tissue repair. We report here that the direct activation of P300/CBP-associated factor (PCAF) by the histone acetylase activator pentadecylidenemalonate 1b (SPV-106) induced Lysine acetylation in the wound area. This intervention was sufficient to enhance repair process by a NO-independent mechanism. Hence, an impairment of PCAF and/or other GCN5 family acetylases may delay skin repair in physiopathological conditions.
- Published
- 2013
- Full Text
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44. Detrimental effect of class-selective histone deacetylase inhibitors during tissue regeneration following hindlimb ischemia.
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Spallotta F, Tardivo S, Nanni S, Rosati JD, Straino S, Mai A, Vecellio M, Valente S, Capogrossi MC, Farsetti A, Martone J, Bozzoni I, Pontecorvi A, Gaetano C, and Colussi C
- Subjects
- Animals, Benzamides pharmacology, Dystrophin metabolism, Hindlimb metabolism, Hindlimb pathology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Hydroxamic Acids pharmacology, Male, Mice, Nitric Oxide Synthase Type I metabolism, Protein Phosphatase 2 metabolism, Pyridines pharmacology, Pyrroles pharmacology, Time Factors, Benzamides adverse effects, Hindlimb blood supply, Histone Deacetylase Inhibitors adverse effects, Hydroxamic Acids adverse effects, Ischemia drug therapy, Ischemia metabolism, Ischemia pathology, Muscle, Skeletal blood supply, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Pyridines adverse effects, Pyrroles adverse effects, Regeneration drug effects
- Abstract
Histone deacetylase inhibitors (DIs) are promising drugs for the treatment of several pathologies including ischemic and failing heart where they demonstrated efficacy. However, adverse side effects and cardiotoxicity have also been reported. Remarkably, no information is available about the effect of DIs during tissue regeneration following acute peripheral ischemia. In this study, mice made ischemic by femoral artery excision were injected with the DIs MS275 and MC1568, selective for class I and IIa histone deacetylases (HDACs), respectively. In untreated mice, soon after damage, class IIa HDAC phosphorylation and nuclear export occurred, paralleled by dystrophin and neuronal nitric-oxide synthase (nNOS) down-regulation and decreased protein phosphatase 2A activity. Between 14 and 21 days after ischemia, dystrophin and nNOS levels recovered, and class IIa HDACs relocalized to the nucleus. In this condition, the MC1568 compound increased the number of newly formed muscle fibers but delayed their terminal differentiation, whereas MS275 abolished the early onset of the regeneration process determining atrophy and fibrosis. The selective DIs had differential effects on the vascular compartment: MC1568 increased arteriogenesis whereas MS275 inhibited it. Capillarogenesis did not change. Chromatin immunoprecipitations revealed that class IIa HDAC complexes bind promoters of proliferation-associated genes and of class I HDAC1 and 2, highlighting a hierarchical control between class II and I HDACs during tissue regeneration. Our findings indicate that class-selective DIs interfere with normal mouse ischemic hindlimb regeneration and suggest that their use could be limited by alteration of the regeneration process in peripheral ischemic tissues.
- Published
- 2013
- Full Text
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45. Ex vivo acidic preconditioning enhances bone marrow ckit+ cell therapeutic potential via increased CXCR4 expression.
- Author
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Cencioni C, Melchionna R, Straino S, Romani M, Cappuzzello C, Annese V, Wu JC, Pompilio G, Santoni A, Gaetano C, Napolitano M, and Capogrossi MC
- Subjects
- Animals, Bone Marrow Cells cytology, Cell Differentiation physiology, Cell Proliferation, Chelating Agents pharmacology, Chemokine CXCL12 metabolism, Egtazic Acid analogs & derivatives, Egtazic Acid pharmacology, Endothelial Cells cytology, Endothelial Cells physiology, Hindlimb blood supply, Hydrogen-Ion Concentration, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Ischemia prevention & control, Ischemic Preconditioning methods, Male, Mice, Nitric Oxide Donors metabolism, Bone Marrow Cells physiology, Bone Marrow Transplantation methods, Proto-Oncogene Proteins c-kit metabolism, Receptors, CXCR4 metabolism, Regeneration physiology
- Abstract
Aims: The chemokine receptor CXCR4 modulates endothelial progenitor cell migration, homing, and differentiation, and plays a key role in cardiovascular regeneration. Here we examined the effect of ex vivo acidic preconditioning (AP) on CXCR4 expression and on the regenerative potential of mouse bone marrow (BM) ckit(+) cells., Methods and Results: Acidic preconditioning was achieved by exposing BM ckit(+) cells to hypercarbic acidosis (pH 7.0) for 24 h; control cells were kept at pH 7.4. Acidic preconditioning enhanced CXCR4 and stromal cell-derived factor 1 (SDF-1) mRNA levels, as well as CXCR4 phosphorylation. Acidic preconditioning ability to modulate CXCR4 expression depended on cytosolic calcium [Ca(2+)]i mobilization and on nitric oxide (NO), as determined by [Ca(2+)]i buffering with BAPTA, and by treatment with the NO donor (DETA/NO) and the NO synthase inhibitor (L-NAME). Further, AP increased SDF-1-driven chemotaxis, transendothelial migration, and differentiation toward the endothelial lineage in vitro. In a mouse model of hindlimb ischaemia, control and AP ckit(+) cells were transplanted into the ischaemic muscle; AP cells accelerated blood flow recovery, increased capillary, and arteriole number as well as the number of regenerating muscle fibres vs. control. These effects were abolished by treating AP cells with L-NAME., Conclusion: Acidic preconditioning represents a novel strategy to enhance BM ckit(+) cell therapeutic potential via NO-dependent increase in CXCR4 expression.
- Published
- 2013
- Full Text
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46. A nitric oxide-dependent cross-talk between class I and III histone deacetylases accelerates skin repair.
- Author
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Spallotta F, Cencioni C, Straino S, Nanni S, Rosati J, Artuso S, Manni I, Colussi C, Piaggio G, Martelli F, Valente S, Mai A, Capogrossi MC, Farsetti A, and Gaetano C
- Subjects
- Animals, Cell Line, Transformed, Enzyme Activators pharmacology, Enzyme Inhibitors pharmacology, Fibroblast Growth Factor 10 metabolism, Group III Histone Deacetylases antagonists & inhibitors, Humans, Insulin-Like Growth Factor I metabolism, Male, Mice, NG-Nitroarginine Methyl Ester pharmacology, Signal Transduction drug effects, Signal Transduction physiology, Wound Healing drug effects, Group III Histone Deacetylases metabolism, Histone Deacetylase 2 metabolism, Nitric Oxide metabolism, Skin enzymology, Skin injuries, Wound Healing physiology
- Abstract
In a mouse model of skin repair we found that the class I-IIa histone deacetylase inhibitor trichostatin A accelerated tissue regeneration. Unexpectedly, this effect was suppressed by Sirtinol, a class III histone deacetylase (HDAC) (sirtuin)-selective inhibitor. The role of sirtuins (SIRTs) was then investigated by using resveratrol and a novel SIRT1-2-3 activator, the MC2562 compound we synthesized recently. Both resveratrol and MC2562 were effective in accelerating wound repair. The local administration of natural or synthetic SIRT activators, in fact, significantly accelerated skin regeneration by increasing keratinocyte proliferation. In vitro experiments revealed that the activation of SIRTs stimulated keratinocyte proliferation via endothelial NO synthase phosphorylation and NO production. In this condition, the class I member HDAC2 was found S-nitrosylated on cysteine, a post-transduction modification associated with loss of activity and DNA binding capacity. After deacetylase inhibitor or SIRT activator treatment, ChIP showed, in fact, a significant HDAC2 detachment from the promoter region of insulin growth factor I (IGF-I), fibroblast growth factor 10 (FGF-10), and Epithelial Growth Factor (EGF), which may be the final recipients and effectors of the SIRT-NO-HDAC signaling cascade. Consistently, the effect of SIRT activators was reduced in the presence of NG-nitro-L-arginine methyl ester (L-NAME), a general inhibitor of NO synthesis. In conclusion, the NO-dependent cross-talk among class III and I histone deacetylases suggests an unprecedented signaling pathway important for skin repair.
- Published
- 2013
- Full Text
- View/download PDF
47. C/EBPγ regulates wound repair and EGF receptor signaling.
- Author
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Melchionna R, Bellavia G, Romani M, Straino S, Germani A, Di Carlo A, Capogrossi MC, and Napolitano M
- Subjects
- CCAAT-Enhancer-Binding Proteins antagonists & inhibitors, CCAAT-Enhancer-Binding Proteins genetics, Cell Movement, Cell Proliferation, Cells, Cultured, Humans, NF-kappa B physiology, Paxillin metabolism, Phosphorylation, RNA, Small Interfering genetics, CCAAT-Enhancer-Binding Proteins physiology, ErbB Receptors physiology, Signal Transduction physiology, Wound Healing
- Abstract
We aimed at identifying novel regulators of skin wound healing (WH), in an epidermal scratch WH assay, by a small interfering RNA (siRNA) silencing approach. Several transcription factors have been previously reported to affect wound repair. We here show that gene silencing of the transcription factor CAAT enhancer-binding protein γ (C/EBPγ), STAT3, REL, RELA, RELB, SP1, and NFkB impaired WH in vitro, in keratinocytes, whereas E2F and CREBBP silencing accelerated the WH process. We further characterized C/EBPγ, as its silencing yielded the maximal impairment (52.2 ± 12.5%) of scratch wounding (SW). We found that C/EBPγ silencing inhibited both EGF- and serum-induced keratinocyte migration, whereas C/EBPγ overexpression enhanced cell migration to EGF and to serum via the EGFR. Further, C/EBPγ silencing impaired scratch-induced Y1068 and Y1173 EGFR phosphorylation, as well as Y118 paxillin phosphorylation, key molecules regulating cell migration and epidermal WH. Moreover, C/EBPγ levels were induced in keratinocytes, following both SW and EGF stimulation. C/EBPγ siRNA silencing in vivo impaired WH at 3, 5, 7, and 14 days following excisional wounding in mice inhibited both re-epithelialization and granulation tissue formation, and induced a decrease of arteriole number. In conclusion, we here report that C/EBPγ positively regulates wound repair both in vitro and in vivo, at least in part, by affecting EGFR signaling.
- Published
- 2012
- Full Text
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48. Molecular imaging of nuclear factor-Y transcriptional activity maps proliferation sites in live animals.
- Author
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Goeman F, Manni I, Artuso S, Ramachandran B, Toietta G, Bossi G, Rando G, Cencioni C, Germoni S, Straino S, Capogrossi MC, Bacchetti S, Maggi A, Sacchi A, Ciana P, and Piaggio G
- Subjects
- Animals, Cell Cycle genetics, Cell Line, Cyclin B2 genetics, DNA-Binding Proteins genetics, Genes, Reporter, Luciferases genetics, Luciferases metabolism, Mice, Mice, Transgenic, Promoter Regions, Genetic, CCAAT-Binding Factor genetics, CCAAT-Binding Factor metabolism, Cell Proliferation, Liver Regeneration, Molecular Imaging, Transcription, Genetic
- Abstract
In vivo imaging involving the use of genetically engineered animals is an innovative powerful tool for the noninvasive assessment of the molecular and cellular events that are often targets of therapy. On the basis of the knowledge that the activity of the nuclear factor-Y (NF-Y) transcription factor is restricted in vitro to proliferating cells, we have generated a transgenic reporter mouse, called MITO-Luc (for mitosis-luciferase), in which an NF-Y-dependent promoter controls luciferase expression. In these mice, bioluminescence imaging of NF-Y activity visualizes areas of physiological cell proliferation and regeneration during response to injury. Using this tool, we highlight for the first time a role of NF-Y activity on hepatocyte proliferation during liver regeneration. MITO-Luc reporter mice should facilitate investigations into the involvement of genes in cell proliferation and provide a useful model for studying aberrant proliferation in disease pathogenesis. They should be also useful in the development of new anti/proproliferative drugs and assessment of their efficacy and side effects on nontarget tissues.
- Published
- 2012
- Full Text
- View/download PDF
49. Combined therapy with sonic hedgehog gene transfer and bone marrow-derived endothelial progenitor cells enhances angiogenesis and myogenesis in the ischemic skeletal muscle.
- Author
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Palladino M, Gatto I, Neri V, Stigliano E, Smith RC, Pola E, Straino S, Gaetani E, Capogrossi M, Leone G, Hlatky L, and Pola R
- Subjects
- Animals, Bone Marrow Cells metabolism, Endothelial Cells metabolism, Hindlimb blood supply, Ischemia physiopathology, Male, Mice, Mice, Inbred C57BL, Muscle Development, Muscle, Skeletal blood supply, Muscle, Skeletal physiology, Neovascularization, Physiologic physiology, Regeneration, Bone Marrow Transplantation, Genetic Therapy methods, Hedgehog Proteins genetics, Ischemia therapy
- Abstract
We have previously demonstrated that sonic hedgehog (Shh) gene transfer improves angiogenesis in the setting of ischemia by upregulating the expression of multiple growth factors and enhancing the incorporation of endogenous bone marrow (BM)-derived endothelial progenitor cells (EPCs). In this study, we hypothesized that combined therapy with Shh gene transfer and BM-derived EPCs is more effective than Shh gene therapy alone in an experimental model of peripheral limb ischemia. We used old mice, which have a significantly reduced angiogenic response to ischemia, and compared the ability of Shh gene transfer, exogenous EPCs, or both to improve regeneration after ischemia. We found a significantly higher capillary density in the Shh + EPC-treated muscles compared to the other experimental groups. We also found that Shh gene transfer increases the incorporation and survival of transplanted EPCs. Finally, we found a significantly higher number of regenerating myofibers in the ischemic muscles of mice receiving combined treatment with Shh and BM-derived EPCs. In summary, the combination of Shh gene transfer and BM-derived EPCs more effectively promotes angiogenesis and muscle regeneration than each treatment individually and merits further investigation for its potential beneficial effects in ischemic diseases., (Copyright © 2012 S. Karger AG, Basel.)
- Published
- 2012
- Full Text
- View/download PDF
50. Pleiotropic beneficial effects of sonic hedgehog gene therapy in an experimental model of peripheral limb ischemia.
- Author
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Palladino M, Gatto I, Neri V, Straino S, Silver M, Tritarelli A, Piccioni A, Smith RC, Gaetani E, Losordo DW, Crea F, Capogrossi M, and Pola R
- Subjects
- Angiopoietin-1 metabolism, Animals, Chemokine CXCL12 metabolism, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Hedgehog Proteins genetics, Ischemia genetics, Ischemia metabolism, Male, Mice, Mice, Inbred C57BL, Polymerase Chain Reaction, Vascular Endothelial Growth Factor A metabolism, Genetic Therapy methods, Hedgehog Proteins metabolism, Hindlimb blood supply, Ischemia therapy
- Abstract
We have previously shown that the signaling pathway of the embryonic morphogen Sonic hedgehog (Shh) is recapitulated in the postnatal skeletal muscle in response to ischemia. We have also demonstrated that Shh is an indirect angiogenic agent upregulating various families of angiogenic growth factors and that Shh gene therapy improves angiogenesis and heart function in experimental models of myocardial ischemia. Based on these findings, we hypothesized that Shh gene therapy is beneficial in an experimental model of peripheral ischemia. We found that intramuscular (i.m.) treatment with a plasmid encoding the Shh human gene (phShh) increased blood flow, capillary density, and arteriole density in mice in which peripheral circulation of the hindlimb was disrupted by removal of the common femoral artery. Shh gene therapy also enhanced vasculogenesis, by increasing the number of circulating bone marrow (BM)-derived endothelial precursors and improving the contribution of these cells to the process of neovascularization. Finally, phShh treatment induced upregulation of prototypical angiogenic, arteriogenic, and vasculogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietin 1 (Ang-1), and stromal cell-derived factor-1 (SDF-1α). These data suggest that Shh gene therapy merits further investigation for its ability to trigger the expression of potent trophic factors and stimulate pleiotropic aspects of neovascularization in the setting of ischemia.
- Published
- 2011
- Full Text
- View/download PDF
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