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Ticks transmit a variety of pathogens, including rickettsia and viruses, when they feed on blood, afflicting humans and other animals. Bioactive components acting on inflammation, coagulation, and the immune system were reported to facilitate ticks' ability to suck blood and transmit tick-borne diseases. In this study, a novel peptide, IstTx, from an Ixodes scapularis cDNA library was analyzed. The peptide IstTx, obtained by recombinant expression and purification, selectively inhibited a potassium channel, TREK-1, in a dose-dependent manner, with an IC50 of 23.46 ± 0.22 µM. The peptide IstTx exhibited different characteristics from fluoxetine, and the possible interaction of the peptide IstTx binding to the channel was explored by molecular docking. Notably, extracellular acidification raised its inhibitory efficacy on the TREK-1 channel. Our results found that the tick-derived peptide IstTx blocked the TREK-1 channel and provided a novel tool acting on the potassium channel.
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Peptídeos , Canais de Potássio de Domínios Poros em Tandem , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Canais de Potássio de Domínios Poros em Tandem/genética , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Canais de Potássio de Domínios Poros em Tandem/química , Animais , Humanos , Peptídeos/farmacologia , Peptídeos/química , Peptídeos/metabolismo , Ixodes/metabolismo , Simulação de Acoplamento Molecular , Sequência de Aminoácidos , Células HEK293 , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/química , Carrapatos/metabolismoRESUMO
Previous studies have verified that celastrol (Cel) protects against rheumatoid arthritis (RA) by inhibiting the NLRP3 inflammasome signaling pathway, but the molecular mechanism by which Cel regulates NLRP3 has not been clarified. This study explored the specific mechanisms of Cel in vitro and in vivo. A type II collagen-induced arthritis (CIA) mouse model was used to study the antiarthritic activity of Cel; analysis of paw swelling, determination of the arthritis score, and pathological examinations were performed. The antiproliferative and antimigratory effects of Cel on TNF-α induced fibroblast-like synoviocytes (FLSs) were tested. Proinflammatory factors were evaluated using enzyme-linked immunosorbent assay (ELISA). The expression of NF-κB/NLRP3 pathway components was determined by western blotting and immunofluorescence staining in vitro and in vivo. The putative binding sites between Cel and Hsp90 were predicted through molecular docking, and the binding interactions were determined using the Octet RED96 system and coimmunoprecipitation. Cel decreased arthritis severity and reduced TNF-α-induced FLSs migration and proliferation. Additionally, Cel inhibited NF-κB/NLRP3 signaling pathway activation, reactive oxygen species (ROS) production, and proinflammatory cytokine secretion. Furthermore, Cel interacted directly with Hsp90 and blocked the interaction between Hsp90 and NLRP3 in FLSs. Our findings revealed that Cel regulates NLRP3 inflammasome signaling pathways both in vivo and in vitro. These effects are induced through FLSs inhibition of the proliferation and migration by blocking the interaction between Hsp90 and NLRP3.
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Understanding the processes and mechanisms that shape the distribution patterns and variations of biodiversity along spatial gradients continues to be a priority for ecological research. We focused on the biodiversity of benthic diatom communities within a large near-natural watershed. The objectives are: (1) to explore the overall spatial patterns of benthic diatom biodiversity; (2) to investigate the effects associated with watercourse position and environmental variables, as well as both common and rare species on two facets (i.e., taxonomic and functional) of alpha and beta diversity; and (3) to unveil the mechanisms underlying their spatial variations. Alpha diversity indices along the stream watercourse showed a clear increasing trend from upstream to downstream sites. Results of random forest regression identified conductivity as the primary factor influencing functional alpha diversity, while elevation emerged as the predominant factor for taxonomic alpha diversity. Beta diversity partitioning revealed that taxonomic beta diversity generally exceeded functional beta diversity. These diversity measures exhibited different patterns along the watercourse position: taxonomic beta diversity remained relatively consistent along the watercourse, whereas functional total beta diversity and its two components of middle stream sites were lower than those of upstream and downstream sites. Functional beta diversity was sustained by dominant and common species, while rare species made significant contributions to taxonomic beta diversity. Both taxonomic and functional beta diversity and its components displayed a stronger influence from spatial factors than from local environmental, geo-climatic, and nutrient variables. Collectively, taxonomic and functional alpha and beta diversity demonstrated distinct responses to the main environmental gradients and spatial factors within our catchment, highlighting their different insights into diatom diversity. Furthermore, research is required to assess the generalizability of our findings to similar ecosystems. In addition, this study presents opportunities for expansion to include other taxa (e.g., macroinvertebrates and fish) to gain a comprehensive understanding of the driving mechanisms behind stream biodiversity.
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In near-natural basins, zooplankton are key hubs for maintaining aquatic food webs and organic matter cycles. However, the spatial patterns and drivers of zooplankton in streams are poorly understood. This study registered 165 species of zooplankton from 147 sampling sites (Protozoa, Rotifers, Cladocera and Copepods), integrating multiple dimensions (i.e., taxonomic, functional, and phylogenetic) and components (i.e., total, turnover, and nestedness) of α and ß diversity. This study aims to reveal spatial patterns, mechanisms, correlations, and relative contribution of abiotic factors (i.e., local environment, geo-climatic, land use, and spatial factors) through spatial interpolation (ordinary kriging), mantel test, and variance partitioning analysis (VPA). The study found that α diversity is concentrated in the north, while ß diversity is more in the west, which may be affected by typical habitat, hydrological dynamics and underlying mechanisms. Taxonomic and phylogenetic ß diversity is dominated by turnover, and metacommunity heterogeneity is the result of substitution of species and phylogeny along environmental spatial gradients. Taxonomic and phylogenetic ß diversity were strongly correlated (r from 0.91 to 0.95), mainly explained by historical/spatial isolation processes, community composition, generation time, and reproductive characteristics, and this correlation provides surrogate information for freshwater conservation priorities. In addition, spatial factors affect functional and phylogenetic α diversity (26%, 28%), and environmental filtering and spatial processes combine to drive taxonomic α diversity (10%) and phylogenetic ß diversity (11%). Studies suggest that spatial factors are key to controlling the community structure of zooplankton assemblages in near-natural streams, and that the relative role of local environments may depend on the dispersal capacity of species. In terms of diversity conservation, sites with high variation in uniqueness should be protected (i) with a focus on the western part of the thousand islands lake catchment and (ii) increasing effective dispersal between communities to facilitate genetic and food chain transmission.
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Biodiversidade , Rios , Zooplâncton , Animais , Zooplâncton/classificação , Filogenia , EcossistemaRESUMO
Given the ongoing development of the global economy, the demand for hazardous materials, which serve as essential components for numerous industrial products, is steadily increasing. Consequently, it becomes imperative to devise a methodology for mitigating the risks associated with the road transportation of hazardous materials. The objective of this study is to establish an integrated quality function deployment and multicriteria decision-making (QFD-MCDM) framework and identify the pivotal factors that propel Industry 5.0 (I5.0), thus fortifying supply chain resilience (SCR) and ameliorating the hazardous material transportation risks (HMTR). These measures encompass various strategic areas, including "establish a safe and inclusive work environment", "customized products and services", "enhance production flexibility and strengthen control redundancy", and "real-time data collection and analysis". By adopting these measures, enterprises can lead to sustainable and stable business operations. The findings of this study demonstrate the synergistic potential of integrating I5.0 and SCR in effectively mitigating HMTR. Additionally, these findings offer valuable insights and practical implications for enterprises across diverse industries.
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The mesenchymal subtype of glioblastoma (GBM) cells characterized by aggressive invasion and therapeutic resistance is thought to be dependent on cell-intrinsic alteration and extrinsic cellular crosstalk. Tumor-associated macrophages (TAMs) are pivotal in tumor progression, chemo-resistance, angiogenesis, and stemness maintenance. However, the impact of TAMs on the shifts in glioma stem cells (GSCs) states remains largely uncovered. Herein, we showed that the triggering receptor expressed on myeloid cells-1 (TREM1) preferentially expressed by M2-like TAMs and induced GSCs into mesenchymal-like states by modulating the secretion of TGFß2, which activated the TGFßR/SMAD2/3 signaling in GSCs. Furthermore, we demonstrated that TREM1 was transcriptionally regulated by HIF1a under the hypoxic environment and thus promoted an immunosuppressive type of TAMs via activating the TLR2/AKT/mTOR/c-MYC axis. Collectively, this study reveals that cellular communication between TAMs and GSCs through the TREM1-mediated TGFß2/TGFßR axis is involved in the mesenchymal-like transitions of GSCs. Our study provides valuable insights into the regulatory mechanisms between the tumor immune microenvironment and the malignant characteristics of GBM, which can lead to potential novel strategies targeting TAMs for tumor control.
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Células-Tronco Neoplásicas , Receptor Gatilho 1 Expresso em Células Mieloides , Microambiente Tumoral , Macrófagos Associados a Tumor , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologia , Animais , Linhagem Celular Tumoral , Transdução de Sinais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/imunologia , Glioma/patologia , Glioma/genética , Glioma/metabolismo , Glioma/imunologia , Camundongos , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/imunologia , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Regulação Neoplásica da Expressão Gênica , Proteína Smad2/metabolismo , Proteína Smad2/genéticaRESUMO
The metacommunity theory proposes that community structure and biodiversity are influenced by both local processes (such as environmental filtering) and regional processes (such as dispersal). Despite the extensive use of traditional bioassessments based on species-environment relationships, the impact of dispersal processes on these assessments has been largely overlooked. This study aims to compare correlations between various bioassessment indices, including Shannon Weiner (H'), Biological Monitoring Working Party (BMWP), average score per taxon (ASPT), biotic index (BI), and EPT taxa index (EPT), based on macroinvertebrates collected from 147 sampling sites in a subtropical Chinese near-natural catchment. Modified indices were calculated by removing species strongly influenced by dispersal processes to address the influence of dispersal processes. Their relationship with environmental factors was then compared to the original indices. The study employed random forest regression (RFR) to compare the explanatory power of environmental factors using the two sets of indices. The spearman rank correlation analysis was conducted to examine the correlation between indices and environmental factors. The river health assessment was performed based on both modified and original indices. The results reveal significant differences between original and modified indices (especially H' and BI) providing a more accurate reflection of environmental conditions. Furthermore, the sensitivity of the different indices to various environmental factors varied, leading to differences in the bioassessment results between the modified and the original indices. Notably, original H', BMWP, and ASPT overestimated the bioassessment results, whereas the original BI underestimated them. These findings offer valuable insights into bioassessment and river health assessment evaluation within the catchment and other interconnected freshwater ecosystems, such as lakes, reservoirs, and wetlands. Our study underscores the importance of assessing and mitigating the impact of dispersal processes on bioassessment to obtain a more precise representation of the status of freshwater ecosystems.
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Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the actin-binding protein, Transgelin (TAGLN), in GBM stem cells (GSCs). Mechanistically, TAGLN regulates HIF1α transcription and stabilizes HDAC2 to deacetylate p53 and maintain GSC self-renewal. To translate these findings into preclinical therapeutic paradigm, it is found that sodium valproate (VPA) is a specific inhibitor of TAGLN/HDAC2 function, with augmented efficacy when combined with natural borneol (NB) in vivo. Thus, TAGLN promotes cancer stem cell survival in hypoxia and informs a novel therapeutic paradigm.
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Neoplasias Encefálicas , Glioblastoma , Proteínas Musculares , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Acetilação , Neoplasias Encefálicas/metabolismo , Proteínas dos Microfilamentos/metabolismo , Hipóxia/metabolismo , Células-Tronco Neoplásicas/metabolismoRESUMO
The study of microplastics and their impact on aquatic ecosystems has received increasing attention in recent years. Drawing from an analysis of 814 papers related to microplastics published between 2013 and 2022 in the Web of Science Core Repository, this paper explores trends, focal points, and national collaborations in freshwater microplastics research, providing valuable insights for future studies. The findings reveal three distinct stages of microplastics: nascent development (2013-2015), slow rise (2016-2018), and rapid development (2019-2022). Over time, the focus of research has shifted from "surface", "effect", "microplastic pollution", and "tributary" to "toxicity", "species", "organism", "threat", "risk", and "ingestion". While international cooperation has become more prevalent, the extent of collaboration remains limited, mostly concentrated among English-speaking countries or English and Spanish/Portuguese-speaking countries. Future research directions should encompass the bi-directional relationship between microplastics and watershed ecosystems, incorporating chemical and toxicological approaches. Long-term monitoring efforts are crucial to assessing the sustained impacts of microplastics.
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BACKGROUND: Glioma stem cells (GSCs) are a subpopulation of tumor cells with self-renewal and tumorigenic capabilities in glioblastomas (GBMs). Diffuse infiltration of GSCs facilitates tumor progression and frustrates efforts at effective treatment. Further compounding this situation is the currently limited understanding of what drives GSC invasion. Here we comprehensively evaluated the significance of a novel invasion-related protein, Family with Sequence Similarity 129 Member A (FAM129A), in infiltrative GSCs. METHODS: Western blotting, immunohistochemistry, and gene expression analysis were used to quantify FAM129A in glioma specimens and cancer datasets. Overexpression and knockdown of FAM129A in GSCs were used to investigate its effects on tumor growth and invasion. RNA-seq, qRT-PCR, western blotting, and co-precipitation assays were used to investigate FAM129A signaling mechanisms. RESULTS: FAM129A is preferentially expressed in invasive frontiers. Targeting FAM129A impairs GSC invasion and self-renewal. Mechanistically, FAM129A acted as a positive regulator of Notch signaling by binding with the Notch1 intracellular domain (NICD1) and preventing its degradation. CONCLUSIONS: FAM129A and NICD1 provide a precise indicator for identifying tumor margins and aiding prognosis. Targeting them may provide a significantly therapeutic strategy for GSCs.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Células-Tronco Neoplásicas/metabolismo , Glioma/patologia , Glioblastoma/patologia , Transdução de Sinais , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Encefálicas/patologiaRESUMO
The current study aims to confirm the positive effects of dietary nano-Se on nutrients deposition and muscle fibre formation in grass carp fed with high-fat diet (HFD) before overwintering and to reveal its possible molecular mechanism. The lipid deposition, protein synthesis and muscle fibre formation in grass carp fed with regular diet (RD), HFD or HFD supplemented with nano-Se (0·3 or 0·6 mg/kg) for 60 d were tested. Results show that nano-Se significantly reduced lipid content, dripping loss and fibre diameter (P < 0·05), but increased protein content, post-mortem pH24 h and muscle fibre density (P < 0·05) in muscle of grass carp fed with HFD. Notably, dietary nano-Se decreased lipid deposition in the muscle by regulating amp-activated protein kinase activity and increased protein synthesis and fibre formation in muscle by activating target of rapamycin and myogenic determining factors pathways. In summary, dietary nano-Se can regulate the nutrients deposition and muscle fibre formation in grass carp fed with HFD, which exhibit potential benefit for improving flesh quality of grass carp fed with HFD.
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Carpas , Dieta Hiperlipídica , Animais , Dieta Hiperlipídica/efeitos adversos , Dieta , Suplementos Nutricionais , Lipídeos , Fibras Musculares Esqueléticas , Ração Animal/análiseRESUMO
A high-efficient energy recovery system of biochar-assisted anaerobic membrane bioreactor (BC-AnMBR) was established for swine wastewater treatment. Comparing with a conventional AnMBR, biochar addition accelerated volatile fatty acids (VFA) degradation during start-up stage, thereby shortened start-up duration by 44.0 %. Under a high organic loading rate (OLR) of 21.1 gCOD/L/d, BC-AnMBR promoted COD removal efficiency from 90.1 % to 95.2 %, and maintained a high methane production rate of 4.8L CH4/L/d. The relative abundance of Methanosaeta declined from 53.9 % in conventional AnMBR to 21.0 % in BC-AnMBR, whereas that of Methanobrevibacter dramatically increased from 10.3 % to 70.9 %, respectively. Metabolic pathway analysis revealed that biochar not only strengthened hydrogenotrophic methanogenesis pathway, but also upregulated the genes encoding electron transfer carriers and riboflavin metabolism, suggesting the role of biochar facilitating direct interspecies electron transfer for syntrophic methanogenesis. The excellent energy yield performances under high OLR confirmed BC-AnMBR as an advanced system for high-strength swine wastewater treatment.
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Metano , Águas Residuárias , Animais , Suínos , Anaerobiose , Reatores Biológicos , Membranas Artificiais , Eliminação de Resíduos LíquidosRESUMO
One of the key targets of community ecology and biogeography concerns revealing the variability and underlying drivers of biodiversity. Most current studies understand biodiversity based on taxonomic information alone, but few studies have shown the relative contributions of multiple abiotic factors in shaping biodiversity based on taxonomic, functional, and phylogenetic information. We collected 179 samples of macroinvertebrates in the Hun-Tai River Basin. We validated the complementarity between the three facets and components of ß-diversity using the Mantel test. Distance-based redundancy analysis and variance partitioning were applied to explore the comparative importance of local environmental, geo-climatic, and spatial factors on each facet and component of ß-diversity. Our study found that taxonomic and phylogenetic total ß-diversity was mainly forced by turnover, while functional total ß-diversity was largely contributed by nestedness. There is a strong correlation between taxonomic and phylogenetic ß-diversity. However, the correlations of functional with both taxonomic and phylogenetic ß-diversity were relatively weak. The findings of variation partitioning suggested that distinct facets and components of macroinvertebrates' ß-diversity were impacted by abiotic factors to varying degrees. The contribution of spatial factors was greater than that of the local environment and geo-climatic factors for taxonomic, functional, and phylogenetic ß-diversity. Thus, studying different facets and components of ß-diversity allows a clearer comprehension of the influence of abiotic factors on diversity patterns. Therefore, future research should investigate patterns and mechanisms of ß-diversity from taxonomic, functional, and phylogenetic perspectives.
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Diffuse intrinsic pontine glioma (DIPG) is the most lethal tumor involving the pediatric central nervous system. The median survival of children that are diagnosed with DIPG is only 9 to 11 months. More than 200 clinical trials have failed to increase the survival outcomes using conventional cytotoxic or myeloablative chemotherapy. Immunotherapy presents exciting therapeutic opportunities against DIPG that is characterized by unique and heterogeneous features. However, the non-inflammatory DIPG microenvironment greatly limits the role of immunotherapy in DIPG. Encouragingly, the induction of immunogenic cell death, accompanied by the release of damage-associated molecular patterns (DAMPs) shows satisfactory efficacy of immune stimulation and antitumor strategies. This review dwells on the dilemma and advances in immunotherapy for DIPG, and the potential efficacy of immunogenic cell death (ICD) in the immunotherapy of DIPG.
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BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor with poor clinical outcomes. Immunotherapy has recently been an attractive and promising treatment of extracranial malignancies, however, most of clinical trials for GBM immunotherapy failed due to predominant accumulation of tumor-associated microglia/macrophages (TAMs). RESULTS: High level of LRIG2/soluble LRIG2 (sLRIG2) expression activates immune-related signaling pathways, which are associated with poor prognosis in GBM patients. LRIG2/sLRIGs promotes CD47 expression and facilitates TAM recruitment. Blockade of CD47-SIRPα interactions and inhibition of sLRIG2 secretion synergistically suppress GBM progression in an orthotropic murine GBM model. CONCLUSIONS: GBM cells with high level LRIG2 escape the phagocytosis by TAM via the CD47-SIRPα axis, highlighting a necessity for an early stage of clinical trial targeting LRIG2 and CD47-SIRPα as a novel treatment for patients with GBM.
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Neoplasias Encefálicas , Glioblastoma , Animais , Neoplasias Encefálicas/patologia , Antígeno CD47/metabolismo , Humanos , Imunidade Inata , Macrófagos , Glicoproteínas de Membrana/metabolismo , CamundongosRESUMO
Glioma stem cells (GSCs) in the hypoxic niches contribute to tumor initiation, progression, and recurrence in glioblastoma (GBM). Hypoxia induces release of high-mobility group box 1 (HMGB1) from tumor cells, promoting the development of tumor. Here, we report that HMGB1 is overexpressed in human GBM specimens. Hypoxia promotes the expression and secretion of HMGB1 in GSCs. Furthermore, silencing HMGB1 results in the loss of stem cell markers and a reduction in self-renewal ability of GSCs. Additionally, HMGB1 knockdown inhibits the activation of RAGE-dependent ERK1/2 signaling pathway and arrests the cell cycle in GSCs. Consistently, FPS-ZM1, an inhibitor of RAGE, downregulates HMGB1 expression and the phosphorylation of ERK1/2, leading to a reduction in the proliferation of GSCs. In xenograft mice of GBM, HMGB1 knockdown inhibits tumor growth and promotes mouse survival. Collectively, these findings uncover a vital function for HMGB1 in regulating GSC self-renewal potential and tumorigenicity.
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Rationale: In the glioblastoma (GBM) microenvironment, tumor-associated macrophages (TAMs) are prominent components and facilitate tumor growth. The exact molecular mechanisms underlying TAMs' function in promoting glioma stem cells (GSCs) maintenance and tumor growth remain largely unknown. We found a candidate molecule, transforming growth factor beta-induced (TGFBI), that was specifically expressed by TAMs and extremely low in GBM and GSC cells, and meanwhile closely related to glioma WHO grades and patient prognosis. The exact mechanism of TGFBI linking TAM functions to GSC-driven tumor growth was explored. Methods: Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), immunohistochemistry staining (IHC) and public datasets were used to evaluate TGFBI origin and level in GBM. The response of GSCs to recombinant human TGFBI was assessed in vitro and orthotopic xenografts were established to investigate the function and mechanism in vivo. Results: M2-like TAMs infiltration was elevated in high-grade gliomas. TGFBI was preferentially secreted by M2-like TAMs and associated with a poor prognosis for patients with GBM. TGFBI promoted the maintenance of GSCs and GBM malignant growth through integrin αvß5-Src-Stat3 signaling in vitro and in vivo. Of clinical relevance, TGFBI was enriched in the serum and CSF of GBM patients and significantly decreased after tumor resection. Conclusion: TAM-derived TGFBI promotes GSC-driven tumor growth through integrin αvß5-Src-Stat3 signaling. High serum or CSF TGFBI may serve as a potential diagnostic and prognostic bio-index for GBMs.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioma/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo , Receptores de Vitronectina , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral , Macrófagos Associados a TumorRESUMO
The pore strategy is one of the important factors affecting the biomedical porous scaffold at the same porosity. In this work, porous scaffolds were designed based on the triply periodic minimal surface (TPMS) structure under the same porosity and different pore strategies (pore size and size continuous gradient distribution) and were successfully prepared using a novel Ni46.5Ti44.5Nb9 alloy and selective laser melting (SLM) technology. After that, the effects of the pore strategies on the microstructure, mechanical properties, and permeability of porous scaffolds were systematically investigated. The results showed that the Ni46.5Ti44.5Nb9 scaffolds have a low elastic modulus (0.80-1.05 GPa) and a high ductility (15.3-19.1%) compared with previous works. The pore size has little effect on their mechanical properties, but increasing the pore size significantly improves the permeability due to the decrease in specific surfaces. The continuous gradient distribution of the pore size changes the material distribution of the scaffold, and the smaller porosity structure has a better load-bearing capacity and contributes primarily to the high compression strength. The local high porosity structure bears more fluid flow, which can improve the permeability of the overall scaffold. This work can provide theoretical guidance for the design of porous scaffolds.
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Toll-like receptor (TLR) stimulation induces glycolysis and the production of mitochondrial reactive oxygen species (ROS), both of which are critical for inflammatory responses in macrophages. Here, we demonstrated that cyclin J, a TLR-inducible member of the cyclin family, reduced cytokine production in macrophages by coordinately controlling glycolysis and mitochondrial functions. Cyclin J interacted with cyclin-dependent kinases (CDKs), which increased the phosphorylation of a subset of CDK substrates, including the transcription factor FoxK1 and the GTPase Drp1. Cyclin J-dependent phosphorylation of FoxK1 decreased the transcription of glycolytic genes and Hif-1α activation, whereas hyperactivation of Drp1 by cyclin J-dependent phosphorylation promoted mitochondrial fragmentation and impaired the production of mitochondrial ROS. In mice, cyclin J in macrophages limited the growth of tumor xenografts and protected against LPS-induced shock but increased the susceptibility to bacterial infection. Collectively, our findings indicate that cyclin J-CDK signaling promotes antitumor immunity and the resolution of inflammation by opposing the metabolic changes that drive inflammatory responses in macrophages.
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Imunidade Inata , Macrófagos , Animais , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Macrófagos/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMO
Purpose: The development and progression of glioma are associated with the tumor immune microenvironment. Diffuse low-grade gliomas (LGGs) with higher immunosuppressive microenvironment tend to have a poorer prognosis. The study aimed to find a biological marker that can reflect the tumor immune microenvironment status and predict prognosis of LGGs. Methods: The target gene tenascin-C (TNC) was obtained by screening the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) databases. Then samples of LGGs were collected for experimental verification with immunohistochemistry, immunofluorescence, immunoblotting, quantitative real-time PCR. ELISA was employed to determine the content of TNC in serum and examine its relationship with the tumor immune microenvironment. Eventually, the sensitivity of immunotherapy was predicted on the basis of the content of TNC in LGGs. Results: In the high-TNC subgroup, the infiltration of immunosuppressive cells was increased (MDSC: r=0.4721, Treg: r=0.3154, etc.), and immune effector cells were decreased [NKT, γδT, etc. (p<0.05)], immunosuppressive factors were elevated [TGF-ß, IL10, etc. (p<0.05)], immunostimulatory factors, such as NKG2D, dropped (p<0.05), hypoxia scores increased (p<0.001), and less benefit from immunotherapy (p<0.05). Serum TNC level could be used to assess the status of tumor immune microenvironment in patients with grade II (AUC=0.8571; 95% CI: 0.6541-1.06) and grade III (AUC=0.8333; 95% CI: 0.6334-1.033) glioma. Conclusions: Our data suggested that TNC could serve as an indicator for the immunosuppressive microenvironment status and the prognosis of LGGs. Moreover, it could also act as a predictor for the effect of immunotherapy on LGG patients.