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Chiral metal-organic frameworks (CMOFs) with chiral selectivity are one of the high-quality stationary phases for capillary electrochromatography (CEC). However, there is a problem of unsatisfactory enantioseparation performance of capillary columns due to insufficient loading. In this work, a lamellar CMOF (Cu-TC) was grown in situ on the surface of the monolith in a capillary monolithic column to obtain a Cu-TC@monolithic column. The CEC system constructed based on the Cu-TC@monolithic column shows a satisfactory chiral separation performance. Compared with the Cu-TC-based coated column (Cu-TC@coated column), the enantioseparation performance of the CEC system based on the Cu-TC@monolithic column was greatly improved, and the resolutions (Rs) of the model analytes were increased by 80-500%. In addition, the effects of experimental conditions such as the number of cycles of Cu-TC in situ growth, buffer concentration, buffer pH, organic solvent addition and applied voltage on the performance of CEC were also investigated. Finally, the chiral selection mechanism of the stationary phase was explored by selective adsorption experiments. The present work provides a new idea for the development of capillary stationary phases, which has great potential considering the diversity of CMOFs.
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BACKGROUND: Whole-brain radiotherapy (WBRT) is a standard and effective approach for brain metastases, but it is linked to neurocognitive complications, specifically issues related to the hippocampus. Innovative strategies are being explored to enhance outcomes. However, a consensus is yet to be reached in this field. Our aim is to investigate the efficacy and safety of WBRT combined with simultaneous integrated boost (SIB), memantine, and hippocampal avoidance (HA) techniques in treatment of brain metastases. METHODS: In this systematic review and meta-analysis, we comprehensively searched PubMed, MEDLINE, Embase, and Cochrane for studies reporting the efficacy and toxicity of WBRT-based combination therapies from inception to September 19, 2023. Data were pooled using random-effects models. Results were reported as risk ratios (RRs) and risk differences (RDs) for dichotomous outcomes, along with their 95% confidence intervals (CIs). Heterogeneity was evaluated using the I2 statistic. RESULTS: Among 2175 articles, 29 studies involving 3460 patients were included. The meta-analysis revealed that compared to WBRT alone, combination therapies significantly mitigated neurocognitive function decline (RD = -0.09, 95% CI [-0.18-0.01]; P = 0.03) and intracranial control failure (RR = 0.86, 95% CI [0.52-1.44]; P = 0.02), without increasing the risk of hippocampal recurrence or high-grade toxicities. Notably, HA-WBRT + SIB/memantine demonstrated improved neurocognitive outcomes and survival benefits. CONCLUSION: WBRT-based combination therapies demonstrate improved efficacy and comparable safety to WBRT alone, with specific emphasis on the effectiveness of HA-WBRT + Memantine and HA-WBRT + SIB in optimizing therapeutic outcomes for brain metastases.
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By combining the porosity of crystalline metal-organic frameworks (MOFs) with the unique processability of the liquid state, melt-quenched MOF glasses offer exciting opportunities for molecular separation. However, progress in this field is limited by two factors. Firstly, only very few MOFs melt at elevated temperatures and transform into stable glasses upon cooling the corresponding MOF liquid. Secondly, the MOF glasses obtained thus far feature only very small porosities and very small pore sizes. Here, we demonstrate solvent-assisted linker exchange (SALE) as a versatile method to prepare highly porous melt-quenched MOF glasses from the canonical ZIF-8. Two additional organic linkers are incorporated into the non-meltable ZIF-8, yielding high-entropy, linker-exchanged ZIF-8 derivatives undergoing crystal-to-liquid-to-glass phase transitions by thermal treatment. The ZIF-8 glasses demonstrate specific pore volumes of about 0.2 cm3g-1, adsorb large amounts of technologically relevant C3 and C4 hydrocarbons, and feature high kinetic sorption selectivities for the separation of propylene from propane.
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Immunotherapy has revolutionized cancer treatment, with the anti-PD-1/PD-L1 axis therapy demonstrating significant clinical efficacy across various tumor types. However, it should be noted that this therapy is not universally effective for all PD-L1-positive patients, highlighting the need to expedite research on the second ligand of PD-1, known as Programmed Cell Death Receptor Ligand 2 (PD-L2). As an immune checkpoint molecule, PD-L2 was reported to be associated with patient's prognosis and plays a pivotal role in cancer cell immune escape. An in-depth understanding of the regulatory process of PD-L2 expression may stratify patients to benefit from anti-PD-1 immunotherapy. Our review focuses on exploring PD-L2 expression in different tumors, its correlation with prognosis, regulatory factors, and the interplay between PD-L2 and tumor treatment, which may provide a notable avenue in developing immune combination therapy and improving the clinical efficacy of anti-PD-1 therapies.
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Antígeno B7-H1 , Neoplasias , Humanos , Ligandos , Neoplasias/terapia , Pronóstico , ApoptosisRESUMEN
Radiological heart damage (RIHD) is damage caused by unavoidable irradiation of the heart during chest radiotherapy, with a long latency period and a progressively increasing proportion of delayed cardiac damage due to conventional doses of chest radiotherapy. There is a risk of inducing diseases such as acute/chronic pericarditis, myocarditis, delayed myocardial fibrosis and damage to the cardiac conduction system in humans, which can lead to myocardial infarction or even death in severe cases. This paper details the pathogenesis of RIHD and gives potential targets for treatment at the molecular and cellular level, avoiding the drawbacks of high invasiveness and immune rejection due to drug therapy, medical device implantation and heart transplantation. Injectable hydrogel therapy has emerged as a minimally invasive tissue engineering therapy to provide necessary mechanical support to the infarcted myocardium and to act as a carrier for various bioactive factors and cells to improve the cellular microenvironment in the infarcted area and induce myocardial tissue regeneration. Therefore, this paper combines bioactive factors and cellular therapeutic mechanisms with injectable hydrogels, presents recent advances in the treatment of cardiac injury after RIHD with different injectable gels, and summarizes the therapeutic potential of various types of injectable hydrogels as a potential solution.
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Hidrogeles , Inyecciones , Hidrogeles/química , Humanos , Animales , Traumatismos por Radiación/terapia , Traumatismos por Radiación/etiología , Cardiopatías/terapia , Cardiopatías/etiología , Ingeniería de Tejidos , Infarto del Miocardio/terapiaRESUMEN
Positron emission tomography/magnetic resonance imaging (PET/MRI) is a hybrid imaging technique that quantitatively combines the metabolic and functional data from positron emission tomography (PET) with anatomical and physiological information from MRI. As PET/MRI technology has advanced, its applications in cancer care have expanded. Recent studies have demonstrated that PET/MRI provides unique advantages in the field of radiotherapy and has become invaluable in guiding precision radiotherapy techniques. This review discusses the rationale and clinical evidence supporting the use of PET/MRI for radiation positioning, target delineation, efficacy evaluation, and patient surveillance.Critical relevance statement This article critically assesses the transformative role of PET/MRI in advancing precision radiotherapy, providing essential insights into improved radiation positioning, target delineation, efficacy evaluation, and patient surveillance in clinical radiology practice.Key points⢠The emergence of PET/MRI will be a key bridge for precise radiotherapy.⢠PET/MRI has unique advantages in the whole process of radiotherapy.⢠New tracers and nanoparticle probes will broaden the use of PET/MRI in radiation.⢠PET/MRI will be utilized more frequently for radiotherapy.
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Non-invasive external energy triggered efficient tumor therapy is a promising specific treatment strategy. Herein, a composite material of bismuth sodium titanate (BNT) and molybdenum disulfide (MoS2) with piezoelectric effect was designed for the synergistic treatment of breast cancer with near-infrared-II (NIR-II) light and ultrasound (US) activation. The BNT@MoS2 exhibit excellent photothermal and acoustic properties upon excitation by 1060 nm NIR-II laser and US, respectively. The synergistic effect of hyperthermia and reactive oxygen species (ROS) under photoacoustic action endows the BNT@MoS2 with remarkable anti-tumor activities, enabling them to eradicate breast cancer cells within 10 min. The work could provide new insights into the treatment of breast cancer.
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BACKGROUND: The U-box gene family encodes E3 ubiquitin ligases involved in plant hormone signaling pathways and abiotic stress responses. However, there has yet to be a comprehensive analysis of the U-box gene family in maize (Zea mays L.) and its responses to abiotic stress. RESULTS: In this study, 85 U-box family proteins were identified in maize and were classified into four subfamilies based on phylogenetic analysis. In addition to the conserved U-box domain, we identified additional functional domains, including Pkinase, ARM, KAP and Tyr domains, by analyzing the conserved motifs and gene structures. Chromosomal localization and collinearity analysis revealed that gene duplications may have contributed to the expansion and evolution of the U-box gene family. GO annotation and KEGG pathway enrichment analysis identified a total of 105 GO terms and 21 KEGG pathways that were notably enriched, including ubiquitin-protein transferase activity, ubiquitin conjugating enzyme activity and ubiquitin-mediated proteolysis pathway. Tissue expression analysis showed that some ZmPUB genes were specifically expressed in certain tissues and that this could be due to their functions. In addition, RNA-seq data for maize seedlings under salt stress revealed 16 stress-inducible plant U-box genes, of which 10 genes were upregulated and 6 genes were downregulated. The qRT-PCR results for genes responding to abiotic stress were consistent with the transcriptome analysis. Among them, ZmPUB13, ZmPUB18, ZmPUB19 and ZmPUB68 were upregulated under all three abiotic stress conditions. Subcellular localization analysis showed that ZmPUB19 and ZmPUB59 were located in the nucleus. CONCLUSIONS: Overall, our study provides a comprehensive analysis of the U-box gene family in maize and its responses to abiotic stress, suggesting that U-box genes play an important role in the stress response and providing insights into the regulatory mechanisms underlying the response to abiotic stress in maize.
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Ubiquitina-Proteína Ligasas , Zea mays , Zea mays/metabolismo , Filogenia , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Perfilación de la Expresión Génica , Estrés Fisiológico/genética , Ubiquitinas/genética , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/metabolismo , Familia de MultigenesRESUMEN
Nucleotidyl transferases (NTPs) are common transferases in eukaryotes and play a crucial role in nucleotide modifications at the 3' end of RNA. In plants, NTPs can regulate RNA stability by influencing 3' end modifications, which in turn affect plant growth, development, stress responses, and disease resistance. Although the functions of NTP family members have been extensively studied in Arabidopsis, rice, and maize, there is limited knowledge about NTP genes in soybeans. In this study, we identified 16 members of the NTP family in soybeans, including two subfamilies (G1 and G2) with distinct secondary structures, conserved motifs, and domain distributions at the protein level. Evolutionary analysis of genes in the NTP family across multiple species and gene collinearity analysis revealed a relatively conserved evolutionary pattern. Analysis of the tertiary structure of the proteins showed that NTPs have three conserved aspartic acids that bind together to form a possible active site. Tissue-specific expression analysis indicated that some NTP genes exhibit tissue-specific expression, likely due to their specific functions. Stress expression analysis showed significant differences in the expression levels of NTP genes under high salt, drought, and cold stress. Additionally, RNA-seq analysis of soybean plants subjected to salt and drought stress further confirmed the association of soybean NTP genes with abiotic stress responses. Subcellular localization experiments revealed that GmNTP2 and GmNTP14, which likely have similar functions to HESO1 and URT1, are located in the nucleus. These research findings provide a foundation for further investigations into the functions of NTP family genes in soybeans.
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Proteínas de Arabidopsis , Arabidopsis , Nucleotidiltransferasas , Glycine max/genética , Respuesta al Choque por Frío , Nucleótidos , ARN NucleotidiltransferasasRESUMEN
With the rising incidence of cancer, radiotherapy has become an increasingly popular treatment modality. However, radiation-induced skin injuries (RSIs) have emerged as a commonly reported side effect of radiotherapy, thereby presenting a significant challenge in the field of radiotherapy. In this study, we report the successful synthesis of a photosensitive hydrogel via amide reaction for grafting the photosensitive group, methacrylate anhydride (MA), onto chitosan (CHI) and gelatin (GEL), with subsequent physical incorporation of epigallocatechin gallate (EGCG). The resulting composite photosensitive hydrogels exhibited favorable swelling properties, rheological properties, and biocompatibility, which promote angiogenesis and demonstrate notable therapeutic efficacy against RSIs. These findings provide valuable insights into the clinical utility of EGCG composite hydrogels for the effective management of RSIs.
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Catequina , Hidrogeles , Catequina/farmacología , Catequina/uso terapéutico , GelatinaRESUMEN
Coconut cadang-cadang viroid (CCCVd) is an infectious single-stranded RNA (ssRNA) pathogen, which leads directly to the death of a large number of coconut palm trees and heavy economic loss to coconut farmers. Herein, a novel electrochemical impedance RNA genosensor is presented based on highly stable gold nanoparticles (AuNPs) decorated phosphorene (BP) nanohybrid with graphene (Gr) for highly sensitive, low-cost, and label-free detection of CCCVd. BP-AuNPs are environmentally friendly prepared by ultrasonic-assisted liquid-phase exfoliation of black phosphorus, accompanying direct reduction of chloroauric acid. Gr/BP-AuNPs are facilely prepared by the in situ growth of AuNPs onto the BP surface and its nanohybrid with Gr to improve environmental stability of BP. Gr/BP-AuNP-based RNA genosensor is fabricated by immobilizing the thiol-functionalized single-stranded DNA (ssDNA) oligonucleotide probe onto the surface of Gr/BP-AuNP-modified glassy carbon electrode via gold-thiol interactions, which served as an electrochemical genosensing platform for the label-free impedance detection of CCCVd by hybridization between the functionalized ssDNA probe and the complementary CCCVd ssRNA sequence in a wide linear range from 1.0 × 10-11 to 1.0 × 10-7 M with a low limit of detection of 2.8 × 10-12 M. This work supplies an experimental support and theoretical direction for the fabrication of RNA biosensors based on graphene-like materials and potential application for a specific diagnosis of plant RNA viral disease in Arecaceae planting industry.
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Grafito , Nanopartículas del Metal , Oro , ADN de Cadena Simple , Compuestos de SulfhidriloRESUMEN
Purpose: To assess the impact of neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment (TIME) in gynaecological tumors, with a focus on understanding the potential for enhanced combination therapies.Methods: We systematically queried the PubMed, Embase, and Cochrane databases, encompassing reviews, clinical trials, and case studies, to undertake a thorough analysis of the impact of NACT on the TIME of gynaecological tumors.Results: NACT induces diverse immune microenvironment changes in gynaecological tumors. In cervical cancer, NACT boosts immune-promoting cells, enhancing tumor clearance. Ovarian cancer studies yield variable outcomes, influenced by patient-specific factors and treatment regimens. Limited research exists on NACT's impact on endometrial cancer's immune microenvironment, warranting further exploration. In summary, NACT-induced immune microenvironment changes display variability. Clinical trials highlight personalized immunotherapy's positive impact on gynaecological tumor prognosis, suggesting potential avenues for future cancer treatments. However, rigorous investigation is needed to determine the exact efficacy and safety of combining NACT with immunotherapy.Conclusion: This review provides a solid foundation for the development of late-stage immunotherapy and highlights the importance of therapeutic strategies targeting immune cells in TIME in anti-tumor therapy.
The abnormal tumour microenvironment in gynaecological tumours can impede the penetration and accumulation of chemotherapeutic drugs, leading to poorer drug therapy efficacy.Neoadjuvant chemotherapy can improve the surgical resection rate of patients while regulating the ratio of each immune cell subpopulation to achieve the regulation of the tumour microenvironment, thus achieving anti-tumour effects.Based on the immune variability of patients after neoadjuvant chemotherapy, selecting the most suitable individualized immunotherapy will become a promising new therapy.
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Neoplasias de los Genitales Femeninos , Neoplasias Ováricas , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Terapia Neoadyuvante , Neoplasias Ováricas/patología , Pronóstico , Quimioterapia Adyuvante , Microambiente TumoralRESUMEN
The chest wall is the most frequent metastatic site of breast cancer (BC) and the metastasis usually occurs in a solitary setting. Chest wall resection is a way to treat solitary BC metastasis, but intraoperative bone defects and local tumor recurrence still affect the life quality of patients. Titanium-based prostheses are widely used for chest wall repair and reconstruction, but their inherent bio-inertness makes their clinical performance unfavorable. Nanostructured surfaces can give titanium substrates the ability to excellently modulate a variety of cellular functions. Ascorbic acid is a potential stimulator of tumor suppression and osteogenic differentiation. An ascorbic acid-decorated nanostructured titanium surface was prepared through alkali treatment and spin-coating technique and its effects on the biological responses of BC cells and osteoblasts were assessed. The results exhibited that the nanorod structure and ascorbic acid synergistically inhibited the proliferation, spreading, and migration of BC cells. Additionally, the ascorbic acid-decorated nanostructured surface significantly promoted the proliferation and osteogenic differentiation of osteoblasts. This work may provide valuable references for the clinical application of titanium materials in chest wall reconstruction after the resection of metastatic BC.
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Neoplasias de la Mama , Nanoestructuras , Humanos , Femenino , Titanio/química , Osteogénesis , Nanoestructuras/química , Diferenciación Celular , Propiedades de Superficie , OsteoblastosRESUMEN
OBJECTIVE: The aim of this study is to identify molecules from traditional Chinese medicine (TCM) with potential activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. METHODS: We applied the Apriori algorithm to identify important combinations of herbs in the TCM prescriptions for the treatment of coronavirus disease 2019 (COVID-19). Then, we explored the active components and core targets using network pharmacology. In addition, the molecular docking approach was performed to investigate the interaction of these components with the main structural and non-structural proteins, as well as the mutants. Furthermore, their stability in the binding pockets was further evaluated with the molecular dynamics approach. RESULTS: A combination of Amygdalus Communis Vas., Ephedra Herba and Scutellaria baicalensis Georgi was selected as the important herbal combination, and 11 main components and 20 core targets against COVID-19 were obtained. These components, including luteolin, naringenin, stigmasterol, baicalein, and so on, were the potentially active compounds against COVID-19. The binding affinity of these compounds with the potential targets was as high as the positive controls. Among them, baicalein could interfere with multiple targets simultaneously, and it also interfered with the interaction between spike protein and angiotensin-converting enzyme 2 receptor. Additionally, almost all the systems reached stability during dynamics simulation. CONCLUSION: The combination of A. communis, Ephedra Herba and S. baicalensis was the most important herbal combination for the treatment of COVID-19. Baicalein may be a potential candidate against SARS-CoV-2 and its variants. Please cite this article as: Song JB, Zhao LQ, Wen HP, Li YP. Herbal combinations against COVID-19: A network pharmacology, molecular docking and dynamics study. J Integr Med. 2023;21(6):593-604.
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COVID-19 , Medicamentos Herbarios Chinos , Humanos , Simulación del Acoplamiento Molecular , SARS-CoV-2 , Farmacología en Red , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional ChinaRESUMEN
After resection of bone tumour, the risk of cancer recurrence and numerous bone defects continues to threaten the health of patients. To overcome the challenge, we developed a novel multifunctional scaffold material consisting mainly of nano-hydroxyapatite particles (n-HA), MXene nanosheets and g-C3N4 to prevent tumour recurrence and promote bone formation. N-HA has the potential to restrict the growth of osteosarcoma cells, and the combination of MXene and g-C3N4 enables the scaffolds to produce photodynamic and photothermal effects simultaneously under near infrared (NIR) irradiation. Surprisingly, n-HA can further enhance the synergistic anti-tumour function of photodynamic and photothermal, and the scaffolds can eradicate osteosarcoma cells in only 10 min at a mild temperature of 45 â. Moreover, the scaffold exhibit exceptional cytocompatibility and possesses the capacity to induce osteogenic differentiation of bone marrow mesenchymal stem cells. Therefore, this multifunctional scaffold can not only inhibits the proliferation of bone tumour cells and rapidly eradicate bone tumour through NIR irradiation, but also enhances osteogenic activity. This promising measure can be used to treat tissue damage after bone tumour resection.
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The liquid phase of metal-organic frameworks (MOFs) is key for the preparation of melt-quenched bulk glasses as well as the shaping of these materials for various applications; however, only very few MOFs can be melted and transformed into stable glasses. Here, the solvothermal and mechanochemical preparation of a new series of functionalized derivatives of ZIF-4 (Zn(im)2, where im- = imidazolate and ZIF = zeolitic imidazolate framework) containing the cyano-functionalized imidazolate linkers CNim- (4-cynanoimidazolate) and dCNim- (4,5-dicyanoimidazolate) is reported. The strongly electron-withdrawing nature of the CN groups facilitates low-temperature melting of the materials (below 310 °C for some derivatives) and the formation of microporous ZIF glasses with remarkably low glass-transition temperatures (down to only about 250 °C) and strong resistance against recrystallization. Besides conventional ZIF-4, the CN-functionalized ZIFs are so far the only MOFs to show an exothermic framework collapse to a low-density liquid phase and a subsequent transition to a high-density liquid phase. By systematic adjustment of the fraction of cyano-functionalized linkers in the ZIFs, we derive fundamental insights into the thermodynamics of the unique polyamorphic nature of these glass formers as well as further design rules for the porosity of the ZIF glasses and the viscosity of their corresponding liquids. The results provide new insights into the unusual phenomenon of liquid-liquid transitions as well as a guide for the chemical diversification of meltable MOFs, likely with implications beyond the archetypal ZIF glass formers.
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OBJECTIVE: To explore the epidemiological characteristics of patients with lymphoepithelial carcinoma (LEC) of the head and neck and the prognostic factors. METHODS: We conducted a retrospective cohort study of cases of head and neck LEC retrieved from the Surveillance, Epidemiology and End Results database. Kaplan-Meier survival analysis and the log-rank test were employed to assess overall survival (OS) and cancer-specific survival (CSS). Univariate and multivariate analyses were used to construct Cox regression models. We established nomograms to predict OS and CSS among patients with nasopharyngeal LEC, who were divided into high- and low-risk groups based on the OS nomograms to compare the effects of treatment using the restricted mean survival time (RMST). RESULTS: The 5-year OS and CSS rates of the cohort were 70.8% and 74.8%, respectively. Advanced age, unmarried status, black race, distant metastasis, and the absence of surgical treatment were significantly associated with decreased survival rates. RMST did not differ between the combined treatment (radiotherapy and chemotherapy) and radiotherapy monotherapy groups, but chemotherapy alone displayed poor efficacy. CONCLUSIONS: Head and neck LEC is associated with a favorable prognosis. Radiotherapy plays a significant role in managing patients with nasopharyngeal LEC, which is influenced by multiple prognostic factors.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Humanos , Pronóstico , Estadificación de Neoplasias , Estudios Retrospectivos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/patologíaRESUMEN
Progesterone is a steroid hormone that performs important functions in mammals. However, studies on its physiological functions in plants have gradually increased in recent years. Therefore, this review summarizes the regulatory functions of progesterone on plant growth and development, as well as its response to stress. Moreover, the plant metabolic processes of progesterone are also discussed. Overall, progesterone is ubiquitous in plants and can regulate numerous plant physiological processes at low concentrations. Since progesterone shares similar characteristics with plant hormones, it is expected to become a candidate for plant hormone. However, most of the current research on progesterone in plants is limited to the physiological level, and more molecular level research is needed to clarify progesterone signaling pathways.
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Reguladores del Crecimiento de las Plantas , Progesterona , Animales , Regulación de la Expresión Génica de las Plantas , Mamíferos/metabolismo , Desarrollo de la Planta , Reguladores del Crecimiento de las Plantas/metabolismo , Plantas/metabolismo , Progesterona/metabolismo , Estrés Fisiológico/fisiologíaRESUMEN
Atypical chemokine receptor 3 (ACKR3) has been linked to the tumor microenvironment. This work investigates the effects of ACKR3 and its regulatory molecules on the chemotactic migration of tumor-associated macrophages (TAMs) in hepatocellular carcinoma (HCC). RT-qPCR and western blot assays identified elevated ACKR3 and HDAC2 levels in HCC tissues and cells. Knockdown or overexpression of ACKR3 was induced in HCC cells through vectors of lentivirus plasmids, and then the conditioned medium of the HCC cells was collected to stimulate TAMs. The stimulated TAMs were co-cultured with CD3+ T cells. ACKR3 knockdown in HCC cells inhibited migration of TAMs and promoted M1 polarization, which restored the activity of T cells. Histone deacetylase 2 (HDAC2) recruited signal transducer and activator of transcription 1 (STAT1) to the ACKR3 promoter to activate ACKR3 transcription. HDAC2 silencing suppressed nuclear translocation of STAT1 and decreased ACKR3 expression. HDAC2 knockdown in HCC cells similarly suppressed TAM migration, promoted M1 polarization, and restored T cell function, but these changes were inversed by ACKR3 upregulation. HDAC2 or ACKR3 silencing weakened tumor growth and immune escape in mice. In conclusion, this study demonstrates that HDAC2 upregulates ACKR3 via STAT1 to induce migration of M2 macrophages and immune escape in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Receptores CXCR/metabolismo , Animales , Línea Celular Tumoral , Medios de Cultivo Condicionados/metabolismo , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/metabolismo , Macrófagos , Ratones , Factor de Transcripción STAT1/metabolismo , Microambiente Tumoral , Regulación hacia ArribaRESUMEN
Liver is a well-known immunological organ with unique microenvironment. In normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as Kupffer cells (KCs). The presence of liver immunosuppressive microenvironment underlines the importance to dissect this interaction to understand how this cross-talk promotes tumor growth in hepatocellular carcinoma (HCC). Therefore, the aim of the study here was to probe the role of methyltransferase-like 3 (METTL3) in the HCC progression and its effect on the polarization of KCs. KCs showed M2 polarization, and METTL3 was overexpressed in our collected HCC tissues relative to adjacent tissues. METTL3 depletion inhibited the M2 polarization of KCs, thereby reverting the malignant phenotype of HCC cells in vitro and growth and metastasis in vivo. Mechanistically, YTH domain-containing family protein 1 (YTHDF1) bound to RNA-binding protein 14 (RBM14), whereas METTL3 knockdown in KCs cells suppressed RBM14 expression by decreasing N-methyladenosine (m6A) methylation. Overexpression of RBM14 mitigated the anti-tumor effects of sh-METTL3 in vitro and in vivo. It is suggested that the mechanism of sh-METTL3 suppressing the polarization of KCs and the progression of HCC is to regulate the RBM14 expression via YTHDF1-dependent m6A modification.