RESUMO
Herein, four zinc phthalocyanines (ZnPcs) with chiral lysine modification were synthesized. We found that the chirality of lysine and the chiral structure position strongly influence the properties of ZnPcs. Among the four ZnPcs, d-lysine-modified ZnPc through -NH2 on Cε [denoted N(ε)-d-lys-ZnPc] showed superior properties, including tumor enrichment, cancer cell uptake, and tumor retention capability, compared to the other three ZnPcs. Thus, chiral molecule modification is a simple and effective strategy to regulate the abovementioned properties to achieve a satisfactory antitumor outcome of drugs.
Assuntos
Aminoácidos/química , Isoindóis/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Estereoisomerismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Células HeLa/efeitos dos fármacos , Humanos , Isoindóis/síntese química , Isoindóis/química , Lisina/química , Camundongos , Transplante de Neoplasias , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/química , Compostos de Zinco/síntese química , Compostos de Zinco/química , Compostos de Zinco/farmacologiaRESUMO
BACKGROUND: Biliary dilatation is a rare disease involving intrahepatic and extrahepatic biliary tract abnormalities. With the development of imaging technology, an increasing number of special cases have been diagnosed, which poses a challenge to the traditional classification method. CASE PRESENTATION: A 50-year-old woman was admitted to the hospital due to right upper quadrant pain for more than 10 days. The patient had previous episodes of similar symptoms, which were relieved after symptomatic treatment at a local community hospital. After the symptoms developed, she underwent a computed tomography scan at the local hospital, which showed biliary dilatation; thus, she was referred to our hospital for further treatment. After admission, her magnetic resonance imaging examination also suggested biliary dilatation, but abnormal signals were found in her duodenum. First, a duodenal diverticulum was considered. Later, endoscopic ultrasonography was conducted, and the results suggested that the dilated biliary tract had herniated into the duodenum. This type of lesion is most closely classified as a Todani type III lesion. The patient finally underwent choledochectomy and RouxenY hepaticojejunostomy, and the postoperative pathology was consistent with our preoperative diagnosis. The patient was followed up for approximately 2 years, and no obvious postoperative complications were found. CONCLUSIONS: The manifestations of this case are relatively rare and involve one of the undiscussed categories of the Todani classification system; therefore, this case has certain clinical value. Moreover, there is no report similar to this experience in the previous literature.
Assuntos
Ductos Biliares Extra-Hepáticos , Procedimentos Cirúrgicos do Sistema Biliar , Duodenopatias , Dilatação , Duodenopatias/diagnóstico por imagem , Duodenopatias/etiologia , Duodenopatias/terapia , Feminino , Humanos , Pessoa de Meia-Idade , ProlapsoRESUMO
Nitric oxide (NO) can play both prosurvival and prodeath roles in photodynamic therapy (PDT). The generation efficiency of peroxynitrite anions (ONOO-), by NO and superoxide anions (O2â¢-), significantly influenced the outcome. Reports indicated that such efficiency is closely related to the distance between NO and O2â¢-. Thus, in this manuscript, l-arginine (Arg) ethyl ester-modified zinc phthalocyanine (Arg-ZnPc) was designed and synthesized as a photosensitizer (PS) and NO donor. Post light irradiation, the guanido of Arg-ZnPc can be effectively oxidized by the generated reactive oxygen species (ROS) in the PDT process to release NO. Such a strategy could ensure O2â¢- and NO generation in the same place at the same time to guarantee effective ONOO- formation. In addition, NO has other multiple synergistic cancer treatment functions, including tumor tissue vasodilatation for drug extravasation promotion, P-glycoprotein (P-gp) downregulation for drug efflux inhibition, and glutathione depletion for cancer cell endogenous antioxidant defense destruction. In vitro and in vivo results indicated that the effective ONOO- formation and multiple functions of Arg-ZnPc could synergistically enhance its PDT activity and ensure satisfactory cancer treatment outcome.
Assuntos
Indóis/química , Indóis/farmacologia , Neoplasias/tratamento farmacológico , Óxido Nítrico/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Superóxidos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Sinergismo Farmacológico , Feminino , Fluorescência , Glutationa/metabolismo , Humanos , Indóis/síntese química , Indóis/efeitos da radiação , Isoindóis , Camundongos , Neoplasias/metabolismo , Óxido Nítrico/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/efeitos da radiação , Ácido Peroxinitroso/química , Espécies Reativas de Oxigênio/química , Superóxidos/química , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto , Compostos de ZincoRESUMO
The visualization of the long noncoding RNA of prostate cancer gene 3 (lncRNA PCA3), a specific biomarker for androgen receptor-positive prostate cancer, in living cells not only directly reflects the gene expression and localization but also offers better insight into its roles in the pathological processes. Here, we loaded an entropy-driven RNA explorer (EDRE) on the TAT peptide-functionalized titanium carbide MXenes (Ti3C2-TAT) for the imaging of nuclear lncRNA PCA3 in live cells. The EDRE was condensed on the Ti3C2-TAT (Ti3C2-TAT@EDRE) by electrostatic interaction. Ti3C2-TAT@EDRE enables the entering of cells and release of TAT peptides and EDRE in the cytoplasm by the glutathione (GSH)-triggered cleavage of the disulfide bonds in Ti3C2-TAT. The released EDRE is delivered into the nucleus by the nucleus-targeted guidance of TAT peptides, and initiated by the target lncRNA PCA3, subsequently leading to the continuous accumulation of fluorescence signals. Consequently, fluorescence analysis of lncRNA PCA3 at low-picomolar concentrations in vitro as well as sensitive live cell imaging of lncRNA PCA3 in the nucleus of androgen receptor-positive LNCaP prostate cancer cells were achieved, providing a versatile strategy for the monitoring of nucleic acid biomarkers in the nucleus of living cells.
Assuntos
Antígenos de Neoplasias/genética , Biomarcadores Tumorais/análise , Imagem Molecular/métodos , Sondas Moleculares/química , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Titânio/química , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/química , Entropia , Produtos do Gene tat/química , Humanos , Masculino , Nanoestruturas/química , Fragmentos de Peptídeos/química , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , RNA Longo não Codificante/análise , RNA Longo não Codificante/química , Células Tumorais CultivadasRESUMO
Acquiring multilayer information on diverse biomarkers with different spatial distributions at the cellular level is crucial for monitoring the progression of cancers. Herein, a dual-signal-tagged chimeric DNA-functionalized titanium carbide MXenes nanoprobe (dcDNA-Ti3C2) that responds to biomarkers with different cellular locations from plasma membrane to cytoplasm was designed toward this end. In the presence of cancer biomarkers, including transmembrane glycoprotein mucin 1 (MUC1) and cytoplasmic microRNA-21 (miR-21), the recognition between MUC1 and its aptamer in the dcDNA-Ti3C2 probe induces the separation of TAMRA-MUC1 aptamer from Ti3C2 MXenes, thereby resulting in an increase in red fluorescence; and the hybridization of miR-21 with the hairpin probe triggers the increase of green fluorescence. As a result, dual analysis of MUC1 and miR-21 at low-nanomolar concentrations in vitro, as well as in situ simultaneous imaging of the biomarkers within MCF-7 breast cancer cells, was achieved. The feasibility of the nanoprobe was further demonstrated by monitoring the expression changes of both the biomarkers in cancer cells under different inhibitor combinations. Therefore, this strategy allows us to acquire the expression levels and spatial distributions of different biomarkers in living cells, providing a helpful tool for reliable diagnosis of cancers and basic understanding their progression.
Assuntos
Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , DNA/química , Sondas Moleculares/química , Nanoestruturas/química , Titânio/química , Aptâmeros de Nucleotídeos/metabolismo , Humanos , Espaço Intracelular/metabolismo , Células MCF-7 , MicroRNAs/metabolismo , Imagem Molecular , Mucina-1/metabolismo , Fatores de TempoRESUMO
Controlled drug release systems can enhance the safety and availability but avoid the side effect of drugs. Herein, the concept of DNA complementary base pairing rules in biology is used to design and prepare a photothermal-triggered drug release system. Adenine (A) modified polydopamine nanoparticles (A-PDA, photothermal reagent) can effectively bind with thymine (T) modified Zinc phthalocyanine (T-ZnPc, photosensitizer) forming A-PDA = T-ZnPc (PATP) complex based on A = T complementary base pairing rules. Similar to DNA, whose base pairing in double strands will break by heating, T-ZnPc can be effectively released from A-PDA after near infrared irradiation-triggered light-thermal conversion to obtain satisfactory photodynamic-photothermal synergistic tumor treatment. In addition, PDA can carry abundant Gd3+ to provide magnetic resonance imaging guided delivery and theranostic function.
Assuntos
Pareamento de Bases/fisiologia , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Hipertermia Induzida/métodos , Neoplasias/terapia , Fotoquimioterapia/métodos , Adenina/química , Animais , Linhagem Celular Tumoral , Terapia Combinada , DNA Complementar/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos/genética , Sinergismo Farmacológico , Feminino , Humanos , Indóis/química , Isoindóis , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacocinética , Fototerapia/métodos , Polímeros/química , Ensaios Antitumorais Modelo de Xenoenxerto , Compostos de ZincoRESUMO
Pancreatic cancer is known to be a fatal disease, which is difficult to be diagnosed in its early stages. Ubiquitin-Specific Protease 34 (USP34) are closely related to human cancers in the development and progression. However, there are rarely studies about the role of USP34 in pancreatic cancer. Thus, we aimed to investigate the effect of USP34 in human pancreatic cancer. Short-hairpin RNA targeting USP34 (USP34-shRNA) and USP34 overexpression lentivirus were used in the current study. The level of USP34 in human pancreatic cancer (PANC-1) cells were then analyzed by quantitative (q)RT-PCR. In addition, Western blotting was used to examine phosphorylated (p)-AKT, p-protein kinase C (PKC) and p-extracellular signal-regulated kinase (ERK) protein levels. CCK-8 assay, flow cytometry, and migration assay were used to detect cell proliferation, apoptosis and migration, respectively in vitro. According to the result of qRT-PCR and Western blotting, USP34-shRNA1 significantly downregulated USP34 gene level in PANC-1 cell. Subsequently, Western blotting assay indicated that USP34 silencing significantly down-regulated the expression of p-AKT and p-PKC in cells. On the other hand, USP34 overexpressing remarkably up-regulated the expression of p-AKT and p-PKC in cells. In addition, USP34 overexpression promoted PANC-1 cell proliferation and migration via up-regulating the proteins of p-AKT and p-PKC. Moreover, USP34 overexpression reversed AKT inhibitor and PKC inhibitor induced PACN-1 cell apoptosis. Our results indicated USP34 regulated h PANC-1 cell survival via AKT and PKC pathways, and which played a pro-survival role in human pancreatic cancer. Therefore, we suggested USP34 could be a potential therapeutic target for pancreatic cancer.
Assuntos
Regulação Enzimológica da Expressão Gênica , Neoplasias Pancreáticas/metabolismo , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteases Específicas de Ubiquitina/genética , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Lentivirus/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Plasmídeos , RNA Interferente Pequeno/genética , Transdução de SinaisRESUMO
Reactive oxygen species (ROS) generated during photodynamic therapy (PDT) can trigger autophagy. However, little research is focused on whether there is a synergistic anticancer effect with PDT if extra autophagy promoter or inhibitor is added. Here, it is found that autophagy promotion significantly enhances the PDT activity to cancer cells. Based on this preliminary result, a ROS-sensitive self-assembled dendrimer nanoparticle is exploited as a carrier to codeliver an autophagy promoter (rapamycin, Rapa) and photosensitizer (phthalocyanine, Pc) to the tumor. After entrapped by cancer cells and irradiated by light, the ROS generated in PDT process of Pc can trigger nanoparticle destruction to release Rapa, thus initiating the autophagy process and remarkably enhancing the efficacy of PDT, leading to efficient tumor suppression.
Assuntos
Autofagia/fisiologia , Dendrímeros/química , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Humanos , Indóis/química , Isoindóis , Fotoquimioterapia/métodosRESUMO
Positively charged drugs usually have enhanced water solubility, cellular uptake efficiency and anticancer activity. However, the common quaternized and protonated cationic photosensitizers both have some drawbacks such as needing potentially dangerous agents for preparation and easily being deprotonated in alkaline circumstance. Arginine is unique among the amino acids as its guanidine group has exceptionally high basicity in aqueous solution, which may make it positively charged in a wide range of pH. In this paper, two arginine substituted zinc phthalocyanines (ArgEZnPc and ArgZnPc) were reported. They can be positively charged in the range of pH 5-9. Moreover, the photobiological, photochemical properties, subcellular localization, and in vitro anticancer activities of the them were also carried out. The results show that ArgZnPc may be not a good photosensitizer because of its poor photobiological activities though it is positively charged in a wide range of pHs. This may be attributed to the formation of inner salts between guanidine and carboxyl groups of ArgZnPc, which weakens its photobiological and in vitro anticancer activity. While in contrast, ArgEZnPc shows preferential localization in the lysosomes of HeLa cells, exhibits high water solubility, excellent 1O2 and intracellular reactive oxygen species generation efficiency as well as high in vitro anticancer activity, making it a promising photosensitizer for photodynamic therapy.
Assuntos
Arginina/química , Indóis/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Isoindóis , Espécies Reativas de Oxigênio/metabolismo , Frações Subcelulares/metabolismoRESUMO
The interaction between the photosensitive antitumour drug, 2(3),9(10),16(17),23(24)-tetra-(((2-aminoethylamino)methyl)phenoxy)phthalocyaninato-zinc(II) (ZnPc) and bovine serum albumin (BSA) has been investigated using various spectroscopic methods. This work may provide some useful information for understanding the interaction mechanism of anticancer drug-albumin binding and gain insight into the biological activity and metabolism of the drug in blood. Based on analysis of the fluorescence spectra, ZnPc could quench the intrinsic fluorescence of BSA and the quenching mechanism was static by forming a ground state complex. Meanwhile, the Stern-Volmer quenching constant (KSV), binding constant (Kb), number of binding sites (n) and thermodynamic parameters were obtained. Results showed that the interaction of ZnPc with BSA occurred spontaneously via hydrogen bond and van der Waal's force. According to Foster's non-radioactive energy transfer theory, the energy transfer from BSA to ZnPc occurred with high possibility. Synchronous fluorescence and circular dichroism (CD) spectra also demonstrated that ZnPc induced the secondary structure of and conformation changes in BSA, especially α helix.
Assuntos
Indóis/química , Compostos Organometálicos/química , Soroalbumina Bovina/química , Animais , Sítios de Ligação , Bovinos , Dicroísmo Circular , Transferência de Energia , Isoindóis , Estrutura Secundária de Proteína , Termodinâmica , Compostos de ZincoRESUMO
KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the inhibitory activity test on Hep G2 growth. We found that KYKZL-1 inhibited the growth of Hep G2 cells via inducing apoptosis. Further studies showed that KYKZL-1 activated caspase-3 through cytochrome c release from mitochondria and down regulation of Bcl-2/Bax ratio and reduced the high level of COX-2 and 5-LOX. As shown in its anti-inflammatory effect, KYKZL-1 also exhibited inhibitory effect on the PGE2 and LTB4 production in Hep G2 cells. Accordingly, exogenous addition of PGE2 or LTB4 reversed the decreases in cell viability. In addition, KYKZL-1 caused cell cycle arrest at the S-G2 checkpoint via the activation of p21(CIP1) protein and down-regulation of cyclin A expression. These data indicate that the growth inhibitory effect of KYKZL-1 is associated with inhibition of AA metabolites and caspase-3 pathway and cell cycle arrest. Combined with our previous findings, KYKZL-1 exhibiting COX/5-LOX inhibition may be a promising potential agent not only for inflammation control but also for cancer prevention/therapy with an enhanced gastric safety profile.
Assuntos
Ácido Araquidônico/antagonistas & inibidores , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Fenilpropionatos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Ácido Araquidônico/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Células Hep G2 , Humanos , Transdução de Sinais/fisiologiaRESUMO
Highly selective carbonylative Suzuki reactions of aryl iodides with arylboronic acids using an in situ generated nanopalladium system furnished products in high yields. The reactions were performed under ambient conditions and in the absence of an added ligand. The key to success is the addition of pivalic acid, which can effectively suppress undesired Suzuki coupling. The synthesis can be easily scaled up, and the catalytic system can be reused up to nine times. The nature of the active catalytic species are discussed.
Assuntos
Hidrocarbonetos Halogenados/química , Nanopartículas/química , Paládio/química , Ácidos Pentanoicos/química , Catálise , Ligantes , Estrutura MolecularRESUMO
The urgent global health problem of antimicrobial resistance (AMR) calls for the discovery of new antibiotics with innovative modes of action while considering the low toxicity to mammalian cells. This paper proposes a novel strategy for designing antibiotics with selective bacterial toxicity by exploiting the positional differences of electron transport chains (ETC) in bacterial and mammalian cells. The focus is on cytochrome c (cyt C) and its maturation system in E. coli. The catalytic oxidative activity of metallophthalocyanine (MPc), which have a distinctive M-N4 structure, is being investigated. Unlike previous applications based on light-activated reactive oxygen species (ROS) generation, this study exploits the ability of MPcs to oxidize Fe2+ to Fe3+ in cyt C and catalyze the formation of disulfide bonds between cysteine residues to interfere with cyt C maturation, disrupt the bacterial respiratory chain and selectively kills bacteria. In contrast, in mammalian cells, these MPcs are located in the lysosomes and cannot access the ETC in the mitochondria, thus achieving selective bacterial toxicity. Two MPcs that showed effective antibacterial activity in a wound infection model were identified. This study provides a valuable reference for the design of novel antibiotics based on M-N4-based metal complex molecules.
Assuntos
Antibacterianos , Escherichia coli , Indóis , Antibacterianos/farmacologia , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Animais , Citocromos c/metabolismo , Citocromos c/química , Isoindóis , Humanos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Espécies Reativas de Oxigênio/metabolismo , OxirreduçãoRESUMO
Sodium-ion batteries (SIBs) represent a promising energy storage technology with great safety. Because of their high operating potential, superior structural stability, and prominent thermal stability, polyanion-type phosphates have garnered significant interest in superior prospective cathode materials for SIBs. Nevertheless, the disadvantages of poor intrinsic electronic conductivity, sluggish kinetics, and volume variation during sodiation/desodiation remain great challenges for satisfactory rate performance and cycle stability, which severely hinder their further practical applications. In this work, by adjusting the amounts of pretreated multiwalled carbon nanotubes (CNT) added intentionally at the beginning of the preparation, biphasic polyanion-type phosphate materials (marked as NFC) are synthesized through a one-pot solid state reaction methodology, which are composed of CNT-interwoven Na3V2(PO4)2F3 (NVPF) and a small amount of Na3V2(PO4)3 (NVP). Benefiting from the improved electronic conductivity and unique composition and structure, the optimized sample (labeled as NFC-2) illustrates exceptional cycle stability and remarkable rate performance. The discharge capacities of the NFC-2 electrode are 114.8 and 78.6 mAh g-1 tested at 20 and 5000 mA g-1, respectively. Notably, such an electrode still gives out 75.7% capacity retention upon 10â¯000 cycles at 5000 mA g-1. In situ X-ray diffraction analysis demonstrates that the NFC-2 cathode has outstanding structural reversibility during charge/discharge cycles. More importantly, such a biphasic material has achieved impressive electrochemical performance within a wide operating temperature range of -20-50 °C. When temperature is decreased to -20 °C, the NFC-2 electrode still delivers an initial discharge capacity of 102.4 mAh g-1 and exhibits a remarkable capacity retention of 97.8% even after 500 cycles at 50 mA g-1. In addition, the sodium-ion full cell assembled by integrating NFC-2 cathode and hard carbon anode shows a satisfying energy density of 431.3 Wh kg-1 at 20 mA g-1 with a better long-term cycle performance. The synergistic effect among high energy NVPF, conductive CNT, and stable NVP may lead to the great improvement in the electrochemical sodium storage performance of the NFC-2 sample. Such biphasic polyanion-type phosphate materials will inject new ideas into the material design for SIBs with excellent electrochemical performance and further promote practical applications of this advanced energy storage technology.
RESUMO
BACKGROUND: The impact of HBV infection on the prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains uncertain, and the underlying mechanism has not been elucidated. This study aims to explore the potential mechanism via clinical perspectives and immune features. METHODS: We retrospectively reviewed 1308 patients with ICC treated surgically from January 2007 to January 2015. Then, we compared immune-related markers using immunohistochemistry staining to obtain the gene expression profile GSE107943 and related literature for preliminary bioinformatics analysis. Subsequently, we conducted a drug sensitivity assay to validate the role of TNFSF9 in the ICC organoid-autologous immune cell coculture system and in the patient-derived organoids-based xenograft platform. RESULTS: The analysis revealed that tumors in patients without HBV infection exhibited greater size and a higher likelihood of lymphatic metastasis, tumor invasion, and relapse. After resection, HBV-infected patients had longer survival time than uninfected patients (p<0.01). Interestingly, the expression of immune-related markers in HBV-positive patients with ICC was higher than that in uninfected patients (p<0.01). The percentage of CD8+ T cells in HBV-positive tissue was higher than that without HBV infection (p<0.05). We screened 21 differentially expressed genes and investigated the function of TNFSF9 through bioinformatics analyses. The expression of TNFSF9 in ICC organoids with HBV infection was lower than that in organoids without HBV infection. The growth of HBV-negative ICC organoids was significantly inhibited by inhibiting the expression of TNFSF9 with a neutralizing antibody. Additionally, the growth rate was faster in HbsAg (-) ICC patient-derived organoids-based xenograft model than in HbsAg (+) group. CONCLUSIONS: The activation of the immune response induced by HBV infection makes the prognosis of HBV-positive patients with ICC differ from that of uninfected patients.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Animais , Humanos , Vírus da Hepatite B , Antígenos de Superfície da Hepatite B , Estudos Retrospectivos , Recidiva Local de Neoplasia , Prognóstico , Colangiocarcinoma/genética , Colangiocarcinoma/cirurgia , Modelos Animais de Doenças , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos , ImunidadeRESUMO
Disulfidptosis, a regulated form of cell death, has been recently reported in cancers characterized by high SLC7A11 expression, including invasive breast carcinoma, lung adenocarcinoma, and hepatocellular carcinoma. However, its role in colon adenocarcinoma (COAD) has been infrequently discussed. In this study, we developed and validated a prognostic model based on 20 disulfidptosis-related genes (DRGs) using LASSO and Cox regression analyses. The robustness and practicality of this model were assessed via a nomogram. Subsequent correlation and enrichment analysis revealed a relationship between the risk score, several critical cancer-related biological processes, immune cell infiltration, and the expression of oncogenes and cell senescence-related genes. POU4F1, a significant component of our model, might function as an oncogene due to its upregulation in COAD tumors and its positive correlation with oncogene expression. In vitro assays demonstrated that POU4F1 knockdown noticeably decreased cell proliferation and migration but increased cell senescence in COAD cells. We further investigated the regulatory role of the DRG in disulfidptosis by culturing cells in a glucose-deprived medium. In summary, our research revealed and confirmed a DRG-based risk prediction model for COAD patients and verified the role of POU4F1 in promoting cell proliferation, migration, and disulfidptosis.
Assuntos
Adenocarcinoma , Biomarcadores Tumorais , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/diagnóstico , Prognóstico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Biomarcadores Tumorais/genética , Feminino , Linhagem Celular Tumoral , Masculino , Proliferação de Células/genética , Perfilação da Expressão Gênica , Transcriptoma , Nomogramas , Fator 3 de Transcrição de Octâmero/genética , Movimento Celular/genéticaRESUMO
KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the anti-inflammatory activity test focusing on its modulation of inflammatory mediators as well as intracellular MAPK and NF-κB signaling pathways. In acute ear edema model, pretreatment with KYKZL-1 (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice with a higher inhibition than diclofenac. In a three-day TPA-induced inflammation, KYKZL-1 also showed significant anti-inflammatory activity with inhibition ranging between 20% and 64%. In gastric lesion test, KYKZL-1 elicited markedly fewer stomach lesions with a low index of ulcer as compared to diclofenac in rats. In further studies, KYKZL-1 was found to significantly inhibit the production of NO, PGE2, LTB4 in LPS challenged RAW264.7, which is parallel to its attenuation of the expression of iNOS, COX-2, 5-LOX mRNAs or proteins and inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB. Taken together, our data indicate that KYKZL-1 comprises dual inhibition of COX and 5-LOX and exerts an obvious anti-inflammatory activity with an enhanced gastric safety profile via simultaneous inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB.
Assuntos
Anti-Inflamatórios , Mediadores da Inflamação/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Fenilpropionatos/farmacologia , Estilbenos/farmacologia , Animais , Western Blotting , Linhagem Celular , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/metabolismo , Edema/induzido quimicamente , Edema/patologia , Indicadores e Reagentes , Leucotrieno B4/metabolismo , Lipopolissacarídeos/toxicidade , Inibidores de Lipoxigenase/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Xilenos/toxicidadeRESUMO
Hypocrellin A (HA), an a natural perylene quinine photosensitizers (PSs), can chelate with heavy metal ions, including Au(III) and Pt(IV), to form a 1:2 complex, which exhibits enhanced (1)O2 generation quantum yield through the increased intersystem crossing efficiency mediated by internal heavy atom effect. Besides, the chelate process greatly improved the water solubility of HA. Comparative studies with HA and complexes have demonstrated that the heavy-atom effect on HA molecules enhances the efficiency of in vitro photodynamic (PDT) efficacy.
Assuntos
Ouro/química , Neoplasias/tratamento farmacológico , Perileno/análogos & derivados , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Platina/química , Quinonas/química , Quinonas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/uso terapêutico , Ouro/farmacologia , Células HeLa , Humanos , Metais Pesados/química , Microscopia de Fluorescência , Modelos Biológicos , Estrutura Molecular , Perileno/química , Perileno/farmacologia , Perileno/uso terapêutico , Fenol , Fármacos Fotossensibilizantes/uso terapêutico , Platina/farmacologia , Quinonas/uso terapêutico , Solubilidade , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The synthesis of Pt nanocrystals with controlled size and morphology has drawn enormous interest due to their particular catalytic activity. We present a facile and green hydrothermal method for synthesizing monodisperse Pt nanocubes (Pt-NCs) with polyallylamine hydrochloride (PAH) as a complex-forming agent, capping agent and facet-selective agent, and formaldehyde as a reductant. The formation mechanism, particle size and surface composition of the Pt-NCs were investigated by Ultraviolet and visible spectroscopy (UV-vis), Fourier transform infrared (FT-IR), transmission electron microscopy (TEM), selected area electron diffraction (SAED), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS), etc. In the proposed PAH-K(2)PtCl(4)-HCHO synthesis system, the raw material could be reutilized to re-synthesize the Pt-NCs, and the particle size of the Pt-NCs could be readily controlled by the reduction rate of the Pt(II) species in the Pt(II)-PAH complex. After UV/Ozone and electrochemical cleaning, the residual PAH on the Pt-NC surfaces still strongly influenced the d-band centre of Pt due to the strong N-Pt interaction. The as-prepared 6 nm Pt-NCs showed superior electrocatalytic activity (mass activity and specific activity) and stability towards the oxygen reduction reaction (ORR) in both H(2)SO(4) and HClO(4) electrolytes compared to the commercial E-TEK Pt black, owing to the combination of the facets effect and electronic effect.