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4. Biophysical and proteomic analyses suggest functions of Pseudomonas syringae pv tomato DC3000 extracellular vesicles in bacterial growth during plant infection

Author

Botzenhardt L, Katarzyna Rybak, Silke Robatzek, Andreas Klingl, Andreas Brachmann, Christina Ludwig, Jacob G. Malone, Jan Sklenar, Stigliano E, Szulc B, Frank L.H. Menke, Martin Janda, and Chen Meng

Subjects
biology, Chemistry, Vesicle, fungi, Cell, Bacterial growth, biology.organism_classification, Extracellular vesicles, Microbiology, medicine.anatomical_structure, medicine, Pseudomonas syringae, Trypsin Digestion, Bacterial outer membrane, Bacteria
Abstract

SummaryVesiculation is a process employed by Gram-negative bacteria to release extracellular vesicles (EVs) into the environment. Bacterial EVs contain molecular cargo from the donor bacterium and play important roles in bacterial survival and growth. Here, we describe EV production in plant-pathogenic Pseudomonas syringae pv. tomato DC3000 (Pto DC3000), the causal agent of bacterial speck disease. Cultured Pto DC3000 exhibited EV structures both on the cell surface and in the vicinity of bacterial cells, observed as outer membrane vesicle (OMV) release. We used in-solution trypsin digestion coupled to mass spectrometry to identify 369 proteins enriched in EVs recovered from cultured Pto DC3000. The predicted localization profile of EV proteins supports the production of EVs also in the form of outer-inner-membrane vesicles (OIMVs). EV production varied slightly between bacterial lifestyles and also occurred in planta. The potential contribution of EVs to Pto DC3000 plant infection was assessed using plant treatments and bioinformatic analysis of the EV-enriched proteins. While these results identify immunogenic activities of the EVs, they also point at roles for EVs in bacterial defences and nutrient acquisition by Pto DC3000.

Published
2021

5. COVID-19 and RA share an SPP1 myeloid pathway that drives PD-L1+ neutrophils and CD14+ monocytes

Author

MacDonald, L., Alivernini, S. (ORCID:0000-0002-7383-4212), Tolusso, B., Elmesmari, A., Somma, D., Perniola, S., Paglionico, A., Petricca, L., Bosello, S. L. (ORCID:0000-0002-4837-447X), Carfi, A., Sali, M., Stigliano, E., Cingolani, A. (ORCID:0000-0002-3793-2755), Murri, R. (ORCID:0000-0003-4263-7854), Arena, V. (ORCID:0000-0002-7562-223X), Fantoni, M., Antonelli, M. (ORCID:0000-0003-3007-1670), Landi, F. (ORCID:0000-0002-3472-1389), Franceschi, F., Sanguinetti, M. (ORCID:0000-0002-9780-7059), McInnes, I. B., McSharry, C., Gasbarrini, A. (ORCID:0000-0002-7278-4823), Otto, T. D., Kurowska-Stolarska, M., Gremese, E. (ORCID:0000-0002-2248-1058), MacDonald, L., Alivernini, S. (ORCID:0000-0002-7383-4212), Tolusso, B., Elmesmari, A., Somma, D., Perniola, S., Paglionico, A., Petricca, L., Bosello, S. L. (ORCID:0000-0002-4837-447X), Carfi, A., Sali, M., Stigliano, E., Cingolani, A. (ORCID:0000-0002-3793-2755), Murri, R. (ORCID:0000-0003-4263-7854), Arena, V. (ORCID:0000-0002-7562-223X), Fantoni, M., Antonelli, M. (ORCID:0000-0003-3007-1670), Landi, F. (ORCID:0000-0002-3472-1389), Franceschi, F., Sanguinetti, M. (ORCID:0000-0002-9780-7059), McInnes, I. B., McSharry, C., Gasbarrini, A. (ORCID:0000-0002-7278-4823), Otto, T. D., Kurowska-Stolarska, M., and Gremese, E. (ORCID:0000-0002-2248-1058)

Abstract

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post–COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post–COVID-19 pathology.

Published
2021

7. Right sinus of Valsalva aneurysm

Author

Fari, G., Pennacchia, Ilaria, Stigliano, Egidio, Oliva, Antonio, Carbone, A., Arena, Vincenzo, Pennacchia I., Stigliano E., Oliva A. (ORCID:0000-0001-7120-616X), Arena V. (ORCID:0000-0002-7562-223X), Fari, G., Pennacchia, Ilaria, Stigliano, Egidio, Oliva, Antonio, Carbone, A., Arena, Vincenzo, Pennacchia I., Stigliano E., Oliva A. (ORCID:0000-0001-7120-616X), and Arena V. (ORCID:0000-0002-7562-223X)

Abstract

Aneurysms in the sinuses of Valsalva (SVA) are the least frequent and occur due to a weakness in the aortic wall that forms part of the sinus. This causes dilatation and the formation of a blind pocket in one of the aortic sinuses (usually he right sinus and less frequently the posterior one). It may be congenital or acquired: in a congenital SVA, the condition is frequently associated with Marfan's syndrome or other connective tissue disorders; instead, acquired forms of sinus of Valsalva aneurysm are associated with infections (syphilis, bacterial endocarditis, and tuberculosis), atherosclerosis and medial cystic necrosis, traumatic and degenerative diseases, abuse of drugs or alcoholism. Despite SVA is a well-known anomaly, autopsy images or reviews of the condition are very uncommon. Indeed we report here a fatal case of SVA in a 58-year-old homeless man found dead on the street. The autopsy, performed to determine the cause of death, releaved a massive aneurysm (in excess of 4 cm) involving the right coronary sinus of the aorta. In this case, the aneurysm may be an accidental finding: in effect we found no tromboses inside the aneurysm and the ostium was not obstructed, therefore the cause of death could be attribuited to fatal arrhythmia.

Published
2020

8. Postmortem Swabs in the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic

Author

Dell'Aquila, Marco, Cattani Franchi, Paola, Fantoni, Massimo, Marchetti, Simona, Aquila, I., Stigliano, Egidio, Carbone, Arnaldo, Oliva, Antonio, Arena, Vincenzo, Dell'Aquila M., Cattani P. (ORCID:0000-0003-4678-4763), Fantoni M. (ORCID:0000-0001-6913-8460), Marchetti S., Stigliano E., Carbone A. (ORCID:0000-0001-9695-5837), Oliva A. (ORCID:0000-0001-7120-616X), Arena V. (ORCID:0000-0002-7562-223X), Dell'Aquila, Marco, Cattani Franchi, Paola, Fantoni, Massimo, Marchetti, Simona, Aquila, I., Stigliano, Egidio, Carbone, Arnaldo, Oliva, Antonio, Arena, Vincenzo, Dell'Aquila M., Cattani P. (ORCID:0000-0003-4678-4763), Fantoni M. (ORCID:0000-0001-6913-8460), Marchetti S., Stigliano E., Carbone A. (ORCID:0000-0001-9695-5837), Oliva A. (ORCID:0000-0001-7120-616X), and Arena V. (ORCID:0000-0002-7562-223X)

Abstract

Context.—Clinical autopsies have historically provided a fundamental contribution in the definition of the clinicopathologic basis of infectious diseases. Even though we are witnessing the decline of the clinical autopsy, its importance remains unchanged as it is the most exhaustive way to investigate diseases. The identification of the virus in postmortem tissues is a fundamental step in the definition of its clinical features. Objective.—To investigate the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in postmortem examination with swabs. Design.—We performed postmortem swabs in 12 autopsy cases of patients with a clinical diagnosis of SARS-CoV-2–related pneumonia. Our protocol consisted of a rhinopharyngeal and a tracheal swab in order to search for the virus in the upper airways, and of 2 swabs on the parenchyma of each lung. We also performed a fifth swab on the parenchyma of both lungs in order to search for other viruses that could evolve in a clinical picture of interstitial pneumonia. Results.—Overall, we found 9 of 12 cases had at least 1 postmortem swab positive for SARS-CoV-2. Moreover, we evaluated the time between the antemortem and postmortem swabs, the time between death and the postmortem swabs, and the time between the postmortem swabs and acceptance to the microbiology laboratory. Of note, we did not find a relationship between the results of the swabs and either the time elapsed from their collection or the time elapsed before their acceptance in the microbiology laboratory. Conclusions.—A thorough knowledge of the eventual persistence of pathogens in deaths related to infectious diseases is fundamental for the safety of the operators during the autopsy practice, especially when referring to emergent pathogens, such as SARS-CoV-2. Our study highlights the importance in performing multiple swabs in the postmortem examination, because SARS-CoV-2 swab positivity can be limited to only a single swab.

Published
2020

11. TOMATO RAB 11 A REGULATES EXOCYTOSIS INVOLVING THE SYNTAXIN SYP122

Author

REHMAN, REIAZ UL, DALESSANDRO, Giuseppe, DI SANSEBASTIANO, Gian Pietro, STIGLIANO E, LYCETT G, STICHER L, FARACO M, SBANO F, Rehman, REIAZ UL, Stigliano, E, Lycett, G, Sticher, L, Faraco, M, Sbano, F, Dalessandro, Giuseppe, and DI SANSEBASTIANO, Gian Pietro

Published
2008

12. Caratterizzazione in vivo di Rab11

Author

DI SANSEBASTIANO, Gian Pietro, DALESSANDRO, Giuseppe, Stigliano E., DI SANSEBASTIANO, Gian Pietro, Stigliano, E., and Dalessandro, Giuseppe

Published
2006

15. Large non-functioning parathyroid cysts: our institutional experience of a rare entity and a possible pitfall in thyroid cytology.

Author

Rossi, Ed, Revelli, Luca, Giustozzi, Erica, Straccia, Patrizia, Stigliano, Egidio, Lombardi, Celestino Pio, Pontecorvi, Alfredo, Fadda, Guido, Revelli L (ORCID:0000-0003-1907-773X), Giustozzi E, Straccia P, Stigliano E, Lombardi CP (ORCID:0000-0001-8910-6693), Pontecorvi A (ORCID:0000-0003-0570-6865), Fadda G. (ORCID:0000-0003-2013-7293), Rossi, Ed, Revelli, Luca, Giustozzi, Erica, Straccia, Patrizia, Stigliano, Egidio, Lombardi, Celestino Pio, Pontecorvi, Alfredo, Fadda, Guido, Revelli L (ORCID:0000-0003-1907-773X), Giustozzi E, Straccia P, Stigliano E, Lombardi CP (ORCID:0000-0001-8910-6693), Pontecorvi A (ORCID:0000-0003-0570-6865), and Fadda G. (ORCID:0000-0003-2013-7293)

Abstract

Large non-functioning parathyroid cysts: our institutional experience of a rare entity and a possible pitfall in thyroid cytology.

Published
2015

16. N-Acetylcysteine and High-Dose Atorvastatin Reduce Oxidative Stress in an Ischemia-Reperfusion Model in the Rat Kidney

Author

Cusumano, G., primary, Romagnoli, J., additional, Liuzzo, G., additional, Ciavarella, L.P., additional, Severino, A., additional, Copponi, G., additional, Manchi, M., additional, Giubilato, S., additional, Zannoni, G.F., additional, Stigliano, E., additional, Caristo, M.E., additional, Crea, F., additional, and Citterio, F., additional

Published
2015
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18. Haemophagocytic syndrome associated with mucormycosis infection

Author

Arena, V., De-Giorgio, F., Pennacchia, I., Raffaele Manna, Vetrugno, G., Stigliano, E., Milic, N., Gasbarrini, G., and Abenavoli, L.

Subjects
Adult, Male, medicine.medical_specialty, Pathology, Biopsy, Immunology, Hemophagocytic, Autopsy, Disease, Lymphohistiocytosis, Hemophagocytic, Malignant lymphoma, Fatal Outcome, Predictive Value of Tests, medicine, Immunology and Allergy, Humans, Mucormycosis, Immunodeficiency, Pharmacology, Lymphohistiocytosis, medicine.diagnostic_test, Haemophagocytic syndrome, business.industry, Settore MED/09 - MEDICINA INTERNA, Bone Marrow Examination, Settore MED/43 - MEDICINA LEGALE, medicine.disease, Dermatology, Bone marrow examination, Treatment Outcome, Liver, Renal transplant, Gastric Mucosa, mucormycosis infection, business, Immunosuppressive Agents
Abstract

Several clinical forms of mucormycosis are recognized. The tendency of mucoraceous zygomycetes to invade the blood vessels often produces a disseminated infection. A case of a disseminated mucormycosis complicated by a haemophagocytic syndrome (HS) in a 32-year-old Caucasian male is reported in this article. Few cases of infection-associated HS (IAHS), involving infections caused by fungi, have been reported. In all the recorded cases, the fungal infection coexists with malignant lymphoma, immunodeficiency and a long-term steroid therapy for renal transplant or Crohn's disease. This is the second described case of the HS due to mucormycosis.

Published
2012

21. Pioglitazone enhances collateral blood flow in ischemic hindlimb of diabetic mice through an Akt-dependent VEGF-mediated mechanism, regardless of PPARgamma stimulation

Author

Biscetti, F, Straface, G, Arena, V, Stigliano, E, Pecorini, G, Rizzo, P, Angelis, De, G, Iuliano, Luigi, Ghirlanda, G, and Flex, A.

Subjects
Blood Glucose, Male, Vascular Endothelial Growth Factor A, lcsh:Diseases of the circulatory (Cardiovascular) system, PPARγ, SMOOTH-MUSCLE-CELLS, Endocrinology, Diabetes and Metabolism, Hindlimb, ANGIOGENESIS, chemistry.chemical_compound, MELLITUS, Mice, Ischemia, GLYCEMIC CONTROL, Anilides, Receptor, Original Investigation, INSULIN-RESISTANCE, VEGF, NONDIABETIC PATIENTS, Up-Regulation, Vascular endothelial growth factor, Oncogene Protein v-akt, ROSIGLITAZONE, Cardiology and Cardiovascular Medicine, Blood Flow Velocity, medicine.drug, Signal Transduction, Agonist, medicine.medical_specialty, medicine.drug_class, Collateral Circulation, diabetic mice, Diabetes Mellitus, Experimental, Benzophenones, Diabetes mellitus, Internal medicine, medicine, ENDOTHELIAL GROWTH-FACTOR, CANCER-CELLS, THIAZOLIDINEDIONES, Animals, Hypoglycemic Agents, Protein kinase B, Pioglitazone, business.industry, Akt, Settore MED/09 - MEDICINA INTERNA, Type 2 Diabetes Mellitus, medicine.disease, Mice, Inbred C57BL, PPAR gamma, ischemic hindlimb, Endocrinology, chemistry, lcsh:RC666-701, Tyrosine, Thiazolidinediones, business
Abstract

Background Type 2 diabetes mellitus (T2DM) is commonly associated with both microvascular and macrovascular complications and a strong correlation exists between glycaemic control and the incidence and progression of vascular complications. Pioglitazone, a Peroxisome proliferator-activated receptor-γ (PPARγ) ligand indicated for therapy of type T2DM, induces vascular effects that seem to occur independently of glucose lowering. Methods By using a hindlimb ischemia murine model, in this study we have found that pioglitazone restores the blood flow recovery and capillary density in ischemic muscle of diabetic mice and that this process is associated with increased expression of Vascular Endothelial Growth Factor (VEGF). Importantly, these beneficial effects are abrogated when endogenous Akt is inhibited; furthermore, the direct activation of PPARγ, with its selective agonist GW1929, does not restore blood flow recovery and capillary density. Finally, an important collateral vessel growth is obtained with combined treatment with pioglitazone and selective PPARγ inhibitor GW9662. Conclusion These data demonstrate that Akt-VEGF pathway is essential for ischemia-induced angiogenic effect of pioglitazone and that pioglitazone exerts this effect via a PPARγ independent manner.

Published
2009

23. Nasal HPpSIS administration enhances NGF and tumor suppressor protein, p73 in human brain cancer tissues: preliminary data.

Author

ALOE, L., ROCCO, M. L., STIGLIANO, E., ANGELINI, F., IACOANGELI, M., FRARI, V., and SALVINELLI, F.

Abstract

OBJECTIVE: Nerve Growth Factor (NGF) is a neurotrophic factor known to play a critical role in growth, survival, differentiation and neuroprotection of peripheral sensory and sympathetic neurons, as well as brain neurons. We have recently reported that nasal administration of high-pressure isotonic physiological saline solution (HPpSIS) enhances the level of NGF and the expression of NGF receptors in neurons of the olfactory bulbs and forebrain cholinergic neurons of laboratory animals. In the present study, we sought to determine whether the same treatment affects the levels of NGF within the brain tumor tissue. PATIENTS AND METHODS: This study was conducted on eight adult patients, 4 males and 4 females with malignant anterior cranial fossa tumor. Before surgery, four subjects, two males and two females received nasal administration of HPpSIS for ten consecutive days. RESULTS: The levels of NGF in surgical removed peripheral tumor brain samples of patients treated with nasal HPpSIS administration are more elevated compared to the levels of NGF in peripheral brain tissues of HPpSIS untreated patients. CONCLUSIONS: We observed that nasal administration of HPpSIS enhances not only the basal brain NGF levels and the expression of NGF receptors but also the tumor suppressor protein p73. The possible functional significance of these observations will be described and discussed. [ABSTRACT FROM AUTHOR]

Published
2017

26. P.06.9 INFLIXIMAB IS NOT INCREASING COLONIC CANCER RISK ASSOCIATED TO CHRONIC COLITIS IN MICE

Author

Scaldaferri, F., primary, Lopetuso, L.R., additional, Petito, V., additional, Bruno, G., additional, Gerardi, V., additional, Cufino, V., additional, Arena, V., additional, Stigliano, E., additional, Caristio, M., additional, Poscia, A., additional, Cammarota, G., additional, Papa, A., additional, Sgambato, A., additional, and Gasbarrini, A., additional

Published
2014
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28. US-guided application of Nd:YAG laser in porcine pancreatic tissue: an ex vivo study and numerical simulation

Author

Di Matteo, F, Martino, M, Rea, R, Pandolfi, M, Panzera, F, Stigliano, E, Schena, E, Saccomandi, P, Silvestri, S, Pacella, Cm, Breschi, L, Perrone, G, Coppola, R, Costamagna, Guido, Costamagna, Guido (ORCID:0000-0002-8100-2731), Di Matteo, F, Martino, M, Rea, R, Pandolfi, M, Panzera, F, Stigliano, E, Schena, E, Saccomandi, P, Silvestri, S, Pacella, Cm, Breschi, L, Perrone, G, Coppola, R, Costamagna, Guido, and Costamagna, Guido (ORCID:0000-0002-8100-2731)

Abstract

Laser ablation (LA) with a neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is a minimally invasive approach able to achieve a high rate of complete tissue necrosis. In a previous study we described the feasibility of EUS-guided Nd:YAG pancreas LA performed in vivo in a porcine model.

Published
2013

29. Haemophagocytic syndrome associated with mucormycosis infection

Author

Arena, Vincenzo, De Giorgio, F, Pennacchia, I, Manna, Raffaele, Vetrugno, Giuseppe, Stigliano, E, Milic, N, Gasbarrini, G, Abenavoli, L., Arena, Vincenzo (ORCID:0000-0002-7562-223X), Manna, Raffaele (ORCID:0000-0003-1560-3907), Vetrugno, G (ORCID:0000-0003-0181-2855), Arena, Vincenzo, De Giorgio, F, Pennacchia, I, Manna, Raffaele, Vetrugno, Giuseppe, Stigliano, E, Milic, N, Gasbarrini, G, Abenavoli, L., Arena, Vincenzo (ORCID:0000-0002-7562-223X), Manna, Raffaele (ORCID:0000-0003-1560-3907), and Vetrugno, G (ORCID:0000-0003-0181-2855)

Abstract

Several clinical forms of mucormycosis are recognized. The tendency of mucoraceous zygomycetes to invade the blood vessels often produces a disseminated infection. A case of disseminate mucormycosis complicated by a haemophagocytic syndrome (HS) in a 32-year-old Caucasian male is reported in this article. Few cases of infection-associated HS (IAHS), involving infections caused by fungi, have been reported. In all the recorded cases, the fungal infection coexists with malignant lymphoma, immunodeficiency and a long-term steroid therapy for renal transplant or Crohn's disease. This is the second described case of the HS due to mucormycosis.

Published
2012

30. High-mobility group box-1 protein promotes angiogenesis after peripheral ischemia in diabetic mice through a VEGF-dependent mechanism

Author

Biscetti, Federico, Straface, Giuseppe, De Cristofaro, Raimondo, Lancellotti, S, Rizzo, P, Arena, Vincenzo, Stigliano, E, Pecorini, G, Egashira, K, De Angelis, G, Ghirlanda, G, Flex, A., Biscetti, Federico (ORCID:0000-0001-7449-657X), De Cristofaro, Raimondo (ORCID:0000-0002-8066-8849), Arena, Vincenzo (ORCID:0000-0002-7562-223X), Biscetti, Federico, Straface, Giuseppe, De Cristofaro, Raimondo, Lancellotti, S, Rizzo, P, Arena, Vincenzo, Stigliano, E, Pecorini, G, Egashira, K, De Angelis, G, Ghirlanda, G, Flex, A., Biscetti, Federico (ORCID:0000-0001-7449-657X), De Cristofaro, Raimondo (ORCID:0000-0002-8066-8849), and Arena, Vincenzo (ORCID:0000-0002-7562-223X)

Abstract

High-mobility group box-1 (HMGB1) protein is a nuclear DNA-binding protein released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. Diabetic human and mouse tissues contain lower levels of HMGB1 than their normoglycemic counterparts. Deficient angiogenesis after ischemia contributes to worse outcomes of peripheral arterial disease in patients with diabetes. To test the hypothesis that HMGB1 enhances ischemia-induced angiogenesis in diabetes, we administered HMGB1 protein in a mouse hind limb ischemia model using diabetic mice.

Published
2010

31. P.03.1 INFLIXIMAB (IFX) ACTS LOCALLY ON INTESTINAL MUCOSA AND ITS PHARMACOKINETIC IS DIFFERENT IN DSS COLITIC MICE COMPARED TO CONTROLS

Author

Scaldaferri, F., primary, Lopetuso, L.R., additional, Petito, V., additional, Gerardi, V., additional, Arena, V., additional, Stigliano, E., additional, Papa, A., additional, Cufino, V., additional, Amato, A., additional, Cammarota, G., additional, Gaetani, E., additional, Sgambato, A., additional, and Gasbarrini, A., additional

Published
2013
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32. OC.07.6 GELENTERUM AMELIORATES SEVERITY OF COLITIS IN DSS MURINE MODEL, WHILE MODULATING GUT MICROBIOTA AND INTESTINAL MUCUS LAYER

Author

Scaldaferri, F., primary, Lopetuso, L.R., additional, Petito, V., additional, Gerardi, V., additional, Bilotta, M., additional, Papi, M., additional, Maolucci, G., additional, Stigliano, E., additional, Cufino, V., additional, Arena, V., additional, De Logu, G., additional, Sanguinetti, M., additional, De Spirito, M., additional, Sgambato, A., additional, and Gasbarrini, A., additional

Published
2013
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33. P071 Gelenterum ameliorates murine colitis while modulating gut microbiota and intestinal mucus layer

Author

Scaldaferri, F., primary, Lopetuso, L.R., additional, Petito, V., additional, Gerardi, V., additional, Bilotta, M., additional, Poscia, A., additional, Papi, M., additional, Maolucci, G., additional, Cufino, V., additional, Stigliano, E., additional, Arena, V., additional, Delogu, G., additional, Sanguinetti, M., additional, De Spirito, M., additional, Sgambato, A., additional, and Gasbarrini, A., additional

Published
2013
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35. Mineral and bone disease - CKD 5D

Author

Hecking, M., primary, Kainz, A., additional, Bielesz, B., additional, Plischke, M., additional, Beilhack, G., additional, Hoerl, W. H., additional, Sunder-Plassmann, G., additional, Bieglmayer, C., additional, Benchetrit, S., additional, Green, J., additional, Bernheim, J., additional, Golan, E., additional, Oyake, N., additional, Suzuki, K., additional, Itoh, S., additional, Tanabe, K., additional, Fujimori, A., additional, Okada, S., additional, Yamamoto, K., additional, Sakai, M., additional, Kamiura, N., additional, Solenne, P., additional, Guebre-Egziabher, F., additional, Bacchetta, J., additional, Drai, J., additional, Richard, M., additional, Chapurlat, R., additional, Fouque, D., additional, Nowak, Z., additional, Grzegorz, K., additional, Maria, K., additional, Zofia, W., additional, Zamboch, K., additional, Zahalkova, J., additional, Kosatikova, Z., additional, Skypalova, P., additional, Skarda, J., additional, Cunha, J., additional, Boim, M., additional, Ferreira, V., additional, Naves, M., additional, Kikuchi, H., additional, Shimada, H., additional, Takimoto, Y., additional, Karasawa, R., additional, Shimotori, M., additional, Ikarashi, K., additional, Saito, N., additional, Miyazaki, S., additional, Sakai, S., additional, Suzuki, M., additional, Ogata, H., additional, Takeshima, A., additional, Yamamoto, M., additional, Asakura, K., additional, Kato, T., additional, Shishido, K., additional, Koiwa, F., additional, Mizobuchi, M., additional, Kinugasa, E., additional, Akizawa, T., additional, Londrino, F., additional, Corbani, V., additional, Ardini, M., additional, Falqui, V., additional, Zattera, T., additional, Rombola', G., additional, Takeshige, Y., additional, Matsuzaka, K., additional, Ciceri, P., additional, Volpi, E., additional, Brenna, I., additional, Elli, F., additional, Borghi, E., additional, Brancaccio, D., additional, Cozzolino, M., additional, Farrand, K., additional, Copley, J. B., additional, Heise, J., additional, Fridman, M., additional, Keith, M., additional, Silverberg, A., additional, Wilson, R., additional, Poole, L., additional, Jean, G., additional, Bresson, E., additional, Chazot, C., additional, Maduell, F., additional, Arias, M., additional, Sentis, A., additional, Rodriguez, N., additional, Jimenez, S., additional, Alemany, B., additional, Perez, N., additional, Vera, M., additional, Fontsere, N., additional, Carrera, M., additional, Cases, A., additional, Sonikian, M., additional, Miha, T., additional, Skarakis, I., additional, Karatzas, I., additional, Karaitianou, A., additional, Tomanoski, V., additional, Petkovic, D., additional, Curic, I., additional, Hrvacevic, R., additional, Kaperonis, N., additional, Kourvelou, C., additional, Sgantzos, A., additional, Nastou, D., additional, Ntatsis, G., additional, Ziakka, S., additional, Karakasis, F., additional, Nikolopoulos, V., additional, Zoubaniotou, D., additional, Koutsovasili, A., additional, Zagorianakos, A., additional, Kolovos, V., additional, Papagalanis, N., additional, Forni, V., additional, Pruijm, M., additional, Tousset, E., additional, Zweiacker, C., additional, Menetrey, I., additional, Berwert, L., additional, Bullani, R., additional, Cherpillod, A., additional, Gabutti, L., additional, Gauthier, T., additional, Halabi, G., additional, Mathieu, C., additional, Meier, P., additional, Phan, O., additional, Pianca, S., additional, Schoenholzer, C., additional, Teta, D., additional, Von Albertini, B., additional, Vrijens, B., additional, Burnier, M., additional, Kurita, N., additional, Fukagawa, M., additional, Onishi, Y., additional, Yamaguchi, T., additional, Hasegawa, T., additional, Fukuma, S., additional, Kurokawa, K., additional, Fukuhara, S., additional, Urena, P., additional, Bridges, I., additional, Christiano, C., additional, Cournoyer, S., additional, Cooper, K., additional, Farouk, M., additional, Kopyt, N., additional, Rodriguez, M., additional, Zehnder, D., additional, Covic, A., additional, Tominaga, Y., additional, Hiramitsu, T., additional, Yamamoto, T., additional, Nanmoku, K., additional, Matsuda, Y., additional, Tsuzuki, T., additional, Lang, C.-L., additional, Lu, K.-C., additional, Wang, M.-H., additional, Liu, S.-Y., additional, Huang, J.-W., additional, Chiang, C.-K., additional, Hung, K.-Y., additional, Bantis, C., additional, Kouri, N.-M., additional, Tsandekidou, E., additional, Frangidis, S., additional, Tsiandoulas, A., additional, Liakou, E., additional, Bamichas, G., additional, Stangou, M., additional, Papagianni, A., additional, Efstratiadis, G., additional, Natse, T., additional, Memmos, D., additional, Messa, P., additional, Cannella, G., additional, Mazzaferro, S., additional, Yu, X., additional, Bieber, B., additional, Guidinger, M., additional, Yang, X., additional, Tentori, F., additional, Pisoni, R., additional, Qian, J., additional, Chen, N., additional, Yan, Y., additional, Wang, M., additional, Zuo, L., additional, Wang, H., additional, Albert, J., additional, Ramirez, S., additional, Caccetta, F., additional, Caroppo, M., additional, Musio, F., additional, Mudoni, A., additional, Accogli, A., additional, Zacheo, M. D., additional, Nuzzo, V., additional, Selim, G., additional, Stojceva-Taneva, O., additional, Tozija, L., additional, Gelev, S., additional, Pusevski, V., additional, Dzekova-Vidimliski, P., additional, Rambabova-Busletic, I., additional, Sikole, A., additional, Esposito, P., additional, Coppo, R., additional, Malberti, F., additional, Dal Canton, A., additional, Moriwaki, K., additional, Komaba, H., additional, Kakuta, T., additional, Cernaro, V., additional, Lupica, R., additional, Donato, V., additional, Lacquaniti, A., additional, Fazio, M. R., additional, Lucisano, S., additional, Buemi, M., additional, Okuno, S., additional, Ishimura, E., additional, Tsuboniwa, N., additional, Norimine, K., additional, Yamakawa, K., additional, Yamakawa, T., additional, Shoji, S., additional, Mori, K., additional, Nishizawa, Y., additional, Inaba, M., additional, Dahaba, M., additional, Seck, S., additional, Cisse, M., additional, Jotoku, Y., additional, Sato, Y., additional, Dimkovic, N., additional, Asicioglu, E., additional, Kahveci, A., additional, Arikan, H., additional, Koc, M., additional, Tuglular, S., additional, Ozener, C., additional, Kido, R., additional, Yamaguch, T., additional, Krasniak, A., additional, Drozdz, M., additional, Chmiel, G., additional, Podolec, P., additional, Pasowicz, M., additional, Kowalczyk-Michalek, M., additional, Sulowicz, W., additional, Perez-Suarez, G., additional, Baamonde, E., additional, Bosch, E., additional, Ramirez, J. I., additional, El Hayek, B., additional, Lago, M. D. M., additional, Garcia, C., additional, Checa, M. D., additional, Hiramatsu, R., additional, Ubara, Y., additional, Salas, K., additional, Vicent, E. S., additional, Gonzalez Oliva, J. C., additional, Fulquet, M., additional, Duarte, V., additional, Pou, M., additional, Saurina, A., additional, Macias, J., additional, Ramirez de Arellano, M., additional, Matias, P., additional, Jorge, C., additional, Mendes, M., additional, Amaral, T., additional, Ferreira, C., additional, Aires, I., additional, Gil, C., additional, Ferreira, A., additional, Arcal, C., additional, Campistol, J. M., additional, Seferi, S., additional, Rroji, M., additional, Likaj, E., additional, Petrela, E., additional, Barbullushi, M., additional, Zeneli, N., additional, Mumajesi, S., additional, Thereska, N., additional, Vulpio, C., additional, Bossola, M., additional, Stigliano, E., additional, Fadda, G., additional, Gueiros, A. P. S., additional, Borba Junior, J. O., additional, Lordsllen, A. B. d. M. D. S., additional, Gueiros, J. E. d. B., additional, Itami, N., additional, Tuneyama, K., additional, Uemura, S., additional, Hamada, H., additional, Takada, J., additional, Takahashi, K., additional, Adamidis, K., additional, Apostolou, T., additional, Pleros, C., additional, Oikonomaki, T., additional, Kyratzi, E., additional, Exarchos, D., additional, Metaxatos, G., additional, Dracopoulos, S., additional, Nikolopoulou, N., additional, Delanaye, P., additional, Dubois, B., additional, Krzesinski, J.-M., additional, Cavalier, E., additional, De la Fuente, V., additional, Gil, M. T., additional, Gutierrez, P., additional, Delgado, P., additional, Ribero, J., additional, Arenas, L., additional, Sezer, S., additional, Tutal, E., additional, Bal, Z., additional, Erkmen Uyar, M., additional, Ozdemir Acar, F. N., additional, Azevedo de Oliveira, R., additional, Carvalho Barreto, F., additional, Dos Reis, L., additional, Cunha Ferreira, J., additional, Maria Leme Britto, Z., additional, Maria Moyses, R., additional, Jorgetti, V., additional, Ozelsancak, R., additional, Gurlek Demirci, B., additional, Torun, D., additional, Veljancic, L., additional, Radojevic, M., additional, Paunic, Z., additional, Vavic, N., additional, Obrencevic, K., additional, Kovacevic, Z., additional, and Pejovic, J., additional

Published
2012
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36. P.06.5 DIRECT EFFECTS OF INFLIXIMAB (IFX) ON INTESTINAL MUCOSA: EXPLORING MECHANISMS OF MUCOSAL HEALING

Author

Scaldaferri, F., primary, Lopetuso, L.R., additional, Petito, V., additional, Gerardi, V., additional, Arena, V., additional, Stigliano, E., additional, Pizzoferrato, M., additional, Pecere, S., additional, Laterza, L., additional, Papa, A., additional, Cufino, V., additional, Cammarota, G., additional, Sgambato, A., additional, and Gasbarrini, A., additional

Published
2012
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38. P.1.188: EFFECTS OF INFLIXIMAB (IFX) ON INTESTINAL EPITHELIAL CELLS: EXPLORING MECHANISMS OF MUCOSAL HEALING

Author

Scaldaferri, F., primary, Lopetuso, L., additional, Petito, V., additional, Gerardi, V., additional, Arena, V., additional, Stigliano, E., additional, Sparano, L., additional, Pizzoferrato, M., additional, Pecere, S., additional, Laterza, L., additional, Papa, A., additional, Cufino, V., additional, Gasbarrini, G., additional, Sgambato, A., additional, and Gasbarrini, A., additional

Published
2011
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41. Selective activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma induces neoangiogenesis through a vascular endothelial growth factor-dependent mechanism.

Author

Biscetti F, Gaetani E, Flex A, Aprahamian T, Hopkins T, Straface G, Pecorini G, Stigliano E, Smith RC, Angelini F, Castellot JJ Jr., and Pola R

Abstract

OBJECTIVE: Peroxisome proliferator-activated receptors (PPARs) are therapeutic targets for fibrates and thiazolidinediones, which are commonly used to ameliorate hyperlipidemia and hyperglycemia in type 2 diabetes. In this study, we evaluated whether activation of PPAR alpha and PPAR gamma stimulates neoangiogenesis. RESEARCH DESIGN AND METHODS: We used selective synthetic PPAR alpha and PPAR gamma agonists and investigated their angiogenic potentials in vitro and in vivo. RESULTS: Activation of PPAR alpha and PPAR gamma leads to endothelial tube formation in an endothelial/interstitial cell co-culture assay. This effect is associated with increased production of the angiogenic cytokine vascular endothelial growth factor (VEGF). Neovascularization also occurs in vivo, when PPAR alpha and PPAR gamma agonists are used in the murine corneal angiogenic model. No vascular growth is detectable when PPAR alpha and PPAR gamma agonists are respectively used in PPAR alpha knockout mice and mice treated with a specific PPAR gamma inhibitor, demonstrating that this angiogenic response is PPAR mediated. PPAR alpha- and PPAR gamma-induced angiogenesis is associated with local VEGF production and does not differ in extent and morphology from that induced by VEGF. In addition, PPAR alpha- and PPAR gamma-induced in vitro and in vivo angiogenesis may be significantly decreased by inhibiting VEGF activity. Finally, in corneas treated with PPAR alpha and PPAR gamma agonists, there is increased phosphorylation of endothelial nitric oxide synthase and Akt. CONCLUSIONS: These findings demonstrate that PPAR alpha and PPAR gamma activation stimulates neoangiogenesis through a VEGF-dependent mechanism. Neoangiogenesis is a crucial pathological event in type 2 diabetes. The ability of PPAR alpha and PPAR gamma agonists to induce neoangiogenesis might have important implications for the clinical and therapeutic management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Published
2008
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45. Increased expression of CD133 and reduced dystroglycan expression are strong predictors of poor outcome in colon cancer patients

Author

Coco Claudio, Zannoni Gian, Caredda Emanuele, Sioletic Stefano, Boninsegna Alma, Migaldi Mario, Rizzo Gianluca, Bonetti Luca, Genovese Giannicola, Stigliano Egidio, Cittadini Achille, and Sgambato Alessandro

Subjects
Colon cancer, Dystroglycan, CD133, Cancer stem cell, Prognostic marker, Survival analysis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Expression levels of CD133, a cancer stem cell marker, and of the α-subunit of the dystroglycan (α-DG) complex, have been previously reported to be altered in colorectal cancers. Methods Expression levels of CD133 and α-DG were assessed by immunohistochemistry in a series of colon cancers and their prognostic significance was evaluated. Results Scattered cells positive for CD133 were rarely detected at the bases of the crypts in normal colonic mucosa while in cancer cells the median percentage of positive cells was 5% (range 0–80). A significant correlation was observed with pT parameter and tumor stage but not with tumor grade and N status. Recurrence and death from disease were significantly more frequent in CD133-high expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor groups for both disease-free (p = 0.002) and overall (p = 0.008) survival. Expression of α-DG was reduced in a significant fraction of tumors but low α-DG staining did not correlate with any of the classical clinical-pathological parameters. Recurrence and death from the disease were significantly more frequent in α-DG-low expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor tumors for both disease-free (p = 0.02) and overall (p = 0.02) survival. Increased expression of CD133, but not loss of α-DG, confirmed to be an independent prognostic parameters at a multivariate analysis associated with an increased risk of recurrence (RR = 2.4; p = 0.002) and death (RR = 2.3; p = 0.003). Conclusions Loss of α-DG and increased CD133 expression are frequent events in human colon cancer and evaluation of CD133 expression could help to identify high-risk colon cancer patients.

Published
2012
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46. Pioglitazone enhances collateral blood flow in ischemic hindlimb of diabetic mice through an Akt-dependent VEGF-mediated mechanism, regardless of PPARγ stimulation

Author

Iuliano Luigi, De Angelis Giulia, Rizzo Paola, Pecorini Giovanni, Stigliano Egidio, Arena Vincenzo, Straface Giuseppe, Biscetti Federico, Ghirlanda Giovanni, and Flex Andrea

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background Type 2 diabetes mellitus (T2DM) is commonly associated with both microvascular and macrovascular complications and a strong correlation exists between glycaemic control and the incidence and progression of vascular complications. Pioglitazone, a Peroxisome proliferator-activated receptor-γ (PPARγ) ligand indicated for therapy of type T2DM, induces vascular effects that seem to occur independently of glucose lowering. Methods By using a hindlimb ischemia murine model, in this study we have found that pioglitazone restores the blood flow recovery and capillary density in ischemic muscle of diabetic mice and that this process is associated with increased expression of Vascular Endothelial Growth Factor (VEGF). Importantly, these beneficial effects are abrogated when endogenous Akt is inhibited; furthermore, the direct activation of PPARγ, with its selective agonist GW1929, does not restore blood flow recovery and capillary density. Finally, an important collateral vessel growth is obtained with combined treatment with pioglitazone and selective PPARγ inhibitor GW9662. Conclusion These data demonstrate that Akt-VEGF pathway is essential for ischemia-induced angiogenic effect of pioglitazone and that pioglitazone exerts this effect via a PPARγ independent manner.

Published
2009
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47. Ex vivo-transduced autologous skin fibroblasts expressing human Lim mineralization protein-3 efficiently form new bone in animal models

Author

Giovanni Pecorini, Raffaella Pecci, Anna Tampieri, Rossella Bedini, Egidio Stigliano, Paul D. Robbins, Enrico Pola, Claudio Parrilla, Annarita Fetoni, Wanda Lattanzi, Giandomenico Logroscino, Giuseppe Straface, Andrea Gambotto, Fabrizio Michetti, Lattanzi, W, Parrilla, C, Fetoni, A, Logroscino, G, Straface, G, Pecorini, G, Stigliano, E, Tampieri, A, Bedini, R, Pecci, R, Michetti, F, Gambotto, A, Robbins, Pd, and Pola, E

Subjects
Male, Pathology, Genetic enhancement, Gene Expression, Mice, Osteogenesis, Transduction, Genetic, Tissue Scaffolds, Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, Osteoblast, LIM Domain Proteins, Lim mineralization protein-3, animal models, Cell biology, medicine.anatomical_structure, Models, Animal, Bone formation, Molecular Medicine, Bone Diseases, Autologous transplantation, medicine.medical_specialty, Genetic Vectors, Skin fibroblasts, Bone healing, Biology, Transplantation, Autologous, Bone and Bones, Article, Adenoviridae, In vivo, Genetics, medicine, Animals, Humans, Rats, Wistar, Fibroblast, Molecular Biology, Adaptor Proteins, Signal Transducing, Settore BIO/16 - ANATOMIA UMANA, LMP, Genetic Therapy, Fibroblasts, Rats, Mice, Inbred C57BL, Transplantation, Cytoskeletal Proteins, Tomography, X-Ray Computed, Ex vivo
Abstract

Local gene transfer of the human LIM Mineralization Protein (LMP), a novel intracellular positive regulator of the osteoblast differentiation program, can induce efficient bone formation in rodents. In order to develop a clinically relevant gene therapy approach to facilitate bone healing, we have used primary dermal fibroblasts transduced ex vivo with Ad.LMP3 and seeded on an hydroxyapatite/collagen matrix prior to autologous implantation. Here we demonstrate that genetically modified autologous dermal fibroblasts expressing Ad.LMP-3 are able to induce ectopic bone formation following implantation of the matrix into the mouse triceps and paravertebral muscles. Moreover, implantation of the Ad.LMP-3-modified dermal fibroblasts into a rat mandibular bone critical size defect model results in efficient healing as determined by X-ray, histology and three dimensional micro computed tomography (3DμCT). These results demonstrate the effectiveness of the non-secreted intracellular osteogenic factor LMP-3, in inducing bone formation in vivo. Moreover, the utilization of autologous dermal fibroblasts implanted on a biomaterial represents a promising approach for possible future clinical applications aimed at inducing new bone formation.

Published
2008

48. Two glycosylated vacuolar GFPs are new markers for ER-to-vacuole sorting

Author

Marianna Faraco, Gian Pietro Di Sansebastiano, Anna Montefusco, Giuseppe Dalessandro, Gabriella Piro, Jean-Marc Neuhaus, Egidio Stigliano, Stigliano, E, Faraco, Marianna, Neuhaus, Jm, Montefusco, Anna, Dalessandro, Giuseppe, Piro, Gabriella, and DI SANSEBASTIANO, Gian Pietro

Subjects
Glycosylation, Physiology, Nicotiana tabacum, Mutant, Green Fluorescent Proteins, Nicotiana benthamiana, Golgi Apparatus, Plant Science, Vacuole, ctSD, GFP, Endoplasmic Reticulum, Green fluorescent protein, symbols.namesake, Cysteine Proteases, Polysaccharides, Tobacco, Golgi, Genetics, COPII, Plant Proteins, Protoplast, biology, Protoplasts, fungi, Chitinases, food and beverages, Hordeum, Golgi apparatus, biology.organism_classification, Cysteine protease, secretion, Plant Leaves, Cysteine Endopeptidases, Protein Transport, Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase, Biochemistry, Mutation, Vacuoles, symbols, COP-Coated Vesicles
Abstract

Vacuolar Sorting Determinants (VSDs) have been extensively studied in plants but the mechanisms for the accumulation of storage proteins in somatic tissues are not yet fully understood. In this work we used two mutated versions of well-documented vacuolar fluorescent reporters, a GFP fusion in frame with the C-terminal VSD of tobacco chitinase (GFPChi) and an N-terminal fusion in frame with the sequence-specific VSD of the barley cysteine protease aleurain (AleuGFP). The GFP sequence was mutated to present an N-glycosylation site at the amino-acid position 133. The reporters were transiently expressed in Nicotiana tabacum protoplasts and agroinfiltrated in Nicotiana benthamiana leaves and their distribution was identical to that of the non-glycosylated versions. With the glycosylated GFPs we could highlight a differential ENDO-H sensitivity and therefore differential glycan modifications. This finding suggests two different and independent routes to the vacuole for the two reporters. BFA also had a differential effect on the two markers and further, inhibition of COPII trafficking by a specific dominant-negative mutant (NtSar1h74I) confirmed that GFPChi transport from the ER to the vacuole is not fully dependent on the Golgi apparatus. (C) 2013 Elsevier Masson SAS. All rights reserved.

Published
2013

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

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

Subjects
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.

Published
2012

50. Sonic Hedgehog Regulates Angiogenesis and Myogenesis During Post-Natal Skeletal Muscle Regeneration

Author

Egidio Stigliano, John J. Castellot, Douglas W. Losordo, Federico Biscetti, Giovanni Pecorini, Roy C. Smith, Flavia Angelini, Eleonora Gaetani, Giuseppe Straface, Roberto Pola, Andrea Flex, Enrico Pola, Tamar Aprahamian, Straface, G, Aprahamian, T, Flex, A, Gaetani, E, Biscetti, F, Smith, Rc, Pecorini, G, Pola, E, Angelini, F, Stigliano, E, Castellot, Jj, Losordo, Dw, and Pola, R

Subjects
medicine.medical_specialty, animal structures, Angiogenesis, Neovascularization, Physiologic, Tissue Regeneration, MyoD, Mice, chemistry.chemical_compound, sonic hedgehog, angiogenesis, Internal medicine, skeletal muscle regeneration, medicine, Animals, Hedgehog Proteins, Sonic hedgehog, skeletal muscle, Muscle, Skeletal, biology, Myogenesis, Settore MED/09 - MEDICINA INTERNA, Skeletal muscle, angiogenesi, Cell Biology, Hedgehog signaling pathway, Cell biology, Mice, Inbred C57BL, Vascular endothelial growth factor, Endocrinology, medicine.anatomical_structure, chemistry, regeneration, Myogenic regulatory factors, embryonic structures, biology.protein, Molecular Medicine, myogenesis
Abstract

Sonic hedgehog (Shh) is a morphogen regulating crucial epithelial-mesenchymal interactions during embryonic development, but its signaling pathway is considered generally silent in post-natal life. In this study, we demonstrate that Shh is de novo expressed after injury and during regeneration of the adult skeletal muscle. Shh expression is followed by significant upregulation of its receptor and target gene Ptc1 in injured and regenerating muscles. The reactivation of the Shh signaling pathway has an important regulatory role on injury-induced angiogenesis, as inhibition of Shh function results in impaired upregulation of prototypical angiogenic agents, such as vascular endothelial growth factor (VEGF) and stromal-derived factor (SDF)-1alpha, decreased muscle blood flow, and reduced capillary density after injury. In addition, Shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors Myf-5 and MyoD, decreases the upregulation of insulin-like growth factor (IGF)-1, and reduces the number of myogenic satellite cells at injured site. Finally, Shh inhibition results in muscle fibrosis, increased inflammatory reaction, and compromised motor functional recovery after injury. These data demonstrate that the Shh pathway is functionally important for adult skeletal muscle regeneration and displays pleiotropic angiogenic and myogenic potentials in post-natal life. These findings might constitute the foundation for new therapeutic approaches for muscular diseases in humans. Sonic hedgehog (Shh) is a morphogen-regulating crucial epithelial-mesenchymal interactions during embryonic development, but its signalling pathway is considered generally silent in post-natal life. In this study, we demonstrate that Shh is de novo expressed after injury and during regeneration of the adult skeletal muscle. Shh expression is followed by significant up-regulation of its receptor and target gene Ptc1 in injured and regenerating muscles. The reactivation of the Shh signalling pathway has an important regulatory role on injury-induced angiogenesis, as inhibition of Shh function results in impaired up-regulation of prototypical angiogenic agents, such as vascular endothelial growth factor (VEGF) and stromal-derived factor (SDF)-1alpha, decreased muscle blood flow and reduced capillary density after injury. In addition, Shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors Myf-5 and MyoD, decreases the up-regulation of insulin-like growth factor (IGF)-1 and reduces the number of myogenic satellite cells at injured site. Finally, Shh inhibition results in muscle fibrosis, increased inflammatory reaction and compromised motor functional recovery after injury. These data demonstrate that the Shh pathway is functionally important for adult skeletal muscle regeneration and displays pleiotropic angiogenic and myogenic potentials in post-natal life. These findings might constitute the foundation for new therapeutic approaches for muscular diseases in humans.

Published
2009

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