RESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. While the role of NSAIDs as cyclooxygenase (COX) inhibitors is well established, other targets may contribute to anti-inflammation. Here we report caspases as a new pharmacological target for NSAID family drugs such as ibuprofen, naproxen, and ketorolac at physiologic concentrations both in vitro and in vivo. We characterize caspase activity in both in vitro and in cell culture, and combine computational modeling and biophysical analysis to determine the mechanism of action. We observe that inhibition of caspase catalysis reduces cell death and the generation of pro-inflammatory cytokines. Further, NSAID inhibition of caspases is COX independent, representing a new anti-inflammatory mechanism. This finding expands upon existing NSAID anti-inflammatory behaviors, with implications for patient safety and next-generation drug design.
Assuntos
Anti-Inflamatórios não Esteroides/química , Inibidores de Caspase/química , Caspases/metabolismo , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Caspase/metabolismo , Inibidores de Caspase/farmacologia , Caspases/química , Caspases Iniciadoras/química , Caspases Iniciadoras/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Ibuprofeno/química , Ibuprofeno/metabolismo , Ibuprofeno/farmacologia , Concentração Inibidora 50 , Cetorolaco/química , Cetorolaco/metabolismo , Cetorolaco/farmacologia , Naproxeno/química , Naproxeno/metabolismo , Naproxeno/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Especificidade por SubstratoRESUMO
PURPOSE: The purpose of this study was to explore the association between specific forms of childhood abuse and neglect with lifetime suicide attempts in women with bulimia nervosa (BN). METHODS: Two hundred and four women aged 18-65 (mean 25.6 years, SD 9.13) with full or subclinical BN were recruited in five US Midwestern communities and specialized eating disorder clinics. Participants completed questionnaires including the Childhood Trauma Questionnaire (CTQ) and self-reported whether they had ever had a lifetime suicide attempt. Logistic regression analyses were used to predict lifetime suicide attempts from each subscale of the CTQ. RESULTS: Childhood emotional, physical, and sexual abuse were significantly associated with the presence of a lifetime suicide attempt in women with BN. Childhood emotional and physical neglect were not associated with suicide attempts. CONCLUSIONS: Individuals with BN who have experienced childhood emotional and sexual abuse are at increased risk of a lifetime suicide attempt. Future research is needed to understand the mechanism to address in treatment and prevention efforts. It is important for clinicians to be aware of the potential increased risk of suicide in individuals with BN with a history of childhood abuse.
