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关键词： EMT   IL-6   OSCC   UBE2T  

摘要： Oral squamous cell carcinoma (OSCC) is a prevalent aggressive malignancy with a high mortality rate. However, the mechanisms underlying the progression of OSCC remain to be elucidated. In the present study, bioinformatics analysis identified ubiquitin-conjugating enzyme E2 T (UBE2T) as a poor prognostic factor in head and neck cancer, showing the strongest association with cancer stage progression. Functional studies revealed that UBE2T can enhance motility and induce epithelial-mesenchymal transition (EMT) in OSCC cells. RNA sequencing and subsequent analyses demonstrated that UBE2T upregulated the expression levels of various motility- and EMT-related factors, including ankyrin repeat domain 1, endothelin-1, interleukin-6 (IL-6), matrix metalloproteinase-9 and plasminogen activator, urokinase. Gene set enrichment analysis indicated that UBE2T activates the IL-6/Janus protein tyrosine kinase (JAK)/signal transducer and activator of transcription 3 signaling pathway. Moreover, treatment of OSCC cells with IL-6 or a JAK inhibitor resulted in the induction of EMT and mesenchymal-epithelial transition, respectively, accompanied by enhanced and suppressed cancer cell motility. These results indicated that IL-6, which is upregulated by UBE2T, may be crucial for maintaining mesenchymal traits and motility in OSCC cells. Collectively, these findings suggested that the UBE2T/IL-6/JAK axis may serve as a potential therapeutic target for OSCC.

关键词： Airway   Allergy   IL-4   Th2   Fibroblast  

摘要： center dot Airway fibroblasts in allergic asthma (AA) mice demonstrated a 2.3-fold increase in IL-4+ cell proportion (p < 0.01), indicating their dominant role in driving Th2 inflammation compared to CD4+ T cells (24.7 % contribution, p < 0.001). center dot Fibroblasts upregulated activation markers CD80/CD83/CD86 (p < 0.0001), which correlated with enhanced IL-4-dependent Th2 polarization (30.01 % Teffs vs. 8.89 % with naive fibroblasts, p < 0.0001), suggesting their capacity to amplify allergic responses. center dot Targeted FbNP therapy reduced pathological fibroblast frequency by 24.6 % and systemic IL-4 levels by 48.83 %, accompanied by significant suppression of Th2 cytokines (IL-5: 46.88 %;IL-13: 50.84 %, all p < 0.001), demonstrating dual anti-inflammatory and immunoregulatory effects. center dot Clinically, FbNP alleviated asthma symptoms (52-65 % reduction in airway resistance) and improved airway hyperresponsiveness (AHR, 41 % correction, p < 0.01), with sustained therapeutic efficacy for 14 days and no detectable toxicity.

关键词： Mammary adipose tissue   Breast cancer   Inflammation   NF-kappa B   Nuclear receptor coactivator 3  

摘要： In breast cancer, adipocytes are the predominant cell type in the microenvironment, and the continuous communication between these tissues alters the adipose phenotype. However, molecular mechanisms promoting these changes are still poorly understood. Previously, we demonstrated that NCoA3 expression is increased in adipose tissue adjacent to breast cancer and that this increase is associated with an inflammatory profile. This study aimed to investigate the mechanisms underlying NCoA3 expression in adipocytes within the breast tumor microenvironment. We demonstrated that breast cancer-secreted TNF increases NCoA3 expression in adipocytes, and this upregulation is dependent on NF-kappa B transcriptional activity. Furthermore, the use of a TNF blocker prevented both coactivator overexpression and macrophages recruitment, mimicking the effects observed when NCoA3 expression was downregulated using a short hairpin RNA. These findings shed light on the molecular mechanisms by which breast cancer cells modulate adipocyte behavior, identifying NCoA3 as a key mediator in the tumor-adipose tissue crosstalk. Targeting this pathway through TNF inhibition offers promising therapeutic strategy to attenuate tumor-associated inflammation and potentially improve outcomes in breast cancer patients.

关键词： cGAS   cGASL   Sting   IFN   Snakehead  

摘要： In mammals, cyclic GMP-AMP synthase (cGAS) senses cytosolic dsDNA to trigger type I interferon (IFN) response via the sting signalling, but its regulatory role in fish remains unclear. In the present study, cGAS and cGAS-like (cGASL) were identified in the snakehead (Channa argus), but they differ in the organization of two domains, NTase domain, MAB21 domain, with an additional transmembrane domain in cGASL. It is further revealed that cGAS can bind with Sting to enhance the production of type I IFN and IFN-stimulated genes (ISGs), such as viperin, mx, and its entire molecule with all domains is necessary for its functioning. However, the co-transfection of cGAS or cGASL with tbk1 and mda5 inhibited the expression of ISGs in EPC cells. It is notable that cGAS may exhibit dual functionality either by promoting sting-dependent IFN response or by suppressing RLR pathway activation, whereas cGASL solely acted as an RLR pathway inhibitor. These findings reveal complexed, pathwayspecific immunoregulatory roles of cGAS/cGASL in fish antiviral immunity.

关键词： Macrophage   Periapical lesions   Osteoclast differentiation  

摘要： Introduction and Aims: Existing research suggests that ARA290 may possess therapeutic potential for apical periodontitis (AP), although the mechanisms involved remain unclear. This study aims to investigate the protective effects and underlying mechanisms of ARA290 in mitigating pro-inflammatory responses of macrophages in the context of AP. Methods: Initially, in vivo models of AP were used to assess the aberrant activation of the SIRT1/NF-kB/IL-1/3 signalling pathway within periapical lesions. Furthermore, the expression levels of the SIRT1/NF-kB/IL-1/3 signalling pathway in ARA290-treated AP models, both in vivo and in vitro, were evaluated using immunohistochemistry (IHC), Western blotting, and immunofluorescence (IF) techniques to elucidate the role of ARA290 in modulating this signalling pathway during AP pathogenesis. Subsequently, the SIRT1/NF-kB/IL-1/3 signalling pathway was inhibited using selisistat, and the resultant changes in inflammatory levels and bone resorption in periapical lesions were assessed through haematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, IHC and micro-computed tomography (Micro CT). Results: The in vivo AP model demonstrated a 50% reduction in SIRT1 expression within periapical lesions, accompanied by a 5-fold increase in the expression of acetylated NF-kB (p65) and IL-1/3. Additionally, the administration of ARA290 in the AP mouse model significantly reduced inflammatory infiltration, the number of osteoclasts and the extent of bone loss in the periapical region. Notably, ARA290 treatment enhanced SIRT1 expression by approximately 40% while concurrently decreasing the levels of acetylated NF-kB (p65) by around 75% and IL-1/3 by approximately 62.5% in both in vivo and in vitro AP models. Importantly, inhibition of the SIRT1/NF-kB/IL-1/3 signalling pathway negated the beneficial effects of ARA290 in attenuating the progression of AP. Conclusions: ARA290 plays a protective role by modulating the SIRT1/NF-k

关键词： Triple negative breast cancer   Anthracycline   Taxane   Interleukin-8   Feedback loop  

摘要： Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is highly metastatic compared with other BC subtypes. Taxane- and anthracycline-based therapies remain the main clinical TNBC regimens. However, TNBC patients usually suffer through chemotherapy owing to the lack of valid biomarkers to predict therapeutic effectiveness. We found that IL-8 upregulation is detected in paclitaxel (PTX)-sensitive/doxorubicin (DOX)resistant TNBC cells. Moreover, transcriptional profiling revealed that, compared with non-TNBC and normal mammary tissues, TNBC tissues highly express IL-8;its upregulation predicted a favorable response to taxane treatment but poor sensitivity to anthracycline-based therapy in TNBC cohorts. Whereas IL-8 supplementation in HCC1937 cells, which exhibit lower IL-8 expression and a PTX-resistant/DOX-sensitive phenotype, enhanced the cellular response to PTX but reduced their sensitivity to DOX, IL-8 knockdown in Hs578t cells, which have higher IL-8 expression and a PTX-sensitive/DOX-resistant phenotype, desensitized those cells to PTX treatment but improved their sensitivity to DOX. Gene set enrichment analysis (GSEA) results indicated that IL-8 upregulation is likely associated with E2F-regulated cell cycle progression and the activation of the NF-kB and MTOC1 pathways in TNBC. IL-8 supplementation promoted but IL-8 knockdown in Hs578t cells suppressed the activity of the E2F, NF-kB and MTOC1 signaling pathways. Immunohistochemistry (IHC) revealed that higher and lower IL8/p-NF-kappa B protein levels predicted good therapeutic outcomes in TNBC patients who initially received taxane and anthracycline-based chemotherapy, respectively. This study revealed that the formation of an IL-8/NF-kB feedback loop is required for maintaining the PTX-sensitive/DOX-resistant phenotype in TNBC.

关键词： avian influenza virus   polymerase basic 2   mitochondrial antiviral signaling protein   duck   type I interferon  

摘要： Type I interferon(IFN)-mediated innate immune responses represent the first line of host defense against viral ***,the molecular mechanisms by which avian influenza virus(AIV)inhibits type I IFN production in ducks are not well ***,we first found that the polymerase basic 2(PB2)protein of H5N1 subtype AIV inhibited the type I IFN responses by targeting duck mitochondrial antiviral signaling protein(MAVS).We further demonstrated that H5N1-PB2 bound to the Δtransmembrane(ΔTM)domain of duck MAVS,and the polymerase basic 1(PB1)binding domain(PBD)and RNA binding nuclear import domain(RND)of H5N1-PB2 interacted with MAVS to inhibit type I IFN expression in ***,our findings contribute to understanding the molecular mechanism by which AIV proteins regulate the retinoic acid-inducible gene I(RIG-I)-like receptor(RLR)signaling pathway to evade host antiviral immune responses in ducks.

关键词： Solid-phase extraction   Ionic liquid-modified carbon nanotubes   Aflatoxin B   HPLC-fluorescence detection  

摘要： Edible oils are prone to contamination by aflatoxin B-1 (AFB(1)), posing significant food safety risks. In this study, a series of imidazolium ionic liquids (ILs) with varying alkyl chain lengths (C-2, C-4, C-6, C-8) were covalently grafted onto multi-walled carbon nanotubes (MWCNTs) via a free-radical method to develop IL@MWCNT adsorbents (EMIM@MWCNT, BMIM@MWCNT, HMIM@MWCNT, OMIM@MWCNT) for solid-phase extraction (SPE) of AFB(1), followed by HPLC-fluorescence detection. Comprehensive characterization revealed that chain length critically influenced material properties: SEM and BET analysis demonstrated that HMIM@MWCNT (C-6) exhibited the highest specific surface area (101.6 m(2)/g) and optimal pore diameter (35.64 nm), while contact angle measurements and dispersion tests in non-polar solvents highlighted its superior hydrophobicity and oil-matrix compatibility. FTIR and XPS confirmed covalent IL grafting and the presence of oxygenated groups (hydroxyl, epoxy), which facilitated pi-pi stacking, hydrogen bonding, and electrostatic interactions with AFB(1). Adsorption studies indicated that HMIM@MWCNT achieved the fastest kinetics (equilibrium within 20 min) and highest capacity (45.2 mg/g), following pseudo-second-order kinetics and Freundlich isotherm models. The C-6 chain length balanced hydrophobicity and steric effects, enhancing AFB(1) affinity compared to shorter chains (C-2, C-4) and mitigating aggregation observed with longer chains (C-8). The optimized SPE-HPLC method demonstrated a wide linear range (0.5 mu g/L-500 mu g/L, R-2 = 0.9997), ultra-low detection limit (0.1 mu g/L), and satisfactory recoveries (88.0-104%) in spiked corn oil with RSD <= 6.0%. The adsorbent retained >98% efficiency over five cycles, underscoring its reusability. This work elucidates the role of IL alkyl chain length in tailoring adsorbent properties for efficient AFB(1) extraction, offering a robust strategy for mycotoxin monitoring in lipid-rich matrices.

关键词： Influenza A virus   Fufang Shuanghua oral liquid   Antiviral immunity   Type I interferon   NLRP3-Inflammasome  

摘要： Ethnopharmacological relevance: As a traditional Chinese medicine (TCM)-originated antiviral prescription, Fufang Shuanghua oral liquid (FS) is extensively used for influenza virus therapy with a satisfying therapeutic efficacy in clinic. Aim of the study: The bioactive compounds (BACs) and the molecular mechanisms of FS against influenza A virus (IAV)-infected acute lung injury were investigated. Materials and methods: IAV-infected acute lung injury mouse model was established infected by IAV (H1N1) strain A/PR/8/34 to evaluate the pharmacological effects of FS. After both in vivo and in vitro chemical profiling using UHPLC-Q-Exactive-Orbitrap-MS/MS system, the clinical transcriptomic-based biomolecular network was analyzed to assess the key underlying mechanism of IAV infection. A series of in vivo experimental validations was carried out. Finally, an integrative research combining mapping network analysis, computational modeling and ADME models in silico was used for candidate BAC identification. Results: Oral administration of FS exhibited prominent improvement in IAV-induced acute lung injury mice, such as reducing the lung viral load, slowing the rate of weight reduction, and ameliorating pathological alterations. After the therapeutic effects validation, a total of 106 chemical compounds were characterized, and subsequently 21 absorbed components in the mice sera samples were identified after intragastric administration of FS using the UHPLC-Q-Exactive-Orbitrap-MS/MS system, including 12 prototype compounds and 9 metabolites. Clinical transcriptomic-based networks indicated that TNF-mediated antiviral immune response may be key mechanism of IAV infection. A series of in vivo validations revealed that FS treatment effectively restored antiviral immunity by regulating the protein expression levels of TNF mediated IFN signaling pathway and NLRP3 inflammatory signaling pathway, thereby downregulating the inflammatory factors/mediators, such as TNF-alpha, CXCL1, I