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1.
Biomed Res Int ; 2019: 7034983, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31380435

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disease. Abundant evidence demonstrates that oxidative stress may be not only an early event in this disease, but also a key factor in the pathogenesis of AD. Ginkgo biloba extract (EGb) has a strong ability to scavenge oxygen free radicals and supply hydrogen. The present study aims to investigate the effects of EGb on Neuro 2A cells transfected with Swedish mutant APP (APPsw). Stably transfected Neuro 2A cell lines expressing human wild-type APP (APP695), APPsw, or empty vector(neo) pEGFP-N2 were treated with 100 µg/ml EGb for 0, 2, 4, 6, 8, and 10 h. Oxidative stress was assessed by measuring free radicals and the activities of antioxidant enzymes. Our studies showed that EGb treatment reduced the production of reactive oxygen species (ROS) and the levels of malondialdehyde (MDA) significantly while total superoxide dismutase (T-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were enhanced in Neuro 2A cells overexpressing APPsw. Meanwhile, Aß levels in these cells were also reduced compared to the levels in untreated cells and control cells (empty vector(neo) pEGFP-N2). These findings suggest that EGb can reduce oxidative stress by decreasing free radical and enhancing antioxidant status, further leading to reduced Aß aggregation; EGb might be a potential therapeutic agent for Alzheimer's disease (AD).

2.
Neuro Endocrinol Lett ; 39(8): 561-566, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30927761

RESUMO

BACKGROUND: Retina degeneration is a set of disease that can be characterized by progressive loss of rod or cone photoreceptors that can experience higher light exposure compared with other parts of our body. MATERIAL AND METHODS: To investigate in diabetic mice the effects of different light on retinal photoreceptor and its related mechanisms, 4-6 weeks male Balb/c mices were randomly divided into control group, light treatment group (light 1 and light 2), light treatment with filter membrane group (LFM1 and LFM2), light treatment filter blue light group (LFB), diabetic group (DM), diabetic with light treatment group (DM+Light), diabetic light treatment with filter membrane group (DM+LFM1 and DM+LFM2), diabetic light treatment with filter blue light group (DM+LFB). Electroretinography (ERG) was used to assess retinal function. H&E staining was used to observe the morphology and measure the outer nuclear layer thickness in the retina. The related gene expression was detected by Real-time PCR. RESULTS: Light can significantly reduce the retinal function, outer nuclear layer thickness, and Trx expression. After different kinds of membranes and blue light filter treatments, the outer nuclear layer thickness, Nrf2, Trx expression can be improved in diabetic mice. However, the expression of Txnip and ASK1 was decreased. CONCLUSTION: Light can increase the photoreceptor damage in diabetic mice. The reduction of light intensity and change in the visible light components can reduce the light-induced damage in diabetic mice, and the mechanism may be related to up-regulation the antioxidant protein Trx expression.

3.
Comput Intell Neurosci ; 2019: 8256723, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936913

RESUMO

The ionic liquid gel (ILG), a new type of soft actuator material, is a mixture of 1-butyl-3-methylimidazolium tetrafluoroborate (BMIMBF4), hydroxyethyl methacrylate (HEMA), diethoxyacetophenone (DEAP), and ZrO2 polymerized into a gel state under ultraviolet (UV) light irradiation. The soft actuator structure consists of a layer of ionic liquid polymer gel sandwiched between two layers of activated carbon capped with gold foil. The volume of the cationic BMIM+ in the ionic liquid BMIMBF4 is much larger than that of the anionic BF4 -. When voltages are applied to both sides of the actuator, the anions and cations move toward the anode and cathode of the electrode, respectively, under the electric field. The volume of the ILG cathode side therefore expands, and the volume of the ILG anode side shrinks, hence bending the entire actuator toward the anode side. The Ogden model was selected as the hyperelastic constitutive model to study the mechanical properties of the ILG by nonlinear analysis. As the ILG is an ideal material for the preparation of a supercapacitor, the equivalent circuit of the ILG can be modeled by the supercapacitor theory to identify the transfer function of the soft actuator. The central pattern generator (CPG) control is widely used in the area of biology, and CPGs based on bioinspired control methods have attracted great attention from researchers worldwide. After the continuum soft actuator is discretized, the CPG-based bioinspired method can be used to control the soft robot drivers. According to the simulation analysis results, the soft actuator can be smooth enough to reach the specified location.


Assuntos
Simulação por Computador , Líquidos Iônicos , Movimento (Física) , Eletricidade , Eletrodos , Polímeros , Raios Ultravioleta
4.
Mater Sci Eng C Mater Biol Appl ; 98: 685-695, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30813073

RESUMO

Adverse effects are pressing challenges produced by chemotherapy and radiotherapy for the treatment of breast cancer. Nontoxic herbal medicines are therefore considered as a favorable alternative. Astragalus membranaceus has attracted growing interest in the field of biomedicine thanks to its various biological activities, among which the anticancer activity is considered to be closely associated with its active component-astragalus polysaccharide (APS). Currently, direct anti-tumor activity and the activation of immune response of the host have been widely acknowledged as the mechanism by which APS exerts its anti-cancer activity. In this study, we aimed to investigate whether APS could inhibit the growth of MCF-7 cells and activate macrophages to further kill cancer cells. The results indicated that the obtained APS was a pyran-type polysaccharide, containing 89.75% total carbohydrate and a minor amount of uronic acid (9.3%). Although APS did not significantly inhibit the growth of MCF-7 cells growth, encouragingly, APS-activated RAW264.7 macrophages present anti-cancer activity as evidenced by (a) cell proliferation inhibition (with an inhibitory rate of 41%), (b) G1-phase cell cycle arrest, as well as (c) the regulation of apoptosis-related genes (Bax/Bcl-2, 13.26-fold increase than untreated cells). In addition, APS could upregulate the level of nitric oxide (NO) and tumor necrosis factor-α (TNF-α), which acted as inducers of tumor cell apoptosis. Collectively, our findings suggest that APS can activate macrophages to release NO and TNF-α, which directly blocks cancer cell growth. The anti-breast cancer effect of APS and the in vivo mechanism will be further elucidated with a review to provide a therapeutic strategy for breast cancer.


Assuntos
Astrágalo (Planta)/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Humanos , Células MCF-7 , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Óxidos de Nitrogênio/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
5.
Drug Metab Dispos ; 47(5): 547-555, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30858239

RESUMO

Duocarmycins [including cyclopropyl pyrroloindole (CPI) or cyclopropyl benzoindole (CBI)] are a class of DNA minor-groove alkylators and seco-CPI/CBIs are synthetic pro-forms that can spirocyclize to CPI/CBI. Bis-CPI/CBIs are potential drug candidates because of their enhanced cytotoxicity from DNA crosslinking, but it is difficult to analyze them for structure-activity correlation because of their DNA reactivity. To study their DNA alkylation, neutral thermal hydrolysis has been frequently applied to process depurination. However, unwanted side reactions under this condition have been reported, which could lead to poor correlation of DNA alkylation data with efficacy results, especially for bis-CPI/CBIs. In this study, an acidic depurination method was developed and applied for analysis of DNA alkylation and shown to be an easier and milder method than the traditional neutral thermal hydrolysis. DNA alkylation and stability of three bis-seco-CBIs were characterized in comparison with two mono-seco-CPIs. The results suggested that: 1) The acidic depurination method was capable of capturing a more representative population, sometimes a different population, of DNA adducts as they existed on DNA compared with the heat depurination method. 2) Di-adenine adducts were captured as expected for the CBI dimers, although the major type of adduct was still mono-adenine adducts. 3) The rate of DNA alkylation, DNA adduct profile, and relative amounts of di-adduct versus mono-adduct were significantly affected by the size, and possibly lipophilicity, of the nonalkylating part of the molecules. 4) Spirocyclization and amide hydrolysis represented two major pathways of degradation. Overall, by applying acidic depurination analyses, this study has illustrated DNA adduct characteristics of novel bis-seco-CBIs with dominating mono-alkylation and provides an alternative method for evaluating DNA minor-groove alkylators. These findings provide an effective analytical tool to evaluate DNA alkylators and to study the DNA alkylation that is a disposition mechanism of these compounds.

6.
Cell Physiol Biochem ; 50(5): 1673-1686, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30384364

RESUMO

BACKGROUND/AIMS: Diabetic retinopathy (DR) is one of the most serious complications of diabetes and is the leading cause of adult blindness in developed countries. Advanced glycation end products (AGEs) accumulation in diabetes is associated with its complications. Thioredoxin (Trx) is a small molecule (12kDa) antioxidant protein widely distributed in mammalian tissues, which has important biological functions including anti-apoptosis and transcriptional regulation. In a previous study, we found that Trx plays a key role in retinal neurodegeneration prior to the occurrence of endothelial damage in diabetic mice. In this study, our aim is to determine the effect of Trx on neurodegeneration induced by AGEs in order to identify new therapeutic targets for the clinical treatment and prevention of DR. METHODS: In vivo, a high-fat diet and Streptozotocin (STZ) injection were used to generate a mouse model of diabetes. Histology was utilized to examine tissue morphology and measure the outer nuclear layer (ONL) thickness. Electroretinography (ERG) was used to assess retinal function and Western blot was used to examine protein expression. In vitro, three methods of Trx up-regulation were used, including a stable cell line that overexpresses Trx, treatment with Sulforaphane, and shRNA down-regulation Txnip. Cells were treated with AGEs, and level of apoptosis was performed to quantify this by flow cytometry and TUNEL. Quantitative Reverse Transcription PCR (qRT-PCR), Western blotting and immunofluorescence were used to measure gene and protein expression. Transmission electron microscopy (TEM) was used to observe autophagosomes. RESULTS: We found that diabetic mice display decreased retinal function and reduced ONL thickness with AGEs accumulation and a reduction of Trx expression. Up-regulation Trx can prevent the ONL thickness decrease in diabetic mice, as observed by H&E staining. In vitro, up-regulation Trx resulted in decreased intracellular ROS generation, reduced apoptosis by inhibited autophagy. CONCLUSION: Up-regulating Trx inhibited neurodegeneration induced by AGEs. The underlying mechanism may be related to inhibit Txnip/mTOR pathway-mediated autophagy.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Tiorredoxinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Eletrorretinografia , Produtos Finais de Glicação Avançada/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Retina/metabolismo , Células Ganglionares da Retina/fisiologia , Epitélio Pigmentado da Retina/fisiologia , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/genética , Regulação para Cima
7.
Biofabrication ; 11(1): 015004, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30229749

RESUMO

Cancer biology and drug discovery are heavily dependent on conventional 2D cell culture systems. However, a 2D culture is significantly limited by its ability to reflect 'true biology' of tumor in vivo. Three-dimensional (3D) in vitro cell culture models have been introduced to aid cancer drug discovery by better modeling the tumor microenvironment. Here, decellularized lung scaffolds cultured with MCF-7 cancer cells were bioengineered as a platform to study tumor development and anti-cancer drug evaluation. Excellent cell compatibility of decellularized lung scaffolds promoted cell growth and proliferation. Multicellular tumor cell spheroids (tumoriods) were formed and enlarged exclusively in decellularized lung scaffolds over time. The expression of breast cancer biomarkers (BRCA1 and HER2) in MCF-7 cells significantly increased in the lung matrix compared to those cultured in 2D systems. Insufficient oxygen and nutrient diffusion into the internal surface of lung scaffolds resulted in intracellular hypoxia, quantified by a significant upregulation of HIF-1α protein expression compared to that of cell monolayers. Higher survival rates after exposure to 5-FU were observed in lung scaffolds (52.04%) compared to that in 2D systems (18.39%) on day 3 of culture. Overall, this new breast tumor system provides a promising platform to study breast cancer progression and develop new targeted therapeutic strategies.

8.
Gene ; 676: 101-109, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30010038

RESUMO

Exosomes have been demonstrated as an important factor to influence cancer invasion and metastasis. Previous studies have shown that CXC chemokine recepter-4 (CXCR4) and stromal cell-derived factor-1α (SDF-1α) mediates matrix metalloproteinases (MMPs) secretions to facilitate lymph node metastasis of hepatocarcinoma cells. In this study, we demonstrated that exosomes containing elevated CXCR4 from high lymph node metastatic mouse hepatocarcinoma Hca-F cells were able to promote the migration and invasion of a paired syngeneic Hca-P cells that have low metastatic potential. Such impact on enhanced migratory and invasive capacities of Hca-P cells was triggered by the internalization of exosomes isolated from Hca-F cells. This was possibly due to the horizontal transferring of CXCR4 via exosomes. The lymphatic endothelial cells (LECs) increased the migration and invasion of Hca-F cells probably by expressing SDF-1α which bound with CXCR4 in the Hca-F cells and subsequently enhanced the secretions of MMP-9, MMP-2 and vascular endothelial growth factor C (VEGF-C). Exosomal CXCR4 from Hca-F cells promoted LECs proliferative rate and lymphatic tube formation ability. Our findings suggest that horizontal transfer of exosomal CXCR4 can promote murine hepatocarcinoma cell migration, invasion and lymphangiogenesis, and exosomal CXCR4 might be a novel therapeutic target against tumor lymphatic metastasis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Quimiocina CXCL12/metabolismo , Exossomos/metabolismo , Neoplasias Hepáticas/metabolismo , Linfangiogênese , Receptores CXCR4/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Técnicas de Cocultura , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Metástase Linfática , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Invasividade Neoplásica , Fator C de Crescimento do Endotélio Vascular/metabolismo
9.
Appl Bionics Biomech ; 2018: 8327867, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29853999

RESUMO

A new type of soft actuator material-an ionic liquid gel (ILG) that consists of BMIMBF4, HEMA, DEAP, and ZrO2-is polymerized into a gel state under ultraviolet (UV) light irradiation. In this paper, we first propose that the ILG conforms to the assumptions of hyperelastic theory and that the Mooney-Rivlin model can be used to study the properties of the ILG. Under the five-parameter and nine-parameter Mooney-Rivlin models, the formulas for the calculation of the uniaxial tensile stress, plane uniform tensile stress, and 3D directional stress are deduced. The five-parameter and nine-parameter Mooney-Rivlin models of the ILG with a ZrO2 content of 3 wt% were obtained by uniaxial tensile testing, and the parameters are denoted as c10, c01, c20, c11, and c02 and c10, c01, c20, c11, c02, c30, c21, c12, and c03, respectively. Through the analysis and comparison of the uniaxial tensile stress between the calculated and experimental data, the error between the stress data calculated from the five-parameter Mooney-Rivlin model and the experimental data is less than 0.51%, and the error between the stress data calculated from the nine-parameter Mooney-Rivlin model and the experimental data is no more than 8.87%. Hence, our work presents a feasible and credible formula for the calculation of the stress of the ILG. This work opens a new path to assess the performance of a soft actuator composed of an ILG and will contribute to the optimized design of soft robots.

10.
Artif Cells Nanomed Biotechnol ; : 1-13, 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29914275

RESUMO

Primary liver cancer (PLC) is one of the most common malignant tumours and has the third highest mortality rate worldwide. An active liver-targeting drug delivery system via the asialoglycoprotein receptors expressed in the hepatic parenchyma cells of mammals has become a research focus for the treatment of PLC. N-acetylaminogalactosyl-poly(lactide-co-glycolide)-succinyl-D-α-tocopherol polyethylene glycol 1000 succinate (GalNAc-PLGA-sTPGS) was synthesized to achieve active liver-targeting properties. Emodin (EMO)-loaded GalNAc-PLGA-sTPGS nanoparticles (EGPTN) were prepared with EMO which was selected for its potential antitumour efficacy. The in vitro cellular uptake, mechanism, cytotoxicity, and apoptosis of HepG2 cells were analyzed. The in vivo therapeutic effects of EGPTN were assessed in a PLC mouse model. The results showed that GalNAc-PLGA-sTPGS was successfully synthesized. The cellular uptake assay demonstrated that coumarin 6-loaded GalNAc-PLGA-sTPGS nanoparticles had superior active liver-targeting properties. The results of the cytotoxity and apoptosis studies indicated that EGPTN achieved the highest levels of cytotoxicity and cell apoptotic rate among the nanoparticles examined. Furthermore, EGPTN showed better in vivo therapeutic effects and anticancer efficacy in the PLC mice than did the other groups. Therefore, EGPTN enhanced the anticancer effect of EMO both in vitro and in vivo, making it a potential option for the treatment of PLC.

11.
Biomed Pharmacother ; 103: 829-837, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29684862

RESUMO

We assessed the neuroprotective effects of Lycium barbarum Polysaccharides (LBP) on photoreceptor degeneration and the mechanisms involved in oxidative stress in light-exposed mouse retinas. Mice were given a gavage of LBP (150 mg/kg or 300 mg/kg) or phosphate buffered saline (PBS) for 7 days before exposure to light (5000 lx for 24 h). We found that LBP significantly improved the electroretinography (ERG) amplitudes of the a- and b-waves that had been attenuated by light exposure. In addition, changes caused by light exposure including photoreceptor cell loss, nuclear condensation, an increased number of mitochondria vacuoles, outer membrane disc swelling and cristae fractures were distinctly ameliorated by LBP. LBP treatment also significantly prevented the generation of reactive oxygen species (ROS) compared with PBS treatment. The levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and thioredoxin reductase (TrxR1) mRNA were decreased in PBS-treated mice compared with controls but increased remarkably in LBP-treated mice. The mRNA levels of the DNA repair gene Poly (ADP-ribose) polymerase (PARP14) was increased in PBS-treated mice but decreased significantly in the LBP-treated mice. Our findings indicate that pretreatment with LBP effectively protected photoreceptor cells against light-induced retinal damage probably through the up-regulation of the antioxidative genes Nrf2 and TrxR1, the elimination of oxygen free radicals, and the subsequent reduction in the mitochondrial reaction to oxidative stress and enhancement in antioxidant capacity. In addition, the decreased level of PARP14 mRNA in LBP-treated mice also indicated a protective effect of LBP on delaying photoreceptor in the light-damaged retina.


Assuntos
Antioxidantes/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Estimulação Luminosa/efeitos adversos , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Degeneração Retiniana/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Eletrorretinografia/efeitos dos fármacos , Eletrorretinografia/métodos , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/ultraestrutura , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/ultraestrutura , Degeneração Retiniana/etiologia , Degeneração Retiniana/metabolismo
12.
Bioconjug Chem ; 29(2): 267-274, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29369629

RESUMO

The valine-citrulline (Val-Cit) dipeptide and p-aminobenzyl (PAB) spacer have been commonly used as a cleavable self-immolating linker in ADC design including in the clinically approved ADC, brentuximab vedotin (Adcetris). When the same linker was used to connect to the phenol of the cyclopropabenzindolone (CBI) (P1), the resulting ADC1 showed loss of potency in CD22 target-expressing cancer cell lines (e.g., BJAB, WSU-DLCL2). In comparison, the conjugate (ADC2) of a cyclopropapyrroloindolone (CPI) (P2) was potent despite the two corresponding free drugs having similar picomolar cell-killing activity. Although the corresponding spirocyclization products of P1 and P2, responsible for DNA alkylation, are a prominent component in buffer, the linker immolation was slow when the PAB was connected as an ether (PABE) to the phenol in P1 compared to that in P2. Additional immolation studies with two other PABE-linked substituted phenol compounds showed that electron-withdrawing groups accelerated the immolation to release an acidic phenol-containing payload (to delocalize the negative charge on the anticipated anionic phenol oxygen during immolation). In contrast, efficient immolation of LD4 did not result in an active ADC4 because the payload (P4) had a low potency to kill cells. In addition, nonimmolation of LD5 did not affect the cell-killing potency of its ADC5 since immolation is not required for DNA alkylation by the center-linked pyrrolobenzodiazepine. Therefore, careful evaluation needs to be conducted when the Val-Cit-PAB linker is used to connect antibodies to a phenol-containing drug as the linker immolation, as well as payload potency and stability, affects the cell-killing activity of an ADC.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Imunoconjugados/química , Imunoconjugados/farmacologia , Fenol/química , Fenol/farmacologia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Ciclopropanos/química , Ciclopropanos/farmacologia , Humanos , Neoplasias/tratamento farmacológico
13.
Oncotarget ; 8(37): 61350-61364, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-28977868

RESUMO

Diabetes is a chronic metabolic syndrome that results in changes in carbohydrate, lipid and protein metabolism. With diabetes for a long time, it increases the risk of diabetic retinopathy (DR) and long-term morbidity and mortality. Moreover, emerging evidence suggests that neuron damage occurs earlier than microvascular complications in DR patients, but the underlying mechanism is unclear. We investigated diabetes-induced retinal neuropathy and elucidated key molecular events to identify new therapeutic targets for the clinical treatment and prevention of DR. For in vivo studies, a high-fat diet and streptozotocin (STZ) injection were used to generate the diabetes model. Hematoxylin-eosin staining was used for morphological observations and measurements of the outer nuclear layer thickness. Electroretinography (ERG) was used to assess retinal function. For in vitro studies, Neuro2a cells were incubated in normal (5.5 mM) and high-glucose (30 mM) conditions. Flow cytometry assays were performed to analyze apoptosis. Additionally, real-time PCR and Western blotting analyses were carried out to determine gene and protein expression in vitro and in vivo. Taken together, the results indicated that retinal neuropathy occurred prior to endothelial damage induced by diabetes, and thioredoxin (Trx) plays a key role in this process. This underlying mechanism may be related to activation of the Trx/ASK1/p-p38/Trx-interacting protein pathway.

14.
Drug Deliv ; 24(1): 1302-1316, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28895767

RESUMO

Liver cancer is one of the major diseases affecting human health. Modified drug delivery systems through the asialoglycoprotein receptor, which is highly expressed on the surface of hepatocytes, have become a research focus for the treatment of liver cancer. Resibufogenin (RBG) is a popular traditional Chinese medicine and natural anti-cancer drug that was isolated from Chansu, but its cardiotoxicity and hydrophobicity have limited its clinical applications. Galactosyl-succinyl-poloxamer 188 and galactosyl-succinyl-poloxamer 188-polylactide-co-glycolide (Gal-SP188-PLGA) were synthesized using galactose, P188, and PLGA to achieve active liver-targeting properties. RBG-loaded Gal-SP188-PLGA nanoparticles (RGPPNs) and coumarin-6-loaded Gal-SP188-PLGA nanoparticles (CGPPNs) were prepared. The in vitro cellular uptake, cytotoxicity, and apoptosis of nanoparticles in HepG2 cells were analyzed. The in vivo therapeutic effects of nanoparticles were assessed in a hepatocarcinogenic mouse model. The results showed that Gal-SP188-PLGA was successfully synthesized. The cellular uptake assay demonstrated that CGPPNs had superior active liver-targeting properties. The ratio of apoptotic cells was increased in the RGPPN group. In comparison to the other groups, RGPPNs showed superior in vivo therapeutic effects and anticancer efficacy. Thus, the active liver-targeting RGPPNs, which can enhance the pharmacological effects and decrease the toxicity of RBG, are expected to become a promising and effective treatment for liver cancer.


Assuntos
Nanopartículas , Animais , Bufanolídeos , Galactose , Humanos , Ácido Láctico , Neoplasias Hepáticas , Camundongos , Poloxâmero , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
15.
Mol Med Rep ; 16(5): 7731-7737, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28944891

RESUMO

Diabetic retinopathy has long been recognized as a microvascular disease, however, recent research has indicated that diabetic retinopathy may also be considered a neurodegenerative disease. The elucidation of the molecular mechanisms underlying the development of diabetic retinopathy is imperative for the development of preventive and treatment strategies for patients with diabetes. In the present study, grape seed proanthocyanidin extract (GSPE) was used to upregulate the expression of thioredoxin (Trx), in order to evaluate its potential as a novel agent for the prevention and treatment of neurodegenerative diseases, including diabetic retinopathy. Hematoxylin and eosin staining was performed to observe the morphology of retinal neurons, whereas flow cytometry and terminal deoxynucleotidyl transferase 2'­deoxyuridine, 5'­triphosphate nick­end labeling were employed to investigate cellular apoptosis. Reverse transcription­quantitative polymerase chain reaction and western blot analysis were performed to assess the mRNA and protein expression of target proteins in order to investigate the underlying molecular mechanisms. In vivo, it was found that the photoreceptor cell was damaged in diabetic mice but following GSPE treatment, the process could be inhibited. In vitro, the results of the current study demonstrated that, under hyperglycemic culture conditions, the expression of 78 kDa glucose­regulated protein, which is an endoplasmic reticulum stress marker, was upregulated. In addition, the expression of Trx was downregulated and cell apoptosis was enhanced. Notably, treatment with GSPE was revealed to inhibit the neurodegenerative process induced by hyperglycemia. However, treatment with the Trx inhibitor PX12 in combination with GSPE was demonstrated to potentiate apoptosis compared with GSPE treatment alone under hyperglycemic conditions. Furthermore, the protein expression of apoptosis signal­regulating kinase (ASK) 1 and Trx­interacting protein (Txnip) was also upregulated by hyperglycemia, whereas GSPE was revealed to counteract this upregulation. In conclusion, the results of the present study indicate that Trx may be implicated in the mechanisms underlying the protective effects of GSPE against hyperglycemia­induced cell degeneration and apoptosis. The molecular mechanisms may also involve inhibition of the activation of the Trx/ASK1/Txnip signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Extrato de Sementes de Uva/farmacologia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Proantocianidinas/farmacologia , Animais , Apoptose/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/induzido quimicamente , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Dissulfetos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Extrato de Sementes de Uva/isolamento & purificação , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hipoglicemiantes/isolamento & purificação , Imidazóis/farmacologia , MAP Quinase Quinase Quinase 5/genética , MAP Quinase Quinase Quinase 5/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Proantocianidinas/isolamento & purificação , Transdução de Sinais , Estreptozocina/administração & dosagem , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
16.
Biochem Biophys Res Commun ; 491(2): 374-381, 2017 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-28728844

RESUMO

While some long noncoding RNAs (lncRNAs) might promote nasopharyngeal carcinoma (NPC) initiation and progression, the involved molecular mechanisms remain largely unclear. Here, we discovered the novel LncRNA, prostate cancer associated transcript 7 (PCAT7), which was overexpressed and associated with worse prognosis in NPC. Decreased PCAT7 expression was found to significantly suppress tumor cell proliferation in vitro, and inhibited tumor growth and reduced the expression of proliferation antigen Ki-67 in vivo. Rescue assay was performed to further confirm that PCAT7 contributed to the progression of NPC through regulating miR-134-5p/ELF2 signal pathway. These results indicated that PCAT7 might contribute to the tumor progression in NPC by functioning as a ceRNA to sponge miR-134-5p.


Assuntos
Carcinoma/diagnóstico , Carcinoma/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Sequência de Bases , Sítios de Ligação , Carcinogênese , Carcinoma/mortalidade , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Genes Reporter , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Luciferases/genética , Luciferases/metabolismo , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Prognóstico , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Análise de Sobrevida , Fatores de Transcrição/metabolismo
17.
Neural Regen Res ; 12(3): 433-439, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28469658

RESUMO

Cytoskeletal proteins are involved in neuronal survival. Brain-derived neurotrophic factor can increase expression of cytoskeletal proteins during regeneration after axonal injury. However, the effect of neural stem cells genetically modified by brain-derived neurotrophic factor transplantation on neuronal survival in the injury site still remains unclear. To examine this, we established a rat model of traumatic brain injury by controlled cortical impact. At 72 hours after injury, 2 × 107 cells/mL neural stem cells overexpressing brain-derived neurotrophic factor or naive neural stem cells (3 mL) were injected into the injured cortex. At 1-3 weeks after transplantation, expression of neurofilament 200, microtubule-associated protein 2, actin, calmodulin, and beta-catenin were remarkably increased in the injury sites. These findings confirm that brain-derived neurotrophic factor-transfected neural stem cells contribute to neuronal survival, growth, and differentiation in the injury sites. The underlying mechanisms may be associated with increased expression of cytoskeletal proteins and the Wnt/ß-catenin signaling pathway.

18.
Life Sci ; 165: 63-74, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27640889

RESUMO

AIM: Heparin sodium (HS)-loaded polylactic-co-glycolic acid-D-α-tocopheryl polyethylene glycol 1000 succinate (PLGA-TPGS) nanoparticles (HPTNs) were prepared as sustained and targeted delivery carriers and combined with oleanolic acid (OA)-loaded PLGA-TPGS nanoparticles (OPTNs) that had been investigated in our previous work to form a combination therapy system for the treatment of liver cancer. MAIN METHODS: To inspect cellular uptake and evaluate liver-targeting performance by analysing drug concentrations and cryosections, fluorescent probe coumarin-6 and eosin was used in preparations of HS/eosin-loaded, HS/coumarin-6-loaded, and OA/coumarin-6-loaded PLGA-TPGS nanoparticles. All of these NPs were characterized in terms of size, size distribution, surface charge, drug loading, encapsulation efficiency, and in vitro release profile. The apoptosis of HepG2 cells induced by OPTNs combined with HPTNs was determined by Annexin V-FITC staining and PI labelling. KEY FINDINGS: Transmission electron microscopy indicated that all of the nanoparticles were stably dispersed spheres with diameters ranging from 100 to 200nm. The results demonstrated that fluorescent nanoparticles were efficiently internalized into HepG2 and HCa-F cells, and that they exhibited enhanced liver targeting. The combination of HPTNs and OPTNs resulted in effective cell inhibition in vitro and a remarkable synergistic anticancer effect in vivo. The cell apoptosis results indicated that OPTNs combined with HPTNs could induce HepG2 cell apoptosis and exert synergistic effects. In vivo pharmacodynamics analysis using a solid tumour-bearing mouse model indicated that OPTNs combined with HPTNs could suppress tumour growth by 67.61%. SIGNIFICANCE: This research suggests that the combined therapy system of OPTNs and HPTNs could be a new means of hepatoma therapy.


Assuntos
Antineoplásicos/uso terapêutico , Heparina/administração & dosagem , Ácido Láctico/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas , Ácido Oleanólico/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Vitamina E/administração & dosagem , Animais , Células Hep G2 , Humanos , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
19.
Neurochem Int ; 100: 52-61, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27567738

RESUMO

Oxidative stress due to excessive light exposure can exacerbate a variety of human retinal diseases by accelerating photoreceptor cell death. The thioredoxin (Trx) system is considered to play a crucial role in reduction/oxidation (redox) regulation of signal transduction and in cell defense against oxidative stresses. Sulforaphane (SF) protects cells from oxidative damage through nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which is responsible for multiple detoxification processes, including elevating the expression of Trx. This study sought to demonstrate whether SF increased Trx expression in retinal tissues in vivo and whether it could preserve the photoreceptors from degeneration induced by oxidative stress. Our data clearly showed that pretreatment with SF abated photoreceptor cell loss, in association with increased expression of Nrf2 and Trx, subsequently activating the Ras/Raf1/Erk signaling pathway and decreasing the expression of Bak1, Cyt-c release and the activity of caspase-3 in light-induced mouse retinas. These data suggested that the therapeutic potential of SF in retinal degeneration due to oxidative stress might partially involve anti-caspase and antioxidant protection mediated by Trx.


Assuntos
Apoptose/efeitos dos fármacos , Isotiocianatos/farmacologia , Animais , Antioxidantes/farmacologia , Luz , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Degeneração Retiniana/induzido quimicamente , Degeneração Retiniana/tratamento farmacológico , Tiorredoxinas/metabolismo
20.
Pharm Res ; 33(11): 2828-43, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27511028

RESUMO

PURPOSE: Heparin sodium (HS)-loaded polylactic-co-glycolic acid-D-α-tocopheryl polyethylene glycol 1000 succinate (PLGA-TPGS) nanoparticles (HPTNs) were prepared as a sustained and targeting delivery carrier and combined with emodin (EMO)-loaded PLGA-TPGS nanoparticles (EPTNs), which were investigated previously to form a combination therapy system for the treatment of liver cancer. METHODS: To assess cellular uptake and evaluate the liver-targeting capacity by analyzing the drug concentrations and frozen slices, HS/eosin-loaded PLGA-TPGS nanoparticles, HS/fluorescein- loaded PLGA-TPGS nanoparticles and EMO/C6-loaded PLGA-TPGS nanoparticles, which contained eosin, fluorescein and C6 as fluorescent probes, respectively, were also prepared. All of these nanoparticles were characterized in terms of their size, size distribution, surface charge, drug loading, encapsulation efficiency, in vitro release profile and cellular uptake. The apoptosis of HepG2 cells induced by EPTNs in combination with HPTNs was determined by Annexin V-FITC staining and PI labelling. RESULTS: Transmission electron microscopy indicated that these nanoparticles were stably dispersed spheres with sizes ranging from 100 to 200 nm. The results demonstrated that fluorescent nanoparticles were internalized into HepG2 and HCa-F cells efficiently and had improved liver-targeting properties. The combination of EPTNs and HPTNs effectively inhibited cell growth in vitro and had a remarkable synergistic anticancer effect in vivo. EPTNs combined with HPTNs induced HepG2 cell apoptosis with synergistic effects. The liver H&E slice images of a hepatocarcinogenic mouse model indicated that EPTNs in combination with HPTNs significantly suppressed tumour growth in vivo. CONCLUSIONS: The research suggests that the combination therapy system of EPTNs and HPTNs could be a new direction for liver cancer therapy.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Antineoplásicos/farmacologia , Emodina/farmacologia , Heparina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/química , Vitamina E/química , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos , Liberação Controlada de Fármacos , Emodina/administração & dosagem , Emodina/química , Corantes Fluorescentes/química , Heparina/administração & dosagem , Heparina/química , Humanos , Masculino , Camundongos , Tamanho da Partícula , Propriedades de Superfície
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