RESUMEN
Recent advances in structural-color cellulose nanocrystal (CNC) materials have been made toward chemical sensing applications; however, such materials lack sufficient color chroma for naked-eye observation, and their selective recognition to given chemicals as well as the corresponding mechanism has rarely been reported. Here, a dopamine-infiltration and post-polymerization approach is proposed to construct vivid structural-color composite films. The chiral nematic structure of CNC enables the structural coloration, while the strong light absorption of the polymeric co-phase, polydopamine (PDA) enhances the color chroma and visibility. By controlling the PDA amount, the composite films can detect organic solvents quantitatively and selectively via visible color changes. From the viewpoint of the compatibility and similitude principle, notably, a critical solubility parameter distance (R0) between PDA and "active" solvents is defined with a three-dimensional Hansen solubility sphere; this well constructs a rule for the sensing selectivity of the chemochromic composite films. The findings pave the foundation for the design of colorimetric sensors with specifically testing objects.
Asunto(s)
Celulosa , Nanopartículas , Celulosa/química , Color , Nanopartículas/química , Óptica y Fotónica , SolventesRESUMEN
AIM: Periodontitis (PD) is the sixth most prevalent disease around the world and is involved in the development and progression of multiple systemic diseases. Previous studies have reported that PD may aggravate liver injuries. The objective of this study was to investigate whether and how PD affects liver fibrosis. MATERIALS AND METHODS: Ligature-induced PD (LIP) was induced in male C57/B6J mice, and sub-gingival plaques (PL) from patients with PD were applied to mouse teeth. Liver fibrosis was induced by carbon tetrachloride (CCl4 ) injection. The mice were randomly divided into six groups: Oil, Oil+LIP, Oil+LIP+PL, CCl4 , CCl4 +LIP, and CCl4 +LIP+PL. Alveolar bone resorption was evaluated by methylene blue staining. Hepatic function was analysed by serum alanine aminotransferase and hepatic hydroxyproline. Picrosirius red and α-smooth muscle actin (SMA) staining were used to evaluate the fibrotic area. RNA sequencing and quantitative RT-PCR were used to measure gene expression. Western blotting was used to measure protein levels. Flow cytometry was used to analyse the accumulation of immune cells. Mouse microbiota were analysed using 16S rRNA gene sequencing. RESULTS: Mice in the CCl4 +LIP+PL group displayed higher serum alanine aminotransferase and hepatic hydroxyproline as well as more Picrosirius red-positive and α-SMA-positive areas in liver samples than those of the CCl4 group, suggesting that PD (LIP+PL) aggravated CCl4 -induced hepatic dysfunction and liver fibrosis. Consistently, the expression of fibro-genic genes and the protein levels of transforming growth factor ß were much higher in the CCl4 +LIP+PL group than in the CCl4 group. Flow cytometry revealed that PD increased the accumulation of immune cells, including Kupffer cells, B cells, and Th17 cells, in the liver of mice with CCl4 treatment. PD also increased the expression of inflammatory genes and activated pro-inflammatory nuclear factor-kappa B pathway in the livers of CCl4 -injected mice. Moreover, PD altered both oral and liver microbiota in CCl4 -injected mice. CONCLUSIONS: PD aggravates CCl4 -induced hepatic dysfunction and fibrosis in mice, likely through the increase of inflammation and alteration of microbiota in the liver.
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Cirrosis Hepática , Microbiota , Periodontitis , Actinas , Alanina Transaminasa , Animales , Compuestos Azo , Tetracloruro de Carbono/efectos adversos , Hidroxiprolina/metabolismo , Cirrosis Hepática/inducido químicamente , Masculino , Azul de Metileno , Ratones , Periodontitis/complicaciones , ARN Ribosómico 16S , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Iridium(III) complexes have gained great attention in cancer treatment in recent years. In this paper, we designed and synthesized a new iridium(III) complex [Ir(piq)2(DQTT)](PF6) Ir1 (piq = 1-phenylisoquinoline, DQTT = 12-(1,4-dihydroquinoxalin-6-yl)-4,5,9,14-tetraazabenzo[b]triphenylene). The Ir1-loaded PEGylated liposomes (Lipo-Ir1) were prepared using the ethanol injection method. The anticancer activity of the complex and Lipo-Ir1 against SGC-7901 (human gastric adenocarcinoma), A549 (human lung carcinoma), HeLa (human cervical carcinoma), HepG2 (human hepatocellular carcinoma), BEL-7402 (human hepatocellular carcinoma), and normal NIH3T3 (mouse embryonic fibroblasts) was tested by the MTT method. The complex Ir1 shows moderate or low cytotoxicity against the selected cancer cells, whereas the Lipo-Ir1 exhibits high anticancer activity toward the same cancer cells. The apoptosis induced by Lipo-Ir1 was assayed by flow cytometry and Lipo-Ir1 induced apoptosis through increasing intracellular reactive-oxygen species levels, decreasing mitochondrial membrane potential, further promoting cytochrome c release and causing the increase of level of intracellular Ca2+. Western blot was used to detect the changes in Bcl-2 family protein and PI3K/AKT pathway proteins. The cloning experiments demonstrated that the Lipo-Ir1 can effectively inhibit cell proliferation. In vivo experiments, Lipo-Ir1 inhibited tumor growth in xenograft nude mice, and the percentage of tumor growth inhibition in vivo was 75.70%. Overall, the liposomes Lipo-Ir1 exhibits higher anticancer activity than Ir1 under the same conditions. These results indicated that Lipo-Ir1 may be a valuable resource for cancer therapy.
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Antineoplásicos/uso terapéutico , Complejos de Coordinación/uso terapéutico , Portadores de Fármacos/química , Liposomas/química , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/toxicidad , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Hemólisis/efectos de los fármacos , Iridio/química , Iridio/toxicidad , Liposomas/toxicidad , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Células 3T3 NIH , Neoplasias/patología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Herein an Ir(III) complex [Ir(Hppy)2(HMNPIP)](PF6) (Ir1, Hppy = 2-phenylpyridine, HMNPIP = 2-(1H-imidazo[4,5-f][1, 10]phenanthroline-3-yl)-6-methoxy-4-nitrophenol) was prepared and characterized. Due to the low anticancer activity of Ir1 when administered free drug, we prepared a liposome Ir1Lipo encapsulated form of Ir1 to improve the antitumor effect, furthermore, we explored the antitumor mechanism of both forms in vitro experiments on HepG2 cells. We investigated the inhibitory efficiency of Ir1 and Ir1Lipo on cell viability and proliferation using MTT (MTT = 3-(4,5-dimethylthiazole)-2,5-diphenltetraazolium bromide) and colony-forming assay. Intracellular accumulation of reactive oxygen species (ROS) was examined using a fluorescence microscope (High Content Screening System, ImageXpress Micro XLS System, Molecular Devices LLC, Sunnyvale, CA), programmed cell death cells stained with acridine orange/ethidium bromide (AO/EB) using flow cytometry detection and western blot have been performed. An in vivo study where HepG2 cells were transplanted into nude nice as xenografts. Tumour volume and body weight were monitored during the 10 days of administration. After encapsulation in liposomes Ir1Lipo displayed high potency against a variety of tumour cells in vitro, especially against HepG2 (IC50 = 4.6 ± 0.5 µM). Mechanism studies indicated that Ir1Lipo initiated apoptosis by generating intracellular ROS that regulate lysosomal-mitochondrial dysfunction, followed by microtubule disruption that subsequently leads to a G0/G1 phase of cell cycle arrest. Additionally, Ir1Lipo significantly curbed tumour growth in nude mice. The tumour inhibitory rate was 51.2% (5.6 mg/kg). Therefore, liposome as a drug delivery system greatly enhances anticancer activity of Ir1 by a factor of relatively minor side effects.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Animales , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Complejos de Coordinación/farmacología , Sistemas de Liberación de Medicamentos , Iridio/farmacología , Liposomas/farmacología , Ratones , Ratones Desnudos , Especies Reactivas de OxígenoRESUMEN
Enterovirus 71 (EV71) is an RNA virus that causes hand-foot-mouth disease (HFMD), and even fatal encephalitis in children. Although EV71 pathogenesis remains largely obscure, host immune responses may play important roles in the development of diseases. Recognition of pathogens mediated by Toll-like receptors (TLRs) induces host immune and inflammatory responses. Intracellular TLRs must traffic from the endoplasmic reticulum (ER) to the endolysosomal network from where they initiate complete signaling, leading to inflammatory response. This study reveals a novel mechanism underlying the regulation of TLR7 signaling during EV71 infection. Initially, we show that multiple cytokines are differentially expressed during viral infection and demonstrate that EV71 infection induces the production of proinflammatory cytokines through regulating TLR7-mediated p38 MAPK, and NF-κB signaling pathways. Further studies reveal that the expression of the endosome-associated protein hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) is upregulated and highly correlated with the expression of TLR7 in EV71 infected patients, mice, and cultured cells. Virus-induced HRS subsequently enhances TLR7 complex formation in early- and late-endosome by interacting with TLR7 and TAB1. Moreover, HRS is involved in the regulation of the TLR7/NF-κB/p38 MAPK and the TLR7/NF-κB/IRF3 signaling pathways to induce proinflammatory cytokines and interferons, respectively, resulting in the orchestration of inflammatory and immune responses to the EV71 infection. Therefore, this study demonstrates that HRS acts as a key component of TLR7 signaling to orchestrate immune and inflammatory responses during EV71 infection, and provides new insights into the mechanisms underlying the regulation of host inflammation and innate immunity during EV71 infection.
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Infecciones por Coxsackievirus/inmunología , Complejos de Clasificación Endosomal Requeridos para el Transporte/inmunología , Enterovirus Humano A/inmunología , Inmunidad Innata/inmunología , Inflamación/inmunología , Fosfoproteínas/inmunología , Animales , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Técnicas de Silenciamiento del Gen , Humanos , Immunoblotting , Inmunoprecipitación , Inflamación/metabolismo , Ratones , Ratones Endogámicos BALB C , Microscopía Fluorescente , Fosfoproteínas/metabolismo , Reacción en Cadena de la Polimerasa , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND: Chronic periodontitis (CP) is a chronic inflammation associated with elevations of several inflammatory and cardiac markers. Studies implicated CP as one of the etiologies in coronary heart disease (CHD). Cardiotoxicity is a major complication of anticancer drugs, including anthracyclines and 5-fluorouracil (5FU). The most severe cardiac complications are heart failure, arrhythmia and coronary heart disease (CHD). In this study, we compared the level of inflammatory factors and cardiac markers between chronic periodontitis patients and cancer patients receiving chemotherapy. METHODS: 108 blood samples of periodontally healthy subjects were obtained on random from Hong Kong Red Cross, and these represented the controlled population. Forty-four patients diagnosed with chronic periodontitis were recruited from the West China Hospital of Stomatology, Sichuan University. They have received scaling and root planning with mean pocket depths of 6.05 mm. Thirty breast cancer patients diagnosed with invasive ductal carcinoma from UNIMED Medical Institute, Hong Kong gave consent to participate in this study. They received 4 cycles of 500mg/m2 5-fluorouracil, 75 mg/m2 epirubicin and 500mg/m2 cyclophosphamide at a 3-week interval between each cycle. Peripheral venous blood from each group was taken for measurement of blood cells, inflammatory marker (P-selectin, high sensitvity C-reactive protein) and cardiac markers (troponin T; troponin I; N-terminal pro brain natriuretic peptide (Nt-proBNP) and Lactate dehydrogenase (LDH). RESULTS: The lymphocyte count was higher (p < 0.05) in periodontitis patients than the other two groups, and more neutrophils (p < 0.05) were seen in cancer patients receiving chemotherapy. The two test groups demonstrated higher levels (p < 0.01) of inflammatory and cardiac markers than the control group. CONCLUSIONS: The elevated cardiac markers found in periodontitis patients suggested that they may carry potential risks in developing cardiac lesions. Troponin T, troponin I, pro-BNP, LDH and high sensitvity C-reactive protein may be used as markers to monitor cardiac lesions in chronic inflammatory patients.
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Biomarcadores/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Periodontitis Crónica/sangre , Miocardio/metabolismo , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Periodontal disease is thought to arise from the interaction of various factors, including the susceptibility of the host, the presence of pathogenic organisms, and the absence of beneficial species. The genetic factors may play a significant role in the risk of periodontal diseases. Cytokines initiate, mediate and control immune and inflammatory responses. The aim of this study is to compare genotypes and soluble protein of pro and anti-inflammatory cytokines (IL-1α, IL-1ß, IL-6, IFN-γ, IL-10, TNF-α and IL-4) in subjects with or free of chronic periodontitis. METHODS: A total of 1,290 Chinese subjects were recruited to this clinical trial: 850 periodontally healthy controls and 440 periodontal patients. All subjects were free of systemic diseases. Oral examinations were performed, and the following parameters were recorded for each subject: supragingival/subgingival calculus, gingival recession, bleeding on probing (BOP), probing depth (PD), clinical attachment loss (CAL), gingival recession and tooth mobility. The peripheral blood samples were collected for genetic and enzyme linked immunosorbent assay (ELISA) analysis. Restriction enzymes were used for digestion of amplified fragments of IL-1α, IL-1ß, IL-6, IFN-γ, IL-10, TNF-α and IL-4. RESULTS: The protein expressions of patient and control samples for IL-1α, IL-1ß, IL-6, TNF-α, IFN-γ, IL-10, and IL-4 measured by ELISA confirmed a statistically significant difference (p < 0.001). The digestion of fragments of various genes showed that the pro-inflammatory cytokines IL-1α and TNF-α, and the anti-inflammatory cytokines IL-4 and IL-10 demonstrated a correlation with chronic inflammation in patients (X2: p < 0.001). The remaining genes investigated in patients and healthy subjects (IL-1ß, IL-6, IFN-γ and IL-10) did not show any significant difference. CONCLUSIONS: The cytokine gene polymorphisms may be used as a marker for periodontitis susceptibility, clinical behaviour and severity. This detection offers early diagnosis and induction of prophylaxis to other family members against disease progression.
Asunto(s)
Antiinflamatorios/metabolismo , Pueblo Asiatico/genética , Periodontitis Crónica/genética , Citocinas/genética , Predisposición Genética a la Enfermedad , Mediadores de Inflamación/metabolismo , Polimorfismo Genético , Adulto , Anciano , Estudios de Casos y Controles , China , Ensayo de Inmunoadsorción Enzimática , Femenino , Frecuencia de los Genes/genética , Salud , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Periodontitis is a common disease that affects the periodontal tissue supporting the teeth. This disease is attributed to multiple risk factors, including diabetes, cigarette smoking, alcohol, pathogenic microorganisms, genetics and others. Human beta-defensin-1 (hBD-1) is a cationic antimicrobial peptide with cysteine-rich ß-sheets and broad-spectrum antimicrobial activity. CD14 is a protein involved in the detection of bacterial lipopolysaccharide (LPS) and has also been associated with periodontitis. This study investigates the single nucleotide polymorphic (SNP) region, -1654(V38I), of the human beta-defensin-1 (hBD-1) gene as well as the -159 region of the CD14 gene in subjects with chronic periodontitis. METHODS: Blood samples from periodontally healthy subjects and periodontitis patients were obtained. DNA was extracted from the blood and was used to perform restriction digest at the polymorphic G1654A site of DEFB1 with the enzyme HincII. The polymorphic site 159TT of CD14 was digested with the enzyme AvaII. Enzyme-linked immunosorbent assay (ELISA) was performed on soluble samples to determine the protein expressions. RESULTS: The control and patient groups expressed 35% and 38% 1654 A/A genotype of DEFB1, respectively. The A allele frequency of the control group was 40%, while the patient blood group was 54%. The mean hBD-1 protein levels of the control and patient samples were 102.83 pg/mL and 252.09 pg/mL, respectively. The genotype distribution of CD14 in healthy subjects was 16% for C/C, 26% for T/T and 58% for C/T. The genotype frequencies of CD14 in periodontitis patients were 10% for C/C, 43% for T/T and 47% for C/T. The CD14 protein expression determined by ELISA showed a mean protein level of the control samples at 76.28ng/mL and the patient blood samples at 179.27ng/mL with a p value of 0.001.Our study demonstrated that patients suffering from chronic periodontitis present more commonly with the 1654A/A genotype on the DEFB1 gene and the 159T/T genotype on the CD14 gene. CONCLUSIONS: This study purely investigated the association between periodontitis and one polymorphic site on both DEFB1 and CD14 gene, with the purpose of expanding knowledge for the future development in diagnostic markers or therapeutic interventions to combat this disease.
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Periodontitis Crónica/genética , Predisposición Genética a la Enfermedad , Inflamación/genética , Receptores de Lipopolisacáridos/genética , Polimorfismo de Nucleótido Simple/genética , beta-Defensinas/genética , Adolescente , Adulto , Alelos , Secuencia de Bases , Estudios de Casos y Controles , Periodontitis Crónica/sangre , Demografía , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inflamación/sangre , Receptores de Lipopolisacáridos/sangre , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Regiones Promotoras Genéticas/genética , Mapeo Restrictivo , Adulto JovenRESUMEN
Increasing evidence suggests that periodontitis, characterized by oral dysbiosis, is a critical player in the progression of multiple systemic diseases in humans. However, there is still a lack of a proper mouse model of periodontitis with the colonization of human periodontitis-associated bacteria. We here established a new mouse periodontitis model by combining ligation of the second molars with application of subgingival plaques from periodontitis patients. Using 16S rRNA gene sequencing and Taxonomic classification, we found that human periodontitis-associated bacteria efficiently colonized in the mouse model and were enriched in both ligature silk and mouse saliva. Furthermore, the well-recognized periodontal pathogens including Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia, and Tannerella forsythia were enriched in the new model, but not in ligature-induced periodontitis model or Sham mice. The human periodontitis-associated bacteria potently aggravated mouse periodontitis, as demonstrated by more severe bone resorption and higher expression of inflammatory and osteoclastogenesis genes. In summary, the new mouse periodontitis model paves the way for studying human periodontitis-associated bacteria in oral diseases and systemic diseases.
Asunto(s)
Aggregatibacter actinomycetemcomitans , Periodontitis , Animales , Humanos , Ratones , Periodontitis/microbiología , Porphyromonas gingivalis/genética , Prevotella intermedia/genética , ARN Ribosómico 16S/genéticaRESUMEN
Due to the serious threat of methanol to human health, the convenient, quick and specific detection of methanol is of great importance. Therefore, in this study, a biomass-derived chiral nematic composite film is fabricated by the co-evaporation of cellulose nanocrystals (CNC) and water-soluble polymer of ß-cyclodextrin (PCD). The freestanding iridescent CNC-PCD film shows distinguishing structural colors of red and yellow green for methanol and ethanol respectively, realizing the identification of the two homologous alcohols by naked eyes. Besides, the quick, reversible and quantitative colorimetric sensing of the CNC-PCD film to methanol is verified. As its structural color and maximum reflection wavelength redshift to the greatest extent for methanol than other alcohols, the CNC-PCD film exhibits the specificity and selectivity for methanol detection in both single and mixed solvents. Such less-consumed and easy-to-handle CNC-PCD film may be useful as a colorimetric sensor to detect or discriminate methanol in some industrial products.
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Nanopartículas , beta-Ciclodextrinas , Celulosa/química , Humanos , Metanol , Nanopartículas/química , PolímerosRESUMEN
Aromatized thioketal (ATK) linked the immunoregulatory molecule (budesonide, Bud) and the cytotoxic molecule (gemcitabine, Gem) to construct a ROS-activated Janus-prodrug, termed as BAG. Benefiting from the hydrogen bonding, π-π stacking, and other intermolecular interactions, BAG could self-assemble into nanoaggregates (BAG NA) with a well-defined spherical shape and uniform size distribution. Compared to the carrier-based drug delivery system, BAG NA have ultrahigh drug loading content and ROS concentration-dependent drug release. Colitis-associated colorectal cancer (CAC) is a typical disease in which chronic inflammation transforms into tumors. BAG NA can be internalized by colon cancer C26 cells and then triggered by excessive intracellular ROS to release nearly 100% of the drugs. Based on this, BAG NA showed a stronger pro-apoptotic effect than free Bud combined with free Gem. What is gratifying is that orally administered BAG NA can precisely accumulate in the diseased colon tissues of CAC mice induced by AOM/DSS and simultaneously release Bud and Gem. Bud can regulate the tumor immune microenvironment to restore and enhance the cytotoxicity of Gem. Therefore, BAG NA maximizes the synergistic therapeutic effect through co-delivery of Bud and Gem. This work provided a cutting-edge method for constructing self-delivery Janus-prodrug based on ATK and confirmed its potential application in inflammation-related carcinogenesis.
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Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Profármacos/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/química , Budesonida/administración & dosificación , Budesonida/química , Budesonida/farmacología , Línea Celular , Neoplasias Asociadas a Colitis/metabolismo , Neoplasias Asociadas a Colitis/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacología , Ensayo de Materiales , Ratones , Ratones Endogámicos BALB C , Simulación de Dinámica Molecular , Estructura Molecular , Profármacos/administración & dosificación , Profármacos/química , GemcitabinaRESUMEN
In this paper, two new iridium(III) complexes [Ir(ppy)2(CBIP)](PF6) (ppy = 2-phenylpyridine, CBIP = 2-(4'-chloro-(1,1'-biphenyl))-1H-imidazo[4,5-f][1,10]phenanthroline) (Ir1) and [Ir(piq)2(CBIP)](PF6) (piq = 1-phenylisoquinoline) (Ir2) were synthesized and characterized. The anticancer activity of the complexes against cancer A549, HepG2, SGC-7901, BEL-7402, HeLa and LO2 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Unexpectedly, the complexes exhibit no or low cytotoxic activity toward the selected cancer cells. To increase the anticancer activity, complexes Ir1 and Ir2 were encapsulated into the liposome to form Ir1lipo and Ir2lipo, while Ir1lipo and Ir2lipo show high cytotoxic efficacy against BEL-7402, SGC-7901 and HeLa cells and Ir2lipo displays moderate cytotoxic activity against A549 and HepG2. The anticancer mechanism was explored through wound healing, cell cycle arrest, apoptosis, the change of mitochondrial membrane potential and antitumor activity in vivo. The antitumor in vivo showed that Ir1Lipo (3.9 mg/kg) exhibited significant antitumor activity with an inhibitory rate of 62.16%. Additionally, the expression of B-cell lymphoma-2 family proteins was studies by western blotting analysis. The results demonstrate that Ir1lipo and Ir2lipo induce apoptosis in BEL-7402 cells via endoplasmic reticulum stress-mitochondrial pathway.
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Antineoplásicos , Complejos de Coordinación , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacología , Retículo Endoplásmico , Células HeLa , Humanos , Iridio/metabolismo , Iridio/farmacología , Liposomas , MitocondriasRESUMEN
Two iridium (III) polypyridine complexes [Ir(ppy)2(BIP)]PF6 (ppy = 2-phenylpyridine, BIP = 2-biphenyl-1H-imidazo[4,5-f][1,10]phenanthroline, Ir1), [Ir(piq)2(BIP)]PF6 (piq = 1-phenylisoquinoline, Ir2) and their liposomes Ir1lipo and Ir2lipo were synthesized and characterized. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cytotoxic activity against several cancer cells (A549, HepG2, SGC-7901, Bel-7402, HeLa) and non-cancer cell (mouse embryonic fibroblast, NIH3T3). The results showed that Ir1lipo displays the high cytotoxicity toward SGC-7901 with IC50 value of 5.8 ± 0.2 µM, while the complexes have no cytotoxicity toward A549, HepG2, Bel-7402 and HeLa cells. The cell colony demonstrated that the iridium (III) complexes-loaded liposomes can inhibit cell proliferation, induce cell cycle arrest at G0/G1 phase. Moreover, they also cause autophagy, induce a decrease of mitochondrial membrane potential and increase intracellular reactive oxygen species (ROS) content. These results suggest that the complexes encapsulated liposomes Ir1lipo and Ir2lipo inhibit the growth of SGC-7901 cells through a ROS-mediated mitochondrial dysfunction and activating the PI3K (phosphoinositide-3 kinase)/ AKT (protein kinase B) signaling pathways.
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Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Portadores de Fármacos/química , Liposomas/química , Piridinas/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Iridio/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Células 3T3 NIH , Piridinas/síntesis química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Three iridium(III) complexes [Ir(ppy)2(CPIP)](PF6) (Ir-1, ppy = 2-phenylpyridine, CPIP = 2-(4-chlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)2(DCPIP)](PF6) (Ir-2, DCPIP = 2-(3,4-dichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)2(TCPIP)](PF6) (Ir-3, TCPIP = 2,3,5-trichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The complexes Ir-1, Ir-2 and Ir-3 were encapsulated in liposomes to form Ir-1-Lipo, Ir-2-Lipo and Ir-3-Lipo. Morphology, size distribution, and zeta potential of liposomes were examined by transmission electron microscopy (TEM) and Zetasizer. The cytotoxic activity in vitro of Ir-1, Ir-2 and Ir-3 against cancer A549, HTC-116, HepG2, BEL-7402, Eca-109, B16, HeLa SGC-7901 and normal NIH3T3 cells was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. Ir-2 and Ir-3 show no cytotoxic activity against the selected cancer cells, and Ir-1 displays moderate cytotoxic effect on the cell growth in A549 cells. However, Ir-1, Ir-2 and Ir-3 were encapsulated in liposomes, the cytotoxic activity was greatly enhanced. In particular, Ir-1-Lipo and Ir-2-Lipo can effectively inhibit the cell growth in A549 cells with a low IC50 value of 3.1 ± 0.3 and 1.2 ± 0.4 µM. The apoptosis was assayed by flow cytometry. Ir-1, Ir-2 and Ir-3 reveal weak apoptotic effect, whereas Ir-1-Lipo, Ir-2-Lipo and Ir-3-Lipo induce an apoptotic percentage of 55.6%, 69.3% and 16.7% in A549 cells, respectively. Specially, in the assay of antitumor activity in vivo, the inhibiting percentage of tumor growth induced by Ir-2 is 27.65%, while inhibiting percentage of tumor growth caused by Ir-2-Lipo is 57.45%. Obviously, the liposomes can enhance anticancer activity in vitro and in vivo compared with the complexes. The results show that the iridium(III) complexes encapsulated liposomes induce apoptosis in A549 cells through ROS-mediated lysosome-mitochondria dysfunction pathway and target the microtubules.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Iridio , Neoplasias Experimentales , Células A549 , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Iridio/química , Iridio/farmacología , Liposomas , Melanoma Experimental , Ratones , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patologíaRESUMEN
Two iridium(III) polypyridyl complexes [Ir(ppy)2(HPIP)](PF6) (Ir-1), [Ir(ppy)2(BHPIP)](PF6) (Ir-2) and their liposomes Ir-1-Lipo and Ir-2-Lipo were synthesized and characterized by elemental analysis, IR, 1H NMR and 13C NMR. The anticancer activity in vitro and in vivo was evaluated. The cytotoxic activity in vitro of the complexes and their liposomes Ir-1-Lipo and Ir-2-Lipo against cancer cells was investigated by MTT methods. Ir-1 and Ir-2 show no cytotoxic activity, while Ir-1-Lipo and Ir-2-Lipo exhibit high cytotoxic effect. The IC50 values range from 5.2⯱â¯0.8 to 22.3⯱â¯1.8⯵M. The apoptosis, reactive oxygen species, the change of mitochondrial membrane potential, intracellular Ca2+ levels and a release of cytochrome c were investigated. The effect of Ir-1-Lipo and Ir-2-Lipo on microtubules was also explored. In the C57BL/6 mice model, Ir-1 only displays a tumor inhibitory rate of 23.21%, while lr-1-Lipo exhibits satisfactory in vivo antitumor efficacy with tumor inhibitory rate of 72.55%. This study demonstrates that complexes encapsulated in liposomes induce apoptosis in B16 through ROS-mediated lysosomal-mitochondria dysfunction, inhibition of polymerization of microtubules and induce cell cycle arrest at S phase.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Iridio/química , Iridio/farmacología , Liposomas/química , Ratones , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Polímeros/química , Polímeros/farmacología , Piridinas/química , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
Shikonin (SHK) is a highly liposoluble naphthoquinone pigment has recently been investigated as a potential antiglioma agent. However, shikonin shows several limitations like poor aqueous solubility, short half-life and non-selective biodistribution. Herein, we have developed a nanoparticles (NPs) prepared from PEG-PLGA using an emulsion solvent evaporation method. Nanoparticle surfaces were modified by coating with lactoferrin (Lf) to improve the crossing of the blood brain barrier and targeting of glioma cells via receptor-mediated path-ways. X-ray powder diffraction and differential scanning calorimetry analysis revealed the amorphous nature of SHK encapsulated within the NPs. Moreover, the drug-loaded NPs exhibit narrow size distribution and high encapsulation efficiency. The in vitro release experiments of the NPs exhibited sustained release for more than 72h. When compared to free SHK and SHK/NPs, in vivo study demonstrated higher brain concentration of SHK, indicating a significant effect of Lf coated NPs on brain targeting. Accordingly, these findings provide evidence for the potential of Lf-modified NPs as a targeted delivery system for brain glioblastomas treatment.
Asunto(s)
Glioma/tratamiento farmacológico , Lactoferrina/química , Nanopartículas/química , Naftoquinonas/química , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Línea Celular Tumoral , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/efectos adversos , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Humanos , Lactoferrina/administración & dosificación , Lactoferrina/efectos adversos , Nanopartículas/administración & dosificación , Nanopartículas/efectos adversos , Naftoquinonas/administración & dosificación , Naftoquinonas/efectos adversos , Naftoquinonas/uso terapéutico , Poliésteres/administración & dosificación , Poliésteres/efectos adversos , Poliésteres/química , Poliésteres/uso terapéutico , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Polietilenglicoles/química , Polietilenglicoles/uso terapéutico , Ratas , Distribución TisularRESUMEN
BACKGROUND: The newly synthesized Aurora-A kinase inhibitor XY-4 is a potential anti-cancer agent, but its hydrophobicity and limited efficiency restrict further application. Nanotechnology based combined therapy provides an optimized strategy for solving these issues. METHODS: In this study, the newly synthesized Aurora-A kinase inhibitor XY-4 and Bcl-xl targeted siRNA were co-delivered by cationic liposomes, creating an injectable co-delivery formulation. The anti-cancer ability and mechanisms of XY-4/Bcl-xl siRNA co-loaded cationic liposomes were studied both in vitro and in vivo. RESULTS: The prepared liposomes had a mean particle size of 91.3±4.5 nm with a zeta potential of 38.5±0.5 mV and were monodispersed (Polydispersity index =0.183) in water solution, with high drug loading capacity and stability. Intriguingly, the positive charges of co-delivery liposomes not only facilitated gene delivery, but also obviously enhanced drug uptake. The XY-4/Bcl-xl siRNA co-loaded cationic liposomes demonstrated enhanced anti-cancer effects on B16 melanoma cells in vitro by activation mitochondrial apoptosis pathway. Moreover, intratumoral injection of this co-delivery formulation efficiently inhibited the growth of a B16 melanoma xenograft model in vivo. CONCLUSION: By co-delivering Aurora-A kinase inhibitor XY-4 and Bcl-xl targeting siRNA in a nanoformulation, our study supplied a potential combination strategy for melanoma therapy.
Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Técnicas de Transferencia de Gen , Melanoma Experimental/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , ARN Interferente Pequeño/administración & dosificación , Proteína bcl-X/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Cationes , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Humanos , Liposomas , Melanoma Experimental/patología , Ratones , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , TransfecciónRESUMEN
A dual-responsive drug delivery system simulating an AND logic gate is developed by core-cross-linking of a disulfide-containing anticancer prodrug with Cu(2+) for safe and efficient delivery of anticancer drugs. These prodrug nanoparticles are stable and exhibit nearly no premature drug release, and allow a fast drug release under simulated intracellular conditions, realizing a precise drug delivery towards cell nuclei.
Asunto(s)
Antineoplásicos/química , Portadores de Fármacos/química , Nanopartículas/química , Profármacos/química , Antineoplásicos/toxicidad , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Cobre/química , Doxorrubicina/química , Doxorrubicina/toxicidad , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Polietilenglicoles/química , Profármacos/toxicidadRESUMEN
OBJECTIVES: This study aimed to compare the epigenetic changes via hypermethylation status of TIMP-3, GSTP-1 and 14-3-3σ genes, between healthy subjects and patients with reversible chronic inflammatory disease, and between healthy subjects and patients with irreversible malignant disease, to highlight the genetic changes that occur in the progression from an inflammatory condition to irreversible genetic changes commonly observed in cancer patients. METHODS: DNA was extracted from the blood of 680 healthy subjects, and tissues and blood of 110 patients with chronic inflammation disease of the gums, as well as neoplastic tissues of 108 breast cancer patients. Methylation-specific polymerase chain reaction (PCR) for TIMP-3, GSTP-1 and 14-3-3σ was performed, and hypermethylation status was analyzed and compared between the 3 groups. RESULTS: The hypermethylation frequencies of TIMP-3 and GSTP-1 of reversible chronic inflammatory gum disease and the control group were similar, but both were significantly lower than those for malignant disease patients (p<0.0001). The methylation frequency of 14-3-3σ in chronic inflammatory gum disease was higher than in the cancer and control groups (p<0.0001). The methylation of CpG islands in TIMP-3 and GSTP-1 in chronic inflammation patients occurred as frequently as in the control group, but less frequently than in breast cancer patients. However, the epigenetic silencing of 14-3-3σ occurred more frequently in the chronic inflammation group than in cancer patients and healthy controls. CONCLUSIONS: The epigenetic silencing of 14-3-3σ might be essential for chronic inflammatory gum disease. The epigenetic changes presented in chronic inflammation patients might demonstrate an irreversible destruction in the tissues or organs similar to cancer.
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Proteínas 14-3-3/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Metilación de ADN , Exorribonucleasas/genética , Gutatión-S-Transferasa pi/genética , Inflamación/genética , Inhibidor Tisular de Metaloproteinasa-3/genética , Estudios de Casos y Controles , Enfermedad Crónica , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Gingivitis/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: This study aims to evaluate and compare cytokines in gingival crevicular fluid (GCF) and saliva of patients with aggressive periodontitis (AP) before and after treatment. METHODS: Forty AP patients and 40 healthy volunteers were enrolled in this study. Clinical parameters included probing depth and sulcus bleeding index. GCF and saliva were collected from both groups. The levels of IL-1ß, IL-2, IL-4, IL-6, IFN-γ and TNF-α were measured using ELISA. RESULTS: The probing depth in AP patients was significantly deeper before treatment than after treatment. The concentrations of cytokines in GCF and saliva were significantly higher in AP patients than in the control group and decreased after periodontal treatment. Positive relationships were found between cytokine levels in GCF and clinical parameters. The reliability of cytokines in GCF and saliva was assessed by Cronbach's alpha analysis, which could be considered satisfactory. CONCLUSION: Cytokine levels in GCF and saliva correlated well with clinical parameters and AP. Measurements of cytokines in saliva may be regarded as a noninvasive and quick method for monitoring periodontal disease activity.