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Chemotherapy-based combination regimens are recommended as first-line treatment for colorectal cancer. However, multidrug resistance (MDR) and limited drug infiltration in tumor microenvironment remain critical challenges. Herein, a pH/redox dual activated supramolecular DAS@CD-OxPt (IV) nanoparticles (NPs) via host-guest molecular recognition to achieve relay drugs delivery of active oxaliplatin (OxPt (IV)) and Src inhibitor dasatinib (DAS) between tumor cells is developed. DAS@CD-OxPt (IV) NPs exhibit prolonged circulation in the blood and intra-tumoral retention. Triggered by the endo/lysosome (pH 5.0), flexible DAS@CD-OxPt (IV) NPs exhibited proton-driven in situ assembly to form nanofiber in tumor cells. Dual chemotherapeutic agents released from DAS@CD-OxPt (IV) NPs synergistically cause irreversible DNA damage by blocking p53-mediated DNA repair. Supramolecular nanofibers can further serve as the "ammunition depot" to continuously release drugs from dying cells and transport them into neighboring tumor cells, leading to domino-like cell death and enhanced immunogenicity. Furthermore, DAS@CD-OxPt (IV) NPs combined with immune checkpoint blockade (ICB) therapy strikingly suppress CT26 tumor growth and pulmonary metastasis.
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PURPOSE: Gastric cancer (GC) is among the deadliest malignancies and the third leading cause of cancer-related deaths worldwide. Galectin-1 (Gal-1) is a primary protein secreted by cancer-associated fibroblasts (CAFs); however, its role and mechanisms of action of Gal-1 in GC remain unclear. In this study, we stimulated GC cells with exogenous human recombinant galectin-1 protein (rhGal-1) to investigate its effects on the proliferation, migration, and resistance to cisplatin. MATERIALS AND METHODS: We used simulated rhGal-1 protein as a paracrine factor produced by CAFs to induce GC cells and investigated its promotional effects and mechanisms in GC progression and cisplatin resistance. Immunohistochemical (IHC) assay confirmed that Gal-1 expression was associated with clinicopathological parameters and correlated with the expression of neuropilin-1 (NRP-1), c-JUN, and Wee1. RESULTS: Our study reveals Gal-1 expression was significantly associated with poor outcomes. Gal-1 boosts the proliferation and metastasis of GC cells by activating the NRP-1/C-JUN/Wee1 pathway. Gal-1 notably increases GC cell resistance to cisplatin The NRP-1 inhibitor, EG00229, effectively counteracts these effects. CONCLUSIONS: These findings revealed a potential mechanism by which Gal-1 promotes GC growth and contributes to chemoresistance, offering new therapeutic targets for the treatment of GC.
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Proliferação de Células , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Galectina 1 , Neuropilina-1 , Neoplasias Gástricas , Neoplasias Gástricas/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Humanos , Galectina 1/genética , Galectina 1/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Neuropilina-1/metabolismo , Neuropilina-1/genética , Proliferação de Células/efeitos dos fármacos , Masculino , Feminino , Progressão da Doença , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Pessoa de Meia-Idade , Camundongos , Animais , Movimento Celular/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/patologiaRESUMO
Acute lung injury is one of the most serious complications of sepsis, which is a common critical illness in clinic. This study aims to investigate the role of caspase-3/ gasdermin-E (GSDME)-mediated pyroptosis in sepsis-induced lung injury in mice model. Cecal ligation (CLP) operation was used to establish mice sepsis-induced lung injury model. Lung coefficient, hematoxylin and eosin staining and transmission electron microscopy were used to observe the lung injury degree. In addition, caspase-3-specific inhibitor Z-DEVD-FMK and GSDME-derived inhibitor AC-DMLD-CMK were used in CLP model, caspase-3 activity, GSDME immunofluorescence, serum lactate dehydrogenase (LDH) and interleukin-6 (IL-6) levels, TUNEL staining, and the expression levels of GSDME related proteins were detected. The mice in CLP group showed the increased expressions of cleaved-caspase-3 and GSDME-N terminal, destruction of lung structure, and the increases of LDH, IL-6, IL-18 and IL-1ß levels, which were improved in mice treated with Z-DEVD-FMK or AC-DMLD-CMK. In conclusion, caspase-3/GSDME mediated pyroptosis is involved in the occurrence of sepsis-induced lung injury in mice model, inhibiting caspase-3 or GSDME can both alleviate lung injury.
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Lesão Pulmonar Aguda , Caspase 3 , Modelos Animais de Doenças , Piroptose , Sepse , Animais , Piroptose/efeitos dos fármacos , Sepse/complicações , Camundongos , Caspase 3/metabolismo , Lesão Pulmonar Aguda/patologia , Masculino , Camundongos Endogâmicos C57BL , Interleucina-6/metabolismo , Inibidores de Caspase/farmacologia , Pulmão/patologia , Pulmão/metabolismo , Oligopeptídeos/farmacologia , GasderminasRESUMO
Nanoscale drug delivery systems derived from natural bioactive materials accelerate the innovation and evolution of cancer treatment modalities. Morusin (Mor) is a prenylated flavonoid compound with high cancer chemoprevention activity, however, the poor water solubility, low active pharmaceutical ingredient (API) loading content, and instability compromise its bioavailability and therapeutic effectiveness. Herein, a full-API carrier-free nanoparticle is developed based on the self-assembly of indocyanine green (ICG), copper ions (Cu2+) and Mor, termed as IMCNs, via coordination-driven and π-π stacking for synergistic tumor therapy. The IMCNs exhibits a desirable loading content of Mor (58.7 %) and pH/glutathione (GSH)-responsive motif. Moreover, the photothermal stability and photo-heat conversion efficiency (42.8 %) of IMCNs are improved after coordination with Cu2+ and help to achieve photothermal therapy. Afterward, the released Cu2+ depletes intracellular overexpressed GSH and mediates Fenton-like reactions, and further synergizes with ICG at high temperatures to expand oxidative damage. Furthermore, the released Mor elicits cytoplasmic vacuolation, expedites mitochondrial dysfunction, and exerts chemo-photothermal therapy after being combined with ICG to suppress the migration of residual live tumor cells. In vivo experiments demonstrate that IMCNs under laser irradiation could excellently inhibit tumor growth (89.6 %) through the multi-modal therapeutic performance of self-enhanced chemotherapy/coordinated-drugs/ photothermal therapy (PTT), presenting a great potential for cancer therapy.
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Hipertermia Induzida , Doenças Mitocondriais , Nanopartículas , Neoplasias , Humanos , Verde de Indocianina/farmacologia , Cobre/farmacologia , Fototerapia , Terapia Fototérmica , Flavonoides , Linhagem Celular TumoralRESUMO
BACKGROUND: Sepsis is characterized by severe inflammation and organ dysfunction resulting from a dysregulated organismal response to infection. Although pyroptosis has been presumably shown to be a major cause of multiple organ failure and septic death, whether gasdermin E (GSDME)-mediated pyroptosis occurs in septic liver injury and whether inhibiting apoptosis and GSDME-mediated pyroptosis can attenuate septic liver injury remain unclear. This study investigated the role of apoptosis and GSDME-mediated pyroptosis in septic liver injury. METHODS: Adult male C57BL/6 mice were randomly divided into four groups: sham, cecal ligation puncture (CLP), CLP + Z-DEVD-FMK (a caspase-3 inhibitor, 5 mg/kg), and CLP + Ac-DMLD-CMK (a GSDME inhibitor, 5 mg/kg). Sepsis severity was assessed using the murine sepsis score (MSS). Hepatic tissue damage was observed by the hematoxylin-eosin staining method, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the levels of malondialdehyde (MDA), the concentrations of interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were measured according to the related kits, and the changes in the hepatic tissue reactive oxygen species (ROS) levels were detected by immunofluorescence (IF). The protein expression levels of cleaved caspase-3, GSDME-N, IL-1ß, B-cell lymphoma-2 (Bcl-2), cytochrome C (Cyt-c), and acetaldehyde dehydrogenase 2 (ALDH2) were detected using western blotting. GSDME expression was detected by immunohistochemistry. RESULTS: Compared with the Sham group, CLP mice showed high sepsis scores and obvious liver damage. However, in the CLP + Z-DEVD-FMK and CLP + Ac-DMLD-CMK groups, the sepsis scores were reduced and liver injury was alleviated. Compared with the Sham group, the serum ALT and AST activities, MDA and ROS levels, and IL-1ß and TNF-α concentrations were increased in the CLP group, as well as the protein expression of cleaved caspase-3, GSDME-N, IL-1ß, Cyt-c, and GSDME positive cells (P < 0.05). However, the expression levels of Bcl-2 and ALDH2 protein were decreased (P < 0.05). Compared with the CLP group, the CLP + Z-DEVD-FMK and CLP + Ac-DMLD-CMK groups showed low sepsis scores, ALT and AST activities, MDA and ROS levels, decreased IL-1ß and TNF-α concentrations, and decreased expression of cleaved caspase-3, GSDME-N, IL-1ß protein expression, and GSDME positive cells (P < 0.05). The expression levels of Bcl-2 and ALDH2 protein were increased (P < 0.05). CONCLUSION: Apoptosis and GSDME-mediated pyroptosis are involved in the development of sepsis-induced hepatic injury. Inhibition of apoptosis and GSDME-mediated pyroptosis attenuates injury. ALDH2 plays a protective role by inhibiting apoptosis and pyroptosis.
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Sepse , Fator de Necrose Tumoral alfa , Camundongos , Animais , Masculino , Piroptose , Caspase 3 , Espécies Reativas de Oxigênio , Aldeído-Desidrogenase Mitocondrial , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Apoptose , Sepse/complicações , Sepse/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2RESUMO
BACKGROUND/AIMS: Gastric cancer is a prevalent malignancy with unfavorable prognosis partially resulting from its high metastasis rate. Clarifying the molecular mechanism of gastric cancer occurrence and progression for improvement of therapeutic efficacy and prognosis is needed. The study tended to delineate the role and regulatory mechanism of aldo-keto reductase 1B10 (AKR1B10) in gastric cancer progression. MATERIALS AND METHODS: The relationship of AKR1B10 expression with survival rate in gastric cancer was analyzed through Kaplan-Meier analysis. The mRNA levels of AKR1B10 and integrin subunit alpha 5 (ITGA5) in gastric cancer tissues and cell lines were measured by real-time quantitative polymerase chain reaction. Protein levels of AKR1B10 and integrin subunit alpha 5 were assayed via western blot. The molecular relationship between AKR1B10 and ITGA5 was analyzed by co-immunoprecipitation assay. Cell viability was assayed through Cell Counting Kit-8, invasion and migration of tumor cells was assessed through wound healing and transwell assays. Transwell assay was utilized to detect invasion. The adhesion of gastric cancer cells was detected using cell adhesion assays. RESULTS: The results unveiled that integrin subunit alpha 5 was upregulated, while AKR1B10 was downregulated in gastric cancer tissues and cells. Overexpressing AKR1B10 hindered gastric cancer cell proliferation, migration, invasion and adhesion. It was striking that we certified the inhibitory effect of AKR1B10 on integrin subunit alpha 5 expression and their (AKR1B10 and ITGA5)) negative relationship via bioinformatics method, real-time quantitative polymerase chain reaction, and co-immunoprecipitation assays. Via rescue experiments, it was concluded that AKR1B10 served as tumor suppressor potentially by ITGA5 expression in gastric cancer. CONCLUSION: Our results indicated that AKR1B10 inhibited migration, invasion, and adhesion of gastric cancer cells via modulation of ITGA5.
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Aldo-Ceto Redutases , Integrinas , Neoplasias Gástricas , Humanos , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Aldo-Ceto Redutases/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Gástricas/patologiaRESUMO
Inflammatory bowel disease (IBD) has been closely associated with immune disorders and excessive M1 macrophage activation, which can be reversed by the M2-polarizing effect of interleukin-4 (IL-4). However, maintaining native IL-4 activity with its specific release in the inflammatory microenvironment and efficient biological performance remain a challenge. Inspired by the multilayered defense mechanism of the earth's atmosphere, we constructed a multilayered protective nanoarmor (NA) for IL-4 delivery (termed as IL-4@PEGRA NAs) into an intricate inflammatory microenvironment. The poly(ethylene glycol) (PEG)-ylated phenolic rosmarinic acid (RA)-grafted copolymer contains two protective layers-the intermediate polyphenol (RA molecules) and outermost shield (PEG) layers-to protect the biological activity of IL-4 and prolong its circulation in blood. Moreover, IL-4@PEGRA NAs scavenge reactive oxygen species with the specific release of IL-4 and maximize its biofunction at the site of inflammation, leading to M2 macrophage polarization and downregulation of inflammatory mediators. Simultaneously, gut microbiota dysbiosis can improve to amplify the M2-polarizing effect and inhibit the phosphatidylinositol 3 kinase/Akt signaling pathway, thereby attenuating inflammation and promoting colitis tissue repair. It provides a nature-inspired strategy for constructing an advanced multilayered NA delivery system with protective characteristics and potential for IBD management.
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Colite , Doenças Inflamatórias Intestinais , Humanos , Interleucina-4/farmacologia , Inflamação/metabolismo , Macrófagos/metabolismoRESUMO
Pyroptosis is a highly inflammatory programmed cell death that activates inflammatory response, reverses immunosuppression and promotes systemic immune response for solid tumors treatment. However, the uncontrollable and imprecise process of pyroptosis stimulation leads to a scanty therapeutic effect. Here, we report a GSH/ROS dual response nanogel system (IMs) that can actively target the overexpressed mannose receptor (MR) of cancer cells, serve ultra-stable photothermal capacity of indocyanine green (ICG), induce cell pyroptosis and achieve enhanced tumor immune response. Photo-triggered IMs induce cytoplasmic Ca2+ introgression and activate caspase-3 through photo-activated ICG. The disconnect of SeSe bonds can break the oxidation and reduction balance of tumor cells, causing oxidative stress and synergistically enhancing caspase-3 cleavage, and regulating cell pyroptosis ultimately. Combined with anti-programmed death receptor 1 (anti-PD-1), the nanogel system not only effectivly suppress both primary tumor and distance tumor but also prolong the survival period of mice. This work introduces a strategy to optimize the photothermal performance of ICG and enhances tumor immune response mediated by triggering pyroptosis, which provides an impressive option for immune checkpoint blockade therapy.
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Neoplasias , Piroptose , Camundongos , Animais , Caspase 3 , Nanogéis , Imunoterapia , Verde de Indocianina/química , Linhagem Celular TumoralRESUMO
Polycyclodextrin-based supramolecular nanoplatform crosslinked by stimuli-responsive moiety shows great promise in cancer therapy owing to its superior bio-stability and feasible modification of architectures. Here, the endogenous glutathione (GSH)-responsive polycyclodextrin supramolecular nanocages (PDOP NCs) are constructed by covalent crosslinking of multiple ß-cyclodextrin (ß-CD) molecules. The polycyclodextrin provide sites for conjugation of chemotherapeutic doxorubicin (DOX). Meanwhile, the PDOP NCs are stabilized by multiple interactions including host-guest interaction between DOX and ß-CD and hydrogen bonds between ß-CD units. The supramolecular crosslinked structure endowed the nanocage with high stability and drug loading capacity. Tons of GSH-sensitive disulfide linkages in PDOP NCs were broken at tumor cells, promoting tumor-specific DOX release. Besides, the redox equilibrium in tumor microenvironment could be disturbed due to GSH depletion, which further sensitized the DOX effects and alleviated drug resistance, facilitating inducing immunogenic cell death effect for enhanced chemotherapy, thereby achieving efficient tumor suppression and prolonged survival. Thus, the versatile polycyclodextrin-based supramolecular nanocage provides a novel and efficient drug delivery strategy for cancer treatment.
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Sistemas de Liberação de Medicamentos , Morte Celular Imunogênica , Doxorrubicina/farmacologia , Microambiente Tumoral , GlutationaRESUMO
Bone loss in inflammatory disorders such as osteomyelitis, septic arthritis, and periodontitis is caused by excessive osteoclastic activity. Meanwhile, reactive oxygen species (ROS) have been identified as contributors to osteoclast differentiation, and the application of ROS scavengers has emerged as a promising strategy to protect against bone loss. Recently, resveratrol (RSV), a polyphenolic phytoalexin, has been demonstrated to inhibit osteoclastogenesis by scavenging ROS; however, the application of RSV as an antioxidant is limited by its low water solubility, structural instability, and short elimination half-life. In this study, we developed a PEGylated cyclodextrin (CD)-based nanoplatform (PCP) for local delivery of RSV as nanomicelles (RSV-NMs). In addition, polymer functionalization with phenylboronic acid ester in RSV-NMs successfully achieved ROS-responsive release of RSV. The RSV-NMs in a well-dispersed state possessed good biocompatibility as well as improved solubility and stability compared with RSV compound. In vitro, RSV-NMs significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells and suppressed F-actin (filamentous actin) ring formation. Additionally, the mRNA expressions of osteoclastic marker genes, including matrix metalloprotein-9 (MMP-9), nuclear factor of activated T cells 1 (NFATc1), TRAP, and cathepsin K, were consequently downregulated in the presence of RSV-NMs. In vivo, RSV-NMs provided protection against LPS-induced bone destruction, as evidenced by a decreased number of osteoclasts, increased bone density, and reduced area of bone resorption. Taken together, these results indicate that our ROS-responsive RSV-NMs can be employed as a potential therapeutic agent for the treatment of inflammatory osteolysis.
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BACKGROUND: Due to its rarity, duodenal papillary carcinoma (DPC) is seldom studied as a unique disease and no specific molecular features or treatment guidelines are provided. METHODS: Whole-exome sequencing was performed to gain new insights into the DPC mutation landscape and to identify potential signalling pathways and therapeutic targets. Mechanistically, immunohistochemistry (IHC), immunofluorescence, RNA-seq, ATAC-seq and in vitro cell function experiments were performed to confirm the underlying mechanisms. RESULTS: We described the mutational landscape of DPC for the first time as a group of rare tumours with a high frequency of dysregulation in the chromatin remodelling pathway, particularly PBRM1-inactivating mutations that are significantly higher than duodenal adenocarcinomas and ampullary adenocarcinoma (27% vs. 0% vs. 7%, p < .01). In vitro cell experiments showed that downregulation of PBRM1 expression could significantly promote the cancer progression and epithelial-to-mesenchymal transition via the PBRM1-c-JUN-VIM axis. The IHC data indicated that PBRM1 deficiency (p = .047) and c-JUN expression (p < .001) were significantly associated with poor prognosis. Meanwhile, the downregulation of PBRM1 expression in HUTU-80 cells was sensitive to radiation, which may be due to the suppression of c-JUN by irradiation. CONCLUSIONS: Our findings define a novel molecular subgroup of PBRM1-inactivating mutations in DPC. PBRM1 play an important role in DPC progression and may serve as a potential therapeutic target and prognostic indicator.
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Carcinoma Papilar , Proteínas de Ligação a DNA , Neoplasias Duodenais , Fatores de Transcrição , Biomarcadores , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/uso terapêutico , Neoplasias Duodenais/diagnóstico , Neoplasias Duodenais/genética , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prognóstico , Fatores de Transcrição/genética , Fatores de Transcrição/uso terapêuticoRESUMO
Periodontitis is a prevalent chronic inflammatory disease that destroys the periodontal supporting tissues, impinges on oral health, and is correlated with an increased risk of systemic disease. Currently, the main drug treatment is antibiotic therapy; however, systemic antibiotic therapy still has various drawbacks such as bacterial resistance, low bioavailability and burst release. It is noteworthy that the local use of non-antibiotic drugs with sustained release characteristics can effectively overcome these problems. It has been documented that chlorogenic acid (CGA) has good anti-inflammatory and antioxidant properties. To achieve the sustained release of CGA, we synthesized CGA-PLGA@PVP nanomicelles by loading CGA onto poly(D,L-lactide-co-glycolide) (PLGA) and modified them with polyvinylpyrrolidone (PVP) for better dispersion. The results demonstrated that CGA-PLGA@PVP nanomicelles could prolong the release time of CGA, and could not only effectively remove reactive oxygen species (ROS) but also downregulate the overexpression of proinflammatory cytokines in lipopolysaccharide (LPS)-treated RAW264.7 cells. Moreover, CGA-PLGA@PVP nanomicelles could remain in gingival tissue for more than 24 hours after local injection, inhibit alveolar bone resorption and prevent the progression of periodontitis in a mouse model, showing good biocompatibility. Therefore, CGA-PLGA@PVP nanomicelles have great properties and are expected to be a novel therapeutic strategy for periodontitis.
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Ácido Clorogênico , Periodontite , Animais , Antibacterianos/farmacologia , Antioxidantes , Citocinas , Preparações de Ação Retardada , Lipopolissacarídeos , Camundongos , Periodontite/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Povidona , Espécies Reativas de OxigênioRESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia with limited therapeutic options. Eucalyptol, a terpenoid oxide isolated from eucalyptus species, reportedly exhibits various biological activities such as anti-inflammatory and antioxidant effects. In the present study, we aimed to determine whether eucalyptol could alleviate bleomycin (BLM)-induced pulmonary fibrosis and inhibit interleukin (IL)-13-induced M2 macrophage polarization. Upon treatment with eucalyptol, BLM-induced pulmonary fibrosis and lung inflammation were significantly reduced. The pulmonary neutrophil accumulation and pulmonary permeability were inhibited and the expression of hydroxyproline, alpha-smooth muscle actin, and fibronectin was significantly down-regulated. Eucalyptol also markedly inhibited the expression of arginase-1, Ym-1, IL-13, and transforming growth factor (TGF)-ß1, reduced the production of IL-13, IL-6, tumor necrosis factor (TNF)-α, and attenuated the activity of TGF-ß1 in bronchoalveolar lavage fluid (BALF). Furthermore, the in vitro assay revealed that eucalyptol disturbed M2 macrophage polarization and reduced the macrophage-mediated secretion of the profibrotic factor TGF-ß1. Eucalyptol inhibited the nuclear location of signal transducer and activator of transcription 6 (STAT6) and the phosphorylation of STAT6 and p38 mitogen-activated protein kinase (p38 MAPK), and reduced the expression of their downstream transcription factors, krupple-like factor 4 (KLF4) and peroxisome proliferator-activated receptor gamma (PPAR-γ). These findings indicated that eucalyptol alleviates BLM-induced pulmonary fibrosis by regulating M2 macrophage polarization, which, in turn, inhibits the activation of signaling molecules (e.g., STAT6 and p38 MAPK) and the expression of transcription factors (e.g., KLF4 and PPAR-γ). Thus, eucalyptol might be a potential therapeutic agent for IPF.
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Bleomicina , Fibrose Pulmonar , Bleomicina/efeitos adversos , Eucaliptol/farmacologia , Eucaliptol/uso terapêutico , Humanos , Interleucina-13/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , PPAR gama/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/prevenção & controle , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Central nervous system leukemia (CNS-L) is caused by leukemic cells infiltrating into the meninges or brain parenchyma and remains the main reason for disease relapse. Currently, it is hard to detect CNS-L accurately by clinically available imaging models due to the relatively low amount of tumor cells, confined blood supply, and the inferior glucose metabolism intensity. Recently, integrin α6-laminin interactions have been identified to mediate CNS-L, which suggests that integrin α6 may be a promising molecular imaging target for the detection of CNS-L. The acute lymphoblastic leukemia (ALL) cell line NALM6 stabled and transfected with luciferase was used to establish the CNS-L mouse model. CNS-L-bearing mice were monitored and confirmed by bioluminescence imaging. Three of our previously developed integrin α6-targeted peptide-based molecular imaging agents, Cy5-S5 for near-infrared fluorescence (NIRF), Gd-S5 for magnetic resonance (MR), and 18F-S5 for positron emission tomography (PET) imaging, were employed for the molecular imaging of these CNS-L-bearing mice. Bioluminescence imaging showed a local intensive signal in the heads among CNS-L-bearing mice; meanwhile, Cy5-S5/NIRF imaging produced intensive fluorescence intensity in the same head regions. Moreover, Gd-S5/MR imaging generated superior MR signal enhancement at the site of meninges, which were located between the skull bone and brain parenchyma. Comparatively, MR imaging with the clinically available MR enhancer Gd-DTPA did not produce the distinguishable MR signal in the same head regions. Additionally, 18F-S5/PET imaging also generated focal radio-concentration at the same head regions, which generated nearly 5-times tumor-to-background ratio compared to the clinically available PET radiotracer 18F-FDG. Finally, pathological examination identified layer-displayed leukemic cells in the superficial part of the brain parenchyma tissue, and immunohistochemical staining confirmed the overexpression of the integrin α6 within the lesion. These findings suggest the potential application of these integrin α6-targeted molecular imaging agents for the accurate detection of CNS-L.
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It remains a conundrum to reconcile the contradiction between effective tumor retention and deep intratumor infiltration for nanotherapeutics due to the sophisticated drug delivery journey. Herein, we reported an acid-sensitive supramolecular nanoassemblies (DCD SNs) based on the multivalent host-gest inclusions of two polymer conjugates for conquering diverse physiological blockages and amplifying therapeutic efficacy. The multiple inclusions of repetitive units on the hydrophilic polymer backbone reinforced the binding affinity and induced robust self-assembly, ameliorating instability of the self-assemblies and facilitating to prolong the drug retention time. By virtue of the acid-sensitive Schiff base linkages, the supramolecular nanoassembly could respond to the unique tumor microenvironment (TME), dissociate, and transform into smaller particles (â¼30 nm), thereby efficiently traversing the complicated extracellular matrix and irregular blood vessels to achieve deep intratumor infiltration. The acid-sensitive DCD SNs can absorb a large number of protons in the acidic lysosomal environment, causing the proton sponge effect, which was conducive to their escape from endolysosomes and accelerated lysosomal disruption, so that the active chemotherapeutic doxorubicin (DOX) could enter the nucleus well and exert severe DNA damage to induce apoptosis. This versatile supramolecular nanoplatform is anticipated to be a promising candidate to overcome the limitations of insufficient stability within the circulation and weak intratumor penetration.
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Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Substâncias Macromoleculares/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Dextranos/síntese química , Dextranos/química , Doxorrubicina/química , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Feminino , Lisossomos/efeitos dos fármacos , Substâncias Macromoleculares/síntese química , Camundongos Endogâmicos BALB C , Ratos Sprague-Dawley , beta-Ciclodextrinas/síntese química , beta-Ciclodextrinas/químicaRESUMO
BACKGROUND: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of lung cancer with less than 700 cases being reported in the literature, and no specialized treatment guidelines have been established. The prognostic significance of metabolic parameters on 18F-FDG PET in pulmonary LELC still remains unknown. METHODS: From July 2011 to September 2020, 76 pulmonary LELC patients undergoing pre-treatment 18F-FDG PET imaging were enrolled, and PET parameters including maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. In addition, whole-body tumor burdens were categorized into primary tumor lesion (PRL), thoracic lymph-node lesion (TRLN), and distant metastasis (DM) for respective metabolic parameters acquisition. ROC curves were generated to evaluate the predictive performance of the PET parameters, and correlations between tumor burdens of the different regional lesions were analyzed using linear correlation analysis. The prognostic significance for progression-free survival (PFS) and overall survival (OS) was assessed using univariate and multivariate survival analyses. RESULTS: Tumor stage, pre-/post-treatment serum EBV-DNA copies, SUVmax (cutoff 17.5), MTV, and TLG were significantly associated with PFS and OS in univariate analysis. MTV and TLG (AUC = 0.862 and 0.857, respectively) showed significantly higher predictive value than SUVmax (AUC = 0.754) and remained independent prognostic indicators for PFS in multivariate analysis (P = 0.026 and 0.019, respectively). Besides, non-colinearity was detected between metabolic burdens of the different regional lesions. MTV-PRL, MTV-DM, TLG-PRL, and TLG-DM were identified to be independent prognostic factors for PFS and OS, whereas MTV-TRLN and TLG-TRLN were not. CONCLUSION: The study demonstrated that MTV and TLG had independent prognostic significance for pulmonary LELC, which supported the incorporation of 18F-FDG PET imaging into clinical treatment protocols for pulmonary LELC and implied multi-disciplinary cooperation for primary and distant metastatic lesions to further improve prognosis.
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To observe the changes in NLR family pyrin domain containing 3 (NLRP3) inflammasome in a rat model of diabetes-induced lung injury, and investigate the effect of low-dose ethanol on the production of NLRP3 inflammasome. The type I diabetic mellitus (DM) rat model was established, and the rats were divided into four groups: normal control group (CON group), low-dose ethanol group (EtOH group), diabetes group (DM group) and DM+EtOH group. The rats were fed for 6 and 12 weeks, respectively. The ratio of lung wet weight/body weight (lung/body coefficient) was calculated, and the changes of pulmonary morphology and fibrosis were observed by HE and Masson staining. The changes in pulmonary ultra-structure were examined by electron microscopy. The expressions of mitochondrial acetaldehyde dehydrogenase 2 (ALDH2) and NLRP3 inflammasome key factors, NLRP3, ASC and caspase-1 proteins were detected by western blot. Compared with the CON group, the lung/body coefficient was increased (P<0.05), lung fibrosis occurred, ALDH2 protein expression was decreased, and NLRP3, ASC and caspase-1 protein expressions were increased in the DM rats (P<0.05). Compared with the DM group, the lung/body coefficient and fibrosis degree were decreased, ALDH2 protein expression was increased (P<0.05), and NLRP3, ASC and caspase-1 protein expressions were decreased in the DM+EtOH group (P<0.05). Hence, low-dose ethanol increased ALDH2 protein expression and alleviated diabetes-induced lung injury by inhibiting the production of NLRP3 inflammasome.
Assuntos
Complicações do Diabetes/fisiopatologia , Etanol/efeitos adversos , Inflamassomos/genética , Lesão Pulmonar/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Complicações do Diabetes/induzido quimicamente , Relação Dose-Resposta a Droga , Inflamassomos/metabolismo , Inflamação/induzido quimicamente , Inflamação/genética , Lesão Pulmonar/induzido quimicamente , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancerassociated mortality worldwide. In the present study, a novel molecular therapeutic target for lung cancer was investigated. The protein expression level of fidgetinlike 1 (FIGNL1) in human lung cancer tissues was determined and its potential functions in the H1299 and A549 lung cancer cell lines was subsequently studied. In addition, the protein expression level of FIGNL1 in 109 lung cancer samples and corresponding paracancerous tissues was investigated, using immunohistochemical staining. RNA interference and overexpression of FIGNL1 was used to determine the role of FIGNL1 in regulating cell proliferation, and cDNA microarray analysis was performed to identify the potential regulatory pathways. Lastly, the potential role of FIGNL1 in regulating tumorigenesis in lungs and also the proliferation of lung cancer cells was investigated. Firstly, lung cancer tissues were found to express higher protein levels of FIGNL1 and was significantly associated with decreased cell proliferation, migration and invasion abilities, and enhanced cell death. Overexpression of FIGNL1 significantly promoted cell proliferation, including decreased arrest at the G1 phase of the cell cycle and apoptosis, as well as increased ability for fission and migration. These in vitro findings were consistent with the results of the cellline derived xenografts in BALB/c nude mice, where tumor growth was decreased when injected with cells transfected with shFIGNL1. Collectively, these results provide suggest that FIGNL1 is involved in cell growth and tumorigenesis.
Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Nucleares/metabolismo , Células A549 , ATPases Associadas a Diversas Atividades Celulares/genética , Animais , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pulmão/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Interferência de RNA , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Malonylation is a recently discovered post-translational modification that is associated with a variety of diseases such as Type 2 Diabetes Mellitus and different types of cancers. Compared with experimental identification of malonylation sites, computational method is a time-effective process with comparatively low costs. RESULTS: In this study, we proposed a novel computational model called Mal-Prec (Malonylation Prediction) for malonylation site prediction through the combination of Principal Component Analysis and Support Vector Machine. One-hot encoding, physio-chemical properties, and composition of k-spaced acid pairs were initially performed to extract sequence features. PCA was then applied to select optimal feature subsets while SVM was adopted to predict malonylation sites. Five-fold cross-validation results showed that Mal-Prec can achieve better prediction performance compared with other approaches. AUC (area under the receiver operating characteristic curves) analysis achieved 96.47 and 90.72% on 5-fold cross-validation of independent data sets, respectively. CONCLUSION: Mal-Prec is a computationally reliable method for identifying malonylation sites in protein sequences. It outperforms existing prediction tools and can serve as a useful tool for identifying and discovering novel malonylation sites in human proteins. Mal-Prec is coded in MATLAB and is publicly available at https://github.com/flyinsky6/Mal-Prec , together with the data sets used in this study.