RESUMO
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. Hypoxia-activated prodrugs (HAPs) have shown promise as potential therapeutic agents for TNBC. While increasing hypoxia levels may promote the HAP activation, it raises concerns regarding HIF1α-dependent drug resistance. It is desirable to develop a targeted approach that enhances tumor hypoxia for HAP activation without promoting HIF1α-dependent drug resistance in TNBC treatment. Herein, we proposed a multi-responsive carrier-free self-assembled nanomedicine named AQ4N@CA4T1ASO. This nanomedicine first targeted tumors by the TNBC-targeting aptamers (T1), and then disassembled in the reductive and acidic conditions within tumors. The released Combretastatin 4 (CA4) could exacerbate hypoxia, thereby promoting the conversion of inactive Banoxantrone (AQ4N) to its active form, AQ4. Simultaneously, the released antisense oligonucleotide (ASO) could attenuate hypoxia-induced HIF1α mRNA expression, thereby sensitizing the tumor to chemotherapy. Overall, this smart nanomedicine represents a profound targeted therapy strategy, combining "hypoxia-potentiating, hypoxia-activated, chemo-sensitization" approaches for TNBC treatment. In vivo study demonstrated significant suppression of tumor growth, highlighting the promising potential of this nanomedicine for future clinical translation.
Assuntos
Aptâmeros de Nucleotídeos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Pró-Fármacos , Neoplasias de Mama Triplo Negativas , Pró-Fármacos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Humanos , Aptâmeros de Nucleotídeos/farmacologia , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Camundongos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Camundongos Endogâmicos BALB C , AntraquinonasRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil. METHODS: We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo. RESULTS: Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo. CONCLUSIONS: This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.
Assuntos
Aptâmeros de Nucleotídeos , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Fluoruracila , Nucleolina , Paclitaxel , Fosfoproteínas , Proteínas de Ligação a RNA , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Aptâmeros de Nucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/química , Humanos , Paclitaxel/uso terapêutico , Paclitaxel/farmacologia , Linhagem Celular Tumoral , Animais , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Proteínas de Ligação a RNA/metabolismo , Fosfoproteínas/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Oligodesoxirribonucleotídeos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Camundongos Endogâmicos BALB CRESUMO
Micro/nanoplastics (M/NPs) are the novel contaminants ubiquitous in the environment. Cadmium (Cd), a kind of heavy metal pollutant widely distributed, could potentially co-exist with PS-NPs in the environment. However, their combined effects on cardiomyocyte and its molecular mechanism in mammals remained ambiguous. Here, we examined whether PANoptosis, an emerging and complicated kind of programmed cell death, was involved in PS-NPs and Cd co-exposure-elicited cardiac injury. In this study, 60 male mice were orally subjected to environmentally relevant concentrations of PS-NPs (1 mg/kg) and/or CdCl2 (1.5 mg/kg) for 35 days. As we speculated, PS-NPs and Cd co-exposure affected the expression of pyroptosis(Caspase-1, Cleaved-Caspase-1, GSDMD, N-GSDMD, AIM2, Pyrin, NLRP3, IL-18, IL-1ß)-, apoptosis(Caspase-3, Cleaved-Caspase-3, Caspase-8, Cleaved-Caspase-8, Caspase-7, BAX)- and necroptosis (t-RIPK3, p-RIPK3, t-RIPK1, p-RIPK1, t-MLKL, p-MLKL, ZBP1)-related genes and protein, resulting in growth restriction and damaged myocardial microstructure in mice. Notably, the combined effects on Cd and PS-NPs even predominantly aggravated the toxic damage. Intriguingly, we fortuitously discovered PS-NPs and/or Cd exposure facilitated linear ubiquitination of certain proteins in mice myocardium. In summation, this study shed light toward the effects of Cd and PS-NPs on cardiotoxicity, advanced the understanding of myocardial PANoptosis and provided a scientific foundation for further exploration of the combined toxicological effects of PS-NPs and heavy metals.
Assuntos
Cádmio , Miócitos Cardíacos , Masculino , Animais , Camundongos , Cádmio/toxicidade , Caspase 3 , Caspase 8 , Microplásticos , Poliestirenos , MamíferosRESUMO
Chemodynamic therapy (CDT), which converts overexpressed hydrogen peroxide (H2O2) in tumor cells to hydroxyl radicals (â¢OH) by Fenton reactions, is considered a prospective strategy in anticancer therapy. However, the high level of glutathione (GSH) and poor Fenton catalytic efficiency contribute to the suboptimal efficiency of CDT. Herein, we present a multifunctional nanoplatform (CuFe2O4@HA) that can induce GSH depletion and combine with photothermal therapy (PTT) to enhance antitumor efficacy. CuFe2O4@HA nanoparticles could release Cu2+ and Fe3+ after entering tumor cells by targeting hyaluronic acid (HA). Subsequently, Cu2+ and Fe3+ were reduced to Cu+ and Fe2+ by GSH, where Cu+/Fe2+ significantly catalyzed H2O2 to produce a higher level of â¢OH, and the depletion of GSH disrupted the antioxidant capacity of the tumor. Therefore, depleting GSH substantially enhances the level of â¢OH in tumor cells. In addition, CuFe2O4@HA nanoparticles have considerable absorption in the near-infrared (NIR) region, which can stimulate excellent PTT effects. More importantly, the heat generated by PTT can further enhance the Fenton catalysis efficiency. In vitro and in vivo experiments have demonstrated the excellent tumor-killing effect of CuFe2O4@HA nanoparticles. This strategy overcomes the problem of insufficient CDT efficacy caused by GSH overexpression and poor catalytic efficiency. Moreover, this versatile nanoplatform provides a reference for self-enhanced CDT and PTT/CDT synergistic targeted therapy.
Assuntos
Ácido Hialurônico , Neoplasias , Humanos , Ácido Hialurônico/farmacologia , Peróxido de Hidrogênio , Glutationa , Antioxidantes , Catálise , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Bone is one of the prone metastatic sites of patients with advanced breast cancer. The "vicious cycle" between osteoclasts and breast cancer cells plays an essential role in osteolytic bone metastasis from breast cancer. In order to inhibit bone metastasis from breast cancer, NIR-II photoresponsive bone-targeting nanosystems (CuP@PPy-ZOL NPs) are designed and synthesized. CuP@PPy-ZOL NPs can trigger the photothermal-enhanced Fenton response and photodynamic effect to enhance the photothermal treatment (PTT) effect and thus achieve synergistic anti-tumor effect. Meanwhile, they exhibit a photothermal enhanced ability to inhibit osteoclast differentiation and promote osteoblast differentiation, which reshaped the bone microenvironment. CuP@PPy-ZOL NPs effectively inhibited the proliferation of tumor cells and bone resorption in the in vitro 3D bone metastases model of breast cancer. In a mouse model of breast cancer bone metastasis, CuP@PPy-ZOL NPs combined with PTT with NIR-II significantly inhibited the tumor growth of breast cancer bone metastases and osteolysis while promoting bone repair to achieve the reversal of osteolytic breast cancer bone metastases. Furthermore, the potential biological mechanisms of synergistic treatment are identified by conditioned culture experiments and mRNA transcriptome analysis. The design of this nanosystem provides a promising strategy for treating osteolytic bone metastases.
Assuntos
Neoplasias Ósseas , Osteólise , Animais , Camundongos , Terapia Fototérmica , Microambiente Tumoral , Osso e Ossos/patologia , Neoplasias Ósseas/terapia , Neoplasias Ósseas/patologia , Osteoclastos , Osteólise/terapia , Osteólise/patologia , Linhagem Celular TumoralRESUMO
RNF31, an atypical E3 ubiquitin ligase of the RING-between-RING protein family, is one of the important components of the linear ubiquitin chain complex LUBAC. It plays a carcinogenic role in a variety of cancers by promoting cell proliferation, invasion and inhibiting apoptosis. However, the specific molecular mechanism by which RNF31 exerts its cancer-promoting effects is still unclear. By analyzing the expression profile of RNF31-depleted cancer cells, we found that loss of RNF31 significantly resulted in the inactivation of the c-Myc pathway. We further showed that RNF31 played an important role in the maintenance of c-Myc protein levels in cancer cells by extending the half-life of c-Myc protein and reducing its ubiquitination. c-Myc protein levels are tightly regulated by the ubiquitin proteasome, in which the E3 ligase FBXO32 is required to mediate its ubiquitin-dependent degradation. We found that RNF31 inhibited the transcription of FBXO32 through EZH2-mediated trimethylation of histone H3K27 in the FBXO32 promoter region, leading to the stabilization and activation of c-Myc protein. Under this circumstance, the expression of FBXO32 was significantly increased in RNF31-deficient cells, promoting the degradation of c-Myc protein, inhibiting cell proliferation and invasion, increasing cell apoptosis, and ultimately blocking the progression of tumors. Consistent with these results, the reduced malignancy phenotype caused by RNF31 deficiency could be partially reversed by overexpression of c-Myc or further knockdown of FBXO32. Together, our results reveal a key association between RNF31 and epigenetic inactivation of FBXO32 in cancer cells, and suggest that RNF31 may be a promising target for cancer therapy.
Assuntos
Neoplasias , Ubiquitina , Humanos , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Neoplasias/genética , Epigênese Genética , Proteínas Musculares/metabolismo , Proteínas Ligases SKP Culina F-Box/genéticaRESUMO
SEMA6A is a multifunctional transmembrane semaphorin protein that participates in various cellular processes, including axon guidance, cell migration, and cancer progression. However, the role of SEMA6A in clear cell renal cell carcinoma (ccRCC) is unclear. Based on high-throughput sequencing data, here we report that SEMA6A is a novel target gene of the VHL-HIF-2α axis and overexpressed in ccRCC. Chromatin immunoprecipitation and reporter assays revealed that HIF-2α directly activated SEMA6A transcription in hypoxic ccRCC cells. Wnt/ß-catenin pathway activation is correlated with the expression of SEMA6A in ccRCC; the latter physically interacted with SEC62 and promoted ccRCC progression through SEC62-dependent ß-catenin stabilization and activation. Depletion of SEMA6A impaired HIF-2α-induced Wnt/ß-catenin pathway activation and led to defective ccRCC cell proliferation both in vitro and in vivo. SEMA6A overexpression promoted the malignant phenotypes of ccRCC, which was reversed by SEC62 depletion. Collectively, this study revealed a potential role for VHL-HIF-2α-SEMA6A-SEC62 axis in the activation of Wnt/ß-catenin pathway. Thus, SEMA6A may act as a potential therapeutic target, especially in VHL-deficient ccRCC.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Semaforinas , Humanos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Semaforinas/genética , Semaforinas/metabolismo , Regulação para Cima , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismoRESUMO
In the complex and severe tumor microenvironment, the antitumor efficiency of nanomedicines is significantly limited by their low-efficacy monotherapy, non-tumor targeting, and systemic toxicity. Herein, to achieve tumor-targeted and enhanced chemodynamic/photothermal therapy (CDT/PTT), we fabricated an "all-in-one" biocompatible transferrin-loaded cobalt ferrate nanoparticle (CoFe2O4@Tf (CFOT)) with multiple functions by a simple solvothermal method and the following transferrin (Tf) functionalization. Upon exposure to 808 nm laser irradiation, CFOT, as a novel photothermal agent, exhibited outstanding phototherapeutic activity because of its excellent photothermal conversion efficiency (η = 46.5%) for high-performance PTT. Moreover, CFOT with multiple redox pairs could efficiently convert endogenous H2O2 to hazardous hydroxyl radicals (ËOH) via Fenton reactions while scavenging overexpressed GSH in the tumor microenvironment to realize self-reinforcing CDT. Importantly, CFOT undergoes a promoted Fenton-type reaction upon increasing the temperature under a photothermal effect and could augment PTT by high-level ËOH, exhibiting a considerably enhanced synergistic therapeutic effect. In vitro and in vivo experimental results demonstrated that CFOT has good potential as an "all-in-one" nanoagent to combine photothermal, chemodynamic, and tumor targeting for efficient tumor elimination.
Assuntos
Nanopartículas , Neoplasias , Humanos , Transferrina , Peróxido de Hidrogênio , Terapia Fototérmica , Neoplasias/tratamento farmacológico , Cobalto/farmacologia , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
BACKGROUND: Bone-related proteins (such as sclerostin and osteoprotegerin [OPG]) are involved in the development of atherosclerosis. However, the relationship between bone-related proteins and acute myocardial infarction (AMI) has not been extensively evaluated. The purpose of this study was to assess the association of serum sclerostin and OPG with the presence, severity and prognosis in patients with AMI. METHODS: This study prospectively enrolled 152 patients attacked by acute chest pain. Serum sclerostin and OPG were detected within the first 24 h after AMI diagnosis by ELISA kits. The AMI predictive efficacy of sclerostin and OPG were analyzed by receiver operating characteristics (ROC) curve. Univariable and multivariable linear regression analyses were performed to determine the association between bone-related proteins and scores indicating the severity of coronary artery occlusion. Moreover, prognostic values were assessed by Kaplan-Meier curves and Cox regression analysis. RESULTS: There were 92 patients in AMI group, 60 in non-AMI group. Serum levels of sclerostin and OPG were significantly higher in AMI group than in non-AMI group (all p < 0.001), which showed predictive value for the presence of AMI (all p < 0.001). The area under the ROC curve values of sclerostin and OPG were 0.744 and 0.897, respectively. A multivariable linear regression analysis demonstrated that Ln-transformed sclerostin (ß = 0.288, p = 0.009) and Ln-transformed OPG (Ln-OPG: ß = 0.295, p = 0.019) levels were associated with GENISINI score, independently of conventional clinical parameters. In addition, Ln-OPG levels were still positively associated with GRACE score after adjustments (ß = 0.320, p = 0.001). During a 1-year follow-up, patients above the median of sclerostin levels had higher incidence of major adverse cardiac events (MACE) than those below the median (p = 0.028). It was also observed that the MACE rates were higher in patients above the median of OPG levels, though no statistic importance (p = 0.060). After adjusting conventional risk factors by multivariate Cox regression, Ln-OPG was associated with incident MACE (hazard ratio = 2.188 [95% confidence intervals 1.102-4.344], p = 0.025). CONCLUSIONS: Bone-related proteins could exert a potential role in early risk stratification and prognosis assessment in patients with AMI.
Assuntos
Infarto do Miocárdio , Osteoprotegerina , Proteínas Adaptadoras de Transdução de Sinal , Biomarcadores , Humanos , Infarto do Miocárdio/epidemiologia , Prognóstico , Curva ROCRESUMO
Metal ions are of widespread interest owing to their brilliant biomedical functions. However, a simple and universal nanoplatform designed for assembling a range of functional metal ions has not been explored. In this study, a concept of polyethylene glycol (PEG)-mediated transport of metal ions is proposed. 31 types of PEG-metal hybrid nanoparticles (P-MNPs) are successfully synthesized through anionic ring-opening polymerization (ROP), "thiol-ene" click reaction, and subsequent incorporation with multiple metal ions. Compared with other methods, the facile method proposed in this study can provide a feasible approach to design MNPs (mostly <200 nm) containing different metal ions and thus to explore their potential for cancer theranostics. As a proof-of-concept demonstration, four types P-MNPs, i.e., PEG-metal hybrid copper nanoparticles (PEG-Cu NPs), ruthenium nanoparticles (PEG-Ru NPs), and manganese nanoparticles (PEG-Mn NPs) or gadolinium nanoparticles (PEG-Gd NPs), are proven to be tailored for chemodynamic therapy, photothermal therapy, and magnetic resonance imaging of tumors, respectively. Overall, this study provides several metal ions-based nanomaterials with versatile functions for broad applications in cancer theranostics. Furthermore, it offers a promising tool that can be utilized for processing other metal-based nanoparticles and exploring their potential in the biomedical field.
Assuntos
Nanopartículas Metálicas , Nanopartículas , Neoplasias , Humanos , Íons , Metais , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Polietilenoglicóis , Medicina de PrecisãoRESUMO
Ubiquitin-specific protease 18 (USP18) is a deubiquitinating enzyme that reverses the post-translational modification of target proteins by ISG15 or ubiquitin, and is involved in a variety of cellular processes, including signal transduction, viral infection, and cancer development. Although high levels of USP18 mRNA have been observed in several types of cancer, its pathological significance in ovarian cancer (OV) is still elusive. Here, by integrating the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Genotypic Tissue Expression (GTEx) databases, we found that USP18 was abnormally up-regulated in OV tissues, and the increased expression of USP18 was associated with poor prognosis. We further showed that activated Jak-STAT3 signaling induced the expression of USP18, which in turn feedback maintained the activity of Jak-STAT3 signaling in OV. In addition, we found that USP18 played a cancer-promoting role in OV mainly through the transcriptional regulation of FBXO6. Silencing USP18 reduced the malignancy of OV, which can be largely reversed by overexpression of FBXO6. On the contrary, silencing FBXO6 significantly weaken the pro-proliferation function of USP18 in OV cells. In summary, our results indicate that USP18 is a downstream target gene of STAT3, and the USP18-FBXO6 axis might be a promising therapeutic target for OV.
Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/patologia , Proteínas Ligases SKP Culina F-Box/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitinas/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , Processamento de Proteína Pós-Traducional , Proteínas Ligases SKP Culina F-Box/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ubiquitina Tiolesterase/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ATPase family AAA domain-containing protein 2 (ATAD2) is highly expressed in a variety of cancer types, and acts as a co-activator of androgen and estrogen receptors, as well as MYC and E2F transcription factors, to promote tumor cell proliferation. However, the regulation of ATAD2 and its related mechanisms are still elusive. Here, we show that ATAD2 protein was stabilized during DNA damage response in colorectal cancer (CRC) cells. TRIM25, an oncogenic ubiquitin E3 ligase, can interact with ATAD2 and stabilize ATAD2 upon genotoxic insult. We further demonstrated that ATAD2 played a tumor promoting role in CRC and acted as a transcriptional co-activator of E2Fs to promote the expression of TRIM25. Thus, our results revealed an unknown ATAD2-E2Fs-TRIM25 positive feedback loop that drove CRC progression.
Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Neoplasias Colorretais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição E2F/metabolismo , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Animais , Proliferação de Células , Progressão da Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Complexo de Endopeptidases do Proteassoma/metabolismo , Interferência de RNARESUMO
UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to small lipophilic chemicals and are associated with a wide range of diseases including cancer. The human genome contains 22 UGT genes which could be classified into four families: UGT1, UGT2, UGT3, and UGT8. The UGT8 family contains only one member which utilizes UDP galactose to galactosidate ceramide. Although higher UGT8 mRNA was observed in some types of cancer, its pathological significances remain elusive. Here, by integrating the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Genotype-Tissue Expression (GTEx) databases, we showed that UGT8 was selectively highly expressed in non-small cell lung cancer (NSCLC) and associated with worse prognosis. The transcription factor SOX9 promoted UGT8 expression in NSCLC by recognizing two putative response elements localized on the promoter region of UGT8. Silencing UGT8 impaired glycolysis and reduced the malignancy of NSCLC cells both in vitro and in vivo. On the contrary, inhibition of glycolysis by 2-deoxy-d-glucose (2-DG) significantly impaired the pro-proliferation function of UGT8 in NSCLC cells. In conclusion, our results suggest that UGT8 maintains the malignancy of NSCLC mainly via enhanced glycolysis and provides a promising therapeutic target for NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Gangliosídeo Galactosiltransferase/genética , Glicólise/genética , Neoplasias Pulmonares/genética , Fatores de Transcrição SOX9/genética , Células A549 , Animais , Atlas como Assunto , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Conjuntos de Dados como Assunto , Gangliosídeo Galactosiltransferase/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição SOX9/antagonistas & inibidores , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Organic small molecules with near-infrared (NIR) absorption hold great promise as the phototheranostic agents for clinical translation by virtue of their inherent merits such as well-defined chemical structure, high purity and good reproducibility. Probes that happen to be based on cyanine dyes exhibit strong NIR-absorbing and efficient photothermal conversion, representing a new class of photothermal agents (PAs) for photothermal therapy (PTT), and taking into account the heat susceptibility of Mitochondria (Mito), we designed and prepared a mitochondria-targeted organic small molecule (Mito-BWQ) based on thiazole orange maternal unit that can effectively kill tumor cells through the hyperpyrexia generated in the lesions under exogenous laser irradiation. The Confocal laser scanning microscope was employed to determine the preferential targeting of Mito-BWQ to the mitochondria of MCF-7 cells and U87 cells. When subjected to 600 nm laser radiation, Mito-BWQ produced an increase in temperature in test systems and this increase was dependent on both the laser power and probe concentration. In vitro tests, cytotoxicity was observed when cells were incubated with Mito-BWQ and exposed to laser irradiation. The PTT in vivo also showed that Mito-BWQ performed remarkably in tumor inhibition. This study thus provides a vital starting point for the creation of thiazole orange-based PTT formulations and promotes further advances in the field of PAs-based anticancer research and therapy.
Assuntos
Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Terapia Fototérmica , Quinolinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzotiazóis/síntese química , Benzotiazóis/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Acanthopanax trifoliatus (L.) Merr (AT) is a medicinal and edible plant with high nutritional value. The biological activity of A. trifoliatus (L.) Merr and its basis for injury treatment are explored in this paper. AT was ethanol-extracted then refined separately with petroleum ether, chloroform, ethyl acetate, and n-butanol. Active ingredients were analyzed, and anti-bacterial, anti-inflammatory, analgesic, and hemostatic effects were explored. Petroleum ether layer (PEL) extract produced the strongest antibacterial effect. Ethyl acetate layer (EAL) extract had the highest active substance content, with strong hemostatic and analgesic activities. Chloroform layer (CL) extract had the strongest anti-inflammatory effect and significantly reduced IL-1ß protein expression. Active ingredients were analyzed using HPLC and UPLC-MS to determine saponin, polyphenol, flavonoid, and characteristic ingredient contents. EAL extract had the highest polyphenol and flavonoid levels, including rutin, chlorogenic acid, isochlorogenic acid A, and isochlorogenic acid C, which may contribute to its nutritional activities. The study provides a reliable theoretical and practical basis for the applications of AT nutraceutical products.
RESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is among the deadliest forms of cancer. While RNA-binding proteins (RBPs) have been shown to be key regulators of oncogenesis and tumor progression, their dysregulation in the context of HCC remains to be fully characterized. METHODS: Data from the Cancer Genome Atlas - liver HCC (TCGA-LIHC) database were downloaded and analyzed in order to identify RBPs that were differentially expressed in HCC tumors relative to healthy normal tissues. Functional enrichment analyses of these RBPs were then conducted using the GO and KEGG databases to understand their mechanistic roles. Central hub RBPs associated with HCC patient prognosis were then detected through Cox regression analyses, and were incorporated into a prognostic model. The prognostic value of this model was then assessed through the use of Kaplan-Meier curves, time-related ROC analyses, univariate and multivariate Cox regression analyses, and nomograms. Lastly, the relationship between individual hub RBPs and HCC patient overall survival (OS) was evaluated using Kaplan-Meier curves. Finally, find protein-coding genes (PCGs) related to hub RBPs were used to construct a hub RBP-PCG co-expression network. RESULTS: In total, we identified 81 RBPs that were differentially expressed in HCC tumors relative to healthy tissues (54 upregulated, 27 downregulated). Seven prognostically-relevant hub RBPs (SMG5, BOP1, LIN28B, RNF17, ANG, LARP1B, and NR0B1) were then used to generate a prognostic model, after which HCC patients were separated into high- and low-risk groups based upon resultant risk score values. In both the training and test datasets, we found that high-risk HCC patients exhibited decreased OS relative to low-risk patients, with time-dependent area under the ROC curve values of 0.801 and 0.676, respectively. This model thus exhibited good prognostic performance. We additionally generated a prognostic nomogram based upon these seven hub RBPs and found that four other genes were significantly correlated with OS. CONCLUSION: We herein identified a seven RBP signature that can reliably be used to predict HCC patient OS, underscoring the prognostic relevance of these genes.
Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas de Ligação a RNA/genética , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
OBJECTIVE: To assess the treatment effect of intra-articular fracture with absorbable screws and rods. METHODS: From June 1998 to August 2004, 35 patients with intra-articular fracture were treated by absorbable screws and rods made of self-reinforced polyglycolic acid (SR-PGA) and self-reinforced poly-L-Lactic acid (SR-PLLA). Of 35 patients, 30 were males and 5 were females (aged from 4 to 62 years). All cases had intra-articular or periarticular fracture. The interval between injury and operation was 3 hours to 29 days. Fracture were fixed with full thread screws of SR-PGA in 9 cases, with tensile screws of SR-PLLA in 26 cases, with rods of SR-PLLA in 15 cases. Bone traction or plaster external fixation were carried out postoperatively. RESULTS: The patients were followed from 3 months to 60 months with an average of 28 months. The wounds healed by first intention, and the healing time of bone was 1-3 months. No dislocation, infection and local effusion occurred. Functional recovery was satisfactory. According to AASO articular function standard, the results were excellent in 26 cases, good in 7 cases, fair in 1 case, and poor in 1 case; the total excellent and good rate was 94.3%. CONCLUSION: Internal fixation of absorbable screws and rods are a perfect procedure in treating intra-articular and periarticular fracture, which can avoid the pain of taking out internal fixation materials because of second operation.
Assuntos
Implantes Absorvíveis , Fraturas Ósseas/cirurgia , Articulações/lesões , Adolescente , Adulto , Pinos Ortopédicos , Criança , Pré-Escolar , Feminino , Fixação Interna de Fraturas/métodos , Articulação do Quadril , Humanos , Fixadores Internos , Masculino , Pessoa de Meia-Idade , Ácido PoliglicólicoRESUMO
AIM: To determine the expression of c-fos in gastric myenteric plexus and spinal cord of rats with cervical spondylosis and its clinical significance. METHODS: A cervical spondylosis model was established in rats by destroying the stability of cervical posterior column, and the cord segments C(4-6) and gastric antrum were collected 3, 4 and 5 mo after the operation. Rats with sham operation were used as controls. c-fos neuronal counter-staining was performed with an immunohistochemistry method. Every third sections from C(4-6) segments were drawn. The 10 most labeled c-fos-immunoreactive (Fos-IR) neurons were counted, and the average number was used for statistical analysis. The mean of Fos-IR neurons in myenteric plexus was calculated after counting Fos-IR neurons in 25 ganglia from each antral preparation, and expressed as a mean count per myenteric ganglion. RESULTS: There were a few c-fos-positive neurons in the cervical cord and antrum in the control group. There was an increased c-fos expression in model group 3, 4 and 5 mo after operation, whereas there was no significant increase in c-fos expression in the control group at 3, 4 and 5 mo. More importantly, there was a significant difference in c-fos expression between rats followed up for 3 mo and those for 5 mo in the model group (11.20+/-2.26 vs 27.68+/-4.36, P<0.05, for the cervical cord; and 11.3+/-2.3 vs 29.3+/-4.6, P<0.05, for the gastric antrum). There was no significant difference between rats followed up for 3 mo and those for 4 mo and between rats followed up for 4 mo and those for 5 mo in the model group. CONCLUSION: c-fos expression in gastric myenteric plexus was dramatically associated with that in the spinal cord in rats with cervical spondylosis, suggesting that the gastrointestinal function may be affected by cervical spondylosis. If this hypothesis is confirmed by further studies, functional gastrointestinal diseases such as functional dyspepsia and irritable bowel syndrome could be explained by neurogastroenterology.