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2. Wagner e l'opera dell'avvenire

Author

Targa, M, Brighenti, M, Diodato, Roberto, Roberto Diodato (ORCID:0000-0002-4100-3676), Targa, M, Brighenti, M, Diodato, Roberto, and Roberto Diodato (ORCID:0000-0002-4100-3676)

Abstract

origini filosofiche del dramma wagneriano

Published
2019

3. Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study

Author

Pett, SL, Amin, J, Horban, A, Andrade-Villanueva, J, Losso, M, Porteiro, N, Madero, JS, Belloso, W, Tu, E, Silk, D, Kelleher, A, Harrigan, R, Clark, A, Sugiura, W, Wolff, M, Gill, J, Gatell, J, Clarke, A, Ruxrungtham, K, Prazuck, T, Kaiser, R, Woolley, I, Alberto Arnaiz, J, Cooper, D, Rockstroh, JK, Mallon, P, Emery, S, Fisher, M, Rockstroh, J, Stellbrink, J, Merlin, K, Yeung, J, Fsadni, B, Marks, K, Suzuki, K, Rismanto, N, Salomon, H, Rubio, AE, Chibo, D, Birch, C, Swenson, L, Chan, D, Berg, T, Obermeier, M, Schuelter, E, Aragon, SS, Luebke, N, Coughlan, S, Dean, J, Iwatani, Y, Teran, GR, Avila, S, Sirivichayakul, S, Naphassanant, M, Ubolyam, S, Kaye, S, Land, S, Walker, S, Haubrich, R, DeJesus, E, Berthon-Jones, N, Espinosa, N, Courtney-Vega, K, Absar, N, Haskelberg, H, Robson, R, Donaldson, A, Guelman, D, Gambardella, L, Valdovinos, M, Arnaiz, J, Beleta, H, Ramos, N, Targa, M, Späth, B, Boesecke, C, Engelhardt, A, Perry, N, Beckthold, B, Drummond, F, Lefevre, E, Corr, S, Grant, C, Lupo, S, Peroni, L, Sanchez, M, De Paz Sierra, M, Viloria, G, Parlante, A, Bissio, E, Luchetti, P, Confalonieri, V, Warley, E, Vieni, I, Vilas, C, Zarate, A, Mayer, G, Elliot, J, Hagenauer, M, Kelley, M, Pett, SL, Amin, J, Horban, A, Andrade-Villanueva, J, Losso, M, Porteiro, N, Madero, JS, Belloso, W, Tu, E, Silk, D, Kelleher, A, Harrigan, R, Clark, A, Sugiura, W, Wolff, M, Gill, J, Gatell, J, Clarke, A, Ruxrungtham, K, Prazuck, T, Kaiser, R, Woolley, I, Alberto Arnaiz, J, Cooper, D, Rockstroh, JK, Mallon, P, Emery, S, Fisher, M, Rockstroh, J, Stellbrink, J, Merlin, K, Yeung, J, Fsadni, B, Marks, K, Suzuki, K, Rismanto, N, Salomon, H, Rubio, AE, Chibo, D, Birch, C, Swenson, L, Chan, D, Berg, T, Obermeier, M, Schuelter, E, Aragon, SS, Luebke, N, Coughlan, S, Dean, J, Iwatani, Y, Teran, GR, Avila, S, Sirivichayakul, S, Naphassanant, M, Ubolyam, S, Kaye, S, Land, S, Walker, S, Haubrich, R, DeJesus, E, Berthon-Jones, N, Espinosa, N, Courtney-Vega, K, Absar, N, Haskelberg, H, Robson, R, Donaldson, A, Guelman, D, Gambardella, L, Valdovinos, M, Arnaiz, J, Beleta, H, Ramos, N, Targa, M, Späth, B, Boesecke, C, Engelhardt, A, Perry, N, Beckthold, B, Drummond, F, Lefevre, E, Corr, S, Grant, C, Lupo, S, Peroni, L, Sanchez, M, De Paz Sierra, M, Viloria, G, Parlante, A, Bissio, E, Luchetti, P, Confalonieri, V, Warley, E, Vieni, I, Vilas, C, Zarate, A, Mayer, G, Elliot, J, Hagenauer, M, and Kelley, M

Abstract

Objectives: The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. Methods: MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < −12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. Results: Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. Conclusions: MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.

Published
2018

4. Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study.

Author

Beckthold B., Kaye S., Land S., Walker S., Haubrich R., DeJesus E., Berthon-Jones N., Espinosa N., Courtney-Vega K., Absar N., Haskelberg H., Robson R., Donaldson A., Guelman D., Tabrett C., Warzywoda E., MacRae K., Sinclair B., Sinn K., Bloch M., Franic T., Vincent T., Stewart N., Jayewardene A., Dwyer D., Kok J., Assam D., Taylor J., King P., Orth D., Youds D., Sowden D., Johnston C., Murray S., Hehir J., Wadham S., Donohue W., Thompson J., Garsia R., Turnham G., Madden T., Nvene J., Gillies A., Bryant M., Walmsley S., Chan W., LeBlanc R., Lanteigne F., Mouawad R., Rahal I., Guber S., Ozturk S., Smith G., Halpenny R., Reko T., Hills J.R., Allendes G., Hocqueloux F.L., Stephan C., Ebeling F., Spath B., Jensen B.-E.O., Feind C., Meyer-Olson D., Stoll M., Hoeper K., Beider R., Faetkenheur G., Thomas E., Baumgarten A., Ingiliz P., Wienbreyer A., Behrendt D., Nienkarken T., Jessen H., Zedlack C., Simelane S., Assmann J., Ghavami-Kia B., Imahashi M., Tanabe K., Yokomaku Y., Imamura J., de Oca M.M., Gonzalez L., Ponce D., Mendoza A., Sierra-Madero J., Hernandez J.E.S., Ballesteros E.J.R., del Moral Ponce S., Ignatowska A., Bakowska E., Pulik P., Sanz-Moreno J., Paredes R., Puig J., Domingo P., Gutierrez M., Gonzalez-Cordon A., Callau P., Aldeguer J.L., Tovar S.C., Noval M.L., Rivas I., Delgado-Fernandez M., Arribas J.R., Castro J.M., Avihingsanon A., Maek-a-nantawat W., Intasan J., Charoenporn W., Cuprasitrut T., Jaisomkom P., Pruksakaew K., Winston A., Mullaney S., Barbour L., Richardson C., Fox J., Murray T., Teague A., Leen C., Morris S., Satyajit D., Sandhu R., Tucker J., Pett S., Amin J., Horban A., Andrade-Villanueva J., Losso M., Porteiro N., Madero J.S., Belloso W., Tu E., Silk D., Kelleher A., Harrigan R., Clark A., Sugiura W., Wolff M.J., Gill J., Gatell J., Clarke A., Ruxrungtham K., Prazuck T., Kaiser R., Woolley I., Alberto Arnaiz J., Cooper D., Rockstroh J.K., Mallon P., Emery S., Fisher M., Rockstroh J., Stellbrink J., Merlin K., Yeung J., Fsadni B., Marks K., Suzuki K., Rismanto N., Salomon H., Rubio A.E., Chibo D., Birch C., Swenson L., Chan D., Berg T., Obermeier M., Schuelter E., Aragon S.S., Luebke N., Coughlan S., Dean J., Iwatani Y., Teran G.R., Avila S., Sirivichayakul S., Naphassanant M., Ubolyam S., Gambardella L., Valdovinos M., Arnaiz J., Beleta H., Ramos N., Targa M., Boesecke C., Engelhardt A., Perry N., Drummond F., Lefevre E., Corr S., Grant C., Lupo S., Peroni L., Sanchez M., De Paz Sierra M., Viloria G., Parlante A., Bissio E., Luchetti P., Confalonieri V., Warley E., Vieni I., Vilas C., Zarate A., Mayer G., Elliot J., Hagenauer M., Kelley M., Rowling D., Gibson A., Latch N., Beckthold B., Kaye S., Land S., Walker S., Haubrich R., DeJesus E., Berthon-Jones N., Espinosa N., Courtney-Vega K., Absar N., Haskelberg H., Robson R., Donaldson A., Guelman D., Tabrett C., Warzywoda E., MacRae K., Sinclair B., Sinn K., Bloch M., Franic T., Vincent T., Stewart N., Jayewardene A., Dwyer D., Kok J., Assam D., Taylor J., King P., Orth D., Youds D., Sowden D., Johnston C., Murray S., Hehir J., Wadham S., Donohue W., Thompson J., Garsia R., Turnham G., Madden T., Nvene J., Gillies A., Bryant M., Walmsley S., Chan W., LeBlanc R., Lanteigne F., Mouawad R., Rahal I., Guber S., Ozturk S., Smith G., Halpenny R., Reko T., Hills J.R., Allendes G., Hocqueloux F.L., Stephan C., Ebeling F., Spath B., Jensen B.-E.O., Feind C., Meyer-Olson D., Stoll M., Hoeper K., Beider R., Faetkenheur G., Thomas E., Baumgarten A., Ingiliz P., Wienbreyer A., Behrendt D., Nienkarken T., Jessen H., Zedlack C., Simelane S., Assmann J., Ghavami-Kia B., Imahashi M., Tanabe K., Yokomaku Y., Imamura J., de Oca M.M., Gonzalez L., Ponce D., Mendoza A., Sierra-Madero J., Hernandez J.E.S., Ballesteros E.J.R., del Moral Ponce S., Ignatowska A., Bakowska E., Pulik P., Sanz-Moreno J., Paredes R., Puig J., Domingo P., Gutierrez M., Gonzalez-Cordon A., Callau P., Aldeguer J.L., Tovar S.C., Noval M.L., Rivas I., Delgado-Fernandez M., Arribas J.R., Castro J.M., Avihingsanon A., Maek-a-nantawat W., Intasan J., Charoenporn W., Cuprasitrut T., Jaisomkom P., Pruksakaew K., Winston A., Mullaney S., Barbour L., Richardson C., Fox J., Murray T., Teague A., Leen C., Morris S., Satyajit D., Sandhu R., Tucker J., Pett S., Amin J., Horban A., Andrade-Villanueva J., Losso M., Porteiro N., Madero J.S., Belloso W., Tu E., Silk D., Kelleher A., Harrigan R., Clark A., Sugiura W., Wolff M.J., Gill J., Gatell J., Clarke A., Ruxrungtham K., Prazuck T., Kaiser R., Woolley I., Alberto Arnaiz J., Cooper D., Rockstroh J.K., Mallon P., Emery S., Fisher M., Rockstroh J., Stellbrink J., Merlin K., Yeung J., Fsadni B., Marks K., Suzuki K., Rismanto N., Salomon H., Rubio A.E., Chibo D., Birch C., Swenson L., Chan D., Berg T., Obermeier M., Schuelter E., Aragon S.S., Luebke N., Coughlan S., Dean J., Iwatani Y., Teran G.R., Avila S., Sirivichayakul S., Naphassanant M., Ubolyam S., Gambardella L., Valdovinos M., Arnaiz J., Beleta H., Ramos N., Targa M., Boesecke C., Engelhardt A., Perry N., Drummond F., Lefevre E., Corr S., Grant C., Lupo S., Peroni L., Sanchez M., De Paz Sierra M., Viloria G., Parlante A., Bissio E., Luchetti P., Confalonieri V., Warley E., Vieni I., Vilas C., Zarate A., Mayer G., Elliot J., Hagenauer M., Kelley M., Rowling D., Gibson A., and Latch N.

Abstract

Objectives: The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. Method(s): MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. Result(s): Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. Conclusion(s): MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.Copyright © 2017 British H

Published
2017

5. Detention dams in hydrographic basin with the use of synthetic triangular hydrograms and volume curves [Barragens de detenção em bacia hidrográfica com o uso de curvas cota-volume e hidrogramas triangulares sintéticos]

Author

Filho P.J.M., dos Santos Targa M., Santos P.S., and Neto N.M.

Subjects
Environmental sciences, Outflow, Basin
Abstract

Made available in DSpace on 2019-09-12T16:26:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2016 This study aimed to apply a flood control proposal, through the use of dams to the runoff of detention for the area of influence of the Itaim stream in Taubaté, Brazil. The basin was divided from upstream to downstream into 4 sections that defined this way, sub-basins A, B, C and D. To calculate the maximum inflow of water into the pond we adopted the maximum rainfall with 100 years of time and return time equal to the concentration time using the PAI-I-Wu method to obtain the C2 volume flow coefficient using the curve number method. To verify the level of flooding, a synthetic triangular hydrograph methodology and the quota-volume curve were observed. Flow coefficients (C) obtained by the method of curve number of values of 0.24 showed; 0.18; 0.24; 0.32 and 0.34, respectively, for the Itaim basin and sub basins A, B, C and D. These values are lower than those recommended by DAEE SP. Flood areas and levels were assigned and the result showed that the bridge over the Itaim stream would be flooded from the leaf 0.5 meters of a maximum precipitation of 100 years. On the other hand, in the construction of dams (A, B, C and D) at the edge of the sub-basins, flows would be contained, and the bridge on the highway would have a difference of about 1.80 meters above the D of water. These results reflect the buffer capacity of the flood of buses, because the flows diminish with the adoption of these practices. © 2016, Institute for Environmental Research in Hydrographic Basins (IPABHi). All rights reserved. Filho, P.J.M., Universidade de Taubaté (UNITAU), Taubaté, SP, Brazil dos Santos Targa, M., Universidade de Taubaté (UNITAU), Taubaté, SP, Brazil Santos, P.S., Universidade de Taubaté (UNITAU), Taubaté, SP, Brazil Neto, N.M., Universidade de Taubaté (UNITAU), Taubaté, SP, Brazil

Published
2016

9. A3 Receptors Are Overexpressed in Pleura from Patients with Mesothelioma and Reduce Cell Growth via Akt/Nuclear Factor-{kappa}B Pathway.

Author

Varani K, Maniero S, Vincenzi F, Targa M, Stefanelli A, Maniscalco P, Martini F, Tognon M, and Borea PA

Abstract

Rationale: A strong link has been established between exposure to asbestos and increased risk for pleural malignant mesothelioma (MM). Adenosine plays a key role in inflammatory processes and cancer, where it is involved in the regulation of cell death and proliferation. Objectives: The primary aim of this study was to investigate the presence of adenosine receptors (ARs) in human MM pleura (MMP) and healthy mesothelial pleura (HMP). To shed some light on the interaction between adenosine and MM, the presence and functionality of ARs were explored in human healthy mesothelial cells (HMC) and in malignant mesothelioma cells (MMC). Methods: ARs were analyzed by using reverse transcriptase-polymerase chain reaction, Western blotting, and saturation binding assays. HMC were treated with crocidolite asbestos, which is the principal risk factor for MM. The role of A(3)ARs on these cellular models, evaluating cAMP production, Akt phosphorylation, and nuclear factor (NF)-[kappa]B activation, was investigated. The dual effect of A(3)AR stimulation on healthy and cancer cell growth was studied by means of proliferation, apoptosis, and cytotoxicity assays. Measurements and Main Results: A(3)AR was up-regulated by 2.5-fold (P < 0.01) in MMP when compared with HMP. Stimulation of A(3)ARs decreased proliferation and exerted a cytotoxic and proapoptotic effect on MMC and on HMC exposed to asbestos and tumor necrosis factor-[alpha], but not on HMC with an involvement of the deregulation of Akt/NF-[kappa]B cell survival pathway. Conclusions: These new findings suggest that A(3)AR could represent a pharmacological target to prevent tumor development after asbestos exposure and to treat full-blown MM. [ABSTRACT FROM AUTHOR]

Published
2011
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11. Pulsed electromagnetic fields increased the anti-inflammatory effect of A₂A and A₃ adenosine receptors in human T/C-28a2 chondrocytes and hFOB 1.19 osteoblasts.

Author

Vincenzi F, Targa M, Corciulo C, Gessi S, Merighi S, Setti S, Cadossi R, Goldring MB, Borea PA, and Varani K

Subjects
Adenosine A2 Receptor Agonists pharmacology, Adenosine A3 Receptor Agonists pharmacology, Cell Line, Cell Proliferation, Chondrocytes drug effects, Cyclic AMP biosynthesis, Enzyme Activation drug effects, Gene Expression, Humans, NF-kappa B metabolism, Osteoblasts drug effects, Protein Binding, RNA, Messenger genetics, RNA, Messenger metabolism, Receptor, Adenosine A2A genetics, Receptor, Adenosine A3 genetics, Receptors, Purinergic P1 genetics, Receptors, Purinergic P1 metabolism, Chondrocytes metabolism, Electromagnetic Fields, Inflammation metabolism, Osteoblasts metabolism, Receptor, Adenosine A2A metabolism, Receptor, Adenosine A3 metabolism
Abstract

Adenosine receptors (ARs) have an important role in the regulation of inflammation and their activation is involved in the inhibition of pro-inflammatory cytokine release. The effects of pulsed electromagnetic fields (PEMFs) on inflammation have been reported and we have demonstrated that PEMFs increased A2A and A3AR density and functionality in different cell lines. Chondrocytes and osteoblasts are two key cell types in the skeletal system that play important role in cartilage and bone metabolism representing an interesting target to study the effect of PEMFs. The primary aim of the present study was to evaluate if PEMF exposure potentiated the anti-inflammatory effect of A2A and/or A3ARs in T/C-28a2 chondrocytes and hFOB 1.19 osteoblasts. Immunofluorescence, mRNA analysis and saturation binding assays revealed that PEMF exposure up-regulated A2A and A3AR expression. A2A and A3ARs were able to modulate cAMP production and cell proliferation. The activation of A2A and A3ARs resulted in the decrease of some of the most relevant pro-inflammatory cytokine release such as interleukin (IL)-6 and IL-8, following the treatment with IL-1β as an inflammatory stimuli. In human chondrocyte and osteoblast cell lines, the inhibitory effect of A2A and A3AR stimulation on the release of prostaglandin E2 (PGE2), an important lipid inflammatory mediator, was observed. In addition, in T/C-28a2 cells, the activation of A2A or A3ARs elicited an inhibition of vascular endothelial growth factor (VEGF) secretion. In hFOB 1.19 osteoblasts, PEMF exposure determined an increase of osteoprotegerin (OPG) production. The effect of the A2A or A3AR agonists in the examined cells was enhanced in the presence of PEMFs and completely blocked by using well-known selective antagonists. These results demonstrated that PEMF exposure significantly increase the anti-inflammatory effect of A2A or A3ARs suggesting their potential therapeutic use in the therapy of inflammatory bone and joint disorders.

Published
2013
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12. A(2A) adenosine receptors are differentially modulated by pharmacological treatments in rheumatoid arthritis patients and their stimulation ameliorates adjuvant-induced arthritis in rats.

Author

Vincenzi F, Padovan M, Targa M, Corciulo C, Giacuzzo S, Merighi S, Gessi S, Govoni M, Borea PA, and Varani K

Subjects
Adenosine administration & dosage, Animals, Anti-Inflammatory Agents administration & dosage, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antirheumatic Agents administration & dosage, Arthritis, Experimental metabolism, Arthritis, Rheumatoid physiopathology, Disease Models, Animal, Humans, Inflammation drug therapy, Longitudinal Studies, Lymphocytes metabolism, Male, Methotrexate administration & dosage, Rats, Receptors, Purinergic P1 metabolism, Rituximab, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Up-Regulation, Adenosine analogs & derivatives, Arthritis, Experimental drug therapy, Arthritis, Rheumatoid drug therapy, Phenethylamines administration & dosage, Purinergic P1 Receptor Agonists administration & dosage
Abstract

A(2A) adenosine receptors (ARs) play a key role in the inhibition of the inflammatory process. The purpose of this study was to evaluate the modulation of A(2A)ARs in rheumatoid arthritis (RA) patients after different pharmacological treatments and to investigate the effect of A(2A)AR stimulation in a rat model of arthritis. We investigated A(2A)AR density and functionality in RA progression by using a longitudinal study in RA patients before and after methotrexate (MTX), anti-TNFα agents or rituximab treatments. A(2A)ARs were analyzed by saturation binding assays in lymphocytes from RA patients throughout the 24-month study timeframe. In an adjuvant-induced arthritis model in rats we showed the efficacy of the A(2A)AR agonist, CGS 21680 in comparison with standard therapies by means of paw volume assessment, radiographic and ultrasonographic imaging. Arthritic-associated pain was investigated in mechanical allodynia and thermal hyperalgesia tests. IL-10 release following A(2A)AR stimulation in lymphocytes from RA patients and in serum from arthritic rats was measured. In lymphocytes obtained from RA patients, the A(2A)AR up-regulation was gradually reduced in function of the treatment time and the stimulation of these receptors mediated a significant increase of IL-10 production. In the same cells, CGS 21680 did not affected cell viability and did not produced cytotoxic effects. The A(2A)AR agonist CGS 21680 was highly effective, as suggested by the marked reduction of clinical signs, in rat adjuvant-induced arthritis and associated pain. This study highlighted that A(2A)AR agonists represent a physiological-like therapeutic alternative for RA treatment as suggested by the anti-inflammatory role of A(2A)ARs in lymphocytes from RA patients. The effectiveness of A(2A)AR stimulation in a rat model of arthritis supported the role of A(2A)AR agonists as potential pharmacological treatment for RA.

Published
2013
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13. The anti-tumor effect of A3 adenosine receptors is potentiated by pulsed electromagnetic fields in cultured neural cancer cells.

Author

Vincenzi F, Targa M, Corciulo C, Gessi S, Merighi S, Setti S, Cadossi R, Borea PA, and Varani K

Subjects
Animals, Apoptosis genetics, Brain Neoplasms metabolism, Caspase 3 genetics, Caspase 3 metabolism, Cell Line, Tumor, Humans, NF-kappa B genetics, NF-kappa B metabolism, PC12 Cells, Rats, Receptor, Adenosine A2A genetics, Receptor, Adenosine A2A metabolism, Receptor, Adenosine A3 metabolism, Tumor Cells, Cultured, Up-Regulation, Brain Neoplasms genetics, Electromagnetic Fields, Neurons metabolism, Receptor, Adenosine A3 genetics
Abstract

A(3) adenosine receptors (ARs) play a pivotal role in the development of cancer and their activation is involved in the inhibition of tumor growth. The effects of pulsed electromagnetic fields (PEMFs) on cancer have been controversially discussed and the detailed mechanisms are not yet fully understood. In the past we have demonstrated that PEMFs increased A(2A) and A(3)AR density and functionality in human neutrophils, human and bovine synoviocytes, and bovine chondrocytes. In the same cells, PEMF exposure increased the anti-inflammatory effect mediated by A(2A) and/or A(3)ARs. The primary aim of the present study was to evaluate if PEMF exposure potentiated the anti-tumor effect of A(3)ARs in PC12 rat adrenal pheochromocytoma and U87MG human glioblastoma cell lines in comparison with rat cortical neurons. Saturation binding assays and mRNA analysis revealed that PEMF exposure up-regulated A(2A) and A(3)ARs that are well coupled to adenylate cyclase activity and cAMP production. The activation of A(2A) and A(3)ARs resulted in the decrease of nuclear factor-kappa B (NF-kB) levels in tumor cells, whilst only A(3)ARs are involved in the increase of p53 expression. A(3)AR stimulation mediated an inhibition of tumor cell proliferation evaluated by thymidine incorporation. An increase of cytotoxicity by lactate dehydrogenase (LDH) release and apoptosis by caspase-3 activation in PC12 and U87MG cells, but not in cortical neurons, was observed following A(3)AR activation. The effect of the A(3)AR agonist in tumor cells was enhanced in the presence of PEMFs and blocked by using a well-known selective antagonist. Together these results demonstrated that PEMF exposure significantly increases the anti-tumor effect modulated by A(3)ARs.

Published
2012
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14. A₃ receptors are overexpressed in pleura from patients with mesothelioma and reduce cell growth via Akt/nuclear factor-κB pathway.

Author

Varani K, Maniero S, Vincenzi F, Targa M, Stefanelli A, Maniscalco P, Martini F, Tognon M, and Borea PA

Subjects
Adult, Apoptosis, Asbestos, Crocidolite, Blotting, Western, Cell Proliferation, Cells, Cultured, Female, Humans, Male, Middle Aged, Pleura metabolism, Pleura pathology, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, Mesothelioma metabolism, Mesothelioma pathology, NF-kappa B metabolism, Pleural Neoplasms metabolism, Pleural Neoplasms pathology, Proto-Oncogene Proteins c-akt metabolism, Receptor, Adenosine A3 metabolism
Abstract

Rationale: A strong link has been established between exposure to asbestos and increased risk for pleural malignant mesothelioma (MM). Adenosine plays a key role in inflammatory processes and cancer, where it is involved in the regulation of cell death and proliferation., Objectives: The primary aim of this study was to investigate the presence of adenosine receptors (ARs) in human MM pleura (MMP) and healthy mesothelial pleura (HMP). To shed some light on the interaction between adenosine and MM, the presence and functionality of ARs were explored in human healthy mesothelial cells (HMC) and in malignant mesothelioma cells (MMC)., Methods: ARs were analyzed by using reverse transcriptase-polymerase chain reaction, Western blotting, and saturation binding assays. HMC were treated with crocidolite asbestos, which is the principal risk factor for MM. The role of A₃ ARs on these cellular models, evaluating cAMP production, Akt phosphorylation, and nuclear factor (NF)-κB activation, was investigated. The dual effect of A₃AR stimulation on healthy and cancer cell growth was studied by means of proliferation, apoptosis, and cytotoxicity assays., Measurements and Main Results: A₃AR was up-regulated by 2.5-fold (P < 0.01) in MMP when compared with HMP. Stimulation of A₃ARs decreased proliferation and exerted a cytotoxic and proapoptotic effect on MMC and on HMC exposed to asbestos and tumor necrosis factor-α, but not on HMC with an involvement of the deregulation of Akt/NF-κB cell survival pathway., Conclusions: These new findings suggest that A₃AR could represent a pharmacological target to prevent tumor development after asbestos exposure and to treat full-blown MM.

Published
2011
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15. A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release.

Author

Varani K, Padovan M, Vincenzi F, Targa M, Trotta F, Govoni M, and Borea PA

Subjects
Adenosine analogs & derivatives, Adenosine pharmacology, Adenosine A2 Receptor Agonists pharmacology, Aged, Arthritis, Rheumatoid metabolism, Arthritis, Rheumatoid pathology, Blotting, Western, Cells, Cultured, Cytokines metabolism, Female, Humans, Inflammation Mediators metabolism, Linear Models, Lymphocytes drug effects, Lymphocytes metabolism, Male, Metalloproteases metabolism, Middle Aged, NF-kappa B metabolism, Phenethylamines pharmacology, Radioligand Assay, Receptor, Adenosine A2A metabolism, Receptor, Adenosine A3 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Severity of Illness Index, Signal Transduction drug effects, Up-Regulation, Arthritis, Rheumatoid genetics, Gene Expression, Receptor, Adenosine A2A genetics, Receptor, Adenosine A3 genetics
Abstract

Introduction: The reduction of the inflammatory status represents one of the most important targets in rheumatoid arthritis (RA). A central role of A2A and A3 adenosine receptors (ARs) in mechanisms of inflammation has been reported in different pathologies. The primary aim of this study was to investigate the A2A and A3ARs and their involvement in RA progression measured by Disease Activity Score in 28 or 44 joints (DAS28 or DAS)., Methods: ARs were analyzed by saturation binding assays, mRNA and Western blotting analysis in lymphocytes from early and established RA patients. The effect of A2A and A3AR agonists in nuclear factor kB (NF-kB) pathway was evaluated. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) release was carried out by A2A and A3AR activation. AR pharmacological regulation in matrix metalloproteinase-1 (MMP-1) and metalloproteinase-3 (MMP-3) release was also studied., Results: In lymphocytes obtained from RA patients, A2A and A3ARs were up-regulated if compared with healthy controls. A2A and A3AR activation inhibited the NF-kB pathway and diminished inflammatory cytokines such as TNF-α, IL-1β and IL-6. A2A and A3AR agonists mediated a reduction of MMP-1 and MMP-3 release. A2A and A3AR density inversely correlated with DAS28 and DAS suggesting a direct role of the endogenous activation of these receptors in the control of RA joint inflammation., Conclusions: Taken together these data demonstrate that the inflammatory and clinical responses in RA are regulated by A2A and A3ARs and support the use of A2A and/or A3AR agonists as novel and effective pharmacological treatment in RA patients.

Published
2011
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