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1. Intraoperative positive end-expiratory pressure and postoperative pulmonary complications: a patient-level meta-analysis of three randomised clinical trials

Author

Hemmes, Sabrine NT., Gama de Abreu, Marcelo, Severgnini, Paolo, Hollmann, Markus W., Binnekade, Jan M., Wrigge, Hermann, Canet, Jaume, Hiesmayr, Michael, Schmid, Werner, Tschernko, Edda, Jaber, Samir, Hedenstierna, Göran, Putensen, Christian, Pelosi, Paolo, Schultz, Marcus J., Marti, Agnes, Bacuzzi, Alessandro, Brodhun, Alexander, Molin, Alexandre, Merten, Alfred, Parera, Ana, Brunelli, Andrea, Cortegiani, Andrea, Güldner, Andreas, Reske, Andreas W., Gratarola, Angelo, Giarratano, Antonino, Bastin, Bea, Heyse, Bjorn, Mazul-Sunko, Branka, Amantea, Bruno, Barberis, Bruno, Uhlig, Christopher, Marín, Conrado Minguez, Celentano, Cristian, La Bella, Daniela, D’Antini, David, Velghe, David, Sulemanji, Demet, De Robertis, Edoardo, Hartmann, Eric, Montalto, Francesca, Tropea, Francesco, Mills, Gary H., Cinnella, Gilda, Della Rocca, Giorgio, Caggianelli, Girolamo, Pellerano, Giulia, Mollica, Giuseppina, Bugedo, Guillermo, Mulier, Jan-Paul, Vandenbrande, Jeroen, Geib, Johann, Yaqub, Jonathan, Florez, Jorge, Mayoral, Juan F., Sprung, Juraj, Van Limmen, Jurgen, Bos, Lieuwe DJ., de Baerdemaeker, Luc, Jamaer, Luc, Spagnolo, Luigi, Strys, Lydia, Gil, Manuel Granell, Vidal Melo, Marcos F., Unzueta, Maria Carmen, Moral, Maria Victoria, Ferner, Marion, Weiss, Martin, Vanoni, Massimo, Schaefer, Maximilian S., Prieto, Mercè, Grio, Michele, Spieth, Peter Markus, Simon, Philipp, Bodger, Phoebe, Sierra, Pilar, Laufenberg-Feldmann, Rita, Rusca, Roberta, Proietti, Rodolfo, Raineri, Santi Maurizio, Caroleo, Santo, Sabaté, Sergi, De Hert, Stefan, Pezzato, Stefano, Treschan, Tanja A., Goranovic, Tatjana, Koch, Thea, Bluth, Thomas, Kiss, Thomas, Perilli, Valter, Cegarra, Virginia, Ferrando, Carlos, Belda, Javier, Soro, Marina, Unzueta, Carmen, Suarez-Sipmann, Fernando, Librero, Julián, Llombart, Alicia, Rovira, Lucas, Granell, Manuel, Aldecoa, César, Diaz-Cambronero, Oscar, Balust, Jaume, Garutti, Ignacio, Gonzalez, Rafael, Gallego, Lucia, Garcia del Valle, Santiago, Redondo, Javier, Pestaña, David, Rodríguez, Aurelio, García, Javier, Matta, Manuel de la, Ibáñez, Maite, Barrios, Francisco, Hernández, Samuel, Torres, Vicente, Peiró, Salvador, Pozo, Natividad, Villena, Abigail, Carramiñana, Albert, Gallego-Casilda, Alberto, Duca, Alejandro, Alcón, Amalia, Miñana, Amanda, Asensio, Ana, Colás, Ana, Galve, Ana Isabel, Izquierdo, Ana, Jurado, Ana, Pérez, Ana María, Mugarra, Ana, Gutierrez, Andrea, De Miguel, Ángeles, Lozano, Angels, Katime, Antonio, Romero, Antonio, Garrigues, Beatriz, Ayas, Begoña, Arocas, Blanca, Delgado, Carlos, Fernández, Carmen, Romero, Carolina, Gallego, Clara, Garcés, Cristina, Lisbona, Cristina, Parrilla, Cristina, López-Herrera, Daniel, González, Domingo, Llamazares, Eduardo, Del Rio, Elena, Lozano, Elena, Pastor, Ernesto, Chamorro, Estefanía, Gracia, Estefanía, Sánchez, Ester, Romero, Esther, Díez, Fernando, Serralta, Ferran, Daviu, Francisco, Sandín, Francisco, Aguilar, Gerardo, Tusman, Gerardo, Azparren, Gonzalo, Martínez-Pallí, Graciela, Mazzinari, Guido, Benítez, Inmaculada, Hernandéz, Inmaculada, India, Inmaculada, León, Irene, Fuentes, Isabel, Ruiz, Isabel, Puig, Jaume, Román, Javie Ignacio, Acosta, Jesús, Rico-Feijoo, Jesús, Olmedo, Jonathan, Carbonell, Jose A., Alonso, Jose M., Pérez, Jose María, Marcos, Jose Miguel, Navarro, Jose, Valdivia, Jose, Carrizo, Juan, Piqueras, Laura, Soriano, Laura, Vaquero, Laura, Miguel, Lisset, Muñoz, Lorena, Valencia, Lucia, Olmedilla, Luis, Etulain, Mᵃ Justina, Tisner, Manuel, Barrio, María, Alonso, María Dolores, García, María, Hernández, María J., Alberola, María José, Parra, María, Argente, María Pilar, Vila, María, De Fez, Mario, Agilaga, Marta, Gine, Marta, Ayuso, Mercedes, García, Mercedes, Bejarano, Natalia, Peña, Natalia, Ojeda, Nazario, Martínez, Nilda, García, Nuria, Padrón, Oto, García, Pablo, Valls, Paola, Cruz, Patricia, Piñeiro, Patricia, Charco, Pedro, Anaya, Rafael, López, Ramiro, Rodríguez, Rayco, Martínez, Rocío, Pujol, Roger, Dosdá, Rosa, Lardies, Rosa, Díaz, Ruben, Villazala, Rubén, Zapatero, Sara, Cabrera, Sergio, Sánchez, Sergio, Martin, Silvia, Diaz, Suzana, Franco, Tania, Moreno, Tania, Socorro, Tania, Gilabert, Vicente, Balandrón, Victor, Moral, Victoria, Cegarra, Virgina, Varón, Viviana, Abelha, Fernando, Abitağaoğlu, Sühayla, Achilles, Marc, Adebesin, Afeez, Adriaensens, Ine, Ahene, Charles, Akbar, Fatima, Al Harbi, Mohammed, Al Khoury al Kallab, Rita, Albanel, Xavier, Aldenkortt, Florence, Saleh Alfouzan, Rawan Abdullah, Alruqaie, Reef, Altermatt, Fernando, Luís de Castro Araujo, Bruno, Arbesú, Genaro, Artsi, Hanna, Aurilio, Caterina, Ayanoglu, Omer Hilmi, Baig, Harris, Baird, Yolanda, Balonov, Konstantin, Banks, Samantha, Bao, Xiaodong, Baumgartner, Mélanie, Tortosa, Isabel Belda, Bergamaschi, Alice, Bergmann, Lars, Bigatello, Luca, Pérez, Elena Biosca, Birr, Katja, Bojaxhi, Elird, Bonenti, Chiara, Bonney, Iwona, Bos, Elke M.E., Bowman, Sara, Braz, Leandro Gobbo, Brugnoni, Elisa, Brull, Sorin J., Brunetti, Iole, Bruni, Andrea, Buenvenida, Shonie L., Busch, Cornelius Johannes, Camerini, Giovanni, Capatti, Beatrice, Carmona, Javiera, Carungcong, Jaime, Carvalho, Marta, Cattan, Anat, Cavaleiro, Carla, Chiumello, Davide, Ciardo, Stefano, Coburn, Mark, Colella, Umberto, Contreras, Victor, Dincer, Pelin Corman, Cotter, Elizabeth, Crovetto, Marcia, Darrah, William, Davies, Simon, Del Cojo Peces, Enrique, Delphin, Ellise, Diaper, John, Junior, Paulo do Nascimento, Donatiello, Valerio, Dong, Jing, Dourado, Maria do Socorro, Dullenkopf, Alexander, Ebner, Felix, Elgendy, Hamed, Ellenberger, Christoph, Arı, Dilek Erdoğan, Ermert, Thomas, Farah, Fadi, Fernandez-Bustamante, Ana, Ferreira, Cristina, Fiore, Marco, Fonte, Ana, Palahí, Christina Fortià, Galimberti, Andrea, Garofano, Najia, Giaccari, Luca Gregorio, Gilsanz, Fernando, Girrbach, Felix, Gobbi, Luca, Godfried, Marc Bernard, Goettel, Nicolai, Goldstein, Peter A., Goren, Or, Gorlin, Andrew, Graterol, Juan, Guyon, Pierre, Haire, Kevin, Harou, Philippe, Helf, Antonia, Hemmes, Sabrine N.T., Hempel, Gunther, Hernández Cádiz, María José, Heyse, Björn, Huercio, Ivan, Ilievska, Jasmina, Jakus, Lien, Jeganath, Vijay, Jelting, Yvonne, Jung, Minoa, Kabon, Barbara, Kacha, Aalok, Ilić, Maja Karaman, Karuppiah, Arunthevaraja, Kavas, Ayse Duygu, Barcelos, Gleicy Keli, Kellogg, Todd A., Kemper, Johann, Kerbrat, Romain, Khodr, Suraya, Kienbaum, Peter, Kir, Bunyamin, Kivrak, Selin, Klarić, Vlasta, Köksal, Ceren, Kowark, Ana, Kranke, Peter, Kuvaki, Bahar, Kuzmanovska, Biljana, Laffey, John, Lange, Mirko, Freitas de Lemos, Marília, Licker, Marc-Joseph, López-Baamonde, Manuel, López-Hernández, Antonio, Lopez-Martinez, Mercedes, Luise, Stéphane, MacGregor, Mark, Magalhães, Danielle, Maillard, Julien, Malerbi, Patrizia, Manimekalai, Natesan, Margarson, Michael, Markstaller, Klaus, Martin, Archer K., Martin, David P., Martin, Yvette N., Martínez-Ocon, Julia, Martin-Loeches, Ignacio, Maseda, Emilio, Matot, Idit, McAuliffe, Niamh, McKenzie, Travis J., Medina, Paulina, Meersch, Melanie, Menzen, Angelika, Mertens, Els, Meurer, Bernd, Meyer-Treschan, Tanja, Miao, Changhong, Micalizzi, Camilla, Milić, Morena, Pinheiro Módolo, Norma Sueli, Moine, Pierre, Mölders, Patrick, Montero-Feijoo, Ana, Moret, Enrique, Muller, Markus K., Murphy, Zoe, Nalwaya, Pramod, Naumovski, Filip, Navalesi, Paolo, Navarro e Lima, Lais Helena, Adam, Višnja Nesek, Neumann, Claudia, Newell, Christopher, Nisnevitch, Zoulfira, Nizamuddin, Junaid, Novazzi, Cecilia, O'Connor, Michael, Oprea, Günther, Sungur, Mukadder Orhan, Özbilgin, Şule, Pace, Maria Caterina, Pacheco, Marcos, Packianathaswamy, Balaji, Gonzalez, Estefania Palma, Papaspyros, Fotios, Paredes, Sebastián, Passavanti, Maria Beatrice, Pedemonte, Juan Cristobal, Peremin, Sanja, Philipsenburg, Christoph, Pinho, Daniela, Pinho, Silvia, Posthuma, Linda M., Pota, Vincenzo, Preckel, Benedikt, Priani, Paolo, Rached, Mohamed Aymen, Radoeshki, Aleksandar, Ragazzi, Riccardo, Rajamanickam, Tamilselvan, Rajamohan, Arthi, Ramakrishna, Harish, Rangarajan, Desikan, Reiterer, Christian, Renew, J. Ross, Reynaud, Thomas, Rhys, Rhidian, Rivas, Eva, Robitzky, Luisa, Rossaint, Rolf, Rubulotta, Francesca, Machado, Humberto S., Nunes, Catarina S., Sabbatini, Giovanni, Samuels, Jon D., Sanahuja, Josep Martí, Sansone, Pasquale, Santos, Alice, Sayedalahl, Mohamed, Scharffenberg, Martin, Schiffer, Eduardo, Schliewe, Nadja, Schorer, Raoul, Schumann, Roman, Selmo, Gabriele, Sendra, Mar, Senturk, Mert, Shaw, Kate, Shosholcheva, Mirjana, Sibai, Abdulrazak, Simonassi, Francesca, Sinno, Claudia, Sivrikoz, Nukhet, Skandalou, Vasiliki, Smith, Neil, Soares, Maria, Artiles, Tania Socorro, Castro, Diogo Sousa, Sousa, Miguel, Spadaro, Savino, Stamatakis, Emmanouil, Steiner, Luzius A., Stevenazzi, Andrea, Suarez-de-la-Rica, Alejandro, Suppan, Mélanie, Teichmann, Robert, Tena Guerrero, José Maria, Thiel, Bram, Tolós, Raquel, Altun, Gulbin Tore, Tucci, Michelle, Turnbull, Zachary A., Turudić, Žana, Unterberg, Matthias, Van Nieuwenhove, Yves, Van Waesberghe, Julia, Vidal Melo, Marcos Francisco, Vitković, Bibiana, Vivona, Luigi, Vizcaychipi, Marcela, Volta, Carlo Alberto, Weber, Anne, Weingarten, Toby N., Wittenstein, Jakob, Wyffels, Piet, Yagüe, Julio, Yates, David, Yavru, Ayşen, Zac, Lilach, Zhong, Jing, Campos, Niklas S., Librero, Julian, Ball, Lorenzo, and Serpa Neto, A.

Published
2022
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2. Ventilation and outcomes following robotic-assisted abdominal surgery: an international, multicentre observational study

Author

Queiroz, Veronica N.F., da Costa, Luis Guilherme V., Takaoka, Flavio, Pelosi, Paolo, de Abreu, Marcelo Gama, Schultz, Marcus J., Serpa Neto, Ary, Barbosa, R.P., Canet, J., Cata, J.P., Cesar, D.S., Chaves, R.C.F., D’Orto, U.C., Da Costa, L.G.V., De Baerdemaeker, L., Galdi, J.R., Gama de Abreu, M., Gottumukkala, V., Hemmes, S.N.T., Hollmann, M.W., Kalmar, A.F., Mariano, R., Matot, I., Mazzinari, G., Mills, G.H., Pelosi, P., Posso, I.P., Queiroz, V.N.F., Schultz, M.J., Serpa Neto, A., Sprung, J., Takaoka, F., Teruya, A., Vidal Melo, M.F., Agarwala, Aalok V., Akeroyd, Louise, Andorlini, Francesco, Anicetti, Lisa, Antonelli, Massimo, Arantes, Bruno S., Ariño Irujo, Jose J., Artsi, Hanna, Babian, Renata, Barbosa, Rogerio P., Barker, Doug, Basagni, Diletta, Basso, Nicola, Beltran, Joan, Bocciero, Vittorio, Bonatti, Giulia, Boriati, Ernesto, Bravo, Mauro, Brazzi, Luca, Brearton, Chris, Brennan, Andrew, Bulinski, Adam M., Cafagna, Sara, Cardoni, Andrea, Castelló Mora, Paula, Cata, Juan P., Cesar, Daniel S., Chaves, Renato CF., Chen, Lee-Lynn, Chukkambotla, Srikanth, Ciccozzi, Alessandra, Cilia, Danae, Cope, Sean, D’Orto, Ulisses C., Da Costa, Luis Guilherme V., Dalton, Claire, Davi, Alessandra, De Bonis, Marina del Barrio, De Gaudio, Angelo Raffaele, De Luca, Lucilla, Delgado, Carlos C., Deljou, Atousa, Di Ruscio, Cecilia, Droger, Sijgje M., Duberley, Stephen, Eidelman, Leonid A., Evans, Alison, Fabiani, Constanza, Fasciano, Umberto, Firth-Gieben, Jennifer, Fitchett, Jillian, Fundarò, Angela, Galdi, Jose Roberto, Gallo, Verdiana, Gavagni, Mattia, Gottumukkala, Vijaya, Graham, Chris, Granell Gil, Manuel, Gratarola, Angelo, Grillandini, Chiara, Groeben, Harald-Thomas, Ismail, Nesrine, Jacob, Reni, Jones, Chris, Jones, Rebecca, Kalmar, Alain F., Kapoor, Ritoo, Kelliher, Leigh, Köhne, Wiebke, Koopman, Joseph SHA., Lanka, Prasad, Lee, Jae-Woo, Liban, Bernard, Livi, Francesca, Mariano, Renato, Martinez Plumed, Ruth, Matot, Idit, Mazzella, Marta, McClure, Stewart, McMonagle, Martina, Mills, Gary H., Mirabella, Lucia, Monsalve, Concepción, Moon, Angela, Morchio, Laura, Morris, Frances, Motroni, Lorenzo, Mura, Benedetta, Nerini, Alessandro, Noumedem Sonna, Elodia C., Oakes, Neil, Orlandi, Marina, Paladini, Antonella, Patil, Anita, Patil, Vishal, Patrone, Valentina, Pinder, Angela, Piroli, Alba, Posso, Irimar P., Queiroz, Veronica NF., Rabbu, Yosef S., Rabenalt, Robert, Romagnoli, Stefano, Ronen, Ariel, Rothman, Felipe, Rusagara, Patrick, Russo, Andrea, Sabov, Moldovan, Saitta, Thomas, Shah, Nirav, Smith, Neil, Sollazzi, Liliana, Sprung, Juraj, Stewart, Emma, Stones, Elizabeth, Storton, Kim, Tena, Beatriz, Terreni, Eleonora, Teruya, Alexandre, Travaglia, Chiara, Treschan, Tanja A., Vanoverschelde, Henk, Venkatesh, Harish, Vidal Melo, Marcos F., Villa, Gianluca, Vossen, Robbert, Webber, Stephen, Weingarten, Toby N., Willcocks, Matt, Winslow, Luke, and Woods, Lindsey

Published
2021
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6. SUN-033 RNA-Seq Analysis of Ovariectomy-Induced Changes in Mouse Liver Reveals New Targets for Menopause-Associated Metabolic Derangement

Author

Rivka Dresner-Pollak, Joshua Stokar, Artsi Hanna, Einav Cohen-Kfir, Elishai Assayag, Oran Yakubovsky, and Irina Gurt

Subjects
Menopause, Metabolic derangement, Text mining, How Genetics and Development Impact the Endocrine System, business.industry, Endocrinology, Diabetes and Metabolism, medicine, RNA-Seq, Biology, medicine.disease, Bioinformatics, business, Genetics and Development (including Gene Regulation)
Abstract

Menopause is associated with significant adverse metabolic changes and an increased cardiovascular risk profile. Though well described, the underlying molecular mechanisms for these changes remain unclear. The liver is both mediator and target of metabolic derangement. In this study we used an unbiased RNA-sequencing approach to discover differently expressed genes in the oophorectomized mouse liver as well as response to treatment with 17-β-estradiol (E2). 5 groups of 9-week-old C57BL/6J female mice (10 per group) were subjected to ovariectomy (OVX) or sham operation and left untreated for 6 weeks to allow for development of metabolic changes. At this point 2 groups were sacrificed and tissues harvested. The rest of the mice were treated with E2 or vehicle for 6 weeks and then sacrificed. RNA-sequencing was performed on liver samples 6 weeks post surgery. Differential gene expression was assessed using DESeq2 and changes in gene sets using Gene set enrichment analyses (GSEA). Quantitative Real Time PCR was used to validate select differently expressed genes, as well as to assess changes with E2 treatment at 12 weeks post surgery. We found a total of 103 genes (35 up and 68 downregulated) to be differently expressed (fold change ≥ 2, adjusted P ≤ 0.05, max count ≥ 30) between OVX and SHAM at 6 weeks post surgery. GSEA showed significant upregulation (FDR < 0.01) in gene sets for: fatty acid metabolism (normalized enrichment score = 5.13), oxidative phosphorylation (3.91), myc targets (3.81), peroxisome (2.94), adipogenesis (2.82), androgen response (2.56), UV response up (2.49) and TNF-α signaling via NF-Kβ (2.17). Significant downregulated gene sets were: mitotic spindle (-2.88) and G2M checkpoint (-2.4). Specific differently expressed genes, known to be related to metabolic pathways, were validated using real-time PCR and analyzed at 6- and 12-weeks post-surgery with or without E2 treatment. Surprisingly, ENHO, encodes for Adropin, a secreted peptide and known regulator of fat metabolism, associated with cardiovascular health, was found to be significantly decreased at 6 weeks (fold change -2.1, adjusted p = 7.2e-9) and 12 weeks after OVX (-1.42, p=0.008), though it wasn’t changed following treatment with E2. Importantly, reduced ENHO expression was found in cardiomyocytes 12 weeks post-surgery (relative mRNA expression for OVX vs SHAM = 0.44, P=0.03). Our results show that ovariectomy induces transcriptional changes in liver expression of gene sets related to metabolism and inflammation. The role of ENHO encoding for adropin as a biomarker and therapeutic target in menopause-associated metabolic derangement remains to be investigated.

Published
2019

7. Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men.

Author

Artsi, Hanna, Gurt, Irina, El-Haj, Madi, Müller, Ralph, Kuhn, Gisela A., Ben Shalom, Gal, Cohen-Kfir, Einav, Abramowitz, Eva, Kandel, Leonid, Safran, Ori, and Dresner-Pollak, Rivka

Subjects
SIRTUINS, ADIPOSE tissues, BONE marrow, MESENCHYMAL stem cells, GENE expression, SCLEROSTIN, OBESITY
Abstract

Bone marrow adipose tissue (MAT) is influenced by nutritional cues, and participates in whole body energy metabolism. To investigate the role of Sirtuin1 (Sirt1), a key player in metabolism, in MAT, marrow adiposity was evaluated in inbred 5-month-old 129/Sv Sirt1 haplo-insufficient (Sirt1 Δ/+) and wild type (WT) mice. Decreased expression of the thermogenic genes: Prdm16, Pgc1 α , Foxc2, Dio2 , and β 3AR was detected in whole tibiae derived from Sirt1 Δ/+ compared to WT female mice. Similarly, decreased expression of Prdm16 and Pgc1 α was observed in primary bone marrow mesenchymal stem cell (BM-MSC) cultures obtained from Sirt1 Δ/+ compared to WT female mice, suggesting a cell autonomous effect of Sirt1 in BM-MSCs. In vitro , Sirt1 over-expression in the mesenchymal embryonic fibroblast stem cell line C3HT101/2 increased Pgc1α and Prdm16 protein level. Similarly, pharmacologic activation of Sirt1 by SRT3025 increased Foxc2, Pgc1 α , Dio2, Tfam , and Cyc1 expression while inhibition of Sirt1 by EX527 down-regulated UCP1 in C3HT101/2 cells. Importantly, in human femoral BM-MSCs obtained from female patients undergoing hip operations for fracture or osteoarthritis, Sirt1 activation by SRT3025 increased PGC1 α mRNA and protein level. Blocking sclerostin, an inhibitor of the WNT pathway and a Sirt1 target, by the monoclonal humanized antibody (Sc-AbII), stimulated β 3AR, PRDM16 , and UCP1 gene expression, and increased PGC1α protein level. These results show that Sirt1 stimulates a thermogenic gene program in marrow adipocytes in mice and humans via PGC1α activation and sclerostin inhibition. The implications of these findings to bone health, hematopoiesis and whole body energy metabolism remain to be investigated. [ABSTRACT FROM AUTHOR]

Published
2019
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8. The Sirt1 Activators SRT2183 and SRT3025 Inhibit RANKL-Induced Osteoclastogenesis in Bone Marrow-Derived Macrophages and Down-Regulate Sirt3 in Sirt1 Null Cells.

Author

Gurt, Irina, Artsi, Hanna, Cohen-Kfir, Einav, Hamdani, Gilad, Ben-Shalom, Gal, Feinstein, Ben, El-Haj, Madi, and Dresner-Pollak, Rivka

Subjects
*SIRTUINS, *TRANCE protein, *OSTEOCLASTOGENESIS, *BONE marrow, *ANTIBODY-dependent cell cytotoxicity, *BONE resorption, *PROTEIN kinase inhibitors
Abstract

Increased osteoclast-mediated bone resorption is characteristic of osteoporosis, malignant bone disease and inflammatory arthritis. Targeted deletion of Sirtuin1 (Sirt1), a key player in aging and metabolism, in osteoclasts results in increased osteoclast-mediated bone resorption in vivo, making it a potential novel therapeutic target to block bone resorption. Sirt1 activating compounds (STACs) were generated and were investigated in animal disease models and in humans however their mechanism of action was a source of controversy. We studied the effect of SRT2183 and SRT3025 on osteoclastogenesis in bone-marrow derived macrophages (BMMs) in vitro, and discovered that these STACs inhibit RANKL-induced osteoclast differentiation, fusion and resorptive capacity without affecting osteoclast survival. SRT2183 and SRT3025 activated AMPK, increased Sirt1 expression and decreased RelA/p65 lysine310 acetylation, critical for NF-κB activation, and an established Sirt1 target. However, inhibition of osteoclastogenesis by these STACs was also observed in BMMs derived from sirt1 knock out (sirt1-/-) mice lacking the Sirt1 protein, in which neither AMPK nor RelA/p65 lysine 310 acetylation was affected, confirming that these effects require Sirt1, but suggesting that Sirt1 is not essential for inhibition of osteoclastogenesis by these STACs under these conditions. In sirt1 null osteoclasts treated with SRT2183 or SRT3025 Sirt3 was found to be down-regulated. Our findings suggest that SRT2183 and SRT3025 activate Sirt1 and inhibit RANKL-induced osteoclastogenesis in vitro however under conditions of Sirt1 deficiency can affect Sirt3. As aging is associated with reduced Sirt1 level and activity, the influence of STACs on Sirt3 needs to be investigated in vivo in animal and human disease models of aging and osteoporosis. [ABSTRACT FROM AUTHOR]

Published
2015
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9. SIRT1 haplo-insufficiency results in reduced cortical bone thickness, increased porosity and decreased estrogen receptor alpha in bone in adult 129/Sv female mice.

Author

Artsi H, Cohen-Kfir E, Shahar R, Kalish-Achrai N, Lishinsky N, and Dresner-Pollak R

Subjects
Animals, Female, Male, Mice, Mice, Inbred C57BL, Porosity, Cortical Bone metabolism, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Sirtuin 1 genetics, Osteoporosis genetics, Osteoporosis metabolism
Abstract

Introduction: Sirtuin 1 (SIRT1) is a key player in aging and metabolism and regulates bone mass and architecture. Sexual dimorphism in skeletal effects of SIRT1 has been reported, with an unfavorable phenotype primarily in female mice., Methods: To investigate the mechanisms of gender differences in SIRT1 skeletal effect, we investigated femoral and vertebral cortical and cancellous bone in global Sirt1 haplo-insufficient 129/Sv mice aged 2,7,12 months lacking Sirt1 exons 5,6,7 ( Sirt1 +/Δ ) and their wild type (WT) counterparts., Results: In females, femoral bone mineral content, peak cortical thickness, and trabecular bone volume (BV/TV%), number and thickness were significantly lower in Sirt1 +/Δ compared to WT mice. Increased femoral cortical porosity was observed in 7-month-old Sirt1 +/Δ compared to WT female mice, accompanied by reduced biomechanical strength. No difference in vertebral indices was detected between Sirt1 +/Δ and WT female mice. SIRT1 decreased with aging in WT female mice and was lower in vertebrae and femur in 18- and 30- versus 3-month-old 129/Sv and C57BL/6J female mice, respectively. Decreased bone estrogen receptor alpha (ERα) was observed in Sirt1 +/Δ compared to WT female mice and was significantly higher in Sirt1 over-expressing C3HT101/2 murine mesenchymal stem cells. In males no difference in femoral indices was detected in Sirt1 +/Δ versus WT mice, however vertebral BV/TV%, trabecular number and thickness were higher in Sirt1 +/Δ vs. WT mice. No difference in androgen receptor (AR) was detected in bone in Sirt1 +/Δ vs. WT male mice. Bone SIRT1 was significantly lower in male compared to female WT mice, suggesting that SIRT1 maybe more significant in female than male skeleton., Discussion: These findings demonstrate that 50% reduction in SIRT1 is sufficient to induce the hallmarks of skeletal aging namely, decreased cortical thickness and increased porosity in female mice, highlighting the role of SIRT1 as a regulator of cortical bone quantity and quality. The effects of SIRT1 in cortical bone are likely mediated in part by its regulation of ERα. The age-associated decline in bone SIRT1 positions SIRT1 as a potential therapeutic target to ameliorate age-related cortical bone deterioration in females. The crosstalk between ERα, AR and SIRT1 in the bone microenvironment remains to be further investigated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Artsi, Cohen-Kfir, Shahar, Kalish-Achrai, Lishinsky and Dresner-Pollak.)

Published
2022
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