RESUMO
Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.
Assuntos
Carcinoma Hepatocelular , Animais , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Espécies Reativas de Oxigênio , Carcinogênese/genéticaRESUMO
BACKGROUND: Traumatic peripheral nerve injury (TPNI) is a major medical problem with no universally accepted pharmacologic treatment. We hypothesized that encapsulation of pro-angiogenic erythropoietin (EPO) in amphiphilic PLGA-PEG block copolymers could serve as a local controlled-release drug delivery system to enhance neurovascular regeneration after nerve injury. METHODS: In this study, we synthesized an EPO-PLGA-PEG block copolymer formulation. We characterized its physiochemical and release properties and examined its effects on functional recovery, neural regeneration, and blood vessel formation after sciatic nerve crush injury in mice. RESULTS: EPO-PLGA-PEG underwent solution-to-gel transition within the physiologically relevant temperature window and released stable EPO for up to 18 days. EPO-PLGA-PEG significantly enhanced sciatic function index (SFI), grip strength, and withdrawal reflex post-sciatic nerve crush injury. Furthermore, EPO-PLGA-PEG significantly increased blood vessel density, number of junctions, and myelinated nerve fibers after injury. CONCLUSION: This study provides promising preclinical evidence for using EPO-PLGA-PEG as a local controlled-release treatment to enhance functional outcomes and neurovascular regeneration in TPNI.
Assuntos
Lesões por Esmagamento , Eritropoetina , Traumatismos dos Nervos Periféricos , Neuropatia Ciática , Camundongos , Animais , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Preparações de Ação Retardada/farmacologia , Regeneração Nervosa , Neuropatia Ciática/tratamento farmacológico , Eritropoetina/farmacologia , Eritropoetina/química , Eritropoetina/uso terapêutico , Lesões por Esmagamento/tratamento farmacológicoRESUMO
Materials with high dielectric constant, εs, are desirable in a wide range of applications including energy storage and actuators. Recently, zwitterionic liquids have been reported to have the largest εs of any liquid and, thus, have the potential to replace inorganic fillers to modulate the material εs. Although the large εs for zwitterionic liquids is attributed to their large molecular dipole, the role of chemical substituents attached to the zwitterion cation on εs is not fully understood, which is necessary to enhance the performance of soft energy materials. Here, we report the impact of zwitterionic liquid cation chemical substituents on εs (50 < εs < 300 at room temperature). Dielectric relaxation spectroscopy reveals that molecular reorientation is the main contributor to the high εs. The low Kirkwood factor g calculated for zwitterionic liquids (e.g., 0.1-0.2) suggests the tendency for the antiparallel zwitterion dipole alignment expected from the strong electrostatic intermolecular interactions. With octyl cation substituents, the g is decreased due to the formation of hydrophobic-rich domains that restrict molecular reorientation under applied electric fields. In contrast, when zwitterion cations are functionalized with ethylene oxide (EO) segments, g increases due to the EO segments interacting with the cations, allowing more zwitterion rotation in response to the applied field. The reported results suggest that high εs zwitterionic liquids require a large molecular dipole, compositionally homogeneous liquids (e.g., no aggregation), a maximized zwitterion number density, and a high g, which is achievable by incorporating polar chemical substituents onto the zwitterion cations.
RESUMO
The aim of this study was to investigate the protective effects of Nano-Se against Ni-induced testosterone synthesis disorder in rats and determine the underlying protective mechanism. Sprague-Dawley rats were co-treated with Ni (5.0 mg/kg, i.p.) and Nano-Se (0.5, 1.0, and 2.0 mg/kg, oral gavage) for 14 days after which various endpoints were evaluated. The Ni-induced abnormal pathological changes and elevated 8-OHdG levels in the testes were attenuated by Nano-Se administration. Importantly, decreased serum testosterone levels in the Ni-treated rats were significantly restored by Nano-Se treatment, particularly at 1.0 and 2.0 mg/kg. Furthermore, the mRNA and protein levels of testosterone synthetase were increased by Nano-Se compared to the Ni group, whereas phosphorylated protein expression levels of mitogen-activated protein kinase (MAPK) pathways were suppressed by Nano-Se administration in the Ni-treated rats. Overall, the results suggest that Nano-Se may ameliorate the Ni-induced testosterone synthesis disturbance via the inhibition of ERK1/2, p38, and JNK MAPK pathways.
Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Níquel/toxicidade , Selênio/farmacologia , Testosterona/biossíntese , Animais , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Nanopartículas , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Testosterona/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Nickel (Ni) is a common environmental pollutant, which has toxic effects on reproductive system. Nowadays, nano-selenium (Nano-Se) has aroused great attention due to its unique antioxidant effect, excellent biological activities and low toxicity. The aim of this study was to explore the protective effects of Nano-Se on NiSO4-induced testicular injury and apoptosis in rat testes. Nickel sulfate (NiSO4) (5 mg/kg b.w.) was administered intraperitoneally and Nano-Se (0.5, 1, and 2 mg Se/kg b.w., respectively) was given by oral gavage in male Sprague-Dawley rats. Histological changes in the testes were determined by H&E staining. The terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and immunohistochemistry were performed to evaluate the apoptosis in testes. Expression levels of mitochondrial apoptosis-related genes and proteins were analyzed by RT-qPCR and Western blot. The results showed that Nano-Se improved lesions of testicular tissue induced by NiSO4. Nano-Se significantly alleviated NiSO4-induced apoptosis in rat testes, as well as significantly downregulated the Bak, cytochrome c, caspase-9 and caspase-3 and upregulated Bcl-2 expression levels, all of which were involved in mitochondria-mediated apoptosis. Altogether, we concluded that Nano-Se may potentially exert protective effects on NiSO4-induced testicular injury and attenuate apoptosis, at least partly, via regulating mitochondrial apoptosis pathways in rat testes.
Assuntos
Apoptose/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Nanopartículas/química , Níquel/toxicidade , Selênio/farmacologia , Testículo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Marcação In Situ das Extremidades Cortadas , Masculino , Tamanho da Partícula , Ratos Sprague-Dawley , Selênio/química , Propriedades de Superfície , Testículo/patologiaRESUMO
Nickel oxide nanoparticles (nano NiO) could induce hepatocyte apoptosis, while its potential mechanisms are unclear. This study aimed to explore the role of endoplasmic reticulum (ER) stress pathways in hepatocyte apoptosis induced by nano NiO. Male Wistar rats were administrated with nano NiO (0.015, 0.06, and 0.24 mg/kg b.w.) and micro NiO (0.24 mg/kg b.w.) by intratracheal instillation twice a week for 6 weeks. We measured the hepatocyte apoptosis levels by TdT-mediated dUTP nick-end labeling (TUNEL) staining, ER stress related gene and protein expression levels in rat liver. The results showed that the TUNEL positive cells increased after exposure nano NiO, hinting hepatocyte apoptosis. The up-regulated gene and protein levels of 78 kD glucose regulated protein and CCAAT/enhancer binding protein homologous protein suggested that nano NiO triggered ER stress. Nano NiO exposure contributed to the increased protein contents of inositol-requiring enzyme 1 (IRE-1)α, p-IRE-1α, X box protein-1S, pancreatic ER kinase (PERK), p-PERK, eukaryotic initiation factor-2 alpha (eIF-2α), p-eIF-2α, caspase-12, -9, and -3, implicating that nano NiO can activate the pathways of ER stress-mediated apoptosis. These findings indicate that the ER stress pathways may play an important role in hepatocyte apoptosis induced by nano NiO.
Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Níquel/toxicidade , Animais , Caspases/metabolismo , Endorribonucleases/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Hepatócitos/metabolismo , Masculino , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Wistar , eIF-2 Quinase/metabolismoRESUMO
Nickel can induce apoptosis of testicular Leydig cells in mice, whereas the mechanisms remain unclear. In this study, we investigated the role of nickel-induced reactive oxygen species (ROS) generation in mitochondria and endoplasmic reticulum stress (ERS) mediated apoptosis pathways in rat Leydig cells. Fluorescent DCF and Annexin-V FITC/PI staining were performed to measure the production of ROS and apoptosis in Leydig cells. RT-qPCR and Western blot were conducted to analyze the key genes and proteins involved in mitochondria and ERS apoptotic pathways. The results showed that nickel sulfate induced ROS generation, consequently resulted in nucleolus deformation and apoptosis in testicular Leydig cells, which were then attenuated by ROS inhibitors of N-acetylcysteine (NAC) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). Nickel sulfate-triggered Leydig cells apoptosis via mitochondria and ERS pathways was characterized by the upregulated mRNA and proteins expression of Bak, cytochrome c, caspase 9, caspase 3, GRP78, GADD153, and caspase 12, which were inhibited by NAC and TEMPO respectively. The findings indicated that nickel-induced ROS generation was involved in apoptosis via mitochondria and ERS pathways in rat Leydig cells.
Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Intersticiais do Testículo/efeitos dos fármacos , Mitocôndrias/metabolismo , Níquel/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 12/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Óxidos N-Cíclicos/farmacologia , Citocromos c/metabolismo , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Células Intersticiais do Testículo/metabolismo , Masculino , Ratos Wistar , Espécies Reativas de Oxigênio/antagonistas & inibidores , Transdução de Sinais , Fator de Transcrição CHOP/metabolismoRESUMO
In an electrowetting experiment on a surface treated hexagonal mesoporous silica, it is noticed that the effective solid-liquid interfacial tension is quite insensitive to the applied voltage, while the accessible nanopore volume decreases significantly as the voltage is increased. When the voltage is higher than 900 V, the liquid infiltration cannot be detected. The liquid defiltration is quite insensitive to the electric field. These unique phenomena may be attributed to the field responsive ion behaviors in the confining nanoenvironment.
RESUMO
In pure water a hydrothermally treated zeolite Y is hydrophilic, while with the addition of an electrolyte it can no longer be soaked up spontaneously. The effective degree of hydrophobicity increases with the ion concentration, which is reflected by the increase in infiltration pressure. The pressure-induced infiltration behavior is not only determined by the cations, but also highly dependent on the anion species. This phenomenon can be attributed to the confinement effect of nanopore walls.
RESUMO
Nickel (Ni) can disorder testosterone synthesis in rat Leydig cells, whereas the mechanisms remain unclear. The aim of this study was to investigate the role of reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) in Ni-induced disturbance of testosterone synthesis in rat Leydig cells. The testosterone production and ROS levels were detected in Leydig cells. The mRNA and protein levels of testosterone synthetase, including StAR, CYP11A1, 3ß-HSD, CYP17A1 and 17ß-HSD, were determined. Effects of Ni on the ERK1/2, p38 and JNK MAPKs were also investigated. The results showed that Ni triggered ROS generation, consequently resulted in the decrease of testosterone synthetase expression and testosterone production in Leydig cells, which were then attenuated by ROS scavengers of N-acetylcysteine (NAC) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), indicating that ROS are involved in the Ni-induced testosterone biosynthesis disturbance. Meanwhile Ni activated the ERK1/2, p38 and JNK MAPKs. Furthermore, Ni-inhibited testosterone synthetase expression levels and testosterone secretion were all alleviated by co-treatment with MAPK specific inhibitors (U0126 and SB203580, respectively), implying that Ni inhibited testosterone synthesis through activating ERK1/2 and p38 MAPK signal pathways in Leydig cells. In conclusion, these findings suggest that Ni causes testosterone synthesis disorder, partly, via ROS and MAPK signal pathways.
Assuntos
Células Intersticiais do Testículo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Níquel/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Testosterona/biossíntese , Animais , Células Cultivadas , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Células Intersticiais do Testículo/metabolismo , Masculino , Ratos , Ratos Wistar , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologiaRESUMO
The aim of the present study was to explore the role of oxidative stress in liver toxicity induced by nickel oxide nanoparticles (nanoNiO) in rats. Male Wistar rats received saline (control), nanoNiO [0.015, 0.06 or 0.24 mg/kg body weight (b.w.)] or microNiO (0.24 mg/kg b.w.) by intratracheal instilling twice a week for 6 weeks. Liver tissues were then collected and examined for biomarkers of nitrative and oxidative stress, as well as mRNA expression of heme oxygenase (HO)1 and metallothionein (MT)1. The results demonstrated that the NiO exposure groups had increased liver wet weight and coefficient to body weight, as well as liver pathological changes, evidenced as cellular edema, hepatic sinus disappeara-nce and binucleated hepatocytes. The activities of total nitric oxide synthase and inducible nitric oxide synthase, and the nitric oxide content, were increased in the 0.24 mg/kg nanoNiO group compared with the control group. The MT1 mRNA expression levels were downregulated, while HO1 mRNA was upregulated in the 0.24 mg/kg nanoNiO exposure group compared with the control group. In addition, abnormal changes of hydroxyl radical, lipid peroxidation, catalase, glutathione peroxidase, total superoxide dismutase and total antioxidative capacity were observed in the liver tissues of the 0.24 mg/kg nanoNiO exposure group, compared with the control group. The present results therefore indicated that nanoNiOinduced liver toxicity may be associated with nitrative and oxidative stress in rats.
Assuntos
Fígado/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Níquel/química , Estresse Oxidativo/efeitos dos fármacos , Animais , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Nanopartículas Metálicas/química , Metalotioneína/genética , Metalotioneína/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Studies have demonstrated that nano NiO could induce liver toxicity in rats, but its mechanism remains unclear. This study aimed to explore the role of the NF-κB signaling pathway in rat liver toxicity after nano NiO exposure. Male Wistar rats were exposed to nano NiO (0.015, 0.06 and 0.24 mg per kg b.w.) and micro NiO (0.24 mg per kg b.w.) by intratracheal instillation twice a week for 6 weeks. To investigate the liver toxicity induced by nano NiO, the indicators of liver function and inflammatory response were detected, and the histopathological changes were observed. The levels of NF-κB signaling pathway related gene and protein expression were examined using RT-qPCR and western blot techniques in the liver tissue. The results showed that the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyltranspeptidase (GGT) increased after nano NiO exposure. Cellular edema, hepatic sinus disappearance, and neutrophil and lymphocyte infiltration were observed. Nano NiO increased the concentrations of pro-inflammatory cytokines (IL-1ß and IL-6), but decreased the levels of anti-inflammatory cytokines (IL-4 and IL-10). It also induced the upregulation of TNF-α, NF-κB-inducible kinase (NIK), IκB kinase alpha (IKK-α) and NF-κB mRNA, while inducing the downregulation of the inhibitor kappa B (IκB) alpha. In addition, we found that the protein content of NIK, IKK-α, p-IKK-α, p-IκB-α and NF-κB was elevated, whereas that of IκB-α was reduced. The results indicated that the NF-κB signaling pathway played an important role in rat liver toxicity induced by nano NiO.
RESUMO
Biogenic silica nanoparticles (25-30 nm in diameter) were synthesized from rice husks. The characterizations revealed that the silica nanoparticles were composed of smaller primary particles (ca. 4.2 nm in diameter), and their clustering led to a porous structure with a surface area of 164 m(2)/g. Under the controlled melting catalyzed by K(+), such silica nanoparticle clusters can gradually fuse to form semicrystalline porous silica frameworks with tunable pore size and structural integrity.
Assuntos
Biomassa , Nanopartículas/química , Oryza/química , Dióxido de Silício/química , Tamanho da Partícula , PorosidadeRESUMO
In the past, electrowetting was usually analyzed on large solid surfaces. In the current study, the effective solid-liquid interfacial tension in a nanoporous silica, which is measured by the ion transport pressure, is investigated experimentally. The interfacial tension decreases as the applied potential difference increases, while the magnitude of variation is much smaller than its bulk counterpart. The effect of the external electric field is saturated at a relatively low voltage. These unique phenomena can be attributed to the confinement effect of nanopore walls.
RESUMO
In both experiment and molecular simulation, it is found that a higher pressure is required to sustain the infiltration of smaller ions in a molecular-sized nanochannel. Simulations indicate that the effective ion solubility of the infiltrated liquid is reduced to nearly zero. Because of the strong interactions between the ion couples and the solid or liquid phases, an external force is required to continuously advance the confined liquid segment. The competition between the probability of ion entry and ion-couple formation causes the observed ion-size-dependent characteristics.
RESUMO
The transport behavior of water molecules inside a model carbon nanotube is investigated by using nonequilibrium molecular dynamcis (NMED) simulations. The shearing stress between the nanotube wall and the water molecules is identified as a key factor in determining the nanofluidic properties. Due to the effect of nanoscale confinement, the effective shearing stress is not only size sensitive but also strongly dependent on the fluid flow rate. Consequently, the nominal viscosity of the confined water decreases rapidly as the tube radius is reduced or when a faster flow rate is maintained. An infiltration experiment on a nanoporous carbon is performed to qualitatively validate these findings.
RESUMO
By analyzing sorption isotherm curves of surface treated MCM-41 samples, it is noticed that if the nanopore size is relatively small, the end group dominates the solid-liquid interaction and the influence of the side group is relatively weak, which can be attributed to the confinement effect of nanopore walls.
Assuntos
Nanoestruturas/química , Dióxido de Silício/química , Água/química , Adsorção , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Porosidade , Propriedades de Superfície , TermodinâmicaRESUMO
By applying an external pressure, an aqueous solution of promoters can be forced into a hydrophobic nanoporous silica gel. The promoter molecule demands a free volume several times larger than itself to enter the nanoenvironment. The free volume size is a function of the promoter concentration. If more than one promoter is used, the system behavior does not follow the principle of superposition. These results have important relevance to intelligent absorption and adsorption, programmable catalysis, and so on.
RESUMO
Affinity index (AT value), adsorption heat, X-ray diffraction (XRD), and 13C and 29Si magic-angle spinning (MAS) NMR, FTIR, and Raman spectroscopies were used to study the interaction of highly siliceous MFI-, FAU-, and FER-type zeolites with adsorbed methylamine (MA). Compared with the data for methanol, the much higher AT values and adsorption heats, and significant changes in XRD patterns, 29Si MAS NMR spectra, and FTIR spectra for the zeolites after adsorption of MA, revealed a strong hydrogen-bonding interaction between the perfect framework of the zeolites and the adsorbed MAs. This interaction results from the fact that the H atom of the amine group attacks the [Si-O] framework to form a Si-OHN bond, which leads to the appearance of Si-N bonds in the zeolites at 323 K. Therefore, the zeolite framework can be modified with MA under mild conditions. The highly siliceous MFI zeolite and the H-ZSM-5 zeolite with SiO2/Al2O3=31:1 were modified with MA and investigated by temperature-programmed desorption of CO2. The modified zeolites exhibited greatly enhanced basic properties in comparison with those of the raw materials. The influence of defects in the zeolite on the adsorption and the interaction with MA is discussed.