RESUMEN
This research investigated the relationships between school climates and bullying behaviors in Chinese adolescents, and tested the mediating effect of prosocial tendency according to the seesaw effect. School climates were operationalized using three constructs: subjective diversity of student development goals, teacher support, and peer trust. Bullying behaviors included traditional (i.e., physical, nonphysical, and relational) and cyber bullying behaviors. We recruited 538 adolescents from three schools in Beijing, China (286 girls, 252 boys; average age = 12.47) and asked them to fill out the surveys measuring school climates and prosocial tendency at the outset and to report school bullying behaviors three months later. The results showed that subjective diversity of student development goals and peer trust were directly associated with less cyber bullying behavior. Moreover, teacher support and peer trust were indirectly associated with less traditional bullying behaviors via prosocial tendency. Our findings extend the existing literature on the relationships between school climates and bullying behaviors by incorporating different types of bullying behaviors, concentrating on Chinese adolescents from a cultural viewpoint, and tapping into the underlying mechanism via revealing prosocial tendency as a mediator. Theoretical and empirical contributions of this study, as well as practical implications are discussed.
Asunto(s)
Conducta del Adolescente , Acoso Escolar , Grupo Paritario , Instituciones Académicas , Humanos , Femenino , Masculino , Adolescente , Acoso Escolar/estadística & datos numéricos , China , Niño , Estudiantes/psicología , Conducta Social , Confianza/psicología , Ciberacoso/estadística & datos numéricos , Ciberacoso/psicología , Pueblos del Este de AsiaRESUMEN
Colorectal cancer (CRC) is trending to be a major health problem throughout the world. Therapeutics with dual modes of action have shown latent capacity to create ideal anti-tumor activity. Signal transducer and activator of transcription 3 (STAT3) has been proved to be a potential target for the development of anti-colon cancer drug. In addition, modulation of tumor redox homeostasis through deploying exogenous reactive oxygen species (ROS)-enhancing agents has been widely applied as anti-tumor strategy. Thus, simultaneously targeting STAT3 and modulation ROS balance would offer a fresh avenue to combat CRC. In this work, we designed and synthesized a novel series of isoxazole-fused quinones, which were evaluated for their preliminary anti-proliferative activity against HCT116 cells. Among these quinones, compound 41 exerted excellent in vitro anti-tumor effect against HCT116 cell line with an IC50 value of 10.18 ± 0.4 nM. Compound 41 was proved to bind to STAT3 by using Bio-Layer Interferometry (BLI) assay, and can significantly inhibit phosphorylation of STAT3. It also elevated ROS of HCT116 cells by acting as a substrate of NQO1. Mitochondrial dysfunction, apoptosis, and cell cycle arrest, which was caused by compound 41, might be partially due to the inhibition of STAT3 phosphorylation and ROS production induced by 41. Moreover, it exhibited ideal anti-tumor activity in human colorectal cancer xenograft model and good safety profiles in vivo. Overall, this study provided a novel quinone derivative 41 with excellent anti-tumor activity by inhibiting STAT3 and elevating ROS level, and gave insights into designing novel anti-tumor therapeutics by simultaneously modulation of STAT3 and ROS.
Asunto(s)
Antineoplásicos , Apoptosis , Proliferación Celular , Neoplasias Colorrectales , Ensayos de Selección de Medicamentos Antitumorales , Isoxazoles , Quinonas , Especies Reactivas de Oxígeno , Factor de Transcripción STAT3 , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Animales , Isoxazoles/farmacología , Isoxazoles/química , Isoxazoles/síntesis química , Quinonas/farmacología , Quinonas/química , Quinonas/síntesis química , Apoptosis/efectos de los fármacos , Estructura Molecular , Ratones , Relación Dosis-Respuesta a Droga , Células HCT116 , Ratones Desnudos , Ratones Endogámicos BALB CRESUMEN
Fe-based Prussian blue (Fe-PB) analogues have emerged as promising cathode materials for sodium-ion batteries, owing to their cost-effectiveness, high theoretical capacity, and environmental friendliness. However, their practical application is hindered by [Fe(CN)6] defects, negatively impacting capacity and cycle stability. This work reports a hollow layered Fe-PB composite material using 1,3,5-benzenetricarboxylic acid (BTA) as a chelating and etching agent by the hydrothermal method. Compared to benzoic acid, our approach significantly reduces defects and enhances the yield of Fe-PB. Notably, the hollow layered structure shortens the diffusion path of sodium ions, enhances the activity of low-spin Fe in the Fe-PB lattice, and mitigates volume changes during Na-ion insertion/extraction into/from Fe-PB. As a sodium-ion battery cathode, this hollow layered Fe-PB exhibits an impressive initial capacity of 95.9 mAh g-1 at a high current density of 1 A g-1. Even after 500 cycles, it still maintains a considerable discharge capacity of 73.1 mAh g-1, showing a significantly lower capacity decay rate (0.048%) compared to the control sample (0.089%). Moreover, the full cell with BTA-PB-1.6 as the cathode and HC as the anode provides a considerable energy density of 312.2 Wh kg-1 at a power density of 291.0 W kg-1. This research not only enhances the Na storage performance of Fe-PB but also increases the yield of products obtained by hydrothermal methods, providing some technical reference for the production of PB materials using the low-yield hydrothermal method.
RESUMEN
This study investigates the bidirectional associations between gender egalitarianism and prosocial behavior in adolescents, and the moderating effect of gender in the associations, as well as gender differences and longitudinal changes in both. We recruited 543 Chinese adolescents (284 girls, 259 boys; mean age at Time 1 = 11.27 years) and collected three waves of data measuring gender egalitarianism and prosocial behavior at one-year intervals. According to the results, girls expressed greater gender egalitarianism than boys did; girls reported more prosocial behavior than boys in the sixth grade, but there were no significant gender differences in the seventh and eighth grades. Adolescents' gender egalitarianism stayed stable from the sixth to the seventh grade then increased from the seventh to the eighth grade, and there was a decrease in prosocial behavior from the sixth to the seventh grade. More importantly, the results of the multi-group cross-lagged panel model revealed that adolescents' gender egalitarianism in the previous year positively predicted prosocial behavior in the next year, and vice versa; such bidirectional associations equally applied to boys and girls. These findings add to the knowledge of adolescent gender egalitarianism and prosocial behavior, and the dynamic interplay between the two.
RESUMEN
Inflammatory bowel disease (IBD) is a chronic immune-mediated disease associated with a high recurrence rate and an elevated risk of colon cancer. In this study, we screened a bioactive compound library using a luciferase reporter assay and identified the compound TAK875 as a novel inhibitor of signal transducer and activator of transcription 3 (STAT3). Surface plasmon resonance analysis, differential scanning fluorimetry, and isothermal titration calorimetry demonstrated that TAK875 directly bound to recombinant STAT3. TAK875 suppressed the lipopolysaccharide (LPS)-induced release of nitric oxide, inducible nitric oxide synthase, and inflammatory factors in RAW264.7 cells, likely by inhibiting STAT3 phosphorylation. In addition, TAK875 inhibited the differentiation of CD4+ T cells into T-helper 17 cells, which may partially account for its anti-inflammatory effect. TAK875 also alleviated the LPS-induced accumulation of intracellular reactive oxygen species, thus displaying its antioxidant effects. Finally, we demonstrated its satisfactory anti-inflammatory effect in a dextran sulfate sodium-induced mouse model of ulcerative colitis. In conclusion, this study presented TAK875 as a novel STAT3 inhibitor and demonstrated its anti-inflammatory and antioxidant effects both in vitro and in vivo.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Ratones , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Lipopolisacáridos , FN-kappa B/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidoresRESUMEN
Economic inequality has been found to reduce individuals' generosity in western contexts. However, whether this effect is cross-culturally consistent and its internal mechanism remain unclear, as well as how to mitigate this impact. Hence, we explored whether and why economic inequality may erode generosity in a sample of Chinese adults from the social norm perspective and introduced the equal allocation norm to mitigate this effect. Four online studies were conducted: two were correlational (Study 1: n = 300; Study 2: n = 568) and two were experimental (Study 3: n = 289; Study 4: n = 500). Results showed that economic inequality predicted less generosity in the dictator game, and perceived unequal allocation norm accounted for this effect. Moreover, introducing the equal allocation norm could buffer this negative effect. Findings suggest economic inequality impairs generosity, and making the equal allocation norm more salient may guide people to act more generously.
RESUMEN
Materialism plays a critical role in adolescent behavioral development, yet whether it affects prosocial and aggressive behaviors and the internal mechanism remains unknown. Therefore, this longitudinal research examined the relationships between adolescent materialism and prosocial and aggressive behaviors, and tested the mediating effect of empathy. In 2015, we recruited 543 adolescents from four junior high schools in Beijing, China (284 girls, 259 boys; M = 11.27 years, SD = 0.51). The participants completed the measures of materialism and demographic information at the initial time point, completed the measure of empathy about one year later, and completed the measures of prosocial and aggressive behaviors after about another year. The hypotheses were tested using a structural model using maximum likelihood estimation. The mediating effects were estimated by taking 1000 bias-corrected bootstraps. The results revealed that materialism was associated with aggressive behavior directly and positively, but had no significant correlation with prosocial behavior. Materialism had an indirect and negative correlation with prosocial behavior via empathy, while no indirect effect of materialism on aggressive behavior was found. The findings add to our knowledge of the dehumanizing nature of materialism by revealing its effect on adolescent behavioral development, as well as the underlying mechanism.
RESUMEN
Chemical modifications of transcripts with a 5' cap occur in all organisms and function in many aspects of RNA metabolism. To facilitate analysis of RNA caps, we developed a systems-level mass spectrometry-based technique, CapQuant, for accurate and sensitive quantification of the cap epitranscriptome. The protocol includes the addition of stable isotope-labeled cap nucleotides (CNs) to RNA, enzymatic hydrolysis of endogenous RNA to release CNs, and off-line enrichment of CNs by ion-pairing high-pressure liquid chromatography, followed by a 17 min chromatography-coupled tandem quadrupole mass spectrometry run for the identification and quantification of individual CNs. The total time required for the protocol can be up to 7 d. In this approach, 26 CNs can be quantified in eukaryotic poly(A)-tailed RNA, bacterial total RNA and viral RNA. This protocol can be modified to analyze other types of RNA and RNA from in vitro sources. CapQuant stands out from other methods in terms of superior specificity, sensitivity and accuracy, and it is not limited to individual caps nor does it require radiolabeling. Thanks to its unique capability of accurately and sensitively quantifying RNA caps on a systems level, CapQuant can reveal both the RNA cap landscape and the transcription start site distribution of capped RNA in a broad range of settings.
Asunto(s)
Caperuzas de ARN , Espectrometría de Masas en Tándem , Caperuzas de ARN/genética , ARN Mensajero/genética , Cromatografía Líquida de Alta Presión , ARN Viral/genética , ARN BacterianoRESUMEN
This study explored whether altruistic behaviour would decrease agent's unhealthy food intake, and whether vitality and state self-control would sequentially mediate this effect based on the Self-Determination Theory Model of Vitality. It included 1019 college students in total across three studies. Study 1 was a laboratory experiment. By framing a physical task as a helping behaviour or a neutral experimental task, we examined whether these framed tasks impacted participants' subsequent unhealthy food intake levels. Study 2 was an online investigation measuring the relationship between donation (vs. no donation) behaviour and participant's estimated unhealthy food intake level. Study 3 was an online experiment with a mediation test. By random assignment of conducting a donation behaviour versus a neutral task, we examined whether these behaviours affected participants' vitality, state self-control, and estimated unhealthy food intake levels. In addition, we tested a sequential mediation model with vitality and state self-control as the mediators. Both unhealthy and healthy foods were included in Study 2 and 3. Results showed that altruistic behaviour could decrease agent's unhealthy (but not healthy) food intake, and this effect was sequentially mediated by vitality and state self-control. The findings highlight that altruistic acts may buffer agents against unhealthy eating behaviour.
Asunto(s)
Conducta Alimentaria , Autocontrol , Humanos , Altruismo , Ingestión de AlimentosRESUMEN
INTRODUCTION: In this study, we examined the relationship between prosocial behavior and school bullying victimization in children and adolescents. We also tested the mediating effects of peer alienation and student-teacher closeness, as well as the moderating effect of the educational stage. METHODS: In total, 538 children and adolescents were recruited from three suburban schools in Beijing, China (252 boys, 286 girls; mean age = 12.47; 237 elementary school students, 101 middle school students, and 200 high school students). The participants were asked to complete the measures of prosocial behavior, peer alienation, and student-teacher closeness at the initial time point and reported school bullying victimization 3 months later. RESULTS: We found that prosocial behavior was directly and negatively associated with traditional bullying victimization (i.e., physical, nonphysical, and relational); however, it had no direct association with cyberbullying victimization. Prosocial behavior was indirectly associated with school bullying victimization (except in the relational dimension) via peer alienation, but no indirect effect of student-teacher closeness was found. Besides, the associations between prosocial behavior, peer alienation, student-teacher closeness, and bullying victimization were found equally among elementary, middle, and high school students. CONCLUSIONS: The findings suggest that prosocial behavior is an important factor associated with decreased school bullying victimization, and peer relationships play a mediating role in this association. Our study extends the current understanding of prosocial behavior primarily as a consequence of child and adolescent development to an antecedent (of school bullying victimization), which contributes to a more comprehensive view of prosocial behavior.
Asunto(s)
Acoso Escolar , Víctimas de Crimen , Masculino , Femenino , Humanos , Niño , Adolescente , Relaciones Interpersonales , Altruismo , Grupo Paritario , EstudiantesRESUMEN
The Fe-based Prussian blue (Fe-PB) composite is considered as one of the most potential cathode materials for sodium-ion batteries because of its abundant iron resources and high theoretical capacity. However, the crystal water and vacancy in the Fe-PB structure will lead to poor capacity and cycle stability. In this work, a Cu-modified Fe-PB composite (FeCu-PB@CuO) is successfully prepared through regulating the Fe-PB structure by Cu doping and engineering the surface by CuO coating. The density functional theory calculation results confirm that Cu preferentially replaces FeHS in the Fe-PB lattice and Cu doping reduces the bandgap. Our experiment results reveal that CuO coating can provide more active sites, inhibit side reactions, and potentially enhance the activity of FeHS. Due to the synergistic effect of Cu doping and CuO coating, FeCu-PB@CuO has a considerable initial discharge capacity of 123.5 mAh g-1 at 0.1 A g-1. In particular, at 2 A g-1, it delivers an impressive initial capacity of 84.3 mAh g-1, and the capacity decreasing rate of each cycle is only 0.02% over 1500 cycles. Therefore, the synergistic modification strategy of metal ion doping and metal oxide coating has tremendous application potential and can be extended to other electrode materials.
RESUMEN
Signal transducers and activators of transcription 5 (Stat5) is known to engage in regulating the differentiation and effector function of various subsets of T helper cells. However, how Stat5 regulates the antitumor activity of tumor-infiltrating CD4+ T cells is largely unknown. Here, we showed that mice with specific deletion of Stat5 in CD4+ T cells were less susceptible to developing subcutaneous and lung metastatic B16 melanoma with CD4+ tumor-infiltrating lymphocytes (TILs) remolding. Especially, we confirmed that Stat5-deficient CD4+ naïve T cells were prone to polarization of two subtypes of Th17 cells: IFN-γ+ and IFN-γ- Th17 cells, which exhibited increased anti-melanoma activity through enhanced activation of Notch1 pathway compared with wild type Th17 cells. Our study therefore revealed a novel function of Stat5 in regulating tumor-specific Th17 cell differentiation and function in melanoma. This study also provided a new possibility for targeting Stat5 and other Th17-associated pathways to develop novel immunotherapies for melanoma patients.
Asunto(s)
Melanoma , Linfocitos T Colaboradores-Inductores , Animales , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular , Linfocitos Infiltrantes de Tumor , Melanoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/patologíaRESUMEN
Iron-based Prussian blue (FeHCF) has great application potential in the large-scale production of sodium-ion (Na+) batteries because of its high theoretical capacity and abundant Fe ore resources. However, the Fe(CN)6 vacancies and crystal water seriously affect the electrochemical performance. Herein, a Cu-doped FeHCF (Cu-FeHCF) cathode material is successfully prepared directly by a coprecipitation method. After Cu doping, the monoclinic structure and the quasi-cubic morphology are retained, but the electrochemical performance is significantly improved. In addition to few Fe(CN)6 vacancies and low crystal water, the improved performance is also related to the enhanced electrochemical activity of low-spin Fe and the stabilizing effect of Cu on the crystal structure. Moreover, Cu doping also controls the side reaction to a certain extent. As a result, after Cu doping, the initial discharge capacity is enhanced from 107.9 to 127.4 mA h g-1 at 100 mA g-1, especially the capacities contributed by low-spin Fe increase from 30.0, 21.7, and 16.7 mA h g-1 to 48.8, 45.4, and 43.7 mA h g-1 for the first three cycles, respectively. Even at 2 A g-1, Cu-FeHCF still has a promising initial capacity of 82.3 mA h g-1 and only a 0.047% capacity decay rate for each cycle over 500 cycles. Therefore, Cu-FeHCF shows excellent application potential in the field of Na+ energy storage batteries.
RESUMEN
INTRODUCTION: This study explores the longitudinal and bidirectional relations between paternal/maternal psychological control and adolescent maladjustment (i.e., internalizing symptoms, aggression, and association with deviant peers). METHODS: This longitudinal investigation was conducted at two time points over a one-year interval with participants comprising 543 Chinese adolescents aged 10 to 13 (mean age at Time 1 = 11.29; 51.93% girls). The performed measurements encompassed paternal/maternal psychological control, adolescent internalizing symptoms, aggression, association with deviant peers, and demographic information. RESULTS: The findings of a cross-lagged model analysis revealed that paternal psychological control was longitudinally and positively related to adolescent internalizing symptoms and aggression. Maternal psychological control was not significantly related to any domain of adolescent maladjustment. In turn, adolescent association with deviant peers was longitudinally and positively associated with both parents' psychological control. CONCLUSIONS: Parental psychological control was bidirectionally associated with adolescent maladjustment in general, and paternal psychological control played a crucial role on adolescent maladjustment in the Chinese cultural context. The study's findings supported the reciprocal model of parent-child interaction, and extended it by highlighting the apprehension of the characteristics of parental impact from a cultural perspective. The study results add to the current scholarly understanding of parental psychological control in the non-western cultural context.
Asunto(s)
Conducta del Adolescente , Relaciones Padres-Hijo , Adolescente , Agresión , Femenino , Humanos , Masculino , Padres , Grupo ParitarioRESUMEN
BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) has been shown to upregulate gene transcription during tumorigenesis. However, how STAT3 initiates transcription remains to be exploited. This study is to reveal the role of CREPT (cell cycle-related and elevated-expression protein in tumours, or RPRD1B) in promoting STAT3 transcriptional activity. METHODS: BALB/c nude mice, CREPT overexpression or deletion cells were employed for the assay of tumour formation, chromatin immunoprecipitation, assay for transposase-accessible chromatin using sequencing. RESULTS: We demonstrate that CREPT, a recently identified oncoprotein, enhances STAT3 transcriptional activity to promote tumorigenesis. CREPT expression is positively correlated with activation of STAT3 signalling in tumours. Deletion of CREPT led to a decrease, but overexpression of CREPT resulted in an increase, in STAT3-initiated tumour cell proliferation, colony formation and tumour growth. Mechanistically, CREPT interacts with phosphorylated STAT3 (p-STAT3) and facilitates p-STAT3 to recruit p300 to occupy at the promoters of STAT3-targeted genes. Therefore, CREPT and STAT3 coordinately facilitate p300-mediated acetylation of histone 3 (H3K18ac and H3K27ac), further augmenting RNA polymerase II recruitment. Accordingly, depletion of p300 abolished CREPT-enhanced STAT3 transcriptional activity. CONCLUSIONS: We propose that CREPT is a co-activator of STAT3 for recruiting p300. Our study provides an alternative strategy for the therapy of cancers related to STAT3.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Transformación Celular Neoplásica/patología , Proteína p300 Asociada a E1A/metabolismo , Proteínas de Neoplasias/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Femenino , Células HEK293 , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células 3T3 NIH , Proteínas de Neoplasias/genética , Trasplante de Neoplasias , Fosforilación , Transcripción GenéticaRESUMEN
Social power predicts numerous important life outcomes and social orientations. Thus far, the research literature has mainly examined how an individual's own power shapes interactions with others, whereas whether a target's power affects social interactions has been relatively neglected. In particular, does a target's power have an effect on the agent's prosocial behavior? Furthermore, could culture along with the power distance dimension alter the effect of a target's power on prosocial behavior? To explore these two research questions, we investigated the effect of a target's power (power unspecified targets vs. powerful targets) on prosocial behavior in both China and the United States. Questionnaires measuring prosocial behavior toward power unspecified or powerful targets were distributed to Chinese and American emerging adults (n in total = 893). According to the results, both Chinese and Americans were less likely to help powerful targets compared with power unspecified targets. Moreover, the Chinese were less prosocial toward both power unspecified and powerful targets in comparison to the Americans. These findings highlight the key roles of a target's power and culture in shaping an individual's prosocial behavior.
Asunto(s)
Altruismo , Poder Psicológico , Adulto , China , Comparación Transcultural , Humanos , Estados UnidosRESUMEN
The liver and gallbladder are among the most important internal organs derived from the endoderm, yet the development of the liver and gallbladder in the early embryonic stages is not fully understood. Using a transgenic Foxa2eGFP reporter mouse line, we performed single-cell full-length mRNA sequencing on endodermal and hepatic cells isolated from ten embryonic stages, ranging from E7.5 to E15.5. We identified the embryonic liver developmental trajectory from gut endoderm to hepatoblasts and characterized the transcriptome of the hepatic lineage. More importantly, we identified liver primordium as the nascent hepatic progenitors with both gut and liver features and documented dynamic gene expression during the epithelial-hepatic transition (EHT) at the stage of liver specification during E9.5-11.5. We found six groups of genes switched on or off in the EHT process, including diverse transcripitional regulators that had not been previously known to be expressed during EHT. Moreover, we identified and revealed transcriptional profiling of gallbladder primordium at E9.5. The present data provides a high-resolution resource and critical insights for understanding the liver and gallbladder development.
Asunto(s)
Factor Nuclear 3-beta del Hepatocito/metabolismo , Hígado/embriología , Animales , Células Cultivadas , Regulación del Desarrollo de la Expresión Génica/fisiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Factor Nuclear 3-beta del Hepatocito/genética , Hígado/metabolismo , Ratones , Análisis de Secuencia de ARN , Análisis de la Célula IndividualRESUMEN
The -1 ribosomal frameshifting is vital for the translation of the open reading frame (ORF)1b in SARS-CoV-2. The products of ORF1b participate in viral replication. Therefore, changing the frameshift frequency reduces the survival of the virus. This study aimed to successfully develop a toolkit for screening antiviral drugs. Finally, the FDA-approved drug library was screened, revealing that ivacaftor and (-)-Huperzine A worked well in changing the -1 ribosomal frameshifting of SARS-CoV-2 in vitro.
RESUMEN
Cholesterol 25-hydroxylase (CH25H) encodes the enzyme that converts cholesterol to 25-hydroxycholesterol (25-HC). 25-HC has been demonstrated to be involved in the pathogenesis of inflammatory bowel disease. However, the role of CH25H in experimental colitis remains unknown. Dextran sulfate sodium (DSS)-induced colitis was monitored in wild type and Ch25h-/- mice in 8-week-old male for 7 days by assessment of body weight, histology, inflammatory cellular infiltration, and colon length. The function of CH25H was investigated using loss-of-function and gain-of-function such as Ch25h-deficient mice, supplementation with exogenous 25-HC and treatment of 25-HC into Caco2 and HCT116 colonic epithelial cells. Ch25h-/- mice with DSS-induced colitis exhibited aggravated injury, including higher clinical colitis scores, severe injury of the epithelial barrier, lower tight junction protein levels and higher levels of IL-6. Supplementation with exogenous 25-HC ameliorated disease symptoms and reduced the extent of damage in DSS-induced colitis, which was characterized by lower colon damage, higher tight junction protein expression, significantly decreased local and systemic production of pro-inflammatory cytokines IL-6. In Caco2 and HCT116 cells, 25-HC induced tight junction genes expression in colon cancer epithelial cells. These effects of CH25H were obtained by promoting ATF3 expression. Taken together, our findings reveal a protective role for 25-HC in DSS-induced colitis and the ability of CH25H to maintain epithelial gut barrier function through ATF3 expression. Supplementation with exogenous 25-HC ameliorates disease symptoms, which provides a new therapeutic strategy for ulcerative colitis.
Asunto(s)
Colitis/tratamiento farmacológico , Mucosa Intestinal/efectos de los fármacos , Esteroide Hidroxilasas/farmacología , Animales , Células CACO-2 , Colitis/inducido químicamente , Colitis/fisiopatología , Colitis Ulcerosa/patología , Colon/metabolismo , Neoplasias del Colon/patología , Citocinas/metabolismo , Sulfato de Dextran/farmacología , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Células HCT116 , Humanos , Mucosa Intestinal/metabolismo , Intestinos/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Permeabilidad/efectos de los fármacos , Esteroide Hidroxilasas/metabolismo , Proteínas de Uniones Estrechas/metabolismo , Uniones Estrechas/metabolismoRESUMEN
Hypertriglyceridemia (HTG) can aggravate acute pancreatitis (AP), but its pathogenesis remains unclear. As autophagic activity is closely related to lipid metabolism and AP, we investigated the autophagic response in models of AP aggravated by HTG and explored whether rapamycin has a protective effect against HTG-related pancreatitis. HTG-associated AP models were established in vivo in rats and in vitro. The degree of inflammation, pancreatic injury, the expression of endoplasmic reticulum (ER) stress, and autophagy markers (P62, LC3) were compared. Autophagic flux were assessed using immunostaining, electron microscopy, and immunoblotting. Compared with the normal diet group, the high-fat diet (HFD) AP group exhibited more severe pancreatic injury, apoptosis, and blocked autophagic flux. In addition, the three branches (PERK-eIF2α, ATF-6-GRP78, and IRE1-sXBP1) of the unfolded protein response and mTORC1/S6K1 pathway were activated in HFD AP models. Moreover, the same phenomena were confirmed in vitro in palmitic acid-stimulated pancreatic acinar cells. Preincubation with the mTOR inhibitor rapamycin restored the autophagic flux and markedly reduced the adverse effects of HTG. In conclusion, the autophagic flux is impaired in HFD-induced AP models and is strongly associated with ER stress. Rapamycin could prevent the aggravation of HTG-associated AP via inhibiting mTORC1/S6K1 pathway.