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Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options1. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit2. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancer cell lines that express EGFR and in vivo in xenografted liver cancer cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition of fibroblast growth factor receptor (FGFR) by lenvatinib treatment leads to feedback activation of the EGFR-PAK2-ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinib treatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR.
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Antineoplásicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Compostos de Fenilureia/farmacologia , Quinolinas/farmacologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Gefitinibe/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptores de Fatores de Crescimento de Fibroblastos , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Black pepper (Piper nigrum L.), the world renown as the King of Spices, is not only a flavorsome spice but also a traditional herb. Piperine, a species-specific piper amide, is responsible for the major bioactivity and pungent flavor of black pepper. However, several key steps for the biosynthesis of piperoyl-CoA (acyl-donor) and piperidine (acyl-acceptor), two direct precursors for piperine, remain unknown. In this study, we used guilt-by-association analysis of the combined metabolome and transcriptome, to identify two feruloyldiketide-CoA synthases responsible for the production of the C5 side chain scaffold feruloyldiketide-CoA intermediate, which is considered the first and important step to branch metabolic fluxes from phenylpropanoid pathway to piperine biosynthesis. In addition, we also identified the first two key enzymes for piperidine biosynthesis derived from lysine in P. nigrum, namely a lysine decarboxylase and a copper amine oxidase. These enzymes catalyze the production of cadaverine and 1-piperideine, the precursors of piperidine. In vivo and in vitro experiments verified the catalytic capability of them. In conclusion, our findings revealed enigmatic key steps of piperine biosynthetic pathway and thus provide a powerful reference for dissecting the biosynthetic logic of other piper amides.
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Piper nigrum , Piper nigrum/genética , Alcamidas Poli-Insaturadas , Piperidinas , Perfilação da Expressão Gênica , MetabolomaRESUMO
Polypyrimidine tract-binding protein 1 (PTBP1) plays an essential role in splicing and post-transcriptional regulation. Moreover, PTBP1 has been implicated as a causal factor in tumorigenesis. However, the involvement of PTBP1 in cellular senescence, a key biological process in aging and cancer suppression, remains to be clarified. Here, it is shown that PTBP1 is associated with the facilitation of tumor growth and the prognosis in lung adenocarcinoma (LUAD). PTBP1 exhibited significantly increased expression in various cancer types including LUAD and showed consistently decreased expression in multiple cellular senescence models. Suppression of PTBP1 induced cellular senescence in LUAD cells. In terms of molecular mechanisms, the silencing of PTBP1 enhanced the skipping of exon 3 in F-box protein 5 (FBXO5), resulting in the generation of a less stable RNA splice variant, FBXO5-S, which subsequently reduces the overall FBXO5 expression. Additionally, downregulation of FBXO5 was found to induce senescence in LUAD. Collectively, these findings illustrate that PTBP1 possesses an oncogenic function in LUAD through inhibiting senescence, and that targeting aberrant splicing mediated by PTBP1 has therapeutic potential in cancer treatment.
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INTRODUCTION: Parthenogenetic chimera is an extremely rare condition in human. Very few patients with parthenogenetic chimerism with XX/XY cells have been identified. CASE PRESENTATION: We report the clinical findings and molecular analysis of chimerism with a 46,XX/46,XY karyotype in a patient presenting idiopathic oligoasthenoteratozoospermia (OAT). To clarify the mechanism of chimera formation, short tandem repeat analysis using 21 loci was carried out. Quantitation of alleles in D6S1043, D12S391, fibrinogen alpha chain, and amelogenin revealed double paternal and one maternal genetic contribution to the patient, which is consistent with a parthenogenetic chimerism. The likely mechanism of chimerism formation was also discussed, followed by a literature review. CONCLUSION: This is the first documented case of parthenogenetic chimerism in an adult male with XX/XY cells presenting OAT. Improved cell sampling and more sensitive and specific detection methods are necessary to identify more patients with XX/XY chimerism for systematic studies on this condition in the future.
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Quimerismo , Humanos , Masculino , Adulto , Oligospermia/genética , Partenogênese/genética , Repetições de Microssatélites/genética , Cromossomos Humanos Y/genética , Cromossomos Humanos X/genética , Azoospermia/genética , CariotipagemRESUMO
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
BACKGROUND: Observational studies have shown that smoking is related to the diffusing capacity of the lungs for carbon monoxide (DLCO) in individuals with idiopathic pulmonary fibrosis (IPF). Nevertheless, further investigation is needed to determine the causal effect between these two variables. Therefore, we conducted a study to investigate the causal relationship between smoking and DLCO in IPF patients using two-sample Mendelian randomization (MR) analysis. METHODS: Large-scale genome-wide association study (GWAS) datasets from individuals of European descent were analysed. These datasets included published lifetime smoking index (LSI) data for 462,690 participants and DLCO data for 975 IPF patients. The inverse-variance weighting (IVW) method was the main method used in our analysis. Sensitivity analyses were performed by MRâEgger regression, Cochran's Q test, the leave-one-out test and the MR-PRESSO global test. RESULTS: A genetically predicted increase in LSI was associated with a decrease in DLCO in IPF patients [ORIVW = 0.54; 95% CI 0.32-0.93; P = 0.02]. CONCLUSIONS: Our study suggested that smoking is associated with a decrease in DLCO. Patients diagnosed with IPF should adopt an active and healthy lifestyle, especially by quitting smoking, which may be effective at slowing the progression of IPF.
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Estudo de Associação Genômica Ampla , Fibrose Pulmonar Idiopática , Humanos , Fumar/efeitos adversos , Fumar/genética , Fumar Tabaco , Fibrose Pulmonar Idiopática/genética , Monóxido de CarbonoRESUMO
BACKGROUND: Persistent pulmonary hypertension of the newborn is a life-threatening condition that affects about 1-2 per 1,000 live births worldwide. Bosentan is an oral dual endothelin receptor antagonist that may have a beneficial effect on persistent pulmonary hypertension of the newborn by reducing pulmonary vascular resistance and improving oxygenation. However, its role in persistent pulmonary hypertension of the newborn remains unclear. OBJECTIVES: To systematically evaluate the efficacy and safety of bosentan as an adjuvant therapy for persistent pulmonary hypertension of the newborn in newborns. METHODS: We searched six English and two Chinese databases from their inception to 1 January 2023 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomised controlled trials and retrospective studies that compared bosentan with placebo or other drugs for persistent pulmonary hypertension of the newborn in newborns. We performed a meta-analysis using random-effects models and assessed the risk of bias and heterogeneity in the included studies. RESULTS: We included 10 studies with a total of 550 participants. Bosentan significantly reduced the treatment failure rate (relative risk = 0.25, P < 0.001), pulmonary artery pressure (mean difference = -11.79, P < 0.001), and length of hospital stay (mean difference = -1.04, P = 0.003), and increased the partial pressure of oxygen (mean difference = 10.02, P < 0.001) and blood oxygen saturation (SpO2) (mean difference = 8.24, P < 0.001) compared with a placebo or other drugs. The occurrence of adverse reactions was not significantly different between bosentan and a placebo or other drugs. CONCLUSIONS: Bosentan is effective in the treatment of persistent pulmonary hypertension of the newborn but adverse reactions such as abnormal liver function should be observed when using it.
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BACKGROUND AND OBJECTIVES: Feeding intolerance (FI) is a common problem in late preterm infants (34 weeks ≤ gestational age < 37 weeks). This study aimed to evaluate the efficacy and safety of phentolamine combined with B vitamins in treating FI in late preterm infants and to explore its effects on gastrointestinal symptoms, inflammation and complications. METHODS AND STUDY DESIGN: We randomly assigned 118 late preterm infants with FI to a treatment group (n = 56) or a control group (n = 62). The treatment group received intravenous phentolamine and intramuscular B vitamins, whereas the control group received basic treatment only. We measured the time of disappearance of gastrointestinal symptoms, the time of basal at-tainment, the time of hospitalisation, the incidence of complications, the concentrations of inflammatory markers and the overall effective rate of treatment. RESULTS: The treatment group had a shorter duration of gastrointestinal symptoms than did the control group (p < 0.01). The treatment group also had lower concentrations of inflammatory markers and a higher overall effective rate than did the control group (p < 0.05). There was no difference between the two groups in the time of hospitalisation, basal attainment, weight re-covery and the incidence of complications (p > 0.05). CONCLUSIONS: Phentolamine and B vitamins can reduce gastrointestinal symptoms and inflammation in late preterm infants with FI but do not affect the occurrence of complications.
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Recém-Nascido Prematuro , Fentolamina , Complexo Vitamínico B , Feminino , Humanos , Recém-Nascido , Masculino , Intolerância Alimentar , Gastroenteropatias/tratamento farmacológico , Fentolamina/administração & dosagem , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/uso terapêuticoRESUMO
TP53 mutation is one of the most common genetic changes in hepatocellular carcinoma (HCC). It is of great clinical significance to tailor specialized prognostication approach and to explore more therapeutic options for TP53-mutant HCCs. In this study, a total of 1135 HCC patients were retrospectively analyzed. We developed a random forest-based prediction model to estimate TP53 mutational status, tackling the problem of limited sample size in TP53-mutant HCCs. A multi-step process was performed to develop robust poor prognosis-associated signature (PPS). Compared with previous established population-based signatures, PPS manifested superior ability to predict survival in TP53-mutant patients. After in silico screening of 2249 drug targets and 1770 compounds, we found that three targets (CANT1, CBFB and PKM) and two agents (irinotecan and YM-155) might have potential therapeutic implications in high-PPS patients. The results of drug targets prediction and compounds prediction complemented each other, presenting a comprehensive view of potential treatment strategy. Overall, our study has not only provided new insights into personalized prognostication approaches, but also thrown light on integrating tailored risk stratification with precision therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular , Neoplasias Hepáticas , Mutação , Medicina de Precisão , Proteína Supressora de Tumor p53 , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Simulação por Computador , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Irinotecano/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Naftoquinonas/administração & dosagem , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Almost all currently approved systemic therapies for hepatocellular carcinoma (HCC) failed to achieve satisfactory therapeutic effect. Exploring tailored treatment strategies for different individuals provides an approach with the potential to maximize clinical benefit. Previously, multiple studies have reported that hepatoma cell lines belonging to different molecular subtypes respond differently to the same treatment. However, these studies only focused on a small number of typical chemotherapy or targeted drugs across limited cell lines due to time and cost constraints. To compensate for the deficiency of previous experimental researches as well as link molecular classification with therapeutic response, we conducted a comprehensive in silico screening, comprising nearly 2000 compounds, to identify compounds with subclass-specific efficacy. Here, we first identified two transcriptome-based HCC subclasses (AS1 and AS2) and then made comparison of drug response between two subclasses. As a result, we not only found that some agents previously considered to have low efficacy in HCC treatment might have promising therapeutic effects for certain subclass, but also identified novel therapeutic compounds that were not routinely used as anti-tumor drugs in clinic. Discovery of agents with subclass-specific efficacy has potential in changing the status quo of population-based therapies in HCC and providing new insights into precision oncology.
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Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Transcriptoma , Antineoplásicos/classificação , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Medicina de PrecisãoRESUMO
Mass spectrometry imaging has become a hot research field owing to its ability to reflect the distribution of multiple metabolites in tissue. However, not all kinds of metabolites have great ionization efficiency in mass spectrometry imaging. The mass signals of low polar metabolites like monoglycerides and diglycerides may be seriously suppressed. Many strategies have been proposed to fix the problem, such as on-tissue derivatization and online derivatization. Also, some challenges were encountered when implementing these approaches. Herein, a platform coupled online quaternized derivatization and laser ablation carbon fiber ionization mass spectrometry imaging has been developed. The mass signals of monoglycerides and diglycerides were drastically increased in the platform, and high-quality mass images of these metabolites could be acquired readily. In the platform, metabolites were first desorbed by a laser and then reacted online with a derivatization reagent transmitted by carbon fiber ionization, which also undertook the postionization of derivatization products. Pyridine acted as the main derivatization reagent to target metabolites with hydroxyl groups. Remarkably, the derivatization reaction proceeded rapidly without any catalyst owing to the high energy provided by the laser. The mass images of eight monoglycerides and 21 diglycerides were achieved after applying the platform into human ovarian cancer tissues. Notably, a higher mass intensity of these glycerides was captured in cancerous tissues than in para-cancerous tissues, which might infer aberrations in glyceride metabolisms of cancerous tissues.
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Terapia a Laser , Neoplasias Ovarianas , Fibra de Carbono , Feminino , Glicerídeos , Humanos , Espectrometria de Massas , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Bronchopulmonary dysplasia (BPD) is an inflammation-related respiratory disorder in infants. MiR-382-5p has displayed low expression in developing lungs with BPD, while the effect of miR-382-5p on BPD remains elusive. Here, a hyperoxia (85% oxygen)-induced BPD model in neonatal mice was established. On postnatal days 10 and 15, hyperoxia reduced miR-382-5p expression in lungs of mice. Besides, CDK8, CD68 and CD86 levels were elevated on day 15 after birth, implying the involvement of CDK8 in M1 macrophage polarization. In addition, in vitro injury in RAW264.7 macrophages was induced by IFN-γ and LPS stimulation. Lentivirus-encoding miR-382-5p decreased CDK8 expression, alleviated the production of inflammatory cytokines TNF-α, IL-1ß and IL-6, and restricted the levels of CD40 and CD86 in response to IFN-γ and LPS. Moreover, miR-382-5p inhibited the phosphorylation of STAT1. Luciferase reporter assay verified that miR-382-5p might target the 3'UTR of CDK8. Rescue assays revealed that CDK8 reversed the mitigating roles of miR-382-5p in inflammatory response and M1 macrophage polarization, as reflected by increased IL-6 and CD40 levels. Taken together, these findings indicate that miR-382-5p may suppress M1 macrophage activation and inflammatory response via inhibiting CDK8, thereby regulating the development of BPD, which is possibly mediated by STAT1 signaling.
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Displasia Broncopulmonar , Quinase 8 Dependente de Ciclina/metabolismo , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Animais , Displasia Broncopulmonar/genética , Modelos Animais de Doenças , Humanos , Recém-Nascido , Ativação de Macrófagos , Macrófagos , Camundongos , MicroRNAs/genética , Fator de Transcrição STAT1/genéticaRESUMO
BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α (PGC1α) is a key regulator of mitochondrial biogenesis and respiration. PGC1α is involved in the carcinogenesis, progression, and metabolic state of cancer. However, its role in the progression of hepatocellular carcinoma (HCC) remains unclear. APPROACH AND RESULTS: In this study, we observed that PGC1α was down-regulated in human HCC. A clinical study showed that low levels of PGC1α expression were correlated with poor survival, vascular invasion, and larger tumor size. PGC1α inhibited the migration and invasion of HCC cells with both in vitro experiments and in vivo mouse models. Mechanistically, PGC1α suppressed the Warburg effect through down-regulation of pyruvate dehydrogenase kinase isozyme 1 (PDK1) mediated by the WNT/ß-catenin pathway, and inhibition of the WNT/ß-catenin pathway was induced by activation of PPARγ. CONCLUSIONS: Low levels of PGC1α expression indicate a poor prognosis for HCC patients. PGC1α suppresses HCC metastasis by inhibiting aerobic glycolysis through regulating the WNT/ß-catenin/PDK1 axis, which depends on PPARγ. PGC1α is a potential factor for predicting prognosis and a therapeutic target for HCC patients.
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Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/secundário , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Biomarcadores Tumorais/sangue , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/sangue , Prognóstico , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Efeito Warburg em Oncologia , Via de Sinalização Wnt/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Focal cortical dysplasia (FCD) is the most common developmental malformation that causes refractory epilepsy. FCD II is a common neuropathological finding in tissues resected therapeutically from patients with drug-resistant epilepsy. However, its molecular genetic etiology remains unclear. This study aimed to identify potential molecular markers of FCD II using bioinformatics analysis. METHODS: We downloaded two datasets for FCD II from the Gene Expression Omnibus data repository. Differentially expressed genes (DEGs) between FCD II and normal brain tissues were identified, and functional enrichment analysis was performed. A protein-protein interaction network was constructed, and hub genes were identified from the DEGs. The hub gene expression was validated using WB in vitro. IHC staining was performed to verify the feasibility of the target molecular markers identified in the bioinformatics analysis. RESULTS: One hundred sixty-seven common DEGs were identified between the datasets. The GO and KEGG analyses showed that variations were prominently enriched in some functions associated with gene expression. Five hub genes (i.e., FANCI, FANCA, BRCA2, RAD18, and KEAP1) were identified. Western blotting confirmed that all hub gene expressions were higher in the FCD II tissue than in the normal brain tissue. IHC staining showed that the FANCI expression significantly increased in the FCD II tissue. CONCLUSION: There are DEGs between FCD II and normal brain tissues, which may be considered biomarkers for FCD II, along with FANCI. The DEGs and hub genes identified in the bioinformatics analysis could serve as candidate targets for diagnosing and treating FCD II.
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Epilepsia , Malformações do Desenvolvimento Cortical do Grupo I , Biomarcadores Tumorais/genética , Biologia Computacional , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Malformações do Desenvolvimento Cortical do Grupo I/genética , Fator 2 Relacionado a NF-E2/genética , Ubiquitina-Proteína LigasesRESUMO
Tumor penetration and the accumulation of nanomedicines are crucial challenges in solid tumor therapy. By taking advantage of the MSC tumor-tropic property, we developed a mesenchymal stem cell (MSC)-based drug delivery system in which paclitaxel (PTX)-encapsulating hyaluronic acid-poly (D,L-lactide-co-glycolide) polymeric micelles (PTX/HA-PLGA micelles) were loaded for glioma therapy. The results indicated that CD44 overexpressed on the surface of both MSCs and tumor cells not only improved PTX/HA-PLGA micelle loading in MSCs, but also promoted the drug transfer between MSCs and adjacent cancer cells. It was hypothesized that CD44-mediated transcytosis played a crucial role and allowed deep glioma penetration depending on sequential intra-intercellular delivery via endocytosis-exocytosis. MSC-micelles were able to infiltrate from normal brain parenchyma towards contralateral tumors and led to the eradication of glioma. The survival of orthotopic glioma-bearing rats was significantly extended. In conclusion, the MSC-based delivery of HA-PLGA micelles is a potential strategy for tumor-targeting drug delivery.
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Glioma , Células-Tronco Mesenquimais , Animais , Linhagem Celular Tumoral , Dioxanos , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Glioma/tratamento farmacológico , Ácido Hialurônico/uso terapêutico , Micelas , Paclitaxel , Polímeros/uso terapêutico , RatosRESUMO
Adequate delivery of therapeutic agents to their intended molecular targets is crucial in tumor therapy. Versatile drug carriers need to overcome the challenges coming from the systemic circulation, membrane barriers, and endo-lysosomal degradation. Herein, hyaluronic acid-conjugated polydopamine (HA-PDA)-shelled mesoporous silica nanoparticles encapsulated with doxorubicin (MSNs-DOX) were successfully fabricated for targeted tumor therapy. Compared with reported studies focusing on the pH-sensitive release in tumors, we especially revealed the significant role of lysosomal release in DOX nuclear accumulation. After active targeting and CD44-mediated endocytosis in tumor cells, the PDA layer of the nanoparticles would be peeled off to trigger drug release owing to MSNs gatekeeper in acidic lysosomes. Subsequently, DOX molecules passively diffused into nuclei. The intracellular DOX transportation was evidenced by DOX accumulation in nuclei, lysosomal location of nanoparticles, and lysosome acidification inhibition test. After discharging of the cargoes from nanoparticles, PDA shells from residual nanoparticles were able to produce localized hyperthermia under NIR irradiation entrapped in lysosomes, inducing synergistic chemo-photothermal effect. Under NIR treatment, HA-PDA@MSNs-DOX presented a prominent tumor inhibition rate without obvious side effects. This study indicated the potent nuclear delivery and synergetic chemo-photothermal therapy achieved by HA-PDA-shelled MSNs.
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Neoplasias , Dióxido de Silício , Humanos , Terapia Fototérmica , Doxorrubicina/farmacologia , Concentração de Íons de HidrogênioRESUMO
Manganese(III) porphyrins (MnIIIPs) as MRI contrast agents (CAs) have drawn particular attention due to their high longitudinal relaxivity (r1) and unique biodistribution. In this work, two MnIIIP-based oligomers, MnPD and MnPT, were designed to further improve the relaxivity with ease of synthesis. The two compounds were fully characterized and their nuclear magnetic relaxation dispersion (NMRD) profiles were acquired with a fast field cycling NMR relaxometer. Both of the compounds exhibited extended high molar r1 at high fields, higher than that of Gd-DTPA, the first clinical gadolinium(III)-based MRI CA. The r1 value of per manganese atom increased with the increasing number of MnIIIP building blocks, suggesting rotational correlation time (τR) played dominant role in the r1 dispersion. The toxicity of the two MnIIIPs and the imaging effectiveness were estimated in vitro and in vivo. With good biocompatibility, significant contrast enhancement, and complete excretion in 24 h, MnPD and MnPT are both promising for high field clinical applications. The applied strategy also potentially provided a facile approach for creation of more MnIIIP oligomer as efficient T1 MRI CAs.
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Meios de Contraste/química , Imageamento por Ressonância Magnética , Metaloporfirinas/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Meios de Contraste/farmacologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Metaloporfirinas/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Estrutura MolecularRESUMO
Metastasis is the main reason for high recurrence and poor survival of hepatocellular carcinoma (HCC). The molecular mechanism underlying HCC metastasis remains unclear. In this study, we found that argininosuccinate synthase 1 (ASS1) expression was significantly decreased and down-regulation of ASS1 was closely correlated with poor prognosis in HCC patients. DNA methylation led to the down-regulation of ASS1 in HCC. Stable silencing of ASS1 promoted migration and invasion of HCC cells, whereas overexpression of ASS1-inhibited metastasis of HCC cells in vivo and in vitro. We also revealed that ASS1-knockdown increased the phosphorylation level of S727STAT3, which contributed to HCC metastasis by up-regulation of inhibitor of differentiation 1 (ID1). These findings indicate that ASS1 inhibits HCC metastasis and may serve as a target for HCC diagnosis and treatment.
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Argininossuccinato Sintase/fisiologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Argininossuccinato Sintase/antagonistas & inibidores , Argininossuccinato Sintase/genética , Carcinoma Hepatocelular/enzimologia , Linhagem Celular Tumoral , Movimento Celular , Metilação de DNA , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Neoplasias Hepáticas/enzimologia , Camundongos , Invasividade Neoplásica , Metástase Neoplásica/prevenção & controle , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/fisiologiaRESUMO
The capacity of liver regeneration is critical for patients with liver diseases. However, cellular and molecular mechanisms of liver regeneration are still incompletely defined. Here, we assessed roles of LASS2 in liver regeneration following partial hepatectomy (PHx) in mice. Our results showed that protein level of LASS2 remarkably increased during liver regeneration after PHx in wildtype (WT) mice. Comparing to WT mice, liver regeneration index after PHx was significantly decreased from day 1 to day 5 in liver-specific LASS2 knockout (LASS2-LKO) mice. Interestingly, liver mass of LASS2-LKO mice could sufficiently recover at day 14 after PHx. Immunohistochemistry (IHC) and western blot analyses revealed that proliferation markers, such as PCNA and Ki67, were potently reduced during liver regeneration in LASS2-LKO mice. In addition, several cell cycle related molecules, such as cyclin A, CDK2 and p-Rb, were decreased in LASS2-LKO mice after PHx. Co-immunoprecipitation assay further revealed a decreased formation of CDK4/cyclin D1 complex after PHx in LASS2-LKO mice. However, phosphorylation of Akt was significantly activated from day 2 after PHx in LASS2-LKO mice when compared with that in WT mice, which may explain the recovery of liver mass at the late stage of liver regeneration in LASS2-LKO mice. Taken together, we conclude that LASS2 plays an important role in efficient liver regeneration in response to PHx.
Assuntos
Hepatectomia/métodos , Regeneração Hepática/fisiologia , Esfingosina N-Aciltransferase/genética , Animais , Ciclo Celular/fisiologia , Proliferação de Células , Tamanho Celular , Hepatócitos/citologia , Hepatócitos/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esfingosina N-Aciltransferase/metabolismoRESUMO
Oriented hierarchical fibrous-like ZnO nanowires with the diameter of about 3050 nm and the length of about 1530 um were successfully synthesized on the seed-coated Zn substrates by a simple two-step process. The morphology and structure of the obtained samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). It is shown that fibrous-like ZnO nanowires with the aspect ratio of about 500Ë1000 present the dense reticular structure, which are grown on ZnO nanowire arrays. But beyond that, as-prepared samples are found to be good single crystalline with hexagonal wurtzite structure and preferential grow along the c-axis. A possible growth mechanism of oriented hierarchical fibrous-like ZnO nanowires is presented in detail, revealing that the synthesis of fibrous-like ZnO nanowires should be attributed to differences in the growth rate of the different crystallographic planes and the two growth ways. The photoluminescence (PL) spectra of oriented hierarchical fibrous-like ZnO nanowires grown at 240 min shows the 5 nm blue-shift and enhanced intensity property in the UV emission.