RESUMEN
Algal blooms threaten water quality and ecosystem stability in aquatic habitats globally, yet dynamics regulating phytoplankton community assembly, the basis of blooms, remain poorly characterized in small water bodies. Here, we employed high-throughput sequencing to analyze drivers structuring phytoplankton across a trophic gradient of 10 small water bodies over 12 consecutive months. Cyanobacteria and Chlorophyta were identified as potential seed banks priming blooms. Temporal variation in community composition was muted in nutrient-limited waters given Cyanobacteria dominance. Environmental factors and interspecific relationships jointly governed temporal phytoplankton dynamics. Phytoplankton, exhibiting greater sensitivity, responded more rapidly than bacterioplankton to environmental and biological fluctuations. This research provides a robust bench mark characterizing planktonic successional trajectories across small water bodies varying in trophic status. Results reinforce ecological mechanisms underpinning biological control strategies to mitigate algal proliferation and inform water quality management of these ubiquitous aquatic ecosystems.
RESUMEN
This study proposes an innovative strategy for achieving PN in synthetic domestic wastewater by side-stream sludge treatment using sulfide as the sole control factor. By conducting controllable batch experiments and response surface analysis, optimal sulfide treatment conditions were firstly determined as 90 mg/L of sulfide, 7.5 of pH, 100 rpm of rotation and 12 h of treatment time. After treatment, half of ammonia oxidizing bacteria (AOB) activity remained, but nitrite oxidizing bacteria (NOB) activity was barely detected. Nitrite accumulation rate of long-term running PN steadily reached 83.9 % with 99.1 % of ammonia removal efficiency. Sulfide treatment increased community diversity and facilitated stability of microbiota functioning with PN phenotype, which might be sustained by the positive correlation between ammonia oxidation gene (amoA) and sulfur oxidation gene (soxB). Correspondingly, the network analysis identified the keystone microbial taxa of persistent PN microbiota as Nitrosomonas, Thauera, Truepera, Defluviimonas and Sulitalea in the later stage of long-term reactor.
Asunto(s)
Amoníaco , Bacterias , Nitrificación , Aguas del Alcantarillado , Sulfuros , Sulfuros/química , Aguas del Alcantarillado/microbiología , Bacterias/metabolismo , Bacterias/genética , Amoníaco/metabolismo , Reactores Biológicos/microbiología , Nitritos/metabolismo , Purificación del Agua/métodos , MicrobiotaRESUMEN
Bacillus velezensis M3-1 strain isolated from the sediment of Myriophyllum aquatium constructed wetlands was found to efficiently convert NO3--N to NO2--N, and the requirements for carbon source addition were not very rigorous. This work demonstrates, for the first time, the feasibility of using the synergy of anammox and Bacillus velezensis M3-1 microorganisms for nitrogen removal. In this study, the possibility of M3-1 that converted NO3--N produced by anammox to NO2--N was verified in an anaerobic reactor. The NO3--N reduction ability of M3-1 and denitrifying bacteria in coupling system was investigated under different C/N conditions, and it was found that M3-1 used carbon sources preferentially over denitrifying bacteria. By adjusting the ratio of NH4+-N to NO2--N, it was found that the NO2--N converted from NO3--N by M3-1 participated in the original anammox.The nitrogen removal efficacy (NRE) of the coupled system was increased by 12.1%, compared to the control group anammox system at C/N = 2:1. Functional gene indicated that it might be a nitrate reducing bacterium.This study shows that the nitrate reduction rate achieved by the Bacillus velezensis M3-1 can be high enough for removing nitrate produced by anammox process, which would enable improve nitrogen removal from wastewater.
Asunto(s)
Amoníaco , Bacillus , Nitratos , Nitrógeno , Oxidación-Reducción , Bacillus/metabolismo , Nitrógeno/metabolismo , Nitratos/metabolismo , Amoníaco/metabolismo , Anaerobiosis , Eliminación de Residuos Líquidos/métodos , DesnitrificaciónRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system, and the exact mechanism of HCC is still unclear. Transcription factor 7 like 2 (TCF7L2) plays a pivotal role in cell proliferation and stemness maintenance. However, the exact mechanism of TCF7L2 in HCC remains unclear. METHODS: Clinical samples and public databases were used to analyze the expression and prognosis of TCF7L2 in HCC. The function of TCF7L2 in HCC was studied in vitro and in vivo. ChIP and luciferase assays were used to explore the molecular mechanism of TCF7L2. The relationship between TCF7L2 and NEDD9 was verified in HCC clinical samples by tissue microarrays. RESULTS: The expression of TCF7L2 was upregulated in HCC, and high expression of TCF7L2 was associated with poor prognosis of HCC patients. Overexpression of TCF7L2 promoted the metastasis of HCC in vitro and in vivo, while Knockdown of TCF7L2 showed the opposite effect. Mechanically, TCF7L2 activated neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) transcription by binding to the -1522/-1509 site of the NEDD9 promoter region, thereby increasing the phosphorylation levels of AKT and mTOR. The combination of TCF7L2 and NEDD9 could distinguish the survival of HCC patients. CONCLUSIONS: This study demonstrated that TCF7L2 promotes HCC metastasis by activating AKT/mTOR pathway in a NEDD9-dependent manner, suggesting that potential of TCF7L2 and NEDD9 as prognostic markers and therapeutic targets for HCC.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Carcinoma Hepatocelular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Proteína 2 Similar al Factor de Transcripción 7 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/mortalidad , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/mortalidad , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/genética , Línea Celular Tumoral , Animales , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Ratones , Pronóstico , Masculino , Metástasis de la Neoplasia , Femenino , Proliferación Celular , Persona de Mediana Edad , Ratones DesnudosRESUMEN
In this study, the activation of peroxydisulfate (PS) by K2FeO4-activation biochar (KFeB) and acid-picking K2FeO4-activation biochar (AKFeB) was investigated to reveal the mechanism differences between iron site and graphitic structure in sulfadiazine (SDZ) degradation and ARB inactivation, respectively. KFeB/PS and AKFeB/PS systems had similar degradation property towards SDZ, but only KFeB/PS system showed excellent bactericidal property. The mechanism study demonstrated that dissolved SDZ was degraded through electron transfer pathway mediated by graphitic structure, while suspended ARB was inactivated through free radicals generated by iron-activated PS, accompanied by excellent removal on antibiotic resistance genes (ARGs). The significant decrease in conjugative transfer frequency indicated the reduced horizontal gene transfer risk of ARGs after treatment with KFeB/PS system. Transcriptome data suggested that membrane protein channel disruption and adenosine triphosphate synthesis inhibition were key reasons for conjugative transfer frequency reduction. Continuous flow reactor of KFeB/PS system can efficiently remove antibiotics and ARB, implying the potential application in practical wastewater purification. In conclusion, this study provides novel insights for classified and collaborative control of antibiotics and ARB by carbon-based catalysts driven persulfate advanced oxidation technology.
Asunto(s)
Antibacterianos , Carbón Orgánico , Grafito , Hierro , Sulfadiazina , Sulfatos , Carbón Orgánico/química , Sulfadiazina/química , Antibacterianos/química , Antibacterianos/farmacología , Hierro/química , Hierro/metabolismo , Grafito/química , Sulfatos/química , Sulfatos/metabolismo , Contaminantes Químicos del Agua/química , Farmacorresistencia Bacteriana/genética , Farmacorresistencia Microbiana/genética , Bacterias/metabolismo , Bacterias/efectos de los fármacos , Bacterias/genética , Purificación del Agua/métodos , Peróxidos/químicaRESUMEN
Emerging pollutants (EPs) are prevalent in aquatic environments globally. Researchers strive to understand their occurrence and behavior prior to their release into the environment. In this study, we examined five wastewater treatment plants (WWTPs), collected 50 wastewater samples and 10 sludge samples. We explored the sources and destinations of phthalic acid esters (PAEs) within these WWTPs using mass balance equations. Wastewater treatment diminished the frequency and concentration of PAEs, and decreased the fraction of short-chain PAEs. We confirmed the increased concentration of PAEs post-primary treatment and modified the mass balance equation. Calculations suggest that weaker "the mix" in winter than in summer and stronger sedimentation in winter than in summer resulted in high efficiency of PAEs removal by winter wastewater treatment. The mass flux of biodegradation was influenced by the combination of biodegradation efficiency and the strength of the particular type of PAEs collected, with no seasonal differences. Mass fluxes for sludge sedimentation were mainly influenced by season and were higher in winter than in summer. This study enhances our understanding of emerging pollutants in manual treatment facilities and offers insights for optimizing wastewater treatment methods for water professionals.
Asunto(s)
Ésteres , Ácidos Ftálicos , Estaciones del Año , Eliminación de Residuos Líquidos , Aguas Residuales , Contaminantes Químicos del Agua , Ácidos Ftálicos/análisis , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/química , Aguas Residuales/química , Ésteres/análisis , Ésteres/química , Eliminación de Residuos Líquidos/métodos , Aguas del Alcantarillado/química , Biodegradación Ambiental , Purificación del Agua/métodosRESUMEN
Electron transfer pathways have been verified as overriding regimes when peroxydisulfate (PDS) was activated by porous carbon. The incorporation of graphitic structure into carbon matrix was favorable to the rapid electron transfer, but excessive graphitization would deteriorate the specific surface area (SSA), weakening the catalytic performance. The reasonable trade-off between SSA and graphitization degree was necessary and challenging for the preparation of efficient carbon based PS-activators. Herein, a series of graphitic porous carbon with discrepant SSA and graphitic structure were fabricated. The incorporation of graphitization tracks into ultra-thin edges on porous carbon film was verified by multifarious structural characterization. After trade-off, the optimum catalyst exhibited superior catalytic performance with degradation rate constant (kobs) exceeding that of ungraphitized precursor by up to 16.0 times. Mechanistic investigations substantiated that the sufficient SSA of catalyst provided favorable conditions for its affinity towards PDS and sulfadiazine (SDZ), resulting in the formation of PDS* complexes and SDZ adsorption, while the appropriate graphitization degree ensured the reinforced electron transfer rate, which collectively accelerated SDZ oxidation through electron-transfer pathway. The multivariate linear regression model linking kobs to SSA and graphitization degree was established providing basis to construct efficient catalysts for PDS activation.
RESUMEN
Transcription factor BTB domain and CNC homology 1 (BACH1) belongs to the Cap 'n' Collar and basic region Leucine Zipper (CNC-bZIP) family. BACH1 is widely expressed in mammalian tissues, where it regulates epigenetic modifications, heme homeostasis, and oxidative stress. Additionally, it is involved in immune system development. More importantly, BACH1 is highly expressed in and plays a key role in numerous malignant tumors, affecting cellular metabolism, tumor invasion and metastasis, proliferation, different cell death pathways, drug resistance, and the tumor microenvironment. However, few articles systematically summarized the roles of BACH1 in cancer. This review aims to highlight the research status of BACH1 in malignant tumor behaviors, and summarize its role in immune regulation in cancer. Moreover, this review focuses on the potential of BACH1 as a novel therapeutic target and prognostic biomarker. Notably, the mechanisms underlying the roles of BACH1 in ferroptosis, oxidative stress and tumor microenvironment remain to be explored. BACH1 has a dual impact on cancer, which affects the accuracy and efficiency of targeted drug delivery. Finally, the promising directions of future BACH1 research are prospected. A systematical and clear understanding of BACH1 would undoubtedly take us one step closer to facilitating its translation from basic research into the clinic.
RESUMEN
Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Accumulating evidence indicates that hypoxia and lactate metabolism play critical roles in tumor progression and therapeutic efficacy. This study aimed to construct a hypoxia- and lactate metabolism-related prognostic model (HLPM) to evaluate survival and treatment responses for HCC patients and develop a nomogram integrated with HLPM and clinical characteristics for prognosis prediction in HCC. Methods: Expression profile and clinical data of HCC were obtained from TCGA and ICGC databases. The univariate, LASSO and stepwise multivariate Cox analyses were used to identify the hypoxia- and lactate metabolism-related biomarkers, whose expression levels were then validated in 14 pairs tissue samples and single-cell RNA sequencing dataset. Kaplan-Meier survival curves were utilized to assess the prognostic values of biomarkers or models. Analyses of ImmuCellAI, TIDE and drug sensitivity were conducted to evaluate the therapeutic responses of patients. Furthermore, the nomogram integrated with hypoxic and lactate metabolic characteristics was established through univariate and multivariate Cox analyses. ROC curves, C-index, and calibration curves were depicted to evaluate the performance of the nomogram. Results: Five hypoxia- and lactate metabolism-related biomarkers (KIF20A, IRAK1, ADM, PPARGC1A and EPO) were used to construct HLPM. The expression of five prognostic biomarkers was validated in 14 pairs tissue samples and single-cell RNA sequencing dataset. Analyses of ImmuCellAI, TIDE and drug sensitivity implied that patients with low-risk score were more sensitive to immunotherapy and major chemotherapeutic agents. The nomogram that contained age, histological grade and risk score of HLPM was developed and exhibited a better capacity in prognosis prediction than HLPM only. Conclusion: A novel nomogram integrated with hypoxic and lactate metabolic characteristics was developed and validated for prognosis prediction in HCC, providing insight into personalized decision-making in clinical management.
RESUMEN
The sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) family, composed of 20 transcription factors, is a conserved family with a highly homologous HMG domain. Due to their crucial role in determining cell fate, the dysregulation of SOX family members is closely associated with tumorigenesis, including tumor invasion, metastasis, proliferation, apoptosis, epithelial-mesenchymal transition, stemness and drug resistance. Despite considerable research to investigate the mechanisms and functions of the SOX family, confusion remains regarding aspects such as the role of the SOX family in tumor immune microenvironment (TIME) and contradictory impacts the SOX family exerts on tumors. This review summarizes the physiological function of the SOX family and their multiple roles in tumors, with a focus on the relationship between the SOX family and TIME, aiming to propose their potential role in cancer and promising methods for treatment.
RESUMEN
Research on liver transplantation (LT) for liver cancer has gained increasing attention. This paper has comprehensively described the current status, hotspots and trends in this field. A total of 2991 relevant articles from 1 January 1963 to 28 February 2023 were obtained from the Web of Science Core Collection. VOSviewer and CiteSpace software were utilized as bibliometric tools to analyze and visualize knowledge mapping. Between 1963 and 2023, the number of papers in the area of LT for liver cancer increased continuously. A total of 70 countries/regions, 2303 institutions and 14 840 researchers have published research articles, with the United States and China being the two most productive countries. Our bibliometric-based visual analysis revealed the expansion of LT indications for liver cancer and the prevention/treatment of cancer recurrence as ongoing research hotspots over the past decades. Meanwhile, emerging studies also focus on downstaging/bridging treatments before LT and the long-term survival of LT recipient, in particular the precise application of immunosuppressants.
Asunto(s)
Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Neoplasias Hepáticas/cirugía , Bibliometría , China , InmunosupresoresRESUMEN
The start-up and stable operation of partial nitritation-anammox (PN/A) treatment of mature landfill leachate (MLL) still face challenges. This study developed an innovative staged pilot-scale PN/A system to enhance nitrogen removal from MLL. The staged process included a PN unit, an anammox upflow enhanced internal circulation biofilm (UEICB) reactor, and a post-biofilm unit. Rapid start-up of the continuous flow PN process (full-concentration MLL) was achieved within 35 days by controlling dissolved oxygen and leveraging free ammonia and free nitrous acid to selectively suppress nitrite-oxidizing bacteria (NOB). The UEICB was equipped with an annular flow agitator combined with the enhanced internal circulation device of the guide tube, which achieved an efficient enrichment of Candidatus Kuenenia in the biofilm (relative abundance of 33.4â¯%). The nitrogen removal alliance formed by the salt-tolerant anammox bacterium (Candidatus Kuenenia) and denitrifying bacteria (unclassified SBR1031 and Denitratisoma) achieved efficient nitrogen removal of UEICB (total nitrogen removal percentage: 90.8â¯%) and at the same time effective treatment of the refractory organic matter (ROM). The dual membrane process of UEICB fixed biofilm combined with post-biofilm is effective in sludge retention, and can stably control the effluent suspended solids (SS) at a level of less than 5â¯mg/L. The post-biofilm unit ensured that effluent total nitrogen (TN) remained below the 40â¯mg/L discharge standard (98.5â¯% removal efficiency). Compared with conventional nitrification-denitrification systems, the staged PN/A process substantially reduced oxygen consumption, sludge production, CO2 emissions and carbon consumption by 22.8â¯%, 67.1â¯%, 87.1â¯% and 87.1â¯%, respectively. The 195-day stable operation marks the effective implementation of the innovative pilot-scale PN/A process in treating actual MLL. This study provides insights into strategies for rapid start-up, robust NOB suppression, and anammox biomass retention to advance the application of PN/A in high-ammonia low-carbon wastewater.
Asunto(s)
Desnitrificación , Contaminantes Químicos del Agua , Amoníaco , Nitritos , Nitrógeno , Aguas del Alcantarillado , Biomasa , Oxidación Anaeróbica del Amoníaco , Reactores Biológicos/microbiología , Oxidación-Reducción , Nitrificación , Bacterias , CarbonoRESUMEN
Gastric cancer is one of the most common causes of cancer-related death worldwide. The N6 -methyladenosine (m6 A) reader IGF2BP1 (insulin-like growth factor-2 mRNA binding protein 1) has been reported to promote cancer progression by stabilizing oncogenic mRNAs through its m6 A-binding activity in some tumors. However, the role of IGF2BP1 in gastric carcinogenesis remains unclear. In this study, we found that IGF2BP1 is significantly downregulated in tumor tissues from patients with gastric cancer. Lower expression of IGF2BP1 is associated with poor prognosis. Gastric cancer cell proliferation is suppressed by IGF2BP1 in an m6 A-dependent manner. Additionally, IGF2BP1 is able to significantly attenuate tumor growth of gastric cancer cells. Further m6 A sequencing and m6 A-RNA immunoprecipitation assays show that MYC (c-myc proto-oncogene) mRNA is a target transcript of IGF2BP1 in gastric cancer cells. IGF2BP1 inhibits gastric cancer cell proliferation by reducing the mRNA and protein expression of MYC. Mechanistically, IGF2BP1 promotes the degradation of MYC mRNA and inhibits its translation efficiency. Taken together, these data suggest that IGF2BP1 plays a tumor-suppressive role in gastric carcinogenesis by downregulating MYC in an m6 A-dependent manner, thereby making the IGF2BP1-MYC axis a potential target for gastric cancer treatment.
Asunto(s)
Neoplasias Gástricas , Humanos , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Neoplasias Gástricas/genéticaRESUMEN
BACKGROUND AND AIMS: RNA splicing is an essential step in regulating the gene posttranscriptional expression. Serine/arginine-rich splicing factors (SRSFs) are splicing regulators with vital roles in various tumors. Nevertheless, the expression patterns and functions of SRSFs in hepatocellular carcinoma (HCC) are not fully understood. METHODS: Flow cytometry and immunofluorescent staining were used to determine the CD8+T cell infiltration. Orthotopic HCC model, lung metastasis model, DEN/CCl4 model, Srsf10â³hep model, and Srsf10HepOE model were established to evaluate the role of SRSF10 in HCC and the efficacy of combination treatment. RESULTS: SRSF10 was one of the most survival-relevant genes among SRSF members and was an independent prognostic factor for HCC. SRSF10 facilitated HCC growth and metastasis by suppressing CD8+T cell infiltration. Mechanistically, SRSF10 down-regulated the p53 protein by preventing the exon 6 skipping (exon 7 in mouse) mediated degradation of MDM4 transcript, thus inhibiting CD8+T cell infiltration. Elimination of CD8+T cells or overexpression of MDM4 removed the inhibitory role of SRSF10 knockdown in HCC growth and metastasis. SRSF10 also inhibited the IFNα/γ signaling pathway and promoted the HIF1α-mediated up-regulation of PD-L1 in HCC. Hepatocyte-specific SRSF10 deficiency alleviated the DEN/CCl4-induced HCC progression and metastasis, whereas hepatocyte-specific SRSF10 overexpression deteriorated these effects. Finally, SRSF10 knockdown enhanced the anti-PD-L1-mediated anti-tumor activity. CONCLUSIONS: SRSF10 promoted HCC growth and metastasis by repressing CD8+T cell infiltration mediated by the MDM4-p53 axis. Furthermore, SRSF10 suppressed the IFNα/γ signaling pathway and induced the HIF1α signal mediated PD-L1 up-regulation. Targeting SRSF10 combined with anti-PD-L1 therapy showed promising efficacy.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Ratones , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/metabolismo , Factores de Empalme Serina-Arginina/genética , Factores de Empalme Serina-Arginina/metabolismo , Proteínas Represoras/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMEN
Ubiquitin-specific protease 22 (USP22) has been identified as a potential marker for cancer stem cells in hepatocellular carcinoma (HCC). It can promote HCC stemness, which is considered a driver of tumorigenesis. Here, we sought to determine the role of USP22 in tumorigenesis, elucidate its underlying mechanism, and explore its therapeutic significance in HCC. As a result, we found that tissue-specific Usp22 overexpression accelerated tumorigenesis, whereas Usp22 ablation decelerated it in a c-Myc/NRasGV12-induced HCC mouse model and that the mammalian target of rapamycin complex 1 (mTORC1) pathway was activated downstream. USP22 overexpression resulted in increased tumorigenic properties that were reversed by rapamycin in vitro and in vivo. In addition, USP22 activated mTORC1 by deubiquitinating FK506-binding protein 12 (FKBP12) and activated mTORC1, in turn, further stabilizing USP22 by inhibiting autophagic degradation. Clinically, HCC patients with high USP22 expression tend to benefit from mTOR inhibitors after liver transplantation (LT). Our results revealed that USP22 promoted tumorigenesis and progression via an FKBP12/mTORC1/autophagy positive feedback loop in HCC. Clinically, USP22 may be an effective biomarker for selecting eligible recipients with HCC for anti-mTOR-based therapy after LT.
RESUMEN
Ferroptosis, which is driven by iron-dependent lipid peroxidation, plays an essential role in liver ischemia-reperfusion injury (IRI) during liver transplantation (LT). Gp78, an E3 ligase, has been implicated in lipid metabolism and inflammation. However, its role in liver IRI and ferroptosis remains unknown. Here, hepatocyte-specific gp78 knockout (HKO) or overexpressed (OE) mice were generated to examine the effect of gp78 on liver IRI, and a multi-omics approach (transcriptomics, proteomics, and metabolomics) was performed to explore the potential mechanism. Gp78 expression decreased after reperfusion in LT patients and mice with IRI, and gp78 expression was positively correlated with liver damage. Gp78 absence from hepatocytes alleviated liver damage in mice with IRI, ameliorating inflammation. However, mice with hepatic gp78 overexpression showed the opposite phenotype. Mechanistically, gp78 overexpression disturbed lipid homeostasis, remodeling polyunsaturated fatty acid (PUFA) metabolism, causing oxidized lipids accumulation and ferroptosis, partly by promoting ACSL4 expression. Chemical inhibition of ferroptosis or ACSL4 abrogated the effects of gp78 on ferroptosis and liver IRI. Our findings reveal a role of gp78 in liver IRI pathogenesis and uncover a mechanism by which gp78 promotes hepatocyte ferroptosis by ACSL4, suggesting the gp78-ACSL4 axis as a feasible target for the treatment of IRI-associated liver damage.
Asunto(s)
Ferroptosis , Hepatocitos , Hepatopatías , Receptores del Factor Autocrino de Motilidad , Daño por Reperfusión , Animales , Humanos , Ratones , Hepatocitos/enzimología , Inflamación/metabolismo , Hepatopatías/metabolismo , Daño por Reperfusión/metabolismo , Trasplante de Hígado , Receptores del Factor Autocrino de Motilidad/genética , Receptores del Factor Autocrino de Motilidad/metabolismo , Coenzima A LigasasRESUMEN
Urban wastewater, as the main influent type of Waste Water Treatment Plants (WWTPs), has the characteristic of low carbon to nitrogen ratio (C/N). In the biological nitrogen removal (BNR) process, insufficient carbon source often affects the nitrogen removal efficiency and leads to more N2O emissions. We review recent researches on N2O emissions in the BNR process of wastewater with low C/N. The availability of carbon sources affects heterotrophic denitrification (HD) and autotrophic nitrification/denitrification processes, which are the main reasons for N2O emissions in BNR. For the sustainable development of BNR in WWTPs, we introduce strategies suitable for reducing N2O emissions in the BNR process of low C/N wastewater from two aspects: traditional process innovation and new process development. These strategies mainly include carbon source addition, adjustment of aeration strategy, optimization of oxidation ditch and biofilm facilities, and application of Anammox related processes. In the future, it is still necessary to further deepen this research direction through the normalization of N2O emission quantification standards, exploration of N2O metabolism mechanisms, assessment of environmental effects of emission reduction strategies, and practical application of new processes.
RESUMEN
BACKGROUND: Immunotherapy has facilitated great breakthroughs in the treatment of hepatocellular carcinoma (HCC). However, the efficacy and response rate of immunotherapy are limited and vary among different patients with HCC. TP53 mutation substantially affects the expression of immune checkpoint molecules in multiple cancers. However, the regulatory relationship between programmed death ligand 1 (PD-L1) and TP53 is poorly studied in HCC. We aimed to elucidate the regulatory mechanism of PD-L1 in HCC with different TP53 statuses and to assess its role in modulating immune evasion in HCC. METHODS: HCC mouse models and cell lines with different TP53 statuses were constructed. PD-L1 levels were detected by PCR, western blotting and flow cytometry. RNA-seqencing, immunoprecipitation, chromatin immunoprecipitation and transmission electron microscopy were used to elucidate the regulatory mechanism in HCC with different TP53 status. HCC mouse models and patient with HCC samples were analyzed to demonstrate the preclinical and clinical significance of the findings. RESULTS: We report that loss of p53 promoted PD-L1 expression and reduced CD8+ T-cell infiltration in patient with HCC samples and mouse models. Mammalian target of rapamycin (mTOR) pathway was activated in p53-loss-of-function HCC or after knocking down TP53. The transcription factor E2F1 was found to bind to the p53 protein in TP53 wild-type HCC cells, and inhibiting mammalian target of rapamycin complex 1 (mTORC1) disrupted this binding and enhanced E2F1 translocation to the nucleus, where it bound to the PD-L1 promoter and transcriptionally upregulated PD-L1. In p53-loss-of-function HCC cells, autophagosomes were activated after mTORC1 suppression, promoting the degradation of PD-L1 protein. The combination of mTOR inhibitor and anti-PD-L1 antibody enhanced CD8+ T-cell infiltration and tumor suppression in TP53 wild-type HCC mouse models, but no benefit was observed in p53-loss-of-function HCC mouse models. In patients with TP53 wild-type HCC, PD-L1 levels were significantly higher in the high E2F1 group than in the low E2F1 group, and the low E2F1 level group had significantly superior survival. CONCLUSION: We revealed the bidirectional regulatory mechanism of PD-L1 mediated by TP53/mTORC1 in HCC. The combination of mTOR inhibitor and anti-PD-L1 antibody could be a novel precise immunotherapy scheme for TP53 wild-type HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/patología , Antígeno B7-H1/metabolismo , Neoplasias Hepáticas/patología , Proteína p53 Supresora de Tumor/genética , Evasión Inmune , Serina-Treonina Quinasas TOR/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Mamíferos/metabolismoRESUMEN
BACKGROUND: Hepatic ischemia-reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous. METHODS: Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2. RESULTS: Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate). CONCLUSIONS: Insig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.
Asunto(s)
Hepatocitos , Insulinas , Hepatopatías , Daño por Reperfusión , Animales , Ratones , Antioxidantes/metabolismo , Apoptosis/genética , Glucosa/metabolismo , Hepatectomía/efectos adversos , Hepatocitos/metabolismo , Hepatocitos/patología , Hipoxia/complicaciones , Hipoxia/genética , Hipoxia/metabolismo , Insulinas/metabolismo , Hígado/irrigación sanguínea , Hígado/lesiones , Hígado/metabolismo , Hígado/patología , Hepatopatías/genética , Hepatopatías/metabolismo , Hepatopatías/patología , Hepatopatías/cirugía , Trasplante de Hígado/efectos adversos , Fosfatos/metabolismo , Fosfatos/farmacología , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/prevención & controlRESUMEN
The squeezed liquid from fruit and vegetable waste (LW) presents a unique wastewater challenge, marked by recalcitrance in treatment and amplified design risks with the application of conventional processes. Following coagulation of the squeezed liquid, the majority of particulate matter precipitates. The resulting precipitated floc (LWF) is reclaimed and subsequently utilized for the synthesis of biochar. The present study primarily explores the viability of repurposing LWF as biochar to enhance soil quality and mitigate N2O emissions. Findings indicate that the introduction of a 2% proportion of LWFB led to a remarkable 99.5% reduction in total N2O emissions in contrast to LWF. Concurrently, LWFB substantially enhanced nutrients content by elevating soil organic carbon (SOC) and nitrogen levels. Utilizing high-throughput sequencing in conjunction with qPCR, the investigation unveiled that the porous structure and substantial specific surface area of LWFB potentially fostered microbial adhesion and heightened diversity within the soil microbial community. Furthermore, LWFB notably diminished the relative abundance of AOB (Nitrosospira, Nitrosomonas), and NOB (Candidatus_Nitrotoga), thereby curbing the conversion of NH4+ into NO3-. The pronounced elevation in nosZ abundance implies that LWFB holds the potential to mitigate N2O emissions through a conversion to N2.