RESUMEN
The efficacy of radiotherapy is significantly constricted by tumor hypoxia. To overcome this obstacle, one promising approach is to use the perfluorocarbon-based O2 carriers combined with hyperoxic respiration to relieve tumor hypoxia. However, this passively transported oxygen carrier during hyperoxic respiration is prone to cause systemic oxidative stress and toxicity, which further limits its clinical application. Herein, we fabricate O2@PFC@FHA NPs for safe and specific oxygen delivery into tumors by using the fluorinated hyaluronic acid to encapsulate O2-saturated perfluorocarbon. Due to the interaction between HA and CD44 receptors, more FHA@PFC NPs accumulated in the tumor and the O2@PFC@FHA NPs significantly relieved tumor hypoxia. Notably, RT plus O2@PFC@FHA NPs resulted in almost threefold therapeutic improvement compared with RT without obvious systemic toxicity. Therefore, the O2@FHA@PFC NPs may have great potential to enhance the therapeutic efficacy of radiotherapy in the clinic.
Asunto(s)
Fluorocarburos , Nanopartículas , Neoplasias , Humanos , Ácido Hialurónico/uso terapéutico , Neoplasias/radioterapia , Neoplasias/tratamiento farmacológico , Oxígeno , Línea Celular TumoralRESUMEN
Sepsis, a systemic inflammatory response syndrome (SIRS) caused by infection, is a major public health concern with limited therapeutic options. Infection disturbs the homeostasis of host, resulting in excessive inflammation and immune suppression. This has prompted the clinical use of immunomodulators to balance host response as an alternative therapeutic strategy. Here, we report that Thymopentin (TP5), a synthetic immunomodulator pentapeptide (Arg-Lys-Asp-Val-Tyr) with an excellent safety profile in the clinic, protects mice against cecal ligation and puncture (CLP)-induced sepsis, as shown by improved survival rate, decreased level of pro-inflammatory cytokines and reduced ratios of macrophages and neutrophils in spleen and peritoneum. Regarding mechanism, TP5 changed the characteristics of LPS-stimulated macrophages by increasing the production of 15-deoxy-Δ12,14 -prostaglandin J2 (15-d-PGJ2). In addition, the improved effect of TP5 on survival rates was abolished by the peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9662. Our results uncover the mechanism of the TP5 protective effects on CLP-induced sepsis and shed light on the development of TP5 as a therapeutic strategy for lethal systemic inflammatory disorders.
Asunto(s)
PPAR gamma/metabolismo , Prostaglandina D2/análogos & derivados , Sepsis/metabolismo , Transducción de Señal/efectos de los fármacos , Timopentina/farmacología , Animales , Ciego/cirugía , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Ligadura/efectos adversos , Masculino , Ratones Endogámicos C57BL , Prostaglandina D2/metabolismo , Punciones/efectos adversos , Sepsis/etiología , Sepsis/mortalidad , Tasa de SupervivenciaRESUMEN
Growing evidence has shown that some pharmaceutical excipients can act on drug transporters. The present study was aimed at investigating the effects of 13 commonly used excipients on the intestinal absorption of metformin (MTF) and the underlying mechanisms using Caco-2 cells and an ex vivo mouse non-everted gut sac model. First, the uptake of MTF in Caco-2 cells was markedly inhibited by nonionic excipients including Solutol HS 15, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and crospovidone. Second, transport profile studies showed that MTF was taken up via multiple cation-selective transporters, among which a novel pyrilamine-sensitive proton-coupled organic cation (H+/OC+) antiporter played a key role. Third, Solutol HS 15, polysorbate 40, and polysorbate 60 showed cis-inhibitory effects on the uptake of either pyrilamine (prototypical substrate of the pyrilamine-sensitive H+/OC+ antiporter) or 1-methyl-4-phenylpyridinium (substrate of traditional cation-selective transporters including OCTs, MATEs, PMAT, SERT, and THTR-2), indicating that their suppression on MTF uptake is due to the synergistic inhibition toward multiple influx transporters. Finally, the pH-dependent mouse intestinal absorption of MTF was significantly decreased by Solutol HS 15, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and pyrilamine. In conclusion, this study revealed that a novel transport process mediated by the pyrilamine-sensitive H+/OC+ antiporter contributes to the intestinal absorption of MTF in conjunction with the traditional cation-selective transporters. Mechanistic understanding of the interaction of excipients with cation-selective transporters can improve the formulation design and clinical application of cationic drugs.
Asunto(s)
Excipientes/farmacología , Hipoglucemiantes/farmacocinética , Absorción Intestinal/efectos de los fármacos , Metformina/farmacocinética , Proteínas de Transporte de Catión Orgánico/metabolismo , Administración Oral , Animales , Células CACO-2 , Cationes/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Composición de Medicamentos/métodos , Interacciones Farmacológicas , Excipientes/química , Humanos , Concentración de Iones de Hidrógeno , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Metformina/administración & dosificación , Metformina/química , Ratones , Ratones Endogámicos ICRRESUMEN
Chronic stress is known to promote inflammatory bowel disease (IBD), but the underlying mechanism remains largely unresolved. Here, we found chronic stress to sensitize mice to dextran sulfate sodium (DSS)-induced colitis; to increase the infiltration of B cells, neutrophils, and proinflammatory ly6Chi macrophages in colonic lamina propria; and to present with decreased thymus and mesenteric lymph node (MLN) coefficients. Circulating total white blood cells were significantly increased after stress, and the proportion of MLN-associated immune cells were largely changed. Results showed a marked activation of IL-6/STAT3 signaling by stress. The detrimental action of stress was not terminated in IL-6-/- mice. Interestingly, the composition of gut microbiota was dramatically changed after stress, with expansion of inflammation-promoting bacteria. Furthermore, results showed stress-induced deficient expression of mucin-2 and lysozyme, which may contribute to the disorder of gut microbiota. Of note is that, in the case of cohousing, the stress-induced immune reaction and decreased body weight were abrogated, and transferred gut microbiota from stressed mice to control mice was sufficient to facilitate DSS-induced colitis. The important role of gut microbiota was further reinforced by broad-spectrum antibiotic treatment. Taken together, our results reveal that chronic stress disturbs gut microbiota, triggering immune system response and facilitating DSS-induced colitis.
Asunto(s)
Colitis/etiología , Microbioma Gastrointestinal/inmunología , Inmunidad Innata/inmunología , Inflamación/etiología , Interleucina-6/fisiología , Estrés Fisiológico , Animales , Colitis/patología , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mucina 2/metabolismo , Muramidasa/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gαi1/3) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Gαi1/3 form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Gαi1/3 deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Gαi1/3 knockdown in bone marrow-derived macrophage cells (Gαi1/3 KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-α, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, Gαi1/3 deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Gαi1/3 were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Gαi1/3 can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Macrófagos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Western Blotting , Línea Celular Tumoral , Células Cultivadas , Endocitosis/efectos de los fármacos , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Humanos , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Receptores de Lipopolisacáridos/genética , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones de la Cepa 129 , Ratones Noqueados , Microscopía Confocal , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfoproteínas/genética , Unión Proteica/efectos de los fármacos , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Supervivencia , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Schisandrin B has received much attention owing to its various biological activities. The present study was aimed at the formulation development of schisandrin B and investigation of the pharmacokinetic profiles, distribution and excretion of schisandrin B in Sprague-Dawley rats. In this study, micronized schisandrin B particles with particle size of 10-20 µm were chosen as the research object. Chromatographic separation was carried out on a BDS Hypersil C18 column (50 × 2.1 mm, i.d. 3.5 µm). Schisandrin B and deoxyschizandrin (internal standard) were detected without interference in the multiple reaction monitoring mode with positive electrospray ionization. The pharmacokinetic parameters were calculated by a noncompartmental method. The area under concentration-time curve and the maximum concentration showed a significant difference in gender. The calculated absolute oral bioavailability of schisandrin B was ~55.0% for female rat and 19.3% for male rat. Schisandrin B exhibited linear pharmacokinetics properties within the range of the tested oral dose (10, 20 and 40 mg/kg). After oral administration of schisandrin B, it was extensively distributed in ovary and adipose tissue. The result also showed very low urinary, biliary and fecal excretion of schisandrin B implying that schisandrin B was excreted mainly in the forms of metabolites.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Lignanos/análisis , Lignanos/farmacocinética , Compuestos Policíclicos/análisis , Compuestos Policíclicos/farmacocinética , Espectrometría de Masas en Tándem/métodos , Animales , Ciclooctanos/análisis , Ciclooctanos/química , Ciclooctanos/farmacocinética , Femenino , Lignanos/química , Modelos Lineales , Masculino , Compuestos Policíclicos/química , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución TisularRESUMEN
Hepatic encephalopathy (HE) is often associated with endogenous serotonin (5-HT) disorders. However, the reason for elevated brain 5-HT levels due to liver failure remains unclear. This study aimed to investigate the mechanism by which liver failure increases brain 5-HT levels and the role in behavioral abnormalities in HE. Using bile duct ligation (BDL) rats as a HE model, we verified the elevated 5-HT levels in the cortex but not in the hippocampus and striatum, and found that this cortical 5-HT overload may be caused by BDL-mediated inhibition of UDP-glucuronosyltransferase 1A6 (UGT1A6) expression and activity in the cortex. The intraventricular injection of the UGT1A6 inhibitor diclofenac into rats demonstrated that the inhibition of brain UGT1A6 activity significantly increased cerebral 5-HT levels and induced HE-like behaviors. Co-immunofluorescence experiments demonstrated that UGT1A6 is primarily expressed in astrocytes. In vitro studies confirmed that NH4Cl activates the ROS-ERK pathway to downregulate UGT1A6 activity and expression in U251 cells, which can be reversed by the oxidative stress antagonist N-acetyl-l-cysteine and the ERK inhibitor U0126. Silencing Hepatocyte Nuclear Factor 4α (HNF4α) suppressed UGT1A6 expression whilst overexpressing HNF4α increased Ugt1a6 promotor activity. Meanwhile, both NH4Cl and the ERK activator TBHQ downregulated HNF4α and UGT1A6 expression. In the cortex of hyperammonemic rats, we also found activation of the ROS-ERK pathway, decreases in HNF4α and UGT1A6 expression, and increases in brain 5-HT content. These results prove that the ammonia-mediated ROS-ERK pathway activation inhibits HNF4α expression to downregulate UGT1A6 expression and activity, thereby increasing cerebral 5-HT content and inducing manic-like HE symptoms. This is the first study to reveal the mechanism of elevated cortical 5-HT concentration in a state of liver failure and elucidate its association with manic-like behaviors in HE.
Asunto(s)
Fallo Hepático , Serotonina , Animales , Ratas , Amoníaco/metabolismo , Conductos Biliares/cirugía , Conductos Biliares/metabolismo , Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Fallo Hepático/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serotonina/metabolismoRESUMEN
The high infiltration of tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment prominently attenuates the efficacy of immune checkpoint blockade (ICB) therapies, yet the underlying mechanisms are not fully understood. Here, we investigate the metabolic profile of TAMs and identify S-2-hydroxyglutarate (S-2HG) as a potential immunometabolite that shapes macrophages into an antitumoral phenotype. Blockage of L-2-hydroxyglutarate dehydrogenase (L2HGDH)-mediated S-2HG catabolism in macrophages promotes tumor regression. Mechanistically, based on its structural similarity to α-ketoglutarate (α-KG), S-2HG has the potential to block the enzymatic activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), consequently reshaping chromatin accessibility. Moreover, S-2HG-treated macrophages enhance CD8+ T cell-mediated antitumor activity and sensitivity to anti-PD-1 therapy. Overall, our study uncovers the role of blockage of L2HGDH-mediated S-2HG catabolism in orchestrating macrophage antitumoral polarization and, further, provides the potential of repolarizing macrophages by S-2HG to overcome resistance to anti-PD-1 therapy.
Asunto(s)
Glutaratos , Macrófagos , Neoplasias , Animales , Femenino , Humanos , Ratones , Oxidorreductasas de Alcohol/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Polaridad Celular/efectos de los fármacos , Glutaratos/metabolismo , Activación de Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Ratones Endogámicos C57BL , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/metabolismo , Microambiente Tumoral , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/efectos de los fármacosRESUMEN
Hepatocellular carcinoma (HCC) is associated with a poor prognosis. Our previous study demonstrated that Pleomorphic adenoma gene like-2 (PLAGL2) was a potential therapeutic target in HCC. However, the mechanisms that lead to the upregulation of PLAGL2 in HCC remain unclear. The present study revealed that stress-induced epinephrine increased the expression of PLAGL2, thereby promoting the progression of HCC. Furthermore, PLAGL2 knockdown inhibited epinephrine-induced HCC development. Mechanistically, epinephrine upregulated ubiquitin-specific protease 10 (USP10) to stabilize PLAGL2 via the adrenergic ß-receptor-2-c-Myc (ADRB2-c-Myc) axis. Furthermore, PLAGL2 acted as a transcriptional regulator of USP10, forming a signaling loop. Taken together, these results reveal that stress-induced epinephrine activates the PLAGL2-USP10 signaling loop to enhance HCC progression. Furthermore, PLAGL2 plays a crucial role in psychological stress-mediated promotion of HCC progression.
Asunto(s)
Carcinoma Hepatocelular , Proteínas de Unión al ADN , Epinefrina , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Proteínas de Unión al ARN , Transducción de Señal , Factores de Transcripción , Ubiquitina Tiolesterasa , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/genética , Epinefrina/metabolismo , Epinefrina/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Animales , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones , Línea Celular Tumoral , Progresión de la Enfermedad , Masculino , Estrés Fisiológico , Proliferación CelularRESUMEN
Targeting tumor stemness is an innovative approach to cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure-activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC50 values ranging from 0.5-2.5 µM for inhibiting sphere formation and 0.5-15 µM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood-brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.
Asunto(s)
Antineoplásicos , Glioma , Humanos , Glioma/tratamiento farmacológico , Glioma/patología , Relación Estructura-Actividad , Apoptosis , Benzamidas/farmacología , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proliferación Celular , Proteínas Asociadas a MicrotúbulosRESUMEN
BACKGROUND: The tumor immune microenvironment (TIME) of adrenocortical carcinoma (ACC) is heterogeneous. However, a classification of ACC based on the TIME remains unexplored. METHODS: We hierarchically clustered ACC based on the enrichment levels of twenty-three immune signatures to identify its immune-specific subtypes. Furthermore, we comprehensively compared the clinical and molecular profiles between the subtypes. RESULTS: We identified two immune-specific subtypes of ACC: Immunity-H and Immunity-L, which had high and low immune signature scores, respectively. We demonstrated that this subtyping method was stable and reproducible by analyzing five different ACC cohorts. Compared with Immunity-H, Immunity-L had lower levels of immune cell infiltration, worse overall and disease-free survival prognosis, and higher tumor stemness, genomic instability, proliferation potential, and intratumor heterogeneity. Furthermore, the ACC driver gene CTNNB1 was more frequently mutated in Immunity-L than in Immunity-H. Several proteins, such as mTOR, ERCC1, Akt, ACC1, Cyclin_E1, ß-catenin, FASN, and GAPDH, were more highly expressed in Immunity-L than in Immunity-H. In contrast, p53, Syk, Lck, PREX1, and MAPK were more highly expressed in Immunity-H. Pathway and gene ontology analysis showed that the immune, stromal, and apoptosis pathways were highly enriched in Immunity-H, while the cell cycle, steroid biosynthesis, and DNA damage repair pathways were highly enriched in Immunity-L. CONCLUSIONS: ACC can be classified into two stable immune-related subtypes, which have significantly different antitumor responses, molecular characteristics, and clinical outcomes. This subtyping may provide clinical implications for prognostic and immunotherapeutic stratification of ACC.
Asunto(s)
Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Humanos , Carcinoma Corticosuprarrenal/genética , Ciclo Celular , División Celular , Supervivencia sin Enfermedad , Neoplasias de la Corteza Suprarrenal/genética , Microambiente Tumoral/genéticaRESUMEN
The transient receptor potential canonical (TRPC) channels, encoded in seven non-allelic genes, are important contributors to calcium fluxes, are strongly associated with various diseases. Here we explored the consequences of ablating all seven TRPCs in mice focusing on colitis. We discovered that absence of all seven TRPC proteins in mice (TRPC HeptaKO mice) promotes the development of dextran sulfate sodium (DSS)-induced colitis. RNA-sequence analysis highlighted an extremely pro-inflammatory profile in colons of DSS-treated TRPC HeptaKO mice, with an amount of increased pro-inflammatory cytokines and chemokines. Flow cytometry analysis showed that the infiltration of Ly6Chi monocytes and neutrophils in colonic lamina propria was significantly increased in DSS-treated TRPC HeptaKO mice. Results also revealed that macrophages from TRPC HeptaKO mice exhibited M1 polarization and enhanced secretion of pro-inflammatory factors. In addition, the composition of gut microbiota was markedly disturbed in DSS-treated TRPC HeptaKO mice. However, upon antibiotic cocktail (Abx)-treatment, TRPC HeptaKO mice showed no significant differences with WT mice in disease severity. Collectively, these data suggest that ablation of all TRPCs promotes the development of DSS-induced colitis by inducing pro-inflammatory macrophages and gut microbiota disorder.
Asunto(s)
Colitis , Microbioma Gastrointestinal , Ratones , Animales , Colitis/inducido químicamente , Colitis/metabolismo , Macrófagos/metabolismo , Colon/metabolismo , Monocitos/metabolismo , Sulfato de Dextran , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Citocinas/metabolismoRESUMEN
Mesoporous organosilicas with both R-(+)-1,1'-binaphthyl-2,2'-diamine and ethane moieties bridging in the framework were synthesized. This mesoporous material was prepared via the one-step co-condensation of N,N'-bis-[(triethoxysilyl)propyl]-(R)-bis-(ureido)-binaphthyl (Si-DABN) with 1,2-bis(triethoxysilyl)ethane (BTSE) using octadecyltrimethylammonium chloride (C(18) TMACl) as a structural directing agent with the aid of a co-solvent (ethanol) in basic medium. The morphology of these bifunctionalized mesoporous organosilicas is sensitive to the Si-DABN mole fraction and the base concentration. And the mesostructure becomes less ordered as the mole fraction of Si-DABN in the initial mixture increases from 10 to 40%. Elemental analysis and Fourier transform infrared (FT-IR) spectrometer indicate that the binaphthyl diamine was successfully introduced to the mesoporous organosilicas. Acidic conditions are more suitable than basic ones for the hydrolysis and condensation of (R)-2,2'-dicyanomethoxy-6,6'-di[(2-triethoxysilyl)ethenyl]-1,1'-binaphthyl, a chiral silane precursors with a short silane side chain on the binaphthyl group. A column packed with these bifunctionalized mesoporous organosilica spheres exhibits greater selectivity for R/S-1,1'-bi-2,2'-naphthol than one packed with commercial SiO(2) grafted with N,N'-bis-[(triethoxysilyl)propyl]-(R)-bis-(ureido)-binaphthyl. Binaphthol and bromosubstituted binaphthol were fully resolved, but two ether derivatives were only partially enantioseparated and the other three ester derivatives were no fully resolved on the column via co-condensation method.
Asunto(s)
Cromatografía Líquida de Alta Presión/instrumentación , Preparaciones Farmacéuticas/análisis , Gel de Sílice/química , Cromatografía Líquida de Alta Presión/métodos , Naftalenos/química , Tamaño de la Partícula , Polímeros/síntesis química , Polímeros/química , Porosidad , Gel de Sílice/síntesis químicaRESUMEN
Magnetic carbon nanotubes (MCNTs), consisting of carbon nanotubes (CNTs) and magnetic nanoparticles (MNPs), have enormous exploration and application potentials due to their superior physical and chemical properties, such as unique magnetism and high enrichment performance. This review concentrates on the rapid advances in the synthesis and application of magnetic carbon nanotubes. Great progress has been made in the preparation of MCNTs by developing methods including chemical vapor deposition, pyrolysis procedure, sol-gel process, template-based synthesis, filling process and hydrothermal/solvothermal method. Various applications of MCNTs as a mediator of the adsorbent in magnetic solid-phase extraction, sensors, antibacterial agents, and imaging system contrast agents, and in drug delivery and catalysis are discussed. In order to overcome the drawbacks of MCNTs, such as sidewall damage, lack of convincing quantitative characterization methods, toxicity and environmental impact, and deficiency of extraction performance, researchers proposed some solutions in recent years. We systematically review the latest advances in MCNTs and discuss the direction of future development.
Asunto(s)
Nanopartículas de Magnetita/química , Nanotubos de Carbono/química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Técnicas Biosensibles/métodos , Catálisis , Medios de Contraste/química , Portadores de Fármacos/química , Técnicas Electroquímicas/métodos , Humanos , Fenómenos Magnéticos , Extracción en Fase Sólida/métodosRESUMEN
In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer but decreased in CRPC compared with normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and enzalutamide resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated prostate cancer progression and enzalutamide resistance in vitro and in vivo. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targeting the IRF8-AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in prostate cancer pathogenesis and a potential alternative therapeutic option to overcome enzalutamide resistance. SIGNIFICANCE: These findings identify IRF8-mediated AR degradation as a mechanism of resistance to AR-targeted therapy, highlighting the therapeutic potential of IFNα in targeting IRF8-AR axis in CRPC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2927/F1.large.jpg.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Retroalimentación Fisiológica , Factores Reguladores del Interferón/metabolismo , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo , Anciano de 80 o más Años , Animales , Apoptosis , Benzamidas , Biomarcadores de Tumor/genética , Proliferación Celular , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Factores Reguladores del Interferón/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nitrilos , Feniltiohidantoína/farmacología , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/genética , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking ß2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer.
Asunto(s)
AMP Cíclico/metabolismo , Depresión/complicaciones , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Neoplasias de la Próstata/patología , Regulación hacia Arriba , Animales , Línea Celular Tumoral , Depresión/genética , Depresión/metabolismo , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Clasificación del Tumor , Invasividad Neoplásica , Metástasis de la Neoplasia , Trasplante de Neoplasias , Fosforilación , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/psicología , Transducción de SeñalRESUMEN
APOBEC3 protein families, a DNA cytidine deaminase, were up-regulated in multiple tumors. However, the relationship between Hepatocellular carcinoma (HCC) and APOBEC3B (A3B) remains unknown. It has been confirmed that interleukin-6 (IL-6) has significant impacts on oncogenesis of HCC. Here, we reported that the expression of IL-6 was substantially up-regulated by A3B in HepG2 cells. A3B induced IL-6 expression through relocating HuR to enhance the IL-6 mRNA stability. Further analysis indicated that IL-6 also increased the expression of A3B through JAK1/STAT3 signaling pathway, which formed a positive feedback to maintain the continuous expression of A3B and IL-6, and thereby promoted the prolonged non-resolving inflammation. Collectively, these findings suggest that A3B is essential for oncogenesis of HCC, and is a potential target for preventive intervention.
Asunto(s)
Carcinoma Hepatocelular/patología , Citidina Desaminasa/metabolismo , Interleucina-6/metabolismo , Neoplasias Hepáticas/patología , Antígenos de Histocompatibilidad Menor/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Retroalimentación , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Ratones Endogámicos C57BLRESUMEN
Enzalutamide, a novel androgen receptor (AR) antagonist, prolongs overall survival of patients with castration-resistant prostate cancer (CRPC); however, patients eventually progress with enzalutamide resistance. We studied the efficacy of sorafenib combined with enzalutamide in a CRPC model and explored a potential strategy to improve enzalutamide efficacy in vitro and in LNCaP xenografts. The results indicated that enzalutamide combined with sorafenib potently decreased cell proliferation and induced apoptosis in the prostate cancer cell lineLNCaP. In castrate-resistant LNCaP xenografts, the combination of enzalutamide with sorafenib significantly suppressed tumor growth compared with eachsingle agent. Western blots and immunohistochemical staining assay showed that the expression of AR was down-regulated, and the extracellular signal-regulated kinase (ERK) signaling pathway was inhibited after combination treatment, suggesting a synergistic inhibitory effect on the AR and ERK pathways. These results demonstrated that sorafenib therapy improved the efficacy of enzalutamide in the CRPC model, indicating a promising therapeutic strategy for clinical CRPC patients.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Niacinamida/análogos & derivados , Feniltiohidantoína/análogos & derivados , Compuestos de Fenilurea/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Apoptosis/efectos de los fármacos , Benzamidas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Niacinamida/farmacología , Nitrilos , Feniltiohidantoína/farmacología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Transducción de Señal/efectos de los fármacos , Sorafenib , Factores de Tiempo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Combretastatin A-1 phosphate (CA1P) is a microtubule polymerization inhibitor that binds to the colchicine-binding site of tubulin. We demonstrated that CA1P has outstanding anti-cancer activity against hepatocellular carcinoma (HCC) in vitro and in vivo. As determined by fluorescence staining and western blots (WBs), CA1P induced reactive oxygen species (ROS) accumulation and apoptosis in HepG2 cells with a down-regulation of Mcl-1. Additional studies indicated that CA1P induced microtubule depolymerization-mediated AKT inactivation, which resulted in GSK-3ß activation, Wnt/ß-Catenin pathway inhibition, and Mcl-1 down-regulation. The induction of HepG2 cell apoptosis by CA1P was prevented by a GSK-3ß-specific inhibitor. Furthermore, immunohistochemistry studies on hepatocellular carcinoma mouse models showed that CA1P had activity against tumor-associated macrophages (TAMs). CA1P induced TAM apoptosis in vitro through the same mechanism observed with HepG2 cells, and it eliminated TAMs in the tumor microenvironment (TME) in vivo. In TME, the expression of TGF-ß and TNF-α was also altered. The adoptive transfer of macrophages partly rescued the growth of tumor inhibited by CA1P. These findings indicate that CA1P has great potential to impact both cancer cells and the microenvironment, and our results should accelerate the application of CA1P for HCC therapy in clinic.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Estilbenos/farmacología , Moduladores de Tubulina/farmacología , Microambiente Tumoral , Vía de Señalización Wnt/efectos de los fármacos , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Carga Tumoral/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Lidocaine hydrochloride ophthalmic gel is a novel ophthalmic preparation for topical ocular anesthesia. The study is aimed at evaluating the ocular and systemic pharmacokinetics of lidocaine hydrochloride 3.5 % ophthalmic gel in rabbits after ocular topical administration. Thirty-six rabbits were randomly placed in 12 groups (3 rabbits per group). The rabbits were quickly killed according to their groups at 0 (predose), 0.0833, 0.167, 0.333, 0.667, 1, 1.5, 2, 3, 4, 6, and 8 h postdose and then the ocular tissue and plasma samples were collected. All the samples were analyzed by a validated LC-MS/MS method. The test result showed that the maximum concentration (C max) of lidocaine in different ocular tissues and plasma were all achieved within 20 min after drug administration, and the data of C max were (2,987 ± 1814) µg/g, (44.67 ± 12.91) µg/g, (26.26 ± 7.19) µg/g, (11,046 ± 2,734) ng/mL, and (160.3 ± 61.0) ng/mL for tear fluid, cornea, conjunctiva, aqueous humor, and plasma, respectively. The data of the elimination half-life in these tissues were 1.5, 3.2, 3.5, 1.9, and 1.7 h for tear fluid, cornea, conjunctiva, aqueous humor, and plasma, respectively. The intraocular lidocaine levels were significantly higher than that in plasma, and the elimination half-life of lidocaine in cornea, conjunctiva, and aqueous humor was relatively longer than that in tear fluid and plasma. The high intraocular penetration, low systemic exposure, and long duration in the ocular tissues suggested lidocaine hydrochloride 3.5 % ophthalmic gel as an effective local anesthetic for ocular anesthesia during ophthalmic procedures.