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Caspase-11 detection of intracellular lipopolysaccharide mediates non-canonical pyroptosis, which could result in inflammatory damage and organ lesions in various diseases such as sepsis. Our research found that lactate from the microenvironment of acetaminophen-induced acute liver injury increased Caspase-11 levels, enhanced gasdermin D activation and accelerated macrophage pyroptosis, which lead to exacerbation of liver injury. Further experiments unveiled that lactate inhibits Caspase-11 ubiquitination by reducing its binding to NEDD4, a negative regulator of Caspase-11. We also identified that lactates regulated NEDD4 K33 lactylation, which inhibits protein interactions between Caspase-11 and NEDD4. Moreover, restraining lactylation reduces non-canonical pyroptosis in macrophages and ameliorates liver injury. Our work links lactate to the exquisite regulation of the non-canonical inflammasome, and provides a basis for targeting lactylation signaling to combat Caspase-11-mediated non-canonical pyroptosis and acetaminophen-induced liver injury.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Piroptosis , Humanos , Acetaminofén/toxicidad , Caspasas Iniciadoras/metabolismo , Caspasas/metabolismo , Ácido LácticoRESUMEN
The evolution of the vertebrate liver is a prime example of the evolution of complex organs, yet the driving genetic factors behind it remain unknown. Here we study the evolutionary genetics of liver by comparing the amphioxus hepatic caecum and the vertebrate liver, as well as examining the functional transition within vertebrates. Using in vivo and in vitro experiments, single-cell/nucleus RNA-seq data and gene knockout experiments, we confirm that the amphioxus hepatic caecum and vertebrate liver are homologous organs and show that the emergence of ohnologues from two rounds of whole-genome duplications greatly contributed to the functional complexity of the vertebrate liver. Two ohnologues, kdr and flt4, play an important role in the development of liver sinusoidal endothelial cells. In addition, we found that liver-related functions such as coagulation and bile production evolved in a step-by-step manner, with gene duplicates playing a crucial role. We reconstructed the genetic footprint of the transfer of haem detoxification from the liver to the spleen during vertebrate evolution. Together, these findings challenge the previous hypothesis that organ evolution is primarily driven by regulatory elements, underscoring the importance of gene duplicates in the emergence and diversification of a complex organ.
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BACKGROUND: Hepatocellular carcinoma (HCC) is an extensive heterogeneous disease where epigenetic factors contribute to its pathogenesis. Polycomb group (PcG) proteins are a group of subunits constituting various macro-molecular machines to regulate the epigenetic landscape, which contributes to cancer phenotype and has the potential to develop a molecular classification of HCC. RESULTS: Here, based on multi-omics data analysis of DNA methylation, mRNA expression, and copy number of PcG-related genes, we established an epigenetic classification system of HCC, which divides the HCC patients into two subgroups with significantly different outcomes. Comparing these two epigenetic subgroups, we identified different metabolic features, which were related to epigenetic regulation of polycomb-repressive complex 1/2 (PRC1/2). Furthermore, we experimentally proved that inhibition of PcG complexes enhanced the lipid metabolism and reduced the capacity of HCC cells against glucose shortage. In addition, we validated the low chemotherapy sensitivity of HCC in Group A and found inhibition of PRC1/2 promoted HCC cells' sensitivity to oxaliplatin in vitro and in vivo. Finally, we found that aberrant upregulation of CBX2 in Group A and upregulation of CBX2 were associated with poor prognosis in HCC patients. Furthermore, we found that manipulation of CBX2 affected the levels of H3K27me3 and H2AK119ub. CONTRIBUTIONS: Our study provided a novel molecular classification system based on PcG-related genes data and experimentally validated the biological features of HCC in two subgroups. Our founding supported the polycomb complex targeting strategy to inhibit HCC progression where CBX2 could be a feasible therapeutic target.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Complejo Represivo Polycomb 1 , Complejo Represivo Polycomb 2 , Humanos , Carcinoma Hepatocelular/clasificación , Carcinoma Hepatocelular/genética , Metilación de ADN , Epigénesis Genética , Neoplasias Hepáticas/clasificación , Neoplasias Hepáticas/genética , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 2/genéticaRESUMEN
Renal cell cancer (RCC) is the most lethal of all the common urologic cancers and constitutes 2.2% of all malignancy diagnoses. The incidence of RCC has been steadily increasing in recent decades. The classic risk factors of RCC include smoking, hypertension, obesity, genetics, and genetic mutations. Recent studies also revealed that RCC was an immunogenic tumor and affected by host immune status. Among the pan-cance, RCC presented with the highest degree of immune infiltration, indicating RCC patients might benefit from immunotherapy. A new immune classification of RCC has been developed by Su et al. based on tumor-infiltrating lymphocytes to guide clinical practice. However, these studies mainly focus on biomarkers derived from tumor microenvironment (TME), the biomarkers based on peripheral blood samples to RCC have rarely been described. We collected peripheral blood samples from RCC patients and their matched healthy controls and detected the number of IL-2 and IFN-γ producing cells by implementing an enzyme-linked immunospot (ELISPOT) assay. This is the first study to report blood-based immune biomarkers for RCC using an ELISPOT assay. Our results suggested the frequency of IFN-γ producing cells but not IL-2 producing cells was associated with RCC risk. These findings warrant further validation in larger prospective studies.
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Carcinoma de Células Renales , Neoplasias Renales , Biomarcadores , Carcinoma de Células Renales/diagnóstico , Humanos , Interferón gamma , Neoplasias Renales/diagnóstico , Estudios Prospectivos , Microambiente TumoralRESUMEN
Organizational scholars concur that job security can attach employees to a workplace and improve their job quality. The relationship between job security and employees' deviant behaviors in the workplace, such as counterproductive work behavior (CWB), lacks insights into how or why this occurs, especially in a diversified employment context. To address these limitations, we developed a theoretical model of job security impact on employees' CWB from the perspective of social identity. Analysis of employees (N = 208) and their supervisors in a China state-owned company were used to test the hypothesis. Results confirmed the negative relationship between job security and CWB; organizational identification partly mediates the relationship between job security and CWB. Moderated mediation analyses further indicate that the indirect effect of job security on CWB via organizational identification are stronger for temporary employees than for permanent employees. This article contributes to the understanding of job security's impact on employees' deviant behavior, practical implications and research aspects are discussed.
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Identificación Social , Lugar de Trabajo , Creatividad , Empleo , Humanos , OrganizacionesRESUMEN
Increasing prevalence of obesityinduced nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has been reported. Ascorbic acid (AA), also known as vitamin C, an excellent antioxidant, has been shown to exert beneficial effects on NAFLD; however, the underlying mechanisms are yet to be fully elucidated. In the present study, the role of AA on cell stress in tumor necrosis factor α (TNFα)treated HepG2 cells was investigated. Our findings revealed that exposure to AA effectively ameliorated TNFαinduced cell stresses, including hypoxia, inflammation and endoplasmic reticulum (ER) stress by reducing the expression of Hif1α and its target genes (glucose transporter 1), proinflammatory genes (monocyte chemoattractant 1) and ER stressrelated genes (glucoseregulated protein, 78 kDa). AA also decreased the protein level of HIF1α. Additionally, AA significantly increased the secretion of total adiponectin and high molecular weight (HMW) adiponectin. Mechanistically, AA was determined to increase the expression of fibroblast growth factor 21 (FGF21) and its receptor, fibroblast growth factor receptor 2 (FGFR2). Knockdown of FGFR2 not only decreased the levels of total adiponectin and HMW adiponectin, but almost abolished the beneficial effects of AA in ameliorating cell stress. Collectively, the findings of our study demonstrated that AA may attenuate hepatocyte stress induced by TNFα via activation of the FGF21/FGFR2/adiponectin pathway. This could a novel mechanism of action of AA, and its potential for the treatment of NAFLD/NASH.