RESUMO
N6-methyladenosine (m6A) messenger RNA methylation is the most widespread gene regulatory mechanism affecting liver functions and disorders. However, the relationship between m6A methylation and arsenic-induced hepatic insulin resistance (IR), which is a critical initiating event in arsenic-induced metabolic syndromes such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), remains unclear. Here, we showed that arsenic treatment facilitated methyltransferase-like 14 (METTL14)-mediated m6A methylation, and that METTL14 interference reversed arsenic-impaired hepatic insulin sensitivity. We previously showed that arsenic-induced NOD-like receptor protein 3 (NLRP3) inflammasome activation contributed to hepatic IR. However, the regulatory mechanisms underlying the role of arsenic toward the post-transcriptional modification of NLRP3 remain unclear. Here, we showed that NLRP3 mRNA stability was enhanced by METTL14-mediated m6A methylation during arsenic-induced hepatic IR. Furthermore, we demonstrated that arsenite methyltransferase (AS3MT), an essential enzyme in arsenic metabolic processes, interacted with NLRP3 to activate the inflammasome, thereby contributing to arsenic-induced hepatic IR. Also, AS3MT strengthened the m6A methylase association with NLRP3 to stabilize m6A-modified NLRP3. In summary, we showed that AS3MT-induced m6A modification critically regulated NLRP3 inflammasome activation during arsenic-induced hepatic IR, and we identified a novel post-transcriptional function of AS3MT in promoting arsenicosis.
Assuntos
Arsênio , Resistência à Insulina , Humanos , Arsênio/toxicidade , Arsênio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inflamassomos/metabolismo , Fígado , Metiltransferases/genética , Metiltransferases/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismoRESUMO
Prolonged exposure to arsenic can cause nonalcoholic steatohepatitis (NASH). The NOD-like receptor protein 3 (NLRP3) inflammasome plays an essential role in the process of NASH. However, the mechanism by which arsenic promotes NLRP3 expression remains unclear. Three-month NaAsO2 gavage led to the nuclear factor-κB (NF-κB) signaling pathway activation and NASH. Additionally, NaAsO2 upregulated the level of Filamin A (FLNA) and pyroptosis, thereby activating the NLRP3 inflammasome in SD rat liver. Using FLNA siRNA, NASH-associated inflammation and pyroptosis were clearly mitigated by reducing activation of the NLRP3 inflammasome. Furthermore, arsenic treatment facilitated activation of the NF-κB signaling pathway and promoted p-p65 translocation into the nucleus. Chromatin immunoprecipitation (Ch-IP) assay indicated that FLNA promoted p65 binding to the NLRP3 gene and upregulated the transcription of NLRP3, ultimately leading to pyroptosis and NASH. Our findings indicate that FLNA and pyroptosis are strongly associated with NASH induced by NaAsO2. Collectively, the findings of this study indicated that FLNA mediates NF-κB signaling pathway-induced activation of the NLRP3 inflammasome and ultimately activates pyroptosis and NASH upon NaAsO2 exposure. This information may be useful for improving therapeutic strategies against arsenic-induced NASH.
Assuntos
Arsênio , Hepatopatia Gordurosa não Alcoólica , Ratos , Animais , Inflamassomos/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , NF-kappa B/metabolismo , Proteínas NLR , Filaminas , Ratos Sprague-DawleyRESUMO
A criminal act can be regarded as an irrational decision-making process. Therefore, understanding differences in the criminal decision-making process would shed light on criminal behavior. We utilized dual processing theory to propose that offenders' differences in decision-making may cause them to adopt non-adaptive behaviors, such as high reference point setting, abnormal reward-punishment sensitivity, delayed discounting rate, and decision-making style. Our study compares differences in these indicators between offenders (n = 518) and non-offenders (n = 636) in a diverse sample of Chinese adults. The results showed that compared with non-offenders, offenders had higher relative deprivation, reward sensitivity, and delayed discounting rates but lower punishment sensitivity and vigilance in decision-making. A logistic regression analysis also shows that the above factors were significant predictive indicators for the commission of crimes.
RESUMO
This study aimed to examine the impact of childhood maltreatment on callous-unemotional (CU) traits among incarcerated male adolescents, focusing primarily on the roles of parental attachment and emotional intelligence. A total of 454 male incarcerated adolescents from two juvenile correctional facilities, ranging in age from 14 to 18 years, completed a set of questionnaires consisting of a childhood trauma questionnaire, parent-attachment scale, emotional intelligence scale, and the Inventory of CU traits. The results revealed that childhood maltreatment, parental attachment, and emotional intelligence were all correlated with CU traits. Structural equation modeling analysis and the bootstrap test indicated that parental attachment and emotional intelligence mediated, in part, the effect of childhood maltreatment on CU traits. These findings expand the outcomes of previous research and shed light on how childhood maltreatment is related to CU traits.
Assuntos
Experiências Adversas da Infância , Maus-Tratos Infantis , Adolescente , Masculino , Humanos , Criança , Pais , Análise de Classes LatentesRESUMO
Hepatic insulin resistance (IR) is the primary pathology of type 2 diabetes (T2D). The role of the NOD-like receptor protein 3 (NLRP3) inflammasome in arsenic-induced hepatic IR has been previously demonstrated. However, the mechanism of the arsenic-induced activation of the NLRP3 inflammasome is still unclear. Here, we demonstrate that NaAsO2 downregulated the mRNA and protein level of Annexin A1 (AnxA1), an anti-inflammatory factor, in rat livers and L-02 cells. Moreover, AnxA1 overexpression significantly alleviated arsenic-induced NLRP3 inflammasome activation and IR in L-02 cells. Importantly, Co-immunoprecipitation (Co-IP) results showed that AnxA1 1-190 peptide could bind to the domain encompassing amino acids 1-210 and 211-550 of NLRP3. In conclusion, our experiments demonstrated that arsenic exposure could activate the NLRP3 inflammasome and IR by inhibiting the AnxA1 activity. These findings suggest that AnxA1 may be a promising therapeutic target of arsenicosis.
Assuntos
Anexina A1 , Arsênio , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Animais , Ratos , Anexina A1/genética , Anexina A1/metabolismo , Arsênio/toxicidade , Arsênio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inflamassomos/metabolismo , Fígado/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismoRESUMO
As an environmental toxicant, arsenic exposure may cause insulin resistance (IR). Previous studies have shown that pyroptosis plays an important role in the occurrence and development of IR. Although gasdermin D (GSDMD) functions as an executor of pyroptosis, the relationship between GSDMD-mediated pyroptosis and hepatic IR remains unclear. Here, we observed that sodium arsenite (NaAsO2) activated NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasomes, promoted GSDMD activation, induced pyroptosis and hepatic IR, while GSDMD knockdown attenuated pyroptosis and hepatic IR caused by NaAsO2. However, GSDMD interference did not affect NLRP3 activation. Ubiquitination modification is widely involved in protein regulation and intracellular signal transduction, and whether it regulates GSDMD and affects its degradation, and exerts effects on arsenic-induced pyroptosis remain unclear. We observed that NaAsO2 reduced the K48- and K63-linked ubiquitination of GSDMD, thereby inhibiting its degradation through the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP), causing GSDMD to accumulate and lyse into GSDMD-N, which promoted pyroptosis. In summary, we demonstrated that GSDMD participated in arsenic-induced hepatic IR. Moreover, NaAsO2 reduced GSDMD ubiquitination and decreased its intracellular degradation, aggravating pyroptosis and hepatic IR. We have revealed the molecular mechanism underpinning arsenic-induced IR, and we provide potential solutions for the prevention and treatment of type 2 diabetes (T2D).
Assuntos
Arsenitos/toxicidade , Resistência à Insulina , Fígado/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Piroptose/efeitos dos fármacos , Compostos de Sódio/toxicidade , Animais , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Ligação a Fosfato/genética , Proteínas Citotóxicas Formadoras de Poros/genética , Ratos , Ratos Sprague-Dawley , Ubiquitinação/efeitos dos fármacosRESUMO
The activation of hepatic stellate cells (HSCs) is a key event during the progression of liver fibrosis (LF). We have previously indicated that NLRP3 inflammasome plays a crucial role in arsenic-induced HSCs activation. However, the mechanism of cascade responses between NLRP3 inflammasome and HSCs activation is unclear. Here, we showed that the transcription and protein level of Hsp47 was upregulated after 4 µM arsenic treatment, both in vivo and in vitro. Additionally, arsenic-induced HSCs activation was remarkably alleviated by the interference of Hsp47. Furthermore, blockage of NLRP3 significantly mitigated the activation of the NLRP3 inflammasome and decreased the expression of Hsp47, thereby attenuating the arsenic-induced HSCs activation. However, the ablation of Hsp47 did not affect the activation of the NLRP3 inflammasome. Notably, the protein-protein interaction between NLRP3 and Hsp47 was observed both in vivo and in vitro, and the target amino acid sequences were further identified. In summary, the present study indicated that NaAsO2 induced HSCs activation via the NLRP3 inflammasome-Hsp47 pathway. These findings provide direct evidence that Hsp47 may be a potential therapeutic target for arsenic-induced LF.
Assuntos
Arsênio , Inflamassomos , Arsênio/metabolismo , Arsênio/toxicidade , Proteínas de Choque Térmico HSP47 , Células Estreladas do Fígado/metabolismo , Humanos , Inflamassomos/metabolismo , Cirrose Hepática/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
Occupational self-efficacy, which refers to the belief that one is competent to fulfill work-related tasks or activities, has attracted increasing attention in recent years. The six-item version of the Occupational Self-Efficacy Scale (OSS-6) is an excellent tool for evaluating occupational self-efficacy; however, there is currently no report of the reliability and validity of the OSS-6 among Chinese people. This study aimed to translate the OSS-6 into Chinese and evaluate its reliability and validity in a sample of Chinese employees. A total of 433 junior staff at several firms completed the Chinese version of the OSS-6, the General Self-Efficacy Scale, the Rosenberg Self-Esteem Scale, the Minnesota Job Satisfaction Questionnaire, the in-role performance scale, and the career calling scale. Four weeks later, 94 participants were recalled and were retested using the OSS-6. Factor analysis results supported the one-factor model of the OSS-6. Excellent internal consistency was obtained with the OSS-6. Additionally, the OSS-6 results were significantly correlated with general self-efficacy, self-esteem, job satisfaction, in-role performance, and career calling. Furthermore, occupational self-efficacy was found to partially mediate the effects of career calling on job satisfaction and in-role performance. The results of this study supported the cross-cultural consistency of the structure of the OSS-6 and showed that the Chinese version of the OSS-6 demonstrated excellent validity and reliability. Therefore, the Chinese version of the OSS-6 can be used as an assessment tool for evaluating occupational self-efficacy in future studies.