White, Thomas A
Mayo Clinic
Mayo Clinic Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
Citations 2
Senotherapeutic drug treatment ameliorates chemotherapy-induced cachexia
Englund, Davis A. , Jolliffe, Alyssa M. , Hanson, Gabriel J., Aversa, Zaira, Zhang, Xu , White, Thomas A. , Zhang, Lei , Monroe, David G. , Niedernhofer, Laura J. , Jiang, Xinyi, Monroe, David G , Niedernhofer, Laura J , White, Thomas A , Zhang, Xu , Zhang, Lei , Englund, Davis A. , Jiang, Xinyi , Robbins, Paul D. , Kamenecka, Theodore M. , Khosla, Sundeep , LeBrasseur, Nathan K.
JCI Insight | December 5, 2023 | Volume: 9 | Issue: 2 | Pages: No page available
Cachexia is a debilitating skeletal muscle wasting condition for which we currently lack effective treatments. In the context of cancer, certain chemotherapeutics cause DNA damage and cellular senescence. Senescent cells exhibit chronic activation of the transcription factor NF-κB, a known mediator of the proinflammatory senescence-associated secretory phenotype (SASP) and skeletal muscle atrophy. Thus, targeting NF-κB represents a logical therapeutic strategy to alleviate unintended consequences of genotoxic drugs. Herein, we show that treatment with the IKK/NF-κB inhibitor SR12343 during a course of chemotherapy reduces markers of cellular senescence and the SASP in liver, skeletal muscle, and circulation and, correspondingly, attenuates features of skeletal muscle pathology. Lastly, we demonstrate that SR12343 mitigates chemotherapy-induced reductions in body weight, lean mass, fat mass, and muscle strength. These findings support senescent cells as a promising druggable target to counteract the SASP and skeletal muscle wasting in the context of chemotherapy.
A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis
Cal, Karina, Leyva, Alejandro , Rodriguez-Duarte, Jorge, Ruiz, Santiago , Santos, Leonardo, Colella, Lucía, Ingold, Mariana , Vilaseca, Cecilia, Galliussi, Germán , Handy, Rachel, Reis, Larissa Menezes dos , Espasandín, Camila , Dapueto, Rosina , Thompson, Katie, Agorrody, Guillermo , DeVallance, Evan , Meadows, Ethan , Barbosa, Gabriele Santana, Souza, Leonardo Osbourne Lai de , Chichierchio, Marina Santos , Valez, Valeria , Aicardo, Adrián , Jakobsen, Steen, Kamaid, Andrés , Porcal, Williams , Calliari, Aldo , Wang, Yekai, Hollander, John M. , White, Thomas A. , Radí, Rafael , O’Doherty, Robert M. , Holloway, Graham P. , Kelley, Eric, Chini, Eduardo N. , Peclat, Thais R , Dos Reis, Larissa Menezes , Thompson, Katie L., Chichierchio, Marina Santos , Aicardo, Adrián , Contreras, Paola , White, Thomas A , Quijano, Celia , Moraes-Vieira, Pedro , Mori, Marcelo A , Lopez, Gloria V , Batthyány, Carlos , Chini, Eduardo Nunes , Escande, Carlos , Rodriguez‐Duarte, Jorge , Ziegler, Lucía , Peclat, Thais , Bresque, Mariana , Handy, Rachel, King, Rachel, Breining, Peter , Lopez, Andres, Lewis, Sara E. , Vendelbo, Mikkel Holm , Verdes, José Manuel , Du, Jianhai , Moyna, Guillermo , Leonardi, Roberta , Camacho-Pereira, Juliana , Durán, Rosario
No container title available | July 12, 2023 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.