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Layered sodium-ion oxides hold considerable promise in achieving high-performance sodium-ion batteries. However, the notorious phase transformation during charging, attributed to increased O2-âO2- repulsion, results in substantial performance decay. Here, a hierarchical layer modification strategy is proposed to stabilize interlayer repulsion. During desodiation, migrated Li+ from the transition metal layer and anchored Ca2+ in sodium sites maintain the cationic content within the sodium layer. Meanwhile, partial oxygen substitution by fluorine and the involvement of oxygen in redox reactions increase the average valence of the oxygen layer. This sustained cation presence and elevated anion valence collectively mitigate increasing O2-âO2- repulsion during sodium extraction, enabling the Na0.61Ca0.05[Li0.1Ni0.23Mn0.67]O1.95F0.05 (NCLNMOF) cathode to retain a pure P2-type structure across a wide voltage range. Unexpected insights reveal the interplay between different doping elements: the robust LiâF bonds and Ca2+ steric effects suppressing Li+ loss. The NCLNMOF electrode exhibits 82.5% capacity retention after 1000 cycles and a high-rate capability of 94 mAh g-1 at 1600 mA g-1, demonstrating the efficacy of hierarchical layer modification for high-performance layered oxide cathodes.
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Mitochondria are crucial organelles responsible for energy generation in eukaryotic cells. Oxidative stress, calcium disorders, and mitochondrial DNA abnormalities can all cause mitochondrial dysfunction. It is now well documented that mitochondrial dysfunction significantly contributes to the pathogenesis of numerous illnesses. Hence, it is vital to investigate innovative treatment methods targeting mitochondrial dysfunction. Extracellular vesicles (EVs) are cell-derived nanovesicles that serve as intercellular messengers and are classified into small EVs (sEVs, < 200 nm) and large EVs (lEVs, > 200 nm) based on their sizes. It is worth noting that certain subtypes of EVs are rich in mitochondrial components (even structurally intact mitochondria) and possess the ability to transfer them or other contents including proteins and nucleic acids to recipient cells to modulate their mitochondrial function. Specifically, EVs can modulate target cell mitochondrial homeostasis as well as mitochondria-controlled apoptosis and ROS generation by delivering relevant substances. In addition, the artificial modification of EVs as delivery carriers for therapeutic goods targeting mitochondria is also a current research hotspot. In this article, we will focus on the ability of EVs to modulate the mitochondrial function of target cells, aiming to offer novel perspectives on therapeutic approaches for diverse conditions linked to mitochondrial dysfunction.
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Vesículas Extracelulares , Mitocôndrias , Vesículas Extracelulares/metabolismo , Humanos , Mitocôndrias/metabolismo , Animais , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo , Apoptose , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/terapia , Sistemas de Liberação de Medicamentos/métodosRESUMO
To understand the land use development trends in Shaanxi Province under different scenarios and effectively assess the spatiotemporal evolution of terrestrial ecological carbon stocks in Shaanxi Province under land use changes, the study used Markov-FLUS and InVEST models to analyze the impact of land use changes in Shaanxi Province from 2000 to 2020. The impact of carbon storage changes and the spatiotemporal changes in land use structure, carbon storage, and carbon density under three different scenarios were simulated and assessed in Shaanxi Province in 2025 and 2030. The results showedï¼ â The ROC values of various categories in the coupled Markov-FLUS model were all above 0.7, showing high accuracy and excellent classification performance. The model had a good ability to explain the land use driving factors in the study area, with high accuracy and excellent classification performance. â¡ From 2000 to 2020, the cultivated land in Shaanxi Province increased significantly. Forest land increased significantly, and the increase in forest land area with high carbon sequestration efficiency caused the carbon storage in Shaanxi Province to increase from 1 546.95 Tg to 1 616.25 Tg. The changes in various regions in Shaanxi Province from 2000 to 2020 were different, among which the carbon storage in Yan'an was significantly increased by 18.89 Tg, whereas the carbon storage in Yulin significantly decreased by 3.29 Tg in 20 years. ⢠Altitude, precipitation, and temperature became the main factors affecting the spatiotemporal changes in carbon storage in Shaanxi Province from 2020 to 2030. In three of the years between 2025 and 2030, under different scenarios, the carbon stocks under the ecological priority scenario were 1 632.27 Tg and 1 647.43 Tg, respectively. The carbon storage and its growth rate were significantly higher than in the natural development scenario and the cultivated land protection scenario. ⣠The proportion of carbon storage increase areas under the ecological priority scenario was high. In the cultivated land protection scenario, the proportion of reduction areas was lower than that of the natural development scenario, and the distribution of carbon storage was the most balanced. At the same time, the southern and northern areas of the Loess Plateau in northern Shaanxi need to focus on the protection of the ecological environment in future development. The research results can, to a certain extent, provide reference for promoting the construction of ecological Shaanxi and formulating carbon neutral strategic planning.
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Floods have a wide range of environmental effects. However, owing to the complex composition of the environment and the numerous factors influencing environmental flood risk, few studies have systematically analyzed the impact of floods on the environment. After reviewing the various impacts of floods on the environment, we summarized them into four indicators (water pollution, erosion and deposition, biomass impact, and biodiversity impact) and analyzed the interrelationships between the four indicators. We then summarized 14 key factors affecting the degree of impact of floods on the environment (flood depth, velocity, duration, sediment concentration, timing of flood, temperature, point source and non-point source, height, age, waterlogging tolerance of plants, migration ability of animals, survival time of animals during floods, species richness, and biomass density) and analyzed their influence mechanisms on each indicator. We then compared the principles, scope of application, accuracy, and limitations of six environmental flood impact evaluation methods and found that the multi-factor evaluation method has great application prospects. Finally, we proposed two recommendations for future research to assess and reduce environmental flood impacts. This review provides a comprehensive understanding of the impact of floods on the environment and a basis for evaluating the impact and formulating measures to mitigate the degree of impact.
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Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC.
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Small extracellular vesicles (sEV) derived from diverse natural killer (NK) cell lines have proven their exceptional antitumor activities. However, sEV from human primary NK cells, especially memory-like NK cells, are rarely utilized for cancer treatment. In this study, we obtained sEV from IL-12, IL-15 and IL-18 cultured human memory-like NK cells (mNK-sEV) that showed strong cytokine-secretory ability. It was uncovered that mNK-sEV entered cancer cells via macropinocytosis and induced cell apoptosis via caspase-dependent pathway. Compared to sEV from conventionally cultured NK cells (conNK-sEV), mNK-sEV inhibited tumor growth to a greater extent. Concomitantly, pharmacokinetics and biodistribution results validated a higher accumulation of mNK-sEV than conNK-sEV in tumors of xenografted murine models. Notably, elevated containment of granulysin (GNLY) within mNK-sEV, at least in part, may contribute to the enhanced therapeutic effect. Herein our results present that mNK-sEV can be a novel class of therapeutic reagent for effective cancer treatment.
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Apoptose , Citocinas , Vesículas Extracelulares , Células Matadoras Naturais , Neoplasias , Animais , Vesículas Extracelulares/metabolismo , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Citocinas/metabolismo , Apoptose/efeitos dos fármacos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto , Pinocitose/efeitos dos fármacos , Feminino , Camundongos Endogâmicos BALB C , Antígenos de Diferenciação de Linfócitos TRESUMO
Small extracellular vesicles (sEVs) are lipid bilayer-enclosed particles secreted by living cells. Here, we present a protocol for the collection and isolation of sEVs derived from human umbilical cord mesenchymal stem cells (hucMSCs). We describe steps for characterizing their morphology and integrity by transmission electron microscopy (TEM) and size distribution using nanoparticle tracking analysis (NTA) and an atomic force microscope (AFM). We then detail procedures for assessing nanoparticle size analysis and molecular markers by western blotting and Flow NanoAnalyzer.
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BACKGROUND: Public health scholars informed by a dominant biomedical paradigm have in their 'rush to risk' emphasised the problematic aspects of chemsex. Meanwhile, critical chemsex scholars have attemped to destigmatise such sexual-chemical practices and foreground how they can be transformative. Taking these two perspectives as points of departure, we make a case for understanding chemsex vis-à-vis Deleuzean lines of flight. METHODS: Semi-structured in-depth interviews were conducted with 33 purposively sampled sexual minority men seeking therapy for chemsex dependency in Singapore. Interview topics included participants' experiences and histories of chemsex, substance use, and their ongoing recovery. Interviews were audio-recorded, transcribed and then analysed according to key themes. RESULTS: We illustrate how chemically inflected sexual encounters can offer deterritorialising flights of fantasy and freedom from a heteronormative social structure that pathologises gay sex. At the same time, we argue that these flight lines are not static, neither do they extend indefinitely in space-time. Rather, we show how flights of freedom can evolve into lines of fright (or non-flight) when chemsex practitioners are met with critical thresholds that reveal the less-than-desirable aspects of being intoxicated. Consequently, they may eventually consider the reterritorialisation of their lives (i.e. abstinence and recovery) as a more constructive option. Regardless of their decisions to ride on chemically-induced flight lines or to take a step back from such deterritorialising pathways, they have troubled stereotypical perspectives of drug users as passive automatons. CONCLUSIONS: This paper enriches the chemsex scholarship by presenting a Deleuzean conceptualisation of chemical-sexual intimacies without romantacising and/or overstating the 'escape'/'freedom' that chemsex can facilitate. Future research in this arena could explore the complicated intimate relationships that users may have with their drug(s) of choice, and their varied lines of (non-)flight over a longitudinal study.
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Comportamento Sexual , Minorias Sexuais e de Gênero , Humanos , Masculino , Adulto , Singapura , Minorias Sexuais e de Gênero/psicologia , Transtornos Relacionados ao Uso de Substâncias , Pessoa de Meia-Idade , Entrevistas como Assunto , Homossexualidade Masculina/psicologia , Adulto JovemRESUMO
Multidrug-resistant P. aeruginosa infections pose a serious public health threat due to the rise in antimicrobial resistance. Phage therapy has emerged as a promising alternative. However, P. aeruginosa has evolved various mechanisms to thwart phage attacks, making it crucial to decipher these resistance mechanisms to develop effective therapeutic strategies. In this study, we conducted a forward-genetic screen of the P. aeruginosa PA14 non-redundant transposon library (PA14NR) to identify dominant-negative mutants displaying phage-resistant phenotypes. Our screening process revealed 78 mutants capable of thriving in the presence of phages, with 23 of them carrying insertions in genes associated with membrane composition. Six mutants exhibited total resistance to phage infection. Transposon insertions were found in genes known to be linked to phage-resistance such as galU and a glycosyl transferase gene, as well as novel genes such as mexB, lasB, and two hypothetical proteins. Functional experiments demonstrated that these genes played pivotal roles in phage adsorption and biofilm formation, indicating that altering the bacterial membrane composition commonly leads to phage resistance in P. aeruginosa. Importantly, these mutants displayed phenotypic trade-offs, as their resistance to phages inversely affected antibiotic resistance and hindered biofilm formation, shedding light on the complex interplay between phage susceptibility and bacterial fitness. This study highlights the potential of transposon mutant libraries and forward-genetic screens in identifying key genes involved in phage-host interactions and resistance mechanisms. These findings support the development of innovative strategies for combating antibiotic-resistant pathogens.
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Elementos de DNA Transponíveis , Biblioteca Gênica , Mutação , Pseudomonas aeruginosa , Pseudomonas aeruginosa/virologia , Pseudomonas aeruginosa/genética , Elementos de DNA Transponíveis/genética , Biofilmes/crescimento & desenvolvimento , Bacteriófagos/genética , Bacteriófagos/fisiologiaRESUMO
Elucidating the absorption and translocation of heavy metal(loid)s by common vegetables across different growth environments and stages is crucial for conducting accurate environmental risk assessments and for associated control. This study investigated temporal variations in the absorption and translocation capacities of pak choi (Brassica rapa L.) for As, Cd, Cr, Cu, Pb, and Zn in polluted soils during the plant growth cycle under greenhouse and open-field cultivation modes. Results showed high root metal(loid) bioconcentration factors and root-to-shoot translocation factors for Cd (0.25 and 1.44, respectively) and Zn (0.26 and 1.01), but low values for As (0.06 and 0.88) and Pb (0.06 and 0.87). The Cd concentration in the aerial edible parts peaked during the early slow growth period, whereas other heavy metal(loid)s peaked during the later stable maturity period. Root bioconcentration and root-to-shoot translocation factors did not significantly differ between cultivation modes. However, greenhouse cultivation exhibited lower average Cd and Zn concentrations in the edible parts and cumulative uptake amounts of most metal(loid)s than open-field cultivation during the typical harvest period spanning days 60 and 90. Short-term transitioning from open-field to greenhouse cultivation may reduce health risks associated with heavy metal(loid) intake via pak choi consumption. These findings facilitate sustainable agricultural practices and food safety management.
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Brassica rapa , Metais Pesados , Raízes de Plantas , Poluentes do Solo , Poluentes do Solo/metabolismo , Metais Pesados/metabolismo , Brassica rapa/crescimento & desenvolvimento , Brassica rapa/metabolismo , Raízes de Plantas/metabolismo , Monitoramento Ambiental/métodos , Brotos de Planta/metabolismo , Brotos de Planta/crescimento & desenvolvimento , Solo/química , Agricultura/métodosRESUMO
The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) - a transcriptional factor downstream of foxo signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that DEAF1 targets to Pik3c3 and Atg16l1 promoter regions and suppresses their expression. Deaf1 depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, Deaf1 overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that Deaf1 depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that Deaf1 expression is altered in aging and cachectic MuSCs. Manipulation of Deaf1 expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.Abbreviations: DEAF1: Deformed epidermal autoregulatory factor-1; FOXO: Forkhead box O; MuSC: Muscle Stem Cell; PAX7: Paired box 7; PIK3C3: Phosphatidylinositol 3-kinase catalytic subunit type 3.
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2(3H)-Furanones are tremendously important not only because of their wide occurrence in bioactive compounds but also due to their versatility in organic synthesis. Here, a straightforward approach to 2(3H)-furanones from readily available tertiary propargylic alcohols with arylboronic acids in the presence of CO using rhodium as a catalyst has been established. The method exhibits a broad substrate scope tolerating useful functional groups with a moderate to high stereoselectivity.
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Renal interstitial fibrosis (RIF) is a prevalent consequence of chronic renal diseases, characterized by excessive extracellular matrix (ECM) deposition. A Disintegrin and Metalloprotease 17 (ADAM17), a transmembrane metalloproteinase, plays a central role in driving renal fibrosis progression by activating Notch 1 protein and the downstream TGF-ß signaling pathway. Our study investigated potential therapeutic interventions for renal fibrosis, focusing on human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EVs). We found that hucMSC-EVs inhibit ADAM17, thereby impeding renal fibrosis progression. Analysis of hucMSC-EVs miRNA profiles revealed significant enrichment of miR-13474, which effectively targeted and inhibited ADAM17 mRNA expression, subsequently suppressing Notch1 activation, TGF-ß signaling, and collagen deposition. Overexpression of miR-13474 enhanced hucMSC-EVs' inhibitory effect on renal fibrosis, while its downregulation abolished this protective effect. Our findings highlight the efficacy of hucMSC-EVs overexpressing miR-13474 in mitigating renal fibrosis via ADAM17 targeting. These insights offer potential therapeutic strategies for managing renal fibrosis.
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Proteína ADAM17 , Vesículas Extracelulares , Fibrose , Rim , Células-Tronco Mesenquimais , MicroRNAs , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína ADAM17/metabolismo , Proteína ADAM17/genética , Humanos , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Rim/metabolismo , Rim/patologia , Transdução de Sinais , Nefropatias/metabolismo , Nefropatias/terapia , Nefropatias/patologia , Nefropatias/genética , Fator de Crescimento Transformador beta/metabolismo , CamundongosRESUMO
The first aerobic protocol of direct transformation of p-methoxybenzyl (PMB) ethers to carboxylic acids efficiently with Fe(NO3)3 â 9H2O and TEMPO as catalysts at room temperature has been developed. The reaction accommodates C-Br bond, terminal/non-terminal C-C triple bond, amide, cyano, nitro, ester, and trifluoromethyl groups. Even highly selective oxidative deprotection of different benzylic PMB ethers has been realized. The reaction has been successfully applied to the total synthesis of natural product, (R)-6-hydroxy-7,9-octadecadiynoic acid, demonstrating the practicality of the method. Based on experimental studies, a possible mechanism involving oxygen-stabilized benzylic cation has been proposed.
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With rapid urbanization and human activities exacerbating threats to the degradation of various ecosystem services in modern urban agglomerations, the exploration of the state of ecological security at the scale of urban agglomerations is of great significance. This study considered the Lanzhou-Xining Urban Agglomeration as the research area, based on the land use data in 2000, 2005, 2010, 2015, and 2020. At the same time, the landscape ecological risk index was introduced. The land use change characteristics of the Lanzhou-Xining Urban Agglomeration were analyzed by using the land use transfer matrix, the value per unit area equivalent factor method, and the bivariate spatial autocorrelation analysis method to elucidate the impacts of the changes in the ecological risk index induced by the land use transition on the value of ecosystem services. This study analyzed the land use change characteristics of the Lanzhou-Xining Urban Agglomeration and elucidated the impacts of changes in the ecological risk index on the value of ecosystem services caused by land use transformation. The results showed that:â During the period from 2000 to 2020, the land use types of the Lanzhou-Xining Urban Agglomeration were mainly dominated by grassland, cropland, and forest land. The construction land area had expanded significantly mainly from cropland and grassland, and the six land use types had strong cross-transformation. The total area of land use change was 6 646.05 km2. â¡ In terms of spatial changes, the spatial pattern of ecosystem service value in the Lanzhou-Xining Urban Agglomeration had not undergone obvious transformation. However, the regional variability was significant, generally showing the distribution characteristics of high in the northwest and low in the southeast. â¢From the perspective of temporal change, the value of ecosystem services in the Lanzhou-Xining Urban Agglomeration showed an upward trend, with the total flow of value increasing from 186.459 billion yuan to 192.156 billion yuan, with a total value-added of 5.697 billion yuan. ⣠There was a rising trend in the overall ecological risk index of the Lanzhou-Xining Urban Agglomeration over the past 20 years. Low ecological risk areas and lower ecological risk areas dominated the ecological risk areas. There was a significant positive correlation between the value of ecosystem services and the ecological risk index. This study aimed to reveal the understanding of the impacts of land-use practices on ecosystem service values and ecological risks, to provide important references for regional ecological risk management and land-use policy formulation, and thus to promote the high-quality development of the ecological environment in the Yellow River Basin.
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Diabetic kidney disease (DKD), a chronic kidney disease, is characterized by progressive fibrosis caused due to persistent hyperglycemia. The development of fibrosis in DKD determines the patient prognosis, but no particularly effective treatment. Here, small extracellular vesicles derived from mesenchymal stem cells (MSC-sEV) have been used to treat DKD fibrosis. Single-cell RNA sequencing was used to analyze 27,424 cells of the kidney, we have found that a novel fibrosis-associated TGF-ß1+Arg1+ macrophage subpopulation, which expanded and polarized in DKD and was noted to be profibrogenic. Additionally, Actin+Col4a5+ mesangial cells in DKD differentiated into myofibroblasts. Multilineage ligand-receptor and cell-communication analysis showed that fibrosis-associated macrophages activated the TGF-ß1/Smad2/3/YAP signal axis, which promotes mesangial fibrosis-like change and accelerates renal fibrosis niche. Subsequently, the transcriptome sequencing and LC-MS/MS analysis indicated that MSC-sEV intervention could restore the levels of the kinase ubiquitin system in DKD and attenuate renal interstitial fibrosis via delivering CK1δ/ß-TRCP to mediate YAP ubiquitination degradation in mesangial cells. Our findings demonstrate the unique cellular and molecular mechanisms of MSC-sEV in treating the DKD fibrosis niche at a single-cell level and provide a novel therapeutic strategy for renal fibrosis.
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Nefropatias Diabéticas , Vesículas Extracelulares , Fibrose , Células-Tronco Mesenquimais , Análise de Célula Única , Transcriptoma , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Camundongos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/terapia , Masculino , Camundongos Endogâmicos C57BL , Humanos , Macrófagos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Células Mesangiais/metabolismo , Rim/patologia , Rim/metabolismoRESUMO
Extracellular vesicles (EVs) are minute sacs released by cells into the extracellular milieu, harboring an array of biomolecules including proteins, nucleic acids, and lipids. Notably, a large number of studies have demonstrated the important involvement of EVs in both physiological and pathological aspects of renal function. EVs can facilitate communication between different renal cells, but it is important to recognize their dual role: they can either transmit beneficial information or lead to renal damage and worsening of existing conditions. The composition of EVs in the context of the kidneys offers valuable insights into the intricate mechanisms underlying specific renal functions or disease states. In addition, mesenchymal stem cell-derived EVs have the potential to alleviate acute and chronic kidney diseases. More importantly, the innate nanoparticle properties of EVs, coupled with their engineering potential, make them effective tools for drug delivery and therapeutic intervention. In this review, we focus on the intricate biological functions of EVs in the kidney. In addition, we explore the emerging role of EVs as diagnostic tools and innovative therapeutic agents in a range of renal diseases.
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Vesículas Extracelulares , Nefropatias , Rim , Humanos , Vesículas Extracelulares/metabolismo , Animais , Rim/metabolismo , Rim/fisiopatologia , Rim/patologia , Nefropatias/terapia , Nefropatias/fisiopatologia , Nefropatias/metabolismo , Sistemas de Liberação de MedicamentosRESUMO
OBJECTIVES: In this study we aimed to assess the impact of acetylation of hepatocyte nuclear factor 4α (HNF4α) on lysine 458 on the differentiation therapy of hepatocellular carcinoma (HCC). METHODS: Periodic acid-Schiff (PAS) staining, Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake, and senescence-associated ß-galactosidase (SA-ß-gal) activity analysis were performed to assess the differentiation of HCC cells. HNF4α protein was detected by western blot and immunohistochemistry (IHC). The effects of HNF4α-K458 acetylation on HCC malignancy were evaluated in HCC cell lines, a Huh-7 xenograft mouse model, and an orthotopic model. The differential expression genes in Huh-7 xenograft tumors were screened by RNA-sequencing analysis. RESULTS: K458R significantly enhanced the inhibitory effect of HNF4α on the malignancy of HCC cells, whereas K458Q reduced the inhibitory effects of HNF4α. Moreover, K458R promoted, while K458Q decreased, HNF4α-induced HCC cell differentiation. K458R stabilized HNF4α, while K458Q accelerated the degradation of HNF4α via the ubiquitin proteasome system. K458R also enhanced the ability of HNF4α to inhibit cell growth of HCC in the Huh-7 xenograft mouse model and the orthotopic model. RNA-sequencing analysis revealed that inhibiting K458 acetylation enhanced the transcriptional activity of HNF4α without altering the transcriptome induced by HNF4α in HCC. CONCLUSION: Our data revealed that inhibiting K458 acetylation of HNF4α might provide a more promising candidate for differential therapy of HCC.
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Carcinoma Hepatocelular , Diferenciação Celular , Fator 4 Nuclear de Hepatócito , Neoplasias Hepáticas , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Acetilação , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Lisina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tripartite motif 8 (TRIM8) is an E3 ligase that plays dual roles in various tumor types. The biological effects and underlying mechanism of TRIM8 in hepatocellular carcinoma (HCC) remain unknown. Hepatocyte nuclear factor 1α (HNF1α) is a key transcriptional factor that plays a significant role in regulating hepatocyte differentiation and liver function. The reduced expression of HNF1α is a critical event in the development of HCC, but the underlying mechanism for its degradation remains elusive. In this study, we discovered that the expression of TRIM8 was upregulated in HCC tissues, and was positively correlated with aggressive tumor behavior of HCC and shorter survival of HCC patients. Overexpression of TRIM8 promoted the proliferation, colony formation, invasion, and migration of HCC cells, while TRIM8 knockdown or knockout exerted the opposite effects. RNA sequencing revealed that TRIM8 knockout suppresses several cancer-related pathways, including Wnt/ß-catenin and TGF-ß signaling in HepG2 cells. TRIM8 directly interacts with HNF1α, promoting its degradation by catalyzing polyubiquitination on lysine 197 in HCC cells. Moreover, the cancer-promoting effects of TRIM8 in HCC were abolished by the HNF1α-K197R mutant in vitro and in vivo. These data demonstrated that TRIM8 plays an oncogenic role in HCC progression through mediating the ubiquitination of HNF1α and promoting its protein degradation, and suggests targeting TRIM8-HNF1α may provide a promising therapeutic strategy of HCC.