407 results on '"Ignarro LJ"'
Search Results
2. Erectile hydraulics: maximizing inflow while minimizing outflow
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Meldrum DR, Burnett AL, Dorey G, Ignarro LJ, ESPOSITO, Katherine, Meldrum, Dr, Burnett, Al, Dorey, G, Esposito, Katherine, and Ignarro, Lj
- Published
- 2014
3. Effects of nitric oxide on cell proliferation: novel insights
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NAPOLI, Claudio, PAOLISSO, Giuseppe, CASAMASSIMI, Amelia, Al Omran M, BARBIERI, Michelangela, SOMMESE, Linda, Infante T, Ignarro LJ, Napoli, Claudio, Paolisso, Giuseppe, Casamassimi, Amelia, Al Omran, M, Barbieri, Michelangela, Sommese, Linda, Infante, T, and Ignarro, Lj
- Abstract
Nitric oxide (NO) has been suggested to be a pathophysiological modulator of cell proliferation, cell cycle arrest and apoptosis. In this context, opposite effects can be exerted by NO under diverse conditions. Indeed, several studies have indicated that low relative concentrations of NO seem to favour cell proliferation and anti-apoptotic responses whereas higher levels of NO favour pathways inducing cell cycle arrest, mitochondria respiration, senescence or apoptosis. Here, we report the NO effects on both promotion and inhibition of cell proliferation with particular concern on cardiovascular disease, diabetes and stem cells. Moreover, we focus on molecular mechanisms of action involved in the control of cell cycle progression, which include both cGMP-dependent and -independent pathways. This growing field may lead to broad and novel targeted therapies against cardiovascular diseases especially during concomitant type 2 diabetes, as well as novel bioimaging NO-based diagnostic tools.
- Published
- 2013
4. The Link Between Erectile and Cardiovascular Health: The Canary in the Coal Mine
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MELDRUM DR, GAMBONE JC, MORRIS MA, MELDRUM DA, IGNARRO LJ, ESPOSITO, Katherine, Meldrum, Dr, Gambone, Jc, Morris, Ma, Meldrum, Da, Esposito, Katherine, and Ignarro, Lj
- Published
- 2011
5. Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases
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NAPOLI, Claudio, IGNARRO LJ, Napoli, Claudio, and Ignarro, Lj
- Published
- 2009
6. Therapeutic dose of nebivolol, a nitric oxide-releasing beta-blocker, reduces atherosclerosis in cholesterol-fed rabbits
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de NIGRIS, Filomena, MANCINI FP, BALESTRIERI, Maria Luisa, BYRNS R, FIORITO C, WILLIAMS IGNARRO S, PALAGIANO A, CRIMI E, IGNARRO LJ, NAPOLI, Claudio, de NIGRIS, Filomena, Mancini, Fp, Balestrieri, Maria Luisa, Byrns, R, Fiorito, C, WILLIAMS IGNARRO, S, Palagiano, A, Crimi, E, Ignarro, Lj, and Napoli, Claudio
- Published
- 2008
7. Nutrition and cardiovascular disease: putting a pathogenic framework into focus
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NAPOLI, Claudio, STANLEY WC, IGNARRO LJ, Napoli, Claudio, Stanley, Wc, and Ignarro, Lj
- Published
- 2007
8. Polymorphisms in endothelial nitric oxide synthase and carotid artery atherosclerosis
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NAPOLI, Claudio, IGNARRO LJ, Napoli, Claudio, and Ignarro, Lj
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- 2007
9. Brain protection using integrative management with autologous bone marrow cells, transgene overexpression of tissue metalloproteinase inhibitors and metabolic treatment in cerebral ischemia
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BAKER AH, CASAMASSIMI, Amelia, WILLIAMS IGNARRO S, de NIGRIS, Filomena, LERMAN LO, SICA V, LANZA, Alessandro, SCHIANO C, WORK L, IGNARRO LJ, NAPOLI, Claudio, BALESTRIERI, Maria Luisa, Baker, Ah, Casamassimi, Amelia, WILLIAMS IGNARRO, S, de NIGRIS, Filomena, Lerman, Lo, Sica, V, Lanza, Alessandro, Schiano, C, Balestrieri, Maria Luisa, Work, L, Ignarro, Lj, and Napoli, Claudio
- Published
- 2007
10. Autologous bone marrow cell therapy and metabolic intervention in the ischemic limb of spontaneously hypertensive rats
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DE NIGRIS F, WILLIAMS IGNARRO S, LERMAN LO, BYRNS R, RIENZO M, FIORITO C, MAIONE C, SCHIANO C, SICA V, IGNARRO LJ, NAPOLI, Claudio, BALESTRIERI, Maria Luisa, DE NIGRIS, F, Balestrieri, Maria Luisa, WILLIAMS IGNARRO, S, Lerman, Lo, Byrns, R, Rienzo, M, Fiorito, C, Maione, C, Schiano, C, Sica, V, Ignarro, Lj, and Napoli, Claudio
- Published
- 2007
11. The role of oxidative stress in adult critical care
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CRIMI E, SICA V, WILLIAMS IGNARRO S, ZHANG H, SLUTSKY AS, IGNARRO LJ, NAPOLI, Claudio, Crimi, E, Sica, V, WILLIAMS IGNARRO, S, Zhang, H, Slutsky, A, Ignarro, Lj, and Napoli, Claudio
- Published
- 2006
12. Novel features of nitric oxide, endothelial nitric oxide synthase, and atherosclerosis
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IGNARRO LJ, NAPOLI, Claudio, Ignarro, Lj, and Napoli, Claudio
- Published
- 2005
13. Beneficial effects ofpomegranate juice on oxidation-sensitive genes and endothelial nitric oxidesynthase activity at sites of perturbed shear stress
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de Nigris F, Williams Ignarro S, Lerman LO, Crimi E, Botti C, Mansueto G, Sica V, Ignarro LJ, Napoli C., D'ARMIENTO, FRANCESCO PAOLO, DE ROSA, GAETANO, de Nigris, F, Williams Ignarro, S, Lerman, Lo, Crimi, E, Botti, C, Mansueto, G, D'Armiento, FRANCESCO PAOLO, DE ROSA, Gaetano, Sica, V, Ignarro, Lj, and Napoli, C.
- Abstract
Atherosclerosis is enhanced in arterial segments exposed to disturbed flow. Perturbed shear stress increases the expression of oxidation-sensitive responsive genes (such as ELK-1 and p-JUN) in the endothelium. Evidence suggests that polyphenolic antioxidants contained in the juice derived from the pomegranate can contribute to the reduction of oxidative stress and atherogenesis. The aim of the present study was to evaluate the effects of intervention with pomegranate juice (PJ) on oxidation-sensitive genes and endothelial NO synthase (eNOS) expression induced by high shear stress in vitro and in vivo. Cultured human coronary artery endothelial cells (EC) exposed to high shear stress in vitro and hypercholesterolemic mice were used in this study. PJ concentrate reduced the activation of redox-sensitive genes (ELK-1 and p-JUN) and increased eNOS expression (which was decreased by perturbed shear stress) in cultured EC and in atherosclerosis-prone areas of hypercholesterolemic mice. Moreover, oral administration of PJ to hypercholesterolemic mice at various stages of disease reduced significantly the progression of atherosclerosis. This experimental study indicates that the proatherogenic effects induced by perturbed shear stress can be reversed by chronic administration of PJ. This approach may have implications for the prevention or treatment of atherosclerosis and its clinical manifestations.
- Published
- 2005
14. Involvement of beta3-adrenergic receptor activation via cyclic GMP in human corpus cavernosum function
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Mirone V, Cirino G, Imbimbo C, Palmieri A, Longo N, Fusco F, Ignarro LJ, Mirone, V., Cirino, G., Imbimbo, Ciro, Palmieri, A., Longo, N., Fusco, Ferdinando, Ignarro, Lj, Mirone, V, Cirino, G, Imbimbo, C, Palmieri, A, Longo, N, and Fusco, F
- Published
- 2004
15. Oxidation-sensitive mechanisms, vascular apoptosis and atherosclerosis
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de NIGRIS, Filomena, LERMAN A, IGNARRO LJ, WILLIAMS IGNARRO S, SICA V, BAKER AH, LERMAN LO, GENG YJ, NAPOLI, Claudio, de NIGRIS, Filomena, Lerman, A, Ignarro, Lj, WILLIAMS IGNARRO, S, Sica, V, Baker, Ah, Lerman, Lo, Geng, Yj, and Napoli, Claudio
- Published
- 2003
16. Nitric oxide-releasing drugs
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NAPOLI, Claudio, IGNARRO LJ, Napoli, Claudio, and Ignarro, Lj
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- 2003
17. Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release
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MA L., ELLIOT S. N., BURET A., IGNARRO LJ, WALLACE JL, CIRINO, GIUSEPPE, Ma, L., Elliot, S. N., Cirino, Giuseppe, Buret, A., Ignarro, Lj, and Wallace, Jl
- Published
- 2001
18. Nitric oxide and atherosclerosis
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NAPOLI, Claudio, IGNARRO LJ, Napoli, Claudio, and Ignarro, Lj
- Published
- 2001
19. Effect of gestational hypercholesterolaemia on omental vasoreactivity, placental enzyme activity and transplacental passage of normal and oxidised fatty acids
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Liguori, A, primary, D’Armiento, FP, additional, Palagiano, A, additional, Balestrieri, ML, additional, Williams-Ignarro, S, additional, De Nigris, F, additional, Lerman, LO, additional, D’Amora, M, additional, Rienzo, M, additional, Fiorito, C, additional, Ignarro, LJ, additional, Palinski, W, additional, and Napoli, C, additional
- Published
- 2007
- Full Text
- View/download PDF
20. eNOS-derived NO participates in lipopolysaccharide-stimulated iNOS expression in murine macrophages via a cGMP-dependent mechanism
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Connelly, L, primary, Ignarro, LJ, additional, and Hobbs, J, additional
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- 2003
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21. F093 effects of acute and short-term estradiol administration on serum nitric oxide levels in postmenopausal women
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Cicinelli, E, primary, Ignarro, LJ, additional, Balzano, G, additional, Romano, F, additional, Ruccia, C, additional, Cataldi, E, additional, and Schönauer, LM, additional
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- 1996
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22. Nitric oxide improves cisplatin cytotoxicity in head and neck squamous cell carcinoma.
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Azizzadeh B, Yip HT, Blackwell KE, Horvath S, Calcaterra TC, Buga GM, Ignarro LJ, and Wang MB
- Published
- 2001
23. Evidence for the inhibitory role of guanosine 3', 5'-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators
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Mellion, BT, Ignarro, LJ, Ohlstein, EH, Pontecorvo, EG, Hyman, AL, and Kadowitz, PJ
- Published
- 1981
- Full Text
- View/download PDF
24. Pathophysiological mechanisms of nitric oxide
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NAPOLI, Claudio, Crtimi E, William Ignarro s, Ignarro L.J., de NIGRIS, Filomena, Ignarro LJ, ignarro LJ., Napoli, Claudio, Crtimi, E, William Ignarro, S, de NIGRIS, Filomena, and Ignarro, L. J.
- Published
- 2010
25. Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice
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Giuseppe Cirino, Mario Condorelli, L.J. Ignarro, Vincenzo Sica, Aldo Pinto, Claudio Napoli, Raffaella Sorrentino, Piero Del Soldato, Napoli, C., Cirino, G. M., DEL SOLDATO, P, Sorrentino, R, Sica, V, Condorelli, Mario, Pinto, A, Ignarro, Lj, Napoli, Claudio, Cirino, G, Condorelli, M, Ignarro, L. J., Napoli, C, Sorrentino, Raffaella, Condorelli, M., and Ignarro, Lj.
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medicine.medical_specialty ,Vascular smooth muscle ,medicine.medical_treatment ,Hypercholesterolemia ,Constriction, Pathologic ,Nitric Oxide ,NO-dependent mechanism ,Nitric oxide ,chemistry.chemical_compound ,Mice ,Restenosis ,Recurrence ,Angioplasty ,Internal medicine ,medicine ,Animals ,restenosi ,Neointimal hyperplasia ,Mice, Knockout ,Aspirin ,Multidisciplinary ,business.industry ,Biological Sciences ,medicine.disease ,Mice, Inbred C57BL ,medicine.anatomical_structure ,chemistry ,Receptors, LDL ,Cardiology ,business ,hypercholesterolemic mice ,medicine.drug ,Artery ,Lipoprotein - Abstract
Restenosis is due to neointimal hyperplasia, which occurs in the coronary artery after percutaneous transluminal coronary angioplasty (PTCA). During restenosis, an impairment of nitric oxide (NO)-dependent pathways may occur. Concomitant hypercholesterolemia may exacerbate restenosis in patients undergoing PTCA. Here, we show that a NO-releasing aspirin derivative (NCX-4016) reduces the degree of restenosis after balloon angioplasty in low-density lipoprotein receptor-deficient mice and this effect is associated with reduced vascular smooth muscle cell (VSMC) proliferation and macrophage deposition at the site of injury. Drugs were administered following both therapeutic or preventive protocols. We demonstrate that NCX-4016 is effective both in prevention and treatment of restenosis in the presence of hypercholesterolemia. These data indicate that impairment of NO-dependent mechanisms may be involved in the development of restenosis in hypercholesterolemic mice. Although experimental models of restenosis may not reflect restenosis in humans in all details, we suggest that a NO-releasing aspirin derivative could be an effective drug in reducing restenosis following PTCA, especially in the presence of hypercholesterolemia and/or gastrointestinal damage.
- Published
- 2001
26. Long-term treatment with sulfhydryl angiotensin-converting enzyme inhibition reduces carotid intima-media thickening and improves the nitric oxide/oxidative stress pathways in newly diagnosed patients with mild to moderate primary hypertension
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Sabina Libardi, Filomena de Nigris, Ettore Crimi, Claudio Napoli, Carmela Fiorito, Giuseppe Bruzzese, Sharon Williams-Ignarro, Linda Sommese, Francesco Cacciatore, Louis J. Ignarro, Francesco Mancini, A. Liguori, Napoli, Claudio, Bruzzese, G, Ignarro, Lj, Crimi, E, de NIGRIS, Filomena, WILLIAMS IGNARRO, S, Libardi, S, Sommese, Linda, Fiorito, C, Mancini, Fp, Cacciatore, F, and Liguori, A.
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Male ,Isoprostane ,Captopril ,Angiotensin-Converting Enzyme Inhibitors ,Carotid imt ,medicine.disease_cause ,Dinoprost ,Gastroenterology ,chemistry.chemical_compound ,Enalapril ,hypertension ,Hyperlipidemia ,Medicine ,Carotid Stenosis ,sulfhydryl angiotensin-converting enzyme ,Ultrasonography ,Primary (chemistry) ,biology ,Middle Aged ,Zofenopril ,Carotid Arteries ,Hypertension ,Female ,Cardiology and Cardiovascular Medicine ,Tunica Media ,medicine.drug ,Adult ,medicine.medical_specialty ,Long term treatment ,Newly diagnosed ,Nitric Oxide ,Nitric oxide ,Diabetes mellitus ,Internal medicine ,Humans ,Diseases of the circulatory (Cardiovascular) system ,cardiovascular diseases ,Antihypertensive Agents ,business.industry ,Angiotensin-converting enzyme ,medicine.disease ,Oxidative Stress ,Endocrinology ,chemistry ,RC666-701 ,ACE inhibitor ,biology.protein ,business ,Tunica Intima ,Oxidative stress ,Follow-Up Studies - Abstract
Aim. Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors exert antiatherosclerotic effects in preclinical models and antioxidant effects in patients. However, whether ACE inhibitors have any clinically significant antiatherogenic effects remains still debated. Objectives. In mildly hypertensive patients, we evaluated the effect of the sulfhydryl ACE inhibitor zofenopril in comparison with the carboxylic ACE inhibitor enalapril on carotid atherosclerosis (intima-media thickness [IMT] and vascular lumen diameter) and systemic oxidative stress (nitrite/nitrate, asymmetrical dimethyl-L-arginine, and isoprostanes). Material and methods. In 2001, we started a small prospective randomized clinical trial on 48 newly diagnosed mildly hypertensive patients with no additional risk factors for atherosclerosis (eg, hyperlipidemia, smoke habit, familiar history of atherosclerosisrelated diseases or diabetes). Patients were randomly assigned either to the enalapril (20 mg/d, n = 24) or the zofenopril group (30 mg/d, n = 24); the planned duration of the trial was 5 years. Carotid IMT and vascular lumen diameter were determined by ultrasonography for all patients at baseline and at 1, 3, and 5 years. Furthermore, nitrite/nitrate, asymmetrical dimethyl-L-arginine, and isoprostane levels were measured. Results. In our conditions, IMT of the right and left common carotid arteries was similar at baseline in both groups (P = NS). Intima-media thickness measurements until 5 years revealed a significant reduction in the zofenopril group but not in the enalapril group (P b .05 vs enalapril-treated group). This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group. Conclusion. Long-term treatment with the sulfhydryl ACE inhibitor zofenopril besides its blood pressure–lowering effects may slow the progression of IMT of the carotid artery in newly diagnosed mildly hypertensive patients. (Am Heart J 2008;156:1154.e1-1154.e8.)
- Published
- 2012
27. Effects of ACE inhibition on circulating endothelial progenitor cells, vascular damage, and oxidative stress in hypertensive patients
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Giuseppe Bruzzese, Francesco Donatelli, Teresa Infante, A. Liguori, Carmela Fiorito, Pellegrino Biagio Minucci, Louis J. Ignarro, Filomena de Nigris, Dino Franco Vitale, Claudio Napoli, Francesco Cacciatore, Cacciatore, F, Bruzzese, G, Vitale, Df, Liguori, A, de NIGRIS, Filomena, Fiorito, C, Infante, T, Donatelli, F, Minucci, Pellegrino Biagio, Ignarro, Lj, and Napoli, Claudio
- Subjects
Adult ,medicine.medical_specialty ,Captopril ,Isoprostane ,Angiotensin-Converting Enzyme Inhibitors ,Cell Count ,Isoprostanes ,medicine.disease_cause ,chemistry.chemical_compound ,Enalapril ,Cell Movement ,Internal medicine ,Humans ,Medicine ,Pharmacology (medical) ,Progenitor cell ,Ace inhibition ,Cells, Cultured ,Nitrites ,Ultrasonography ,Pharmacology ,Nitrates ,business.industry ,Stem Cells ,Confounding ,Endothelial Cells ,General Medicine ,Middle Aged ,Zofenopril ,Carotid Arteries ,Treatment Outcome ,Endocrinology ,chemistry ,Intima-media thickness ,Hypertension ,cardiovascular system ,Regression Analysis ,Tunica Intima ,business ,Oxidative stress ,Follow-Up Studies ,circulatory and respiratory physiology ,medicine.drug - Abstract
PURPOSE: The pathogenic role of angiotensin-converting enzyme (ACE) inhibition in hypertensive patients regarding endothelial progenitor-cell (EPC) function is still poorly understood. The aim of the study was to evaluate EPC number, function, and relationship to carotid intima media thickness (IMT) progression. METHODS: We studied 36 newly diagnosed mildly hypertensive patients free of cardiovascular disease and related risk factors without prior or concurrent therapy with ACE inhibitors. Patients were randomized to receive enalapril 20 mg/day (n = 18) or zofenopril 30 mg/day (n = 18). EPC number and migrating capacity, plasma nitrite and nitrate (NOx), and isoprostane concentrations were evaluated. Carotid IMT was determined by ultrasonography at baseline and after 1 and 5 years of follow-up. RESULTS: EPC number increased during the follow-up, with no statistical differences between treatment groups. There was an inverse correlation between circulating EPCs and IMT increase over time. Plasma NOx decreased during the study without evident differences between treatment groups. Isoprostanes decreased more markedly in zofenopril-treated patients. Multiple linear regression model demonstrated that carotid IMT was significantly inversely correlated with EPC but not with migratory cells after adjusting for confounders. CONCLUSIONS: The study demonstrated that EPC levels increased during the follow-up in both groups of newly diagnosed hypertensive patients treated with ACE inhibitors. These drugs prevented progression of vascular damage, with an inverse correlation between circulating EPC levels and IMT values.
- Published
- 2011
28. Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation
- Author
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Louis J. Ignarro, Ferdinando Fusco, Ciro Imbimbo, Roberta d'Emmanuele di Villa Bianca, Raffaella Sorrentino, Vincenzo Mirone, Raffaele De Palma, Giuseppe Cirino, Pasquale Maffia, D'EMMANUELE DI VILLA BIANCA, R, Sorrentino, R, Maffia, P, Mirone, V, Imbimbo, C, Fusco, F, DE PALMA, Raffaele, Ignarro, Lj, Cirino, G., D'EMMANUELE DI VILLA BIANCA, Roberta, Sorrentino, Raffaella, Maffia, Pasquale, Mirone, Vincenzo, Imbimbo, Ciro, Fusco, Ferdinando, De Palma, R, and Cirino, Giuseppe
- Subjects
Male ,medicine.medical_specialty ,Muscle Relaxation ,Sodium ,H2S ,Vascular Disease ,Gasotrasmitters ,chemistry.chemical_element ,Penile artery ,chemistry.chemical_compound ,Internal medicine ,parasitic diseases ,medicine ,Animals ,Humans ,L-cysteine ,Cysteine ,Hydrogen Sulfide ,cystathionine -synthase (CBS) ,Cysteine metabolism ,chemistry.chemical_classification ,Multidisciplinary ,Dose-Response Relationship, Drug ,biology ,Penile Erection ,Muscle, Smooth ,Biological Sciences ,equipment and supplies ,Cystathionine beta synthase ,Rats ,Dose–response relationship ,Muscle relaxation ,medicine.anatomical_structure ,Enzyme ,Endocrinology ,chemistry ,biology.protein ,cystathionine-lyase (CSE) ,Penis - Abstract
Hydrogen sulfide (H 2 S) is synthesized by 2 enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). l -Cysteine ( l -Cys) acts as a natural substrate for the synthesis of H 2 S. Human penile tissue possesses both CBS and CSE, and tissue homogenates efficiently convert l -Cys to H 2 S. CBS and CSE are localized in the muscular trabeculae and the smooth-muscle component of the penile artery, whereas CSE but not CBS is also expressed in peripheral nerves. Exogenous H 2 S [sodium hydrogen sulfide (NaHS)] or l -Cys causes a concentration-dependent relaxation of strips of human corpus cavernosum. l -Cys relaxation is inhibited by the CBS inhibitor, aminoxyacetic acid (AOAA). Electrical field stimulation of human penile tissue, under resting conditions, causes an increase in tension that is significantly potentiated by either propargylglycine (PAG; CSE inhibitor) or AOAA. In rats, NaHS and l -Cys promote penile erection, and the response to l -Cys is blocked by PAG. Our data demonstrate that the l -Cys/H 2 S pathway mediates human corpus cavernosum smooth-muscle relaxation.
- Published
- 2009
29. Therapeutic targeting of the stem cell niche in experimental hindlimb ischemia
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Mario Felice Tecce, Pellegrino Biagio Minucci, Ettore Crimi, Antonio Giordano, Claudio Napoli, Louis J. Ignarro, Ettore Varricchio, Carmela Fiorito, Russell E. Byrns, Florio A, Angelo Matarazzo, Bartolomeo Farzati, Maurizio D’Amora, Alfonso Giovane, Filomena de Nigris, Sharon William-Ignarro, Ciro Abbondanza, Antonio Pavan, Francesco Mancini, Antonio Palagiano, Maria Luisa Balestrieri, Napoli, Claudio, WILLIAM IGNARRO, S, Byrns, R, Balestrieri, Maria Luisa, Crimi, E, Farzati, B, Mancini, Fp, de NIGRIS, Filomena, Matarazzo, A, D'Amora, M, Abbondanza, C, Fiorito, C, Giovane, Alfonso, Florio, Anna, Varricchio, E, Palagiano, A, Minucci, Pellegrino Biagio, Tecce, Mf, Giordano, A, Pavan, A, and Ignarro, Lj
- Subjects
Vascular Endothelial Growth Factor A ,Time Factors ,Parathyroid hormone ,Apoptosis ,Hindlimb ,Neovascularization ,Mice ,Cell Movement ,Ischemia ,Granulocyte Colony-Stimulating Factor ,Receptor ,vascular niche ,Hematopoietic stem cell ,General Medicine ,ischemic vascular diseases ,Hematopoietic Stem Cell Mobilization ,Recombinant Proteins ,medicine.anatomical_structure ,Parathyroid Hormone ,Drug Therapy, Combination ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Blood Flow Velocity ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,neoangiogenesis ,bone marrow ,Filgrastim ,Hematopoietic stem cell niche ,Neovascularization, Physiologic ,neoangiogenesi ,Angiopoietin-1 ,medicine ,Animals ,Humans ,RNA, Messenger ,Muscle, Skeletal ,ischemic vascular disease ,Inflammation ,business.industry ,Hematopoietic Stem Cells ,Fibrosis ,Peptide Fragments ,Capillaries ,Rats ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,Regional Blood Flow ,Immunology ,Cancer research ,Bone marrow ,business - Abstract
Background The custom microenvironment ‘vascular niche’ is a potential therapeutic target for several pathophysiological conditions. Osteoblasts regulate the hematopoietic stem cell niche, and activation of the parathyroid hormone (PTH) receptor can increase the number of cells mobilized into the bloodstream. Methods C57Bl/6 mice were randomly assigned treatment with granulocyte-colony stimulating factor (G-CSF), PTH, G-CSF plus PTH or saline. All mice underwent hindlimb ischemia. Blood flow was measured by laser Doppler imaging. Indices of capillary activity were determined by electron microscopy in muscle tissue. CD34+ and Ki67+ cells were detected and evaluated by immunofluorescence, apoptosis by TUNEL, surface antigen and endothelial progenitor cells by fluorescence-activated cell sorting analysis, and vascular endothelial growth factor-164 and angiopoietin-1 expression by reverse-transcriptase polymerase chain reaction. Frozen bone marrow sections were stained for antigen-specific B cells and fibronectin and analyzed by confocal laser scanning microscopy. Results Following mobilization induced by G-CSF treatment, mice also treated with PTH showed increases in blood flow, capillary density, nitrite/nitrate release, angiogenic factors and circulating progenitor cells, as well as reduced apoptosis, fibrosis, oxidative stress and inflammation in ischemic muscles. Furthermore, hematopoietic antigen-specific B cells in the bone marrow were also increased by G-CSF alone and in combination with PTH. Conclusions PTH might increase the efficiency of hematopoietic stem-cell-based therapy in a recognized model of peripheral ischemia. Our translational experimental therapeutic targeting of the vascular niche points to novel clinical targets for the hematopoietic stem-cell treatment of ischemic vascular diseases.
- Published
- 2008
30. Therapeutic Approaches in Vascular Repair Induced by Adult Bone Marrow Cells and Circulating Progenitor Endothelial Cells
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Louis J. Ignarro, Antonio Balestrieri, Claudio Napoli, Napoli, Claudio, Balestrieri, A, and Ignarro, Lj
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Adult ,Angiogenesis ,Bone Marrow Cells ,Regenerative medicine ,Drug Discovery ,medicine ,Humans ,Progenitor cell ,Aged ,Bone Marrow Transplantation ,Peripheral Vascular Diseases ,Pharmacology ,Clinical Trials as Topic ,business.industry ,Stem Cells ,Age Factors ,Endothelial Cells ,Hematopoietic stem cell ,Combined Modality Therapy ,Endothelial stem cell ,medicine.anatomical_structure ,Immunology ,Cancer research ,Bone marrow ,Stem cell ,business ,Stem Cell Transplantation ,Adult stem cell - Abstract
Strong evidence indicates that bone marrow cells (BMCs) can contribute to the healing process of injured vascular system via CXCR4/Thymosin beta4/Integrin alpha4beta1/SDF-1 molecular pathways. We discuss the therapeutic approaches of BMCs and circulating endothelial progenitor cells (EPCs) to restore vascularization. Today some clinical trials employing BMCs in the treatment of peripheral vascular diseases have been completed with encouraging results. When large clinical controlled studies will be completed, the scientific community will evaluate this novel and promising therapeutic approach. Although some basic studies suggest the potential use of adult/somatic stem cell for vascular repair, other stringent data suggest that this potential is dependent also on growth factor synthesis rather than the formation of new arterial vessels. Considering the limitations of adult stem cells especially in elderly subjects, our point of view is that BMCs or exogenous BMC/EPC are candidate for adjunct cell-therapy applications in vascular repair.
- Published
- 2007
31. Therapeutic Effects of Autologous Bone Marrow Cells and Metabolic Intervention in the Ischemic Hindlimb of Spontaneously Hypertensive Rats Involve Reduced Cell Senescence and CXCR4/Akt/eNOS Pathways
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Gennaro Fatigati, Maria Luisa Balestrieri, Louis J. Ignarro, Russell E. Byrns, Sharon Williams-Ignarro, Antonio Palagiano, Ettore Crimi, Claudio Napoli, Filomena de Nigris, Lilach O. Lerman, F. P. D'armiento, de Nigris, F, Balestrieri, Ml, Williams Ignarro, S, D'Armiento, FRANCESCO PAOLO, Lerman, Lo, Byrns, R, Crimi, E, Palagiano, A, Fatigati, Giulio, Ignarro, Lj, Napoli, C., de NIGRIS, Filomena, Balestrieri, Maria Luisa, WILLIAMS IGNARRO, S, D'Armiento, Fp, Fatigati, G, and Napoli, Claudio
- Subjects
Male ,Nitric Oxide Synthase Type II ,Apoptosis ,Hindlimb ,medicine.disease_cause ,Rats, Inbred WKY ,Antioxidants ,Neovascularization ,chemistry.chemical_compound ,Ischemia ,Enos ,Rats, Inbred SHR ,Leukocytes ,Phosphorylation ,Cellular Senescence ,Bone Marrow Transplantation ,Peripheral Vascular Diseases ,biology ,Nitric Oxide Synthase Type III ,Arteries ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Senescence ,spontaneously hypertensive rat ,Receptors, CXCR4 ,medicine.medical_specialty ,Arginine ,Nitric Oxide ,Nitric oxide ,Internal medicine ,medicine ,Animals ,autologous bone marrow cell ,cell senescence and CXCR4/Akt/eNOS pathways ,Progenitor cell ,Muscle, Skeletal ,Cell Proliferation ,Pharmacology ,business.industry ,Endothelial Cells ,Mesenchymal Stem Cells ,biology.organism_classification ,Capillaries ,Rats ,Oxidative Stress ,Endocrinology ,chemistry ,Regional Blood Flow ,Immunology ,business ,Proto-Oncogene Proteins c-akt ,Oxidative stress - Abstract
Peripheral arterial disease (PAD) is a major health problem, especially when associated with severe hypertension. Administration of autologous bone marrow cells (BMCs) is emerging as a novel intervention to induce neoangiogenesis in ischemic limb models and in patients with PAD. This study evaluates the neovascularization capacity of BMCs alone or in combination with metabolic cotreatment (0.8% vitamin E, 0.05% vitamin C, and 5% of L-arginine) in a rat model of ischemic hindlimbs of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Molecular mechanisms were investigated in bone marrow-derived endothelial progenitor cells (BM-EPC) derived from rats. BMC therapy increased blood flow and capillary densities and Ki67 proliferative marker, and it decreased interstitial fibrosis. These effects were amplified by metabolic cotreatment, an intervention that induces vascular protection at least partly through the nitric oxide (NO)/endothelial nitric oxide synthase (eNOS) pathway, reduction of systemic oxidative stress, and macrophage activation. In addition, BMC therapy alone and, more consistently, in combination with metabolic treatment, ameliorated BM-EPC functional activity via decreased cellular senescence and improved homing capacity by increasing CXCR4-expression levels. These data suggest potential therapeutic effects of autologous BMCs and metabolic treatment in hypertensive PAD patients.
- Published
- 2007
32. Role of oxidative stress in experimental sepsis and multisystem organ dysfunction
- Author
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Ettore Crimi, Claudio Napoli, Arthur S. Slutsky, Vincenzo Sica, Louis J. Ignarro, Sharon Williams-Ignarro, Haibo Zhang, Crimi, E, Sica, V, Slutsky, A, Zhang, H, WILLIAMS IGNARRO, S, Ignarro, Lj, and Napoli, Claudio
- Subjects
Pathology ,medicine.medical_specialty ,Reactive oxygen species metabolism ,medicine.disease_cause ,Bioinformatics ,Biochemistry ,Antioxidants ,Sepsis ,medicine ,Overall survival ,Animals ,Humans ,Respiratory Distress Syndrome ,business.industry ,Organ dysfunction ,Cell injury ,General Medicine ,medicine.disease ,Disease Models, Animal ,Oxidative Stress ,Critical illness ,medicine.symptom ,Reactive Oxygen Species ,business ,Oxidative stress - Abstract
Massive increase in radical species can lead to oxidative stress, promoting cell injury and death. This review focuses on experimental evidence of oxidative stress in critical illnesses, sepsis and multisystem organ dysfunction. Oxidative stress could negatively affect organ injury and thus overall survival of experimental models. Based on this experimental evidence, we could improve the rationale of supplementation of antioxidants alone or in combination with standard therapies aimed to reduce oxidative stress as novel adjunct treatment in critical care.
- Published
- 2006
33. Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress
- Author
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Gaetano De Rosa, Ettore Crimi, Louis J. Ignarro, Chiara Botti, Claudio Napoli, Sharon Williams-Ignarro, Francesco Paolo D'Armiento, Filomena de Nigris, Gelsomina Mansueto, Lilach O. Lerman, Vincenzo Sica, de NIGRIS, Filomena, WILLIAMS IGNARRO, S, Lerman, Lo, Crimi, E, Botti, C, Mansueto, G, D'Armiento, Fp, DE ROSA, G, Sica, V, Ignarro, Lj, and Napoli, Claudio
- Subjects
Male ,Nitric Oxide Synthase Type III ,Endothelium ,Arteriosclerosis ,Blotting, Western ,Nitric Oxide Synthase Type II ,Isoprostanes ,Pharmacology ,medicine.disease_cause ,Antioxidants ,Gene Expression Regulation, Enzymologic ,Mice ,In vivo ,Oral administration ,Enos ,Coronary Circulation ,Proto-Oncogene Proteins ,Shear stress ,medicine ,Animals ,Humans ,Receptor ,ets-Domain Protein Elk-1 ,Lythraceae ,Mice, Knockout ,Analysis of Variance ,Multidisciplinary ,biology ,Chemistry ,Biological Sciences ,biology.organism_classification ,DNA-Binding Proteins ,Cholesterol ,medicine.anatomical_structure ,Receptors, LDL ,Biochemistry ,Fruit ,Endothelium, Vascular ,Plant Preparations ,Nitric Oxide Synthase ,Oxidative stress ,Transcription Factors - Abstract
Atherosclerosis is enhanced in arterial segments exposed to disturbed flow. Perturbed shear stress increases the expression of oxidation-sensitive responsive genes (such as ELK-1 and p -JUN) in the endothelium. Evidence suggests that polyphenolic antioxidants contained in the juice derived from the pomegranate can contribute to the reduction of oxidative stress and atherogenesis. The aim of the present study was to evaluate the effects of intervention with pomegranate juice (PJ) on oxidation-sensitive genes and endothelial NO synthase (eNOS) expression induced by high shear stress in vitro and in vivo . Cultured human coronary artery endothelial cells (EC) exposed to high shear stress in vitro and hypercholesterolemic mice were used in this study. PJ concentrate reduced the activation of redox-sensitive genes (ELK-1 and p -JUN) and increased eNOS expression (which was decreased by perturbed shear stress) in cultured EC and in atherosclerosis-prone areas of hypercholesterolemic mice. Moreover, oral administration of PJ to hypercholesterolemic mice at various stages of disease reduced significantly the progression of atherosclerosis. This experimental study indicates that the proatherogenic effects induced by perturbed shear stress can be reversed by chronic administration of PJ. This approach may have implications for the prevention or treatment of atherosclerosis and its clinical manifestations.
- Published
- 2005
34. Long-term combined beneficial effects of physical training and metabolic treatment on atherosclerosis in hypercholesterolemic mice
- Author
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Vincenzo Sica, Loredana Rossi, Orlando Pignalosa, Carmen Guarino, Lilach O. Lerman, Gaetano De Rosa, Claudio Napoli, Louis J. Ignarro, Gelsomina Mansueto, Francesco Di Tuoro, Sharon Williams-Ignarro, Filomena de Nigris, Napoli, Claudio, WILLIAMS IGNARRO, S, de NIGRIS, Filomena, Lerman, Lo, Rossi, L, Guarino, C, Mansueto, G, DI TUORO, F, Pignalosa, O, DE ROSA, G, Sica, V, and Ignarro, Lj
- Subjects
Male ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Arteriosclerosis ,medicine.medical_treatment ,Nitric Oxide Synthase Type II ,Physical exercise ,Ascorbic Acid ,Arginine ,medicine.disease_cause ,Antioxidants ,Nitric oxide ,Hyperlipoproteinemia Type II ,Mice ,chemistry.chemical_compound ,Physical Conditioning, Animal ,Internal medicine ,Animals ,Vitamin E ,Medicine ,Mice, Knockout ,Multidisciplinary ,Vitamin C ,biology ,business.industry ,Biological Sciences ,Ascorbic acid ,medicine.disease ,Nitric oxide synthase ,Oxidative Stress ,Endocrinology ,Receptors, LDL ,chemistry ,biology.protein ,Diet, Atherogenic ,Nitric Oxide Synthase ,business ,Oxidative stress - Abstract
The pathogenic mechanisms by which physical exercise influences atherosclerotic lesion formation remain poorly understood. Because vigorous physical training increases oxidative stress, this study tested the hypothesis that graduated and moderate physical exercise together with metabolic intervention ( l -arginine and antioxidants) may contribute to increased vascular protection. Exercise training in mice was induced by graduated swimming. In hypercholesterolemic male mice on an atherogenic high-cholesterol diet, graduated and moderate exercise lowered plasma cholesterol and decreased atherosclerotic lesions compared with sedentary control mice. Antioxidants (1.0% vitamin E added to the chow and 0.05% vitamin C added to the drinking water) and l -arginine (6% in drinking water) supplementation to exercising hypercholesterolemic mice further and synergistically reduced atherosclerosis compared with untreated exercised mice. Arterial oxidation-specific epitopes and systemic oxidative stress were reduced by metabolic intervention. Graduated chronic exercise elicited an increase in production of nitric oxide through increased endothelial nitric oxide synthase expression and ameliorated scavenger activities. Thus, metabolic intervention with l -arginine and antioxidants together with graduated and moderate exercise training reduce atherosclerotic lesion formation.
- Published
- 2004
35. Glycoxydation promotes vascular damage Via MAPK-ERK/JNK pathways
- Author
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Claudio Napoli, Louis J. Ignarro, Elena Cesario, Wulf Palinski, Antonio Giordano, Teresa Infante, Mohammed Al-Omran, Filomena de Nigris, Monica Rienzo, Marcella Sessa, de NIGRIS, Filomena, Rienzo, Monica, Sessa, M, Infante, T, Cesario, E, Ignarro, Lj, Al Omran, M, Giordano, A, Palinski, W, and Napoli, Claudio
- Subjects
MAPK/ERK pathway ,Glycation End Products, Advanced ,medicine.medical_specialty ,Physiology ,medicine.drug_class ,MAP Kinase Signaling System ,Clinical Biochemistry ,Mitogen-activated protein kinase kinase ,Muscle, Smooth, Vascular ,Diabetes Mellitus, Experimental ,Mice ,Apolipoproteins E ,Glycation ,LDL, ERK, MAPK , angiogenesis ,Internal medicine ,medicine ,Animals ,Humans ,Phosphorylation ,Protein Kinase Inhibitors ,Cells, Cultured ,Foam cell ,Mitogen-Activated Protein Kinase Kinases ,Chemistry ,Tumor Necrosis Factor-alpha ,Cell Biology ,Protein kinase inhibitor ,Coronary Vessels ,Cell biology ,Lipoproteins, LDL ,Transcription Factor AP-1 ,Endocrinology ,Macrophages, Peritoneal ,Tumor necrosis factor alpha ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,Oxidation-Reduction ,Foam Cells - Abstract
Oxidation and glycation enhance foam cell formation via MAPK/JNK in euglycemic and diabetic subjects. Here, we investigated the effects of glycated and oxidized LDL (glc-oxLDL) on MAPK-ERK and JNK signaling pathways using human coronary smooth muscle cells. Glc-oxLDL induced a broad cascade of MAPK/JNK-dependent signaling transduction pathways and the AP-1 complex. In glc-oxLDL treated coronary arterioles, tumor necrosis factor (TNF) a increased JNK phosphorylation, whereas protein kinase inhibitor dimethylaminopurine (DMAP) prevented the TNF-induced increase in JNK phosphorylation. The role of MKK4 and JNK were then investigated in vivo, using apolipoprotein E knockout (ApoE-/-) mice. Peritoneal macrophages, isolated from spontaneously hyperlipidemic but euglycemic mice showed increases in both proteins and phosphorylated proteins. Compared to streptozotocin-treated diabetic C57BL6 and nondiabetic C57BL6 Wt mice, in streptozotocin-diabetic ApoE-/- mice, the increment of foam cell formation corresponded to an increment of phosphorylation of JNK1, JNK2, and MMK4. Thus, we provide a first line of evidence that MAPK-ERK/JNK pathways are involved in vascular damage induced by glycoxidation. J. Cell. Physiol. 227: 36393647, 2012. (C) 2012 Wiley Periodicals, Inc.
- Published
- 2012
36. Endothelial progenitor cells as therapeutic agents in the microcirculation: an update
- Author
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Mohammed Al-Omran, Louis J. Ignarro, Costanza Casini, Toshio Hayashi, Claudio Napoli, Amelia Casamassimi, Francesco Cacciatore, Napoli, Claudio, Hayashi, T, Cacciatore, F, Casamassimi, Amelia, Casini, C, AL OMRAN, M, and Ignarro, Lj
- Subjects
Neovascularization, Physiologic ,Regenerative Medicine ,Regenerative medicine ,Microcirculation ,medicine ,Humans ,Therapeutic angiogenesis ,Progenitor cell ,Progenitor ,Clinical Trials as Topic ,business.industry ,Stem Cells ,Endothelial Cells ,Cell Differentiation ,Endothelial stem cell ,medicine.anatomical_structure ,Cardiovascular Diseases ,embryonic structures ,Immunology ,cardiovascular system ,Cancer research ,Bone marrow ,Cardiology and Cardiovascular Medicine ,business ,Stem Cell Transplantation ,circulatory and respiratory physiology ,Homing (hematopoietic) - Abstract
This review evaluates novel beneficial effects of circulating endothelial progenitor cells (EPCs) as shown by several preclinical studies and clinical trials carried out to test the safety and feasibility of using EPCs. There are 31 registered clinical trials (and many others still ongoing) and 19 published studies. EPCs originate in the bone marrow and migrate into the bloodstream where they undergo a differentiation program leading to major changes in their antigenic characteristics. EPCs lose typical progenitor markers and acquire endothelial markers, and two important receptors, (VEGFR and CXCR-4), which recruit circulating EPCs to damaged or ischemic microcirculatory (homing to damaged tissues) beds. Overall, therapeutic angiogenesis will likely change the face of regenerative medicine in the next decade with many patients worldwide predicted to benefit from these treatments.
- Published
- 2011
37. Directed in vivo angiogenesis assay and the study of systemic neoangiogenesis in cancer
- Author
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Amelia Casamassimi, Louis J. Ignarro, Antonio Giordano, Francesca Pentimalli, Filomena de Nigris, Claudio Napoli, Napoli, Claudio, Giordano, A, Casamassimi, Amelia, Pentimalli, F, Ignarro, Lj, and de NIGRIS, Filomena
- Subjects
Dorsum ,Cancer Research ,Pathology ,medicine.medical_specialty ,Biomedical Research ,endothelium ,Angiogenesis ,Antineoplastic Agents ,Biology ,Medical Oncology ,Metastasis ,Neovascularization ,Mice ,In vivo ,Neoplasms ,medicine ,cancer ,Animals ,Humans ,Neoplasm Metastasis ,Neovascularization, Pathologic ,angiogenesi ,Cancer ,medicine.disease ,Disease Models, Animal ,Oncology ,Cancer research ,Subcutaneous implantation ,Disease Progression ,Signal transduction ,medicine.symptom ,Signal Transduction - Abstract
Targeting neoangiogenesis is a well-established anticancer strategy, however, one of the major problems in angiogenesis research, both at the basic and applied levels, remains the development of suitable in vivo methods for assessing and quantifying the systemic angiogenic response. Therefore, there is an urgent need to adopt technically simple and reproducible methodologies which allow to easily quantify neoangiogenesis independently of morphological parameters. Recently, a reproducible and quantitative method was developed, the directed in vivo angiogenesis assay (DIVAA) consisting of the subcutaneous implantation of surgical grade silicone cylinders closed at one end, called angioreactors, into the dorsal flanks of nude mice. In the past few years, DIVAA has been successfully used in evaluating the inhibition and or enhancement of systemic perturbation of angiogenesis by several molecules. Thus, DIVAA studies systemic angiogenesis and its therapeutic modulation associated to cancer progression and metastasis.
- Published
- 2010
38. Therapeutic angiogenesis in diabetic apolipoprotein E-deficient mice using bone marrow cells, functional hemangioblasts and metabolic intervention
- Author
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Gianluca Testa, Qiang Feng, Gaetano De Rosa, Louis J. Ignarro, Francesco Salvatore, Antonio Giordano, Maria Luisa Balestrieri, Claudio Napoli, Robert Lanza, Luigi Servillo, Sharon Williams-Ignarro, Carmela Fiorito, Bartolomeo Farzati, Filomena de Nigris, Shi-Jiang Lu, Pellegrino Biagio Minucci, Lucio Pastore, Francesco Cacciatore, Franco Rengo, Andrew Baker, Monica Rienzo, Alfonso Giovane, Francesco Mancini, Caterina Pagliarulo, F. P. D'armiento, Balestrieri, Maria Luisa, Lu, Sj, de NIGRIS, Filomena, Giovane, Alfonso, WILLIAMS IGNARRO, S, D'Armiento, Fp, Feng, Q, Fiorito, C, Testa, G, Pastore, L, Cacciatore, F, Mancini, Fp, Servillo, Luigi, DE ROSA, G, Pagliarulo, C, Rienzo, M, Minucci, Pellegrino Biagio, Farzati, B, Salvatore, F, Rengo, F, Ignarro, Lj, Giordano, A, Baker, A, Lanza, R, Napoli, Claudio, Balestrieri, Ml, de Nigris, F, Giovane, A, Williams Ignarro, S, D'Armiento, FRANCESCO PAOLO, Pastore, Lucio, Servillo, L, DE ROSA, Gaetano, Minucci, Pb, and Napoli, C.
- Subjects
Apolipoprotein E ,medicine.medical_specialty ,Bone marrow cell ,Hemangioblasts ,Angiogenesis ,Ischemia ,Neovascularization, Physiologic ,Ascorbic Acid ,Arginine ,medicine.disease_cause ,Diabete ,L-Arginine ,Diabetes Mellitus, Experimental ,Neovascularization ,Mice ,Apolipoproteins E ,Internal medicine ,Peripheral arterial disease ,medicine ,Animals ,Vitamin E ,Therapeutic angiogenesis ,Bone Marrow Transplantation ,Peripheral Vascular Diseases ,business.industry ,Nitric oxide ,Ascorbic acid ,medicine.disease ,Hemangioblast ,Ischemic hindlimb ,Hindlimb ,Endocrinology ,medicine.anatomical_structure ,Regional Blood Flow ,Immunology ,Bone marrow ,medicine.symptom ,Antioxidant ,Cardiology and Cardiovascular Medicine ,business ,Oxidative stress - Abstract
BMC or HS alone, and BMC plus HS increased blood flow and capillary densities and decreased interstitial fibrosis. These effects were amplified by additional MT, at least in part, through the nitric oxide pathway, reduction of systemic oxidative stress and macrophage infiltration. Investigation of molecular mechanisms in bone marrow (BM)-derived progenitor cells from mice revealed that BMC therapy and Objective: Peripheral arterial disease (PAD) is a major health problem especially when associated to concomitant diabetes and hypercholesterolemia. Hyperglycemia with an overwhelming generation of oxygen radicals and formation of glycation end-products exacerbates oxidation-sensitive mechanisms activated by tissue ischemia. Administration of autologous bone marrow cells (BMC) is an increasing notable intervention to induce therapeutic angiogenesis, ameliorated by metabolic intervention (MT). Recently, hemangioblasts (HS) with functional properties were isolated. Methods: The effects of integrate regimen with intravenous BMC, HS, and MT (1.0% vitamin E, 0.05% vitamin C, and 6% l-arginine) were examined in the ischemic hindlimb of ApoE-/- diabetic and non-diabetic. Blood flow ratio was monitored by use of a laser Doppler blood flowmeter. Capillary density was determined in sections of the adductor and semimembranous muscles with antibody against CD31. Results: BMC or HS alone, and BMC plus HS increased blood flow and capillary densities and decreased interstitial fibrosis. These effects were amplified by additional MT, at least in part, through the nitric oxide pathway, reduction of systemic oxidative stress and macrophage infiltration. Investigation of molecular mechanisms in bone marrow (BM)-derived progenitor cells from mice revealed that BMC therapy and, more consistently, in combination with MT ameliorated functional activity via decreased cellular senescence and increased telomerase and chemokine CXCR4 activities. Telomerase activity was also increased by HS alone or HS. +. MT and, more consistently, by BMC. +. HS alone or in combination with MT. Conclusions/interpretation: Intravenous autologous BMC and HS intervention together with MT increased therapeutic angiogenesis in the ApoE-/- diabetic mouse hindlimb. © 2009 Elsevier Ireland Ltd.
- Published
- 2010
39. CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy
- Author
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Antonio Giordano, Mario Petrillo, Diana C. Márquez-Garbán, Toshio Hayashi, Alfonso Giovane, Valeria Crudele, Louis J. Ignarro, Letizia Cito, Amelia Casamassimi, Hermes Garban, Antonella Petrillo, Linda Sommese, Alfredo Siani, Claudio Arra, Franco Rengo, Antonio Barbieri, Filomena de Nigris, Andrea Fiore, Claudio Napoli, Francesco Cacciatore, Francesca Pentimalli, Mohammed Al-Omran, de Nigris, F, Crudele, V, Giovane, A, Casamassimi, A, Giordano, A, Garban, Hj, Cacciatore, F, Pentimalli, F, Marquez Garban, Dc, Petrillo, A, Cito, L, Sommese, L, Fiore, A, Petrillo, M, Siani, A, Barbieri, A, Arra, C, Rengo, Franco, Hayashi, T, Al Omran, M, Ignarro, Lj, Napoli, C., de NIGRIS, Filomena, Giovane, Alfonso, Casamassimi, Amelia, MARQUEZ GARBAN, Dc, Sommese, Linda, Rengo, F, AL OMRAN, M, and Napoli, Claudio
- Subjects
Multidisciplinary ,Oncogene ,CXCR4/SDF-1 inhibitor ,Angiogenesis ,medicine.medical_treatment ,Biology ,Biological Sciences ,VEGF ,Vascular endothelial growth factor B ,Chemokine receptor ,Cytokine ,embryonic structures ,medicine ,Cancer research ,neoangiogenesi ,Gene silencing ,Transcription factor ,Protein kinase B - Abstract
Tumor growth requires neoangiogenesis. VEGF is the most potent proangiogenic factor. Dysregulation of hypoxia-inducible factor (HIF) or cytokine stimuli such as those involving the chemokine receptor 4/stromal-derived cell factor 1 (CXCR4/SDF-1) axis are the major cause of ectopic overexpression of VEGF in tumors. Although the CXCR4/SDF-1 pathway is well characterized, the transcription factors executing the effector function of this signaling are poorly understood. The multifunctional Yin Yang 1 (YY1) protein is highly expressed in different types of cancers and may regulate some cancer-related genes. The network involving CXCR4/YY1 and neoangiogenesis could play a major role in cancer progression. In this study we have shown that YY1 forms an active complex with HIF-1α at VEGF gene promoters and increases VEGF transcription and expression observed by RT-PCR, ELISA, and Western blot using two different antibodies against VEGFB. Long-term treatment with T22 peptide (a CXCR4/SDF-1 inhibitor) and YY1 silencing can reduce in vivo systemic neoangiogenesis ( P < 0.01 and P < 0.05 vs. control, respectively) during metastasis. Moreover, using an in vitro angiogenesis assay, we observed that YY1 silencing led to a 60% reduction in branches ( P < 0.01) and tube length ( P < 0.02) and a 75% reduction in tube area ( P < 0.001) compared with control cells. A similar reduction was observed using T22 peptide. We demonstrated that T22 peptide determines YY1 cytoplasmic accumulation by reducing its phosphorylation via down-regulation of AKT, identifying a crosstalk mechanism involving CXCR4/YY1. Thus, YY1 may represent a crucial molecular target for antiangiogenic therapy during cancer progression.
- Published
- 2010
40. Mechanisms by which exercise training benefits patients with heart failure
- Author
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Louis J. Ignarro, Ettore Crimi, Francesco Cacciatore, Claudio Napoli, Crimi, E, Ignarro, Lj, Cacciatore, F, and Napoli, Claudio
- Subjects
medicine.medical_specialty ,Cardiovascular System ,Nervous System ,Quality of life ,Regular exercise ,medicine ,Risk of mortality ,Humans ,In patient ,Muscle, Skeletal ,Heart Failure ,Inflammation ,Exercise Tolerance ,business.industry ,Recovery of Function ,Training effect ,Exercise capacity ,medicine.disease ,Exercise Therapy ,Treatment Outcome ,Heart failure ,Quality of Life ,Physical therapy ,Moderate exercise ,Endothelium, Vascular ,Cardiology and Cardiovascular Medicine ,business - Abstract
Clinical consequences of heart failure are fatigue, dyspnea, and progressive impairment of exercise tolerance. Regular exercise training is associated with health-improving effects. In patients with stable heart failure, exercise training can relieve symptoms, improve exercise capacity and quality of life, as well as reduce hospitalization and, to some extent, risk of mortality. Progressive exercise training is associated with pulmonary, cardiovascular, and skeletal muscle metabolic adaptations that increase oxygen delivery and energy production. This Review focuses on current knowledge of mechanisms by which progressive and moderate exercise training can have sustained beneficial effects on patients with heart failure.
- Published
- 2009
41. Detrimental effects of Bartonella henselae are counteracted by l-arginine and nitric oxide in human endothelial progenitor cells
- Author
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Louis J. Ignarro, Bice Avallone, Monica Rienzo, Paola Salvatore, Alfredo Ciccodicola, Claudio Napoli, Vincenzo Grimaldi, Maria Evelina Prudente, Amelia Casamassimi, Ciro Abbondanza, Maria Antonietta Tufano, Florentia Lamberti, Sharon Williams-Ignarro, Roberta Colicchio, Carmela Fiorito, Caterina Pagliarulo, Adone Baroni, Bartolomeo Farzati, Valerio Costa, Elisabetta Buommino, Linda Sommese, Raffaele Rossiello, Salvatore, Paola, A., Casamassimi, L., Sommese, C., Fiorito, A., Ciccodicola, R., Rossiello, Avallone, Bice, V., Grimaldi, V., Costa, Rienzo, Monica, Colicchio, Roberta, S., Williams Ignarro, C., Pagliarulo, M. E., Prudente, C., Abbondanza, F., Lamberti, A., Baroni, Buommino, Elisabetta, B., Farzati, M. A., Tufano, L. J., Ignarro, C., Napoli, Salvatore, P, Casamassimi, Amelia, Sommese, Linda, Fiorito, C, Ciccodicola, A, Rossiello, Raffaele, Avallone, B, Grimaldi, V, Costa, V, Rienzo, M, Colicchio, R, WILLIAMS IGNARRO, S, Pagliarulo, C, Prudente, Me, Abbondanza, Ciro, Lamberti, F, Baroni, Adone, Farzati, B, Tufano, Ma, Ignarro, Lj, and Napoli, Claudio
- Subjects
Sepsi ,Angiogenesis ,Cell Survival ,Cell Count ,Arginine ,Nitric Oxide ,p38 Mitogen-Activated Protein Kinases ,ANGIOGENESIS ,DISEASE ,Bacterial Adhesion ,Nitric oxide ,chemistry.chemical_compound ,endothelial progenitor cell ,Immune system ,IMMUNONUTRITION ,Humans ,Immune response ,Progenitor cell ,Multidisciplinary ,Bartonella henselae ,biology ,Tumor Necrosis Factor-alpha ,Stem Cells ,CRITICAL-CARE ,PROLIFERATION ,Endothelial Cells ,Biological Sciences ,biology.organism_classification ,Flow Cytometry ,Enzyme Activation ,chemistry ,Gene Expression Regulation ,Immunology ,TEM ,cardiovascular system ,Tumor necrosis factor alpha ,Stem cell ,Bartonella Infection ,circulatory and respiratory physiology - Abstract
The recruitment of circulating endothelial progenitor cells (EPCs) might have a beneficial effect on the clinical course of several diseases. Endothelial damage and detachment of endothelial cells are known to occur in infection, tissue ischemia, and sepsis. These detrimental effects in EPCs are unknown. Here we elucidated whether human EPCs internalize Bartonella henselae constituting a circulating niche of the pathogen. B. henselae invades EPCs as shown by gentamicin protection assays and transmission electron microscopy (TEM). Dil-Ac-LDL/lectin double immunostaining and fluorescence-activated cell sorting (FACS) analysis of EPCs revealed EPC bioactivity after infection with B. henselae . Nitric oxide (NO) and its precursor l -arginine ( l -arg) exert a plethora of beneficial effects on vascular function and modulation of immune response. Therefore, we tested also the hypothesis that l -arg (1–30 mM) would affect the infection of B. henselae or tumor necrosis factor (TNF) in EPCs. Our data provide evidence that l -arg counteracts detrimental effects induced by TNF or Bartonella infections via NO (confirmed by DETA-NO and L-NMMA experiments) and by modulation of p38 kinase phosphorylation. Microarray analysis indicated several genes involved in immune response were differentially expressed in Bartonella -infected EPCs, whereas these genes returned in steady state when cells were exposed to sustained doses of l -arg. This mechanism may have broad therapeutic applications in tissue ischemia, angiogenesis, immune response, and sepsis.
- Published
- 2008
42. Deletion of Yin Yang 1 protein in osteosarcoma cells on cell invasion and CXCR4/angiogenesis and metastasis
- Author
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Filomena de Nigris, M. Giuliano, Claudio Arra, Alessandro Lanza, Raffaele Rossiello, Antonio Balestrieri, Louis J. Ignarro, Concetta Schiano, Claudio Napoli, Antonio Barbieri, Sharon Williams-Ignarro, Rossiello, Raffaele, Schiano, Carlo, Arra, C, Williams ignarro, S, Barbieri, A, Lanza, A, Balestrieri, Antonio, Giuliano, Mariateresa, Ignarro, Lj, Napoli, C., and de NIGRIS, Filomena
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Receptors, CXCR4 ,Lung Neoplasms ,Angiogenesis ,Cell ,Bone Neoplasms ,Cell Growth Processes ,Biology ,Transfection ,CXCR4 ,Metastasis ,Neovascularization ,chemistry.chemical_compound ,Mice ,Cell Line, Tumor ,medicine ,Cell Adhesion ,Animals ,Humans ,Neoplasm Invasiveness ,Gene Silencing ,RNA, Messenger ,Neoplasm Metastasis ,RNA, Small Interfering ,YY1 Transcription Factor ,Osteosarcoma ,Neovascularization, Pathologic ,Gene Expression Profiling ,medicine.disease ,Yin Yang 1 Protein ,Vascular endothelial growth factor ,Angiogenesi ,medicine.anatomical_structure ,Oncology ,chemistry ,Cancer research ,Female ,Sarcoma ,medicine.symptom ,Osteosarcoma Cell - Abstract
We know that the Yin Yang 1 protein (YY1) overexpression is positively and strongly correlated with the degree of malignancy of bone tumors. Therefore, we questioned whether we could influence cell invasiveness by deleting YY1 in human osteosarcoma cells (SaOs-2), as tested in Matrigel-coated filters and metastasis implantation of such osteosarcoma cells in vivo, by serial analysis with nuclear magnetic resonance. Moreover, we focused our work on the chemokine receptor CXCR4 and its inhibition by T22 antibody, as well as on systemic (direct in vivo assay) and computer-assisted imaging of angiogenesis-related metastasis. Results showed that cell invasiveness and metastasis implantation by wild-type SaOs-2 cells, as evaluated by histology and immunohistochemistry, are associated with up-regulation of CXCR4 expression, which in turn was significantly reduced by T22. In addition, deletion of YY1 (siRNAYY1-SaOs-2) induced a significant decrease of cell invasion and metastasis growth. This phenomenon was associated with decreased vascular endothelial growth factor (VEGF)/angiogenesis and a complex rearrangement of the gene expression profile as evaluated by microarray analysis. In conclusion, YY1 and VEGF/CXCR4 seem to intervene in the pathogenesis of the malignant phenotype of osteosarcoma by acting on cell invasiveness and metastasis growth. [Cancer Res 2008;68(6):1797–808]
- Published
- 2008
43. Microcirculation and oxidative stress
- Author
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Louis J. Ignarro, Etorre Crimi, Claudio Napoli, Crimi, E, Ignarro, Lj, and Napoli, Claudio
- Subjects
medicine.medical_specialty ,Aging ,Endothelium ,Hypercholesterolemia ,Inflammation ,Vascular permeability ,Biology ,medicine.disease_cause ,Biochemistry ,Models, Biological ,Microcirculation ,Internal medicine ,Sepsis ,medicine ,Diabetes Mellitus ,Humans ,Endothelial dysfunction ,General Medicine ,medicine.disease ,Cell biology ,Oxidative Stress ,medicine.anatomical_structure ,Endocrinology ,Cardiovascular Diseases ,Reperfusion Injury ,Hypertension ,Endothelium, Vascular ,medicine.symptom ,Signal transduction ,Homeostasis ,Oxidative stress - Abstract
The microcirculation is a complex and integrated system, transporting oxygen and nutrients to the cells. The key component of this system is the endothelium, contributing to the local balance between pro and anti-inflammatory mediators, hemostatic balance, as well as vascular permeability and cell proliferation. A constant shear stress maintains vascular endothelium homeostasis while perturbed shear stress leads to changes in secretion of vasodilator and vasoconstrictor agents. Increased oxidative stress is a major pathogenetic mechanism of endothelial dysfunction by decreasing NO bioavailability, promoting inflammation and participating in activation of intracellular signals cascade, so influencing ion channels activation, signal transduction pathways, cytoskeleton remodelling, intercellular communication and ultimately gene expression. Targeting the microvascular inflammation and oxidative stress is a fascinating approach for novel therapies in order to decrease morbidity and mortality of chronic and acute diseases.
- Published
- 2007
44. Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia
- Author
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Louis J. Ignarro, Lilach O. Lerman, Sharon Williams-Ignarro, Filomena de Nigris, Alessandro Lanza, Monica Rienzo, Concetta Schiano, Vincenzo Sica, Claudio Napoli, Andrew H. Baker, Lorraine M. Work, Amelia Casamassimi, Baker, Ah, Sica, Vincenzo, Work, Lm, Williams ignarro, S, de NIGRIS, Filomena, Lerman, Lo, Casamassimi, Amelia, Lanza, Alessandro, Schiano, C, Rienzo, Monica, Ignarro, Lj, and Napoli, Claudio
- Subjects
Male ,Middle Cerebral Artery ,Matrix metalloproteinase inhibitor ,medicine.medical_treatment ,Genetic Vectors ,Ischemia ,Brain damage ,Hematopoietic stem cell transplantation ,Pharmacology ,Matrix Metalloproteinase Inhibitors ,Nitric Oxide ,stem cell therapy ,Brain Ischemia ,Brain ischemia ,Cell therapy ,medicine ,Animals ,Rats, Wistar ,Stroke ,DNA Primers ,Analysis of Variance ,Tissue Inhibitor of Metalloproteinase-2 ,Multidisciplinary ,Tissue Inhibitor of Metalloproteinase-1 ,business.industry ,NO bioavailability ,Hematopoietic Stem Cell Transplantation ,Stem-cell therapy ,Genetic Therapy ,TIMP1 and TIMP2 ,Biological Sciences ,medicine.disease ,Combined Modality Therapy ,Immunohistochemistry ,Rats ,Bromodeoxyuridine ,Rotarod Performance Test ,Immunology ,medicine.symptom ,business - Abstract
Despite advances in imaging, understanding the underlying pathways, and clinical translation of animal models of disease there remains an urgent need for therapies that reduce brain damage after stroke and promote functional recovery in patients. Blocking oxidant radicals, reducing matrix metalloproteinase-induced neuronal damage, and use of stem cell therapy have been proposed and tested individually in prior studies. Here we provide a comprehensive integrative management approach to reducing damage and promoting recovery by combining biological therapies targeting these areas. In a rat model of transient cerebral ischemia (middle cerebral artery occlusion) gene delivery vectors were used to overexpress tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1 and TIMP2) 3 days before ischemia. After occlusion, autologous bone marrow cells alone or in combination with agents to improve NO bioavailability were administered intraarterially. When infarct size, BrdU incorporation, and motor function recovery were determined in the treatment groups the largest beneficial effect was seen in rats receiving the triple combined therapy, surpassing effects of single or double therapies. Our study highlights the utility of combined drug, gene, and cell therapy in the treatment of stroke. © 2007 by The National Academy of Sciences of the USA.
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- 2007
45. The influence of pomegranate fruit extract in comparison to regular pomegranate juice and seed oil on nitric oxide and arterial function in obese Zucker rats
- Author
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Maria Luisa Balestrieri, Louis J. Ignarro, Claudio Napoli, Carmela Fiorito, Sharon Williams-Ignarro, F. P. D'armiento, Filomena de Nigris, de Nigris, F, Balestrieri, Ml, Williams Ignarro, S, D'Armiento, FRANCESCO PAOLO, Fiorito, C, Ignarro, Lj, Napoli, C., de NIGRIS, Filomena, Balestrieri, Maria Luisa, WILLIAMS IGNARRO, S, D'Armiento, F. P., Ignarro, L. J., and Napoli, Claudio
- Subjects
Nitroprusside ,Cancer Research ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Physiology ,medicine.medical_treatment ,Clinical Biochemistry ,Nitric Oxide ,Biochemistry ,Antioxidants ,Nitric oxide ,Beverages ,chemistry.chemical_compound ,Enos ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Nitrite ,Lythraceae ,Metabolic Syndrome ,biology ,Plant Extracts ,Arteries ,biology.organism_classification ,medicine.disease ,Obesity ,obese Zucker rat ,Acetylcholine ,arterial function ,Rats ,Rats, Zucker ,Endocrinology ,Cytokine ,chemistry ,Polyphenol ,Female ,Metabolic syndrome ,Thrombospondins - Abstract
Metabolic syndrome includes most widely distributed clinical conditions such as obesity, hypertension, dislipidemia, and diabetes. Pomegranate fruit extract (PFE), rich in polyphenolic antioxidants, reduces the expression of oxidation-sensitive genes at the sites of perturbed shear-stress. The aim of this study was to evaluate the effect of PFE in comparison to regular pomegranate juice (PJ) and seed oil on the biological actions of nitric oxide (NO) and the arterial function in obese Zucker rats, a model of metabolic syndrome. Our results indicated that supplementation with PFE or PJ significantly decreased the expression of vascular inflammation markers, thrombospondin (TSP), and cytokine TGFbeta1 (P
- Published
- 2007
46. Therapeutic effects of concurrent autologous bone marrow cell infusion and metabolic intervention in ischemia-induced angiogenesis in the hypercholesterolemic mouse hindlimb
- Author
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Lilach O. Lerman, F. P. D'armiento, Louis J. Ignarro, Carmela Fiorito, Filomena de Nigris, Giacomo Sica, Sharon Williams-Ignarro, Russell E. Byrns, Claudio Napoli, Vincenzo Sica, de Nigris, F, Williams Ignarro, S, Sica, V, D'Armiento, FRANCESCO PAOLO, Lerman, Lo, Byrns, Re, Sica, G, Fiorito, C, Ignarro, Lj, Napoli, C., de NIGRIS, Filomena, WILLIAMS IGNARRO, S, D'Armiento, Fp, and Napoli, Claudio
- Subjects
Male ,Bone marrow cell ,schemia-induced angiogenesi ,Angiogenesis ,medicine.medical_treatment ,Ischemia ,Neovascularization, Physiologic ,Hindlimb ,Pharmacology ,Arginine ,medicine.disease_cause ,Transplantation, Autologous ,Antioxidants ,L-Arginine ,Nitric oxide ,Mice ,chemistry.chemical_compound ,Apolipoproteins E ,Peripheral arterial disease ,Laser-Doppler Flowmetry ,Animals ,Medicine ,Bone Marrow Transplantation ,Ultrasonography ,Mice, Knockout ,Peripheral Vascular Diseases ,hypercholesterolemia ,business.industry ,Vascular disease ,Macrophages ,Vitamin E ,medicine.disease ,Combined Modality Therapy ,Ischemic hindlimb ,Disease Models, Animal ,Oxidative Stress ,medicine.anatomical_structure ,chemistry ,Regional Blood Flow ,Immunology ,Bone marrow ,Antioxidant ,mouse hindlimb ,Cardiology and Cardiovascular Medicine ,business ,Oxidative stress - Abstract
Lower-limb ischemia is a major health problem especially when associated to hypercholesterolemia. Because of the absence of effective treatment in the advanced stages of the disease, amputation is undertaken to alleviate unbearable symptoms. Since tissue ischemia and hypercholesterolemia are associated with an overwhelming generation of oxygen radicals, metabolic intervention with antioxidants and l-arginine can induce beneficial effects beyond those achieved by a novel therapeutic approach represented by the use of autologous bone marrow cells (BMCs). The protective effect of BMCs and vascular protection by metabolic cotreatment (1.0% vitamin E added to the chow, 0.05% vitamin C and 6% l-arginine added to the drinking water) were examined in ischemia-induced angiogenesis in the hypercholesterolemic mouse hindlimb. Intravenous BMC therapy improved blood flow and increased capillary densities. This beneficial effect was amplified by metabolic cotreatment, an intervention inducing vascular protection, at least in part, through the nitric oxide pathway, reduction of systemic oxidative stress and macrophage activation.
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- 2007
47. Effects of a pomegranate fruit extract rich in punicalagin on oxidation-sensitive genes and eNOS activity at sites of perturbed shear stress and atherogenesis
- Author
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Louis J. Ignarro, Russell E. Byrns, Vincenzo Sica, Daigo Sumi, Filomena de Nigris, Carmela Fiorito, Concetta Schiano, Daniela Carpentiero, Amelia Casamassimi, Lilach O. Lerman, Francesco Paolo D'Armiento, Claudio Napoli, Sharon Williams-Ignarro, DE NIGRIS, F, WILLIAMS IGNARRO, S, Sica, V, Lerman, Lo, D'Armiento, FRANCESCO PAOLO, Byrns, Re, Casamassimi, A, Carpentiero, D, Schiano, C, Sumi, D, Fiorito, C, Ignarro, Lj, Napoli, C., de NIGRIS, Filomena, Williams Ignarro, S, D'Armiento, Fp, Casamassimi, Amelia, and Napoli, Claudio
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Male ,Antioxidant ,Isoprostane ,Physiology ,medicine.medical_treatment ,Pharmacology ,medicine.disease_cause ,Pomegranate ,Antioxidants ,chemistry.chemical_compound ,Mice ,Enos ,Cyclic AMP ,p-CREB ,Cells, Cultured ,Lythraceae ,Mice, Knockout ,pomegranate fruit ,biology ,Chemistry ,atherogenesis ,Coronary Vessels ,Hydrolyzable Tannins ,Shear stre ,Nitric oxide synthase ,medicine.anatomical_structure ,Biochemistry ,eNOS activity ,eNOS ,Cardiology and Cardiovascular Medicine ,Oxidation-Reduction ,Polyphenol ,Endothelium ,Nitric Oxide Synthase Type III ,Blotting, Western ,Hypercholesterolemia ,In Vitro Techniques ,Nitric oxide ,Beverages ,Physiology (medical) ,medicine ,Animals ,Humans ,Punicalagin ,ELK-1 ,Analysis of Variance ,Plant Extracts ,biology.organism_classification ,Atherosclerosis ,Receptors, LDL ,biology.protein ,Endothelium, Vascular ,Stress, Mechanical ,Oxidative stress - Abstract
BACKGROUND: Atherosclerosis is enhanced in arterial segments exposed to disturbed flow. Perturbed shear stress increases the expression of oxidation-sensitive responsive genes (such as ELK-1 and p-CREB). Polyphenolic antioxidants contained in the juice derived from the pomegranate contribute to the reduction of oxidative stress and atherogenesis during disturbed shear stress. AIM OF THE STUDY: To evaluate the effects of intervention with the Pomegranate Fruit Extract (PFE) rich in polyphones (punicalagin, which is a potent antioxidant) on ELK-1, p-CREB, and endothelial nitric oxide synthase (eNOS) expression induced by high shear stress in vitro and in vivo. RESULTS: At the doses used in the study, both the PFE and the regular pomegranate juice concentrate reduced the activation of ELK-1 and p-CREB and increased eNOS expression (which was decreased by perturbed shear stress) in cultured human endothelial cells and in atherosclerosis-prone areas of hypercholesterolemic mice. PFE and pomegranate juice increased cyclic GMP levels while there was no significant effect of both compounds on the conversion of L-arginine to L-citrulline. Administration of these compounds to hypercholesterolemic mice significantly reduced the progression of atherosclerosis and isoprostane levels and increased nitrates. This protective effect was relevant with PFE. Vasomotor reactivity was improved and EC(25) values in response to Ach and NONOate were significantly increased in treated mice in comparison to controls. CONCLUSION: This study indicates that the proatherogenic effects induced by perturbed shear stress can be also reversed by chronic administration of PFE.
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- 2007
48. Effect of gestational hypercholesterolaemia on omental vasoreactivity, placental enzyme activity and transplacental passage of normal and oxidised fatty acids
- Author
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Antonio Palagiano, Maria Luisa Balestrieri, Monica Rienzo, Sharon Williams-Ignarro, Carmela Fiorito, Louis J. Ignarro, Lilach O. Lerman, Claudio Napoli, F. de Nigris, Francesco Paolo D'Armiento, Wulf Palinski, A. Liguori, Maurizio D’Amora, Liguori, A, D'Armiento, F, Palagiano, A, Balestrieri, Maria Luisa, WILLIAMS IGNARRO, S, DE NIGRIS, F, Lerman, L, D'Amora, M, Rienzo, M, Fiorito, C, Ignarro, L, Palinski, W, Napoli, Claudio, Liguori, Aurelio, D'Armiento, FRANCESCO PAOLO, Balestrieri, Ml, Williams Ignarro, S, de Nigris, F, Lerman, Lo, Rienzo, Monica, Ignarro, Lj, and Napoli, C.
- Subjects
Adult ,Leptin ,medicine.medical_specialty ,Maternal hypercholesterolaemia ,oxidised fatty acids ,Placenta ,Hypercholesterolemia ,Gestational Age ,medicine.disease_cause ,Muscle, Smooth, Vascular ,Developmental programming ,gestational hypercholesterolaemia ,Lipid peroxidation ,chemistry.chemical_compound ,Pregnancy ,Internal medicine ,Medicine ,Humans ,Vasoconstrictor Agents ,Fetus ,business.industry ,Fatty Acids ,Obstetrics and Gynecology ,Transplacental ,Arteries ,medicine.disease ,Fetal Blood ,Immunohistochemistry ,Lipids ,enzyme activity ,Pregnancy Complications ,Vasomotor System ,Oxidative Stress ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Cord blood ,Oxidative stre ,Female ,Lipid Peroxidation ,business ,Omentum ,Oxidation-Reduction ,Vascular reactivity ,Oxidative stress ,Lipoprotein ,Muscle Contraction - Abstract
Objective Maternal hypercholesterolaemia during pregnancy increases lipid peroxidation in mothers and fetuses and programs increased susceptibility to atherosclerosis later in life. The objective of this study was to elucidate the role of the placenta in mediating oxidative stress from mother to offspring. Design Comparison between normo- and hypercholesterolaemic mothers (n = 36 each) and their children. Setting Obstetric wards, hospitals of the University of Naples and Regione Campania. Population Healthy primiparas delivering by caesarean section. Methods Biochemical measurements of oxidative stress and serum leptin in cord plasma and placenta, immunochemistry of placenta microvessels, and vasoreactivity studies were performed. Main outcome measures Oxidative status (i.e. lipid composition and content of oxidised fatty acids, activity of pro- and antioxidant enzymes, immunohistochemical presence of oxidation-specific epitopes) in maternal and cord blood and in placental tissue, as well as vascular reactivity in omental arteries. Results Hypercholesterolaemia during pregnancy was associated with extensive changes in fatty acid composition of both maternal and cord blood lipids, sufficient to alter vasoreactivity of omental vessels. Results also indicated that the placenta is not only subject to substantial oxidative stress, but that it may further increase fetal oxidative stress through changes of pro- and antioxidant enzyme activities. Conclusions The placenta plays an important role in both transmitting and enhancing pathogenic effects of gestational hypercholesterolaemia.
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- 2007
49. Autologous bone marrow cell therapy and metabolic intervention in ischemia-induced angiogenesis in the diabetic mouse hindlimb
- Author
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Filomena de Nigris, Louis J. Ignarro, Luigi Rossiello, Ciro Maione, Francesco Paolo D'Armiento, Vincenzo Sica, Lilach O. Lerman, Maria Luisa Balestrieri, Antonio Palagiano, Claudio Napoli, Sharon Williams-Ignarro, Sica, V, WILLIAMS IGNARRO, S, de NIGRIS, Filomena, D'Armiento, Fp, Lerman, Lo, Balestrieri, Maria Luisa, Maione, C, Palagiano, A, Rossiello, L, Ignarro, Lj, Napoli, Claudio, Sica, Vincenzo, Williams Ignarro, S, de Nigris, F, D'Armiento, FRANCESCO PAOLO, Balestrieri, Ml, Maione, Ciro, Rossiello, Raffaele, and Napoli, C.
- Subjects
Male ,Angiogenesis ,medicine.medical_treatment ,Ischemia ,Neovascularization, Physiologic ,Bone Marrow Cells ,Hindlimb ,Pharmacology ,Biology ,Transplantation, Autologous ,Nitric oxide ,Diabetes Mellitus, Experimental ,bone marrow cell therapy ,metabolic intervention ,chemistry.chemical_compound ,Mice ,Diabetes mellitus ,medicine ,Laser-Doppler Flowmetry ,Animals ,Humans ,Therapeutic angiogenesis ,Molecular Biology ,Bone Marrow Transplantation ,Cell Proliferation ,Inflammation ,Vitamin C ,Vitamin E ,Muscles ,Cell Biology ,medicine.disease ,diabetic mouse hindlimb ,Fibrosis ,Ki-67 Antigen ,chemistry ,Regional Blood Flow ,Immunology ,Developmental Biology - Abstract
Peripheral arterial disease (PAD) is a major health problem especially when associated to diabetes. Administration of autologous bone marrow cells (BMC) is emerging as a novel intervention to induce therapeutic angiogenesis in experimental ischemic limb models and in patients with PAD. Since tissue ischemia and diabetes are associated with an overwhelming generation of oxygen radicals and detrimental effects due to formation of glycosylation end-products, metabolic intervention with antioxidants and L-arginine can confer beneficial effects beyond those achieved by BMC alone. The effects of cotreatment with intravenous BMCs and metabolic vascular protection (1.0% vitamin E, 0.05% vitamin C, and 6% L-arginine) were examined in the ischemic hindlimb of diabetic and non diabetic mice. BMC therapy increased blood flow and capillary densities and Ki67 proliferative marker, and decreased interstitial fibrosis. This effect was amplified by metabolic cotreatment, an intervention inducing vascular protection, at least in part, through the nitric oxide pathway, reduction of systemic oxidative stress, and macrophage activation.
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- 2006
50. Bone marrow cell-mediated cardiovascular repair: potential of combined therapies
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Claudio Napoli, Carmela Fiorito, Ciro Maione, Louis J. Ignarro, Concetta Schiano, Napoli, Claudio, Maione, C, Schiano, C, Fiorito, C, and Ignarro, Lj
- Subjects
Genetic enhancement ,Bone Marrow Cells ,CXCR4 ,Cardiovascular System ,Models, Biological ,Nitric oxide ,Neovascularization ,Cardiovascular Physiological Phenomena ,chemistry.chemical_compound ,Chemokine receptor ,Medicine ,Animals ,Humans ,Regeneration ,Molecular Biology ,Bone Marrow Transplantation ,Cell Proliferation ,Peripheral Vascular Diseases ,Clinical Trials as Topic ,Wound Healing ,business.industry ,Regeneration (biology) ,Stem Cells ,Ascorbic acid ,Combined Modality Therapy ,Transplantation ,chemistry ,Cardiovascular Diseases ,Immunology ,Cancer research ,Molecular Medicine ,medicine.symptom ,business - Abstract
Recent evidence indicates that bone-marrow cells (BMCs) can contribute to the healing process of the injured cardiovascular system via the chemokine receptor CXCR4/SDF-1, thymosin beta(4) and integrin alpha(4)beta(1) molecular pathways. During tissue ischemia overwhelming numbers of detrimental oxygen radicals are generated, and therefore treatment with antioxidants and L-arginine, the precursor of nitric oxide (NO), could induce beneficial effects beyond those achieved by BMC transplantation alone. Recent studies have reported that BMCs have enhanced neovascularization capacity in cotreatment with alpha-tocopherol (vitamin E), ascorbic acid (vitamin C) and L-arginine. Moreover, BMC therapy can be combined with gene therapy. Clinical trials employing BMCs in the treatment of cardiovascular diseases have been completed with mixed or positive results, and several trials are ongoing. Here, we discuss the clinical potential of BMC transplantation alone and in combined therapy that aims to restore organ vascularization and function. We also consider the mechanisms of mobilization, differentiation and incorporation of BMCs.
- Published
- 2006
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