ABSTRACT
BC-1215, bis-pyridinyl benzyl ethanediamine, is an inhibitor of F-box only protein 3 (FBXO3) and exerts anti-inflammatory effects. BC-1215 inhibits interactions between FBXO3-F-box and the leucine rich repeat protein 2 (FBXL2), leading to the upregulation of FBXL2 expression, FBXL2-mediated ubiquitination and the degradation of tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) or NOD-, LRR- and the pyrin domain-containing protein 3 (NLRP3), which subsequently results in the down-regulation of inflammatory cytokine production. In the current study, we investigated the issue of whether or how BC-1215 suppresses the ATP-induced secretion of IL-1ß in LPS-primed human macrophage-like cells, THP-1 cells. Our result show that pre-treatment with BC-1215 attenuated the ATP-induced secretion of IL-1ß in LPS-primed THP-1 cells. Treatment of the LPS-primed THP-1 cells with BC-1215 resulted in a decrease in the level of NLRP3 and pro-IL-1ß at the protein level, but not at the mRNA level. In addition, treatment with MG-132, but not leupeptin, inhibited the BC-1215-induced degradation of NLRP3 and pro-IL-1ß proteins, and restored their levels, suggesting that BC-1215 decreases the stability of NLRP3 and pro-IL-1ß at the protein level via proteasome-dependent degradation. Our results also show that FBXL2, which is increased by BC-1215, bound to and ubiquitinated NLRP3 and pro-IL-1ß, but not pro-caspase-1. These collective results indicate that treatment with BC-1215, an inhibitor of FBXO3, inhibits ATP-induced IL-1ß secretion via the FBXL2-mediated ubiquitination and degradation of pro-IL-1ß as well as NLRP3 in LPS-primed THP-1 cells, suggesting that FBXO3 is a potential therapeutic target for developing agents against inflammatory diseases.
Subject(s)
F-Box Proteins , NLR Family, Pyrin Domain-Containing 3 Protein , Humans , Adenosine Triphosphate/metabolism , Caspase 1/metabolism , F-Box Proteins/metabolism , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Lipopolysaccharides , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , THP-1 Cells , UbiquitinationABSTRACT
Childhood emotional abuse has been linked to problematic alcohol use in later life but there is a paucity of empirically based knowledge about the developmental pathways linking emotional abuse and alcohol use in young adulthood. Using a community sample of young individuals aged 18-25 (N=268; female 52%), we performed structural equation modeling to investigate whether emotional abuse influences alcohol use through urgent personality trait and to determine pathways for these effects in a multivariate context. We also examined variations in these pathways by four different alcohol use outcomes including frequency of alcohol use, binge drinking, alcohol-related problems, and alcohol use disorders (AUD). The present study found that emotional abuse was related to urgency, which in turn influenced four types of alcohol use. Urgency may play a significant role in linking childhood maltreatment to alcohol use in young adulthood.
Subject(s)
Adult Survivors of Child Abuse/psychology , Alcohol Drinking/psychology , Alcohol-Related Disorders/psychology , Child Abuse/psychology , Emotions , Impulsive Behavior , Adolescent , Adult , Alcoholism/psychology , Binge Drinking/psychology , Child , Child of Impaired Parents/psychology , Female , Humans , Male , Prospective Studies , Stress, Psychological/etiology , Young AdultABSTRACT
BACKGROUND AND OBJECTIVES: Although the significant role of impulsive personality on substance use has been widely documented, distinct aspects of impulsivity and their relation to substance use during young adulthood have received scant attention. We sought to fill this research gap and explored impulsivity subtraits in relation to hazardous drinking and illicit substance use in young adulthood. METHODS: The present study used cross-sectional survey data collected from a community sample of 257 young adults aged 18-25 (53% female). Data were primarily analyzed by three different types of regression models. RESULTS: We found impulsivity to be more strongly associated with illicit substance use than hazardous drinking during young adulthood. Among the four impulsivity subtraits examined, lack of premeditation (p < .01) and sensation seeking (p < .05) were significantly related to illicit substance use in young adulthood. CONCLUSIONS AND SIGNIFICANCE: These findings suggest that each impulsivity subtrait might play different roles in illicit substance use during young adulthood. For young adults, assessment of differential patterns of impulsive personality in individuals with substance use problems may have important implication for treatment strategies.
Subject(s)
Impulsive Behavior/psychology , Substance-Related Disorders/psychology , Adolescent , Adult , Alcohol Drinking/psychology , Cross-Sectional Studies , Female , Humans , Impulsive Behavior/complications , Impulsive Behavior/diagnosis , Logistic Models , Male , Personality Assessment , Substance-Related Disorders/complicationsABSTRACT
Research has shown that personality traits associated with impulsivity influence alcohol use during emerging adulthood, yet relatively few studies have examined how distinct facets of impulsivity are associated with alcohol use and abuse. We examine the influence of impulsivity traits on four patterns of alcohol use including frequency of alcohol use, alcohol-related problems, binge drinking, and alcohol use disorders (AUDs) in a community sample of young individuals (N=190). In multivariate regression analyses that controlled for peer and parental alcohol use, psychological distress, and developmental correlates (i.e., college, marriage, employment) in emerging adulthood, we found that urgency and sensation seeking were consistently related to all four constructs of alcohol use. The present study suggests that distinct impulsivity traits may play different roles in escalation of alcohol use and development of AUDs during emerging adulthood.
