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1.
Oxid Med Cell Longev ; 2022: 1733834, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35035656

RESUMO

Calycosin (CAL) is the main active component present in Astragalus and reportedly possesses diverse pharmacological properties. However, the cardioprotective effect and underlying mechanism of CAL against doxorubicin- (DOX-) induced cardiotoxicity need to be comprehensively examined. Herein, we aimed to investigate whether the cardioprotective effects of CAL are related to its antipyroptotic effect. A cardiatoxicity model was established by stimulating H9c2 cells and C57BL/6J mice using DOX. In vitro, CAL increased H9c2 cell viability and decreased DOX-induced pyroptosis via NLRP3, caspase-1, and gasdermin D signaling pathways in a dose-dependent manner. In vivo, CAL-DOX cotreatment effectively suppressed DOX-induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis via the same molecular mechanism. Next, we used nigericin (Nig) and NLRP3 forced overexpression to determine whether CAL imparts antipyroptotic effects by inhibiting the NLRP3 inflammasome in vitro. Furthermore, CAL suppressed DOX-induced mitochondrial oxidative stress injury in H9c2 cells by decreasing the generation of reactive oxygen species and increasing mitochondrial membrane potential and adenosine triphosphate. Likewise, CAL attenuated the DOX-induced increase in malondialdehyde content and decreased superoxide dismutase and glutathione peroxidase activities in H9c2 cells. In vivo, CAL afforded a protective effect against DOX-induced cardiac injury by improving myocardial function, inhibiting brain natriuretic peptide, and improving the changes of the histological morphology of DOX-treated mice. Collectively, our findings confirmed that CAL alleviates DOX-induced cardiotoxicity and pyroptosis by inhibiting NLRP3 inflammasome activation in vivo and in vitro.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Inflamassomos/efeitos dos fármacos , Isoflavonas/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Isoflavonas/farmacologia , Masculino , Camundongos , Piroptose
2.
Biomed Pharmacother ; 143: 112133, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34474337

RESUMO

MCC950, an NLRP3 inflammasome inhibitor, displays multiple pharmacological properties. However, the protective potential and underlying mechanism of MCC950 against doxorubicin (DOX)-induced myocardial injury has not been well investigated yet. Herein, DOX-induced myocardial injury in mice and in H9c2 myocardial cells was investigated, and the protective effects and underlying mechanism of MCC950 were fully explored. The results showed that MCC950 co-treatment significantly improved myocardial function, inhibited inflammatory and myocardial fibrosis, and attenuated cardiomyocyte pyroptosis in DOX-treated mice. Mechanismly, MCC950 had the potential to inhibit DOX-induced the cleavage of NLRP3, ASC, Caspase-1, IL-18, IL-1ß and GSDMD in vivo. Moreover, MCC950 co-treatment in vivo suppressed DOX-induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis through the same molecular mechanism. Taken together, our findings validated that MCC950, an NLRP3 inflammasome inhibitor, has the potential to attenuate doxorubicin-induced myocardial injury in vivo and in vitro by inhibiting NLRP3-mediated pyroptosis.


Assuntos
Anti-Inflamatórios/farmacologia , Furanos/farmacologia , Cardiopatias/prevenção & controle , Indenos/farmacologia , Inflamassomos/antagonistas & inibidores , Miócitos Cardíacos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Piroptose/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Cardiotoxicidade , Linhagem Celular , Modelos Animais de Doenças , Doxorrubicina , Fibrose , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
3.
Biomed Res Int ; 2021: 6612592, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33977107

RESUMO

Glioblastoma is a highly invasive primary malignant tumor of the central nervous system. Cannabinoid analogue WIN 55,212-2 (WIN) exhibited a novel anticancer effect against human tumors. However, the anticancer potential and underlying mechanism of WIN against human glioma remain unclear. Herein, the anticancer efficiency and mechanism of WIN in U251 human glioma cells were investigated. The results showed that WIN dose-dependently inhibited U251 cell proliferation, migration, and invasion in vitro. WIN treatment also effectively suppressed U251 tumor spheroids growth ex vivo. Further studies found that WIN induced significant apoptosis as convinced by the caspase-3 activation and release of cytochrome C. Mechanism investigation revealed that WIN triggered ROS-mediated DNA damage and caused dysfunction of VEGF-AKT/FAK signal axis. However, ROS inhibition effectively attenuated WIN-induced DNA damage and dysfunction of VEGF-AKT/FAK signal axis and eventually improved U251 cell proliferation, migration, and invasion. Taken together, our findings validated that WIN had the potential to inhibit U251 cell proliferation, migration, and invasion and induce apoptosis by triggering ROS-dependent DNA damage and dysfunction of VEGF-AKT/FAK signal axis.


Assuntos
Benzoxazinas/farmacologia , Glioma/metabolismo , Morfolinas/farmacologia , Naftalenos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos
4.
J Nanobiotechnology ; 19(1): 98, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827604

RESUMO

BACKGROUND: Nano-Fenton reactors as novel strategy to selectively convert hydrogen peroxide (H2O2) into active hydroxyl radicals in tumor microenvironment for cancer therapy had attracted much attention. However, side effects and low efficiency remain the main drawbacks for cancer precise therapy. RESULTS: Here, ruthenium-loaded palmitoyl ascorbate (PA)-modified mesoporous silica (Ru@SiO2-PA) was successfully fabricated and characterized. The results indicated that Ru@SiO2-PA under pH6.0 environment displayed enhanced growth inhibition against human cancer cells than that of pH7.4, which indicated the super selectivity between cancer cells and normal cells. Ru@SiO2-PA also induced enhanced cancer cells apoptosis, followed by caspase-3 activation and cytochrome-c release. Mechanism investigation revealed that Ru@SiO2-PA caused enhanced generation of superoxide anion, which subsequently triggered DNA damage and dysfunction of MAPKs and PI3K/AKT pathways. Moreover, Ru@SiO2-PA effectively inhibited tumor spheroids and tumor xenografts growth in vivo by induction of apoptosis. The real-time imaging by monitoring Ru fluorescence in vitro and in vivo revealed that Ru@SiO2-PA mainly accumulated in cell nucleus and tumor xenografts. Importantly, Ru@SiO2-PA showed no side effects in vivo, predicting the safety and potential application in clinic. CONCLUSIONS: Our findings validated the rational design that Ru@SiO2-PA can act as novel tumor microenvironment-response nano-Fenton reactors for cancer precise therapy.


Assuntos
Rutênio/química , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio , Camundongos , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Fosfatidilinositol 3-Quinases , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Neurochem Res ; 46(5): 1112-1118, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33555527

RESUMO

Immune response plays a vital role in the pathogenesis of neuropathic pain. Immune response-targeted therapy becomes an effective strategy for treating neuropathic pain. Licochalcone A (Lic-A) possesses anti-inflammatory and neuroprotective effects. However, the potential of Lic-A to attenuate neuropathic pain has not been well explored. To investigate the protective effect and evaluate the underlying mechanism of Lic-A against neuropathic pain in a rat model. Chronic constriction injury (CCI) surgery was employed in rats to establish neuropathic pain model. Rats were intraperitoneally administrated with Lic-A (1.25, 2.50 and 5.00 mg/kg) twice daily. Mechanical withdrawal threshold and thermal withdrawal latency were used to evaluate neuropathic pain. After administration, the lumbar spinal cord enlargement of rats was collected for ELISA, Western blot and immunofluorescence analysis. Mechanical withdrawal threshold and thermal withdrawal latency results showed that Lic-A significantly attenuated CCI-evoked neuropathic pain in dose-dependent manner. Lic-A administration also effectively blocked microglia activation. Moreover, Lic-A suppressed p38 phosphorylation and the release of inflammatory factors such as tumor necrosis factor-α, interleukin-1 and interleukin-6. Our findings provide evidence that Lic-A may have the potential to attenuate CCI-evoked neuropathic pain in rats by inhibiting microglia activation and inflammatory response.


Assuntos
Chalconas/uso terapêutico , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Doença Crônica/tratamento farmacológico , Constrição Patológica , Inflamação/complicações , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Neuralgia/complicações , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Front Bioeng Biotechnol ; 9: 781608, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35004643

RESUMO

Chemotherapy is still one of the most common ways to treat human glioblastoma in clinic. However, severe side effects limited its clinic application. Design of cancer-targeted drugs with high efficiency and low side effect is urgently needed. Herein, silver nanoparticles (Ag NPs) and nano-selenium (Se NPs) conjugated with RGD peptides (Ag@Se@RGD NPs) to target integrin high-expressed glioma were designed. The results found that Ag@Se@RGD NPs displayed stable particle size and morphology in physiological condition, and induced significant integrin-targeted intracellular uptake. Ag@Se@RGD NPs in vitro dose-dependently inhibited U251 human glioma cells growth by induction of cells apoptosis through triggering the loss of mitochondrial membrane potential, overproduction of reactive oxygen species (ROS), and MAPKs activation. However, ROS inhibition dramatically attenuated Ag@Se@RGD NPs-induced MAPKs activation, indicating the significant role of ROS as an early apoptotic event. Importantly, Ag@Se@RGD NPs administration in vivov effectively inhibited U251 tumor xenografts growth by induction of apoptosis through regulation MAPKs activation. Taken together, our findings validated the rational design that Ag-Se NPs conjugated with RGD peptides was a promising strategy to combat human glioma by induction of apoptosis through triggering mitochondrial dysfunction and ROS-dependent MAPKs activation.

8.
Biomater Sci ; 8(24): 7154-7165, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33155581

RESUMO

Co-delivery of H2O2-generating agent and catalyst via a nano-Fenton reactor to the tumor acidic microenvironment for amplified tumor oxidation therapy has been widely studied. However, high side effects and low efficiency remain the limitations of the design and development of this process. Herein, a new nano-Fenton reactor in which mesoporous silica is integrated with Fe3O4 and palmitoyl ascorbate (Fe3O4@SiO2-PA) was designed, with the product exhibiting good dispersion, stability, uniformity and consistent spectral characteristics. The results show that Fe3O4@mSiO2-PA successfully enters cancer cells, significantly inhibits HeLa cells and 3D tumor spheroid growth in vitro via the induction of apoptosis. Meanwhile, Fe3O4@mSiO2-PA administration in vivo markedly suppresses HeLa tumor xenografts growth via the induction of apoptosis, followed by caspase-3 activation and cytochrome C release. Further investigation revealed that Fe3O4@mSiO2-PA causes enhanced production of reactive oxygen species (ROS), which subsequently triggers DNA damage and causes dysfunction of the MAPK and PI3K/AKT pathways. Importantly, Fe3O4@mSiO2-PA shows few side effects and good biocompatibility in vivo. Taken together, these results suggest that Fe3O4@mSiO2-PA inhibits HeLa cell growth in vitro and in vivo by triggering enhanced oxidative damage and regulating multiple signal pathways. Our findings validate the rational design that mesoporous silica integrated with Fe3O4 and palmitoyl ascorbate can act as a new nano-Fenton reactor for amplified tumor oxidation therapy.


Assuntos
Peróxido de Hidrogênio , Dióxido de Silício , Animais , Ácido Ascórbico/análogos & derivados , Compostos Férricos , Óxido Ferroso-Férrico , Células HeLa , Humanos , Nanopartículas , Fosfatidilinositol 3-Quinases , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Biosens Bioelectron ; 168: 112415, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32937233

RESUMO

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the co-Editors in Chief and with the agreement of the authors, after a reader observed that Figure 3b had been partially duplicated with Figure 3a published in a previous publication by the same authors (Anal. Chem. (2017) 89:1163-1169) https://doi.org/10.1021/acs.analchem.6b03536.

10.
Biomed Pharmacother ; 130: 110544, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32721630

RESUMO

Osteosarcoma is a highly invasive primary malignant bone tumor. PI3K/mTOR pathway plays a key role in tumor progression, and inhibition of PI3K/mTOR pathway represents a novel strategy in therapy of osteosarcoma. CCT128930 and VS5584 are both inhibitors of PI3K/mTOR, but the anticancer mechanism of CCT128930 or/and VS5584 against human osteosarcoma cells remains unclear. Herein, U2OS and MG63 human osteosarcoma cells were cultured, and the anticancer effects of CCT128930 alone and the combined effect of CCT128930 and VS5584 against human osteosarcoma cells were explored. The results showed that CCT128930 as PI3K/mTOR inhibitor effectively inhibited p-p70 and p-AKT expression and dose-dependently inhibited U2OS cells and MG63 human osteosarcoma cells growth. Further studies found that CCT128930 triggered significant G-1 phase arrest and apoptosis, as convinced by the dysfunction of p27, Cyclin B1, Cyclin D1 and Cdc2, and PARP cleavage and caspase-3 activation. Moreover, CCT128930 treatment obviously enhanced VS5584-induced growth inhibition and apoptosis in human osteosarcoma cells, followed by enhanced PARP cleavage and caspase-3 activation. Taken together, CCT128930 alone or combined treatment with CCT128930 and VS5584 both effectively inhibited human osteosarcoma cells growth by induction of G1-phase arrest and apoptosis through regulating PI3K/mTOR and MAPKs pathways.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Morfolinas/farmacologia , Osteossarcoma/tratamento farmacológico , Purinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Caspase 3/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores
11.
Curr Cancer Drug Targets ; 20(8): 616-623, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32286946

RESUMO

BACKGROUND: Activation of the PI3K/mTOR signaling pathway plays a key role in the progression of human osteosarcoma. Studies have confirmed that VS-5584 was a novel inhibitor of the PI3K/mTOR pathway, and displayed potential anticancer activity. OBJECTIVE: To explore the anticancer effect and underlying mechanism of VS-5584 against the growth of human osteosarcoma cells. METHODS: U2OS and MG-63 human osteosarcoma cells were cultured and the cytotoxicity, cell apoptosis in VS-5584-treated cells were explored by the CCK8 assay, flow cytometric analysis and western blot. Cell migration and tube formation were also employed to examine the anticancer potential. RESULTS: The results showed that VS-5584 treatment dose-dependently inhibited the growth of U2OS and MG-63 cells by induction of G1-phase arrest through regulating p21, p27, Cyclin B1 and Cdc2. Further investigation revealed that VS-5584 treatment effectively inhibited the PI3K/mTOR signaling pathway and triggered MAPK phosphorylation. Moreover, VS-5584 treatment dramatically suppressed cell migration and tube formation of HUVECs, followed by the down-regulation of HIF-1α and VEGF. CONCLUSION: Our findings validated that VS-5584 may be a promising anticancer agent with potential application in the chemotherapy and chemoprevention of human osteosarcoma.


Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Morfolinas/farmacologia , Osteossarcoma/tratamento farmacológico , Fosfatidilinositol 3-Quinase/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Purinas/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Proliferação de Células , Humanos , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Células Tumorais Cultivadas
12.
Biomed Pharmacother ; 122: 109677, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31810012

RESUMO

Acetylshikonin, a natural naphthoquinone derivative compound from Lithospermum erythrorhyzon, has been reported to kill bacteria, suppress inflammation, and inhibit tumor growth. However, the effect of acetylshikonin on human chronic myelocytic leukemia (CML) cells apoptosis and its detailed mechanisms remains unknown. The purpose of the present study was to investigate whether acetylshikonin could inhibit proliferation or induce apoptosis of the K562 cells, and whether by regulating the NF-κB signaling pathway to suppress the development of CML. K562 cells were treated with serial diluted acetylshikonin at different concentrations. Our data showed that K562 cell growth was significantly inhibited by acetylshikonin with an IC50 of 2.03 µM at 24 h and 1.13 µM at 48 h, with increased cell cycle arrest in S-phase. The results of annexin V-FITC/PI and AO/EB staining showed that acetylshikonin induced cell apoptosis in a dose-dependent manner. K562 cells treated with acetylshikonin underwent massive apoptosis accompanied by a rapid generation of reactive oxygen species (ROS). Scavenging the ROS completely blocked the induction of apoptosis following acetylshikonin treatment. The levels of the pro-apoptotic proteins Bax, cleaved caspase-9, cleaved PARP and cleaved caspase-3 increased with increased concentrations of acetylshikonin, while the level of the anti-apoptotic protein Bcl-2 was downregulated. The levels of Cyt C and AIF, which are characteristic proteins of the mitochondria-regulated intrinsic apoptotic pathway, also increased in the cytosol after acetylshikonin treatment. However, the mitochondrial fraction of Cyt C and AIF were decreased under acetylshikonin treatment. In addition, acetylshikonin decreased Bcr-Abl expression and inhibited its downstream signaling. Acetylshikonin could lead to a blockage of the NF-κB signaling pathway via decreasing nuclear NF-κB P65 and increasing cytoplasmic NF-κB P65. Moreover, acetylshikonin significantly inhibited the phosphorylation of IkBα and IKKα/ß in K562 cells. These results demonstrated that acetylshikonin significantly inhibited K562 cell growth and induced cell apoptosis through the mitochondria-regulated intrinsic apoptotic pathway. The mechanisms may involve the modulating ROS accumulation, inhibition of NF-κB and BCR-ABL expression. The inhibition of BCR-ABL expression and the inactivation of the NF-κB signaling pathway caused by acetylshikonin treatment resulted in K562 cell apoptosis. Together, our results indicate that acetylshikonin could serve as a potential therapeutic agent for the future treatment of CML.


Assuntos
Antraquinonas/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Fusão bcr-abl/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Vero
13.
Theranostics ; 9(19): 5610-5625, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534506

RESUMO

Photothermal therapy as novel strategy to convert near-infrared (NIR) light into heat for treatment cancers has attracted great attention and been widely studied. However, side effects and low efficiency remain the main challenge of precise cancer photothermal therapy. Methods: In this study, we have successfully fabricated and characterized the dual-targeted gold nanoprisms, whereby bare gold nanoprisms (Au NPR) were conjugated to a phenanthroline derivatives-functionalized tetraphenylethene (TPE) and further stabilized with target peptide aptamers via Au-S bonds (Au-Apt-TPE). Then, the remaining nitrogen atoms of the Au-Apt-TPE could effectively chelate with Zn2+ ions (Au-Apt-TPE@Zn) for monitoring early stage apoptotic cells. Results: The as-synthesized Au-Apt-TPE@Zn exhibited good monodispersity, size stability and consistent spectral characteristics. TPE synthesized here showed aggregation-induced emission (AIE) characteristics, and zinc conjunction (TPE@Zn) endowed Au-Apt-TPE@Zn with the cell membrane-targeted ability to selectively recognize the membranes of early stage apoptotic cells but not respond to healthy cells, which provided valuable diagnosis information on therapeutic efficacy. Au-Apt-TPE@Zn achieved specifically nuclear-targeted ability by surface decoration of AS1411 DNA aptamer. Au-Apt-TPE@Zn under NIR irradiation showed effective photothermal therapy against SGC-7901 human gastric carcinoma cells growth in vitro by inducing apoptosis through triggering reactive oxygen species (ROS) overproduction and regulating multiple signal crosstalk. In vivo studies revealed that Au-Apt-TPE@Zn under NIR irradiation showed deep penetration and dual-model imaging application (cancer-targeted fluorescence imaging and light-up photoacoustic imaging). Au-Apt-TPE@Zn under NIR irradiation also displayed strong photothermal therapy against gastric carcinoma xenograft growth in vivo by induction of apoptosis. Importantly, analysis of histopathology, hematotoxicity and immunocytotoxicity indicated that Au-Apt-TPE@Zn had less side effect and high biocompatibility. Conclusions: Our findings validated the design of using Au nanoprism with AIE materials and dual-targeted decoration could be an effective strategy in recognition of early apoptosis, dual-model imaging and precise cancer photothermal therapy.


Assuntos
Apoptose/efeitos dos fármacos , Ouro/química , Fototerapia , Neoplasias Gástricas/terapia , Animais , Sistemas de Liberação de Medicamentos , Ouro/administração & dosagem , Humanos , Masculino , Nanopartículas Metálicas , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/fisiopatologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Biosens Bioelectron ; 141: 111432, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31299628

RESUMO

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the co-Editors in Chief and with the agreement of the authors, after a reader observed that Figure 3b had been partially duplicated with Figure 3a published in a previous publication by the same authors (Anal. Chem. (2017) 89:1163-1169) https://doi.org/10.1021/acs.analchem.6b03536


Assuntos
Técnicas Biossensoriais/instrumentação , Interleucina-6/sangue , Análise Espectral Raman/instrumentação , Desenho de Equipamento , Ouro/química , Humanos , Limite de Detecção , Nanopartículas Metálicas/química , Testes Imediatos , Fitas Reagentes/análise
15.
Mol Med Rep ; 19(6): 4753-4760, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059085

RESUMO

Increased plasma levels of homocysteine (Hcy) can cause severe damage to vascular endothelial cells. Hcy­induced endothelial cell dysfunction contributes to the occurrence and development of human cerebrovascular diseases (CVDs). Our previous studies have revealed that astaxanthin (ATX) exhibits novel cardioprotective activity against Hcy­induced cardiotoxicity in vitro and in vivo. However, the protective effect and mechanism of ATX against Hcy­induced endothelial cell dysfunction requires further investigation. In the present study, treatment of human umbilical vascular endothelial cells (HUVECs) with Hcy inhibited the migration, invasive and tube formation potentials of these cells in a dose­dependent manner. Hcy treatment further induced a time­dependent increase in the production of reactive oxygen species (ROS), and downregulated the expression of vascular endothelial growth factor (VEGF), phosphorylated (p)­Tyr­VEGF receptor 2 (VEGFR2) and p­Tyr397­focal adhesion kinase (FAK). On the contrary, ATX pre­treatment significantly inhibited Hcy­induced cytotoxicity and increased HUVEC migration, invasion and tube formation following Hcy treatment. The mechanism of action may involve the effective inhibition of Hcy­induced ROS generation and the recovery of FAK phosphorylation. Collectively, our findings suggested that ATX could inhibit Hcy­induced endothelial dysfunction by suppressing Hcy­induced activation of the VEGF­VEGFR2­FAK signaling axis, which indicates the novel therapeutic potential of ATX in treating Hcy­mediated CVD.


Assuntos
Células Endoteliais/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Homocisteína/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/patologia , Relação Dose-Resposta a Droga , Regulação para Baixo , Células Endoteliais/patologia , Quinase 1 de Adesão Focal/metabolismo , Humanos , Fosforilação , Xantofilas/antagonistas & inibidores
17.
J Agric Food Chem ; 67(8): 2212-2219, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30688446

RESUMO

Fucoxanthin, a natural carotenoid derived from algae, exhibits novel anticancer potential. However, fucoxanthin with high purity is hard to prepare, and the anticancer mechanism remains elusive. In the present study, fucoxanthin with high purity was prepared and purified from the marine microalgae Nitzschia sp. by silica-gel column chromatography (SGCC), and the underlying mechanism against human glioma cells was evaluated. The results showed that fucoxanthin time- and dose-dependently inhibited U251-human-glioma-cell growth by induction of apoptosis (64.4 ± 4.8, P < 0.01) accompanied by PARP cleavage and caspase activation (244 ± 14.2, P < 0.01). Mechanically, fucoxanthin time-dependently triggered reactive-oxygen-species (ROS)-mediated DNA damage (100 ± 7.38, P < 0.01), as evidenced by the phosphorylation activation of Ser1981-ATM, Ser428-ATR, Ser15-p53, and Ser139-histone. Moreover, fucoxanthin treatment also time-dependently caused dysfunction of MAPKs and PI3K-AKT pathways, as demonstrated by the phosphorylation activation of Thr183-JNK, Thr180-p38, and Thr202-ERK and the phosphorylation inactivation of Ser473-AKT. The addition of kinase inhibitors further confirmed the importance of MAPKs and PI3K-AKT pathways in fucoxanthin-induced cell-growth inhibition (32.5 ± 3.6, P < 0.01). However, ROS inhibition by the antioxidant glutathione (GSH) effectively inhibited fucoxanthin-induced DNA damage, attenuated the dysfunction of MAPKs and PI3K-AKT pathways, and eventually blocked fucoxanthin-induced cytotoxicity (54.3 ± 5.6, P < 0.05) and cell apoptosis (32.7 ± 2.5, P < 0.05), indicating that ROS production, an early apoptotic event, is involved in the fucoxanthin-mediated anticancer mechanism. Taken together, these results suggested that fucoxanthin induced U251-human-glioma-cell apoptosis by triggering ROS-mediated oxidative damage and dysfunction of MAPKs and PI3K-AKT pathways, which validated that fucoxanthin may be a candidate for potential applications in cancer chemotherapy and chemoprevention.


Assuntos
Apoptose/efeitos dos fármacos , Glioma/fisiopatologia , Microalgas/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Xantofilas/farmacologia , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Xantofilas/química , Xantofilas/isolamento & purificação
18.
Cell Death Discov ; 4: 50, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30374413

RESUMO

Elevated plasma level of homocysteine (Hcy) represents an independent risk for neurological diseases, and induction of oxidative damage is considered as one of the most important pathomechanisms. Astaxanthin (ATX) exhibits strong antioxidant activity in kinds of experimental models. However, the potential of ATX against Hcy-induced neurotoxicity has not been well explored yet. Herein, the neuroprotective effect of ATX against Hcy-induced neurotoxicity in rat hippocampal neurons was examined, and the underlying mechanism was evaluated. The results showed that ATX pre-treatment completely reversed Hcy-induced neurotoxicity through inhibiting cell apoptosis in rat primary hippocampal neurons. The mechanical investigation revealed that ATX effectively blocked Hcy-induced mitochondrial dysfunction by regulating Bcl-2 family and opening of mitochondrial permeability transition pore (MPTP). ATX pre-treatment also attenuated Hcy-induced oxidative damage via inhibiting the release of intracellular reactive oxide species (ROS) and superoxide anion through regulating MPTP opening. Moreover, normalization of MAPKs and PI3K/AKT pathways also contributed to ATX-mediated protective effects. Taken together, these results above suggested that ATX has the potential to reverse Hcy-induced neurotoxicity and apoptosis by inhibiting mitochondrial dysfunction, ROS-mediated oxidative damage and regulation of MAKPs and AKT pathways, which validated the strategy of using ATX could be a highly effective way in combating Hcy-mediated neurological disorders.

19.
Onco Targets Ther ; 11: 5429-5439, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233204

RESUMO

Background: Temozolomide (TMZ)-based chemotherapy represents an effective way for treating human glioma. However, its clinical application is limited because of its side effects and resistance to standard chemotherapy. Hence, the search for novel chemosensitizers to augment their anticancer efficiency has attracted much attention. Natural borneol (NB) has been identified as a potential chemosensitizer in treating human cancers. However, the synergistic effect and mechanism of NB and TMZ in human glioma have not been investigated yet. Materials and methods: U251 human glioma cells were cultured, and the cytotoxicity and apoptosis of NB and/or TMZ were examined by MTT assay, flow cytometric analysis and Western blot. Nude mice tumor model was also employed to evaluate the in vivo anticancer effect and mechanism. Results: The results showed that the combined treatment of NB and TMZ more effectively inhibited human glioma growth via triggering mitochondria-mediated apoptosis in vitro, accompanied by the caspase activation. Combined treatment of NB and TMZ also caused mitochondrial dysfunction through disturbing Bcl-2 family expression. Further investigation revealed that NB enhanced TMZ-induced DNA damage through inducing reactive oxide species (ROS) overproduction. Moreover, glioma tumor xenograft growth in vivo was more effectively inhibited by the combined treatment with NB and TMZ through triggering apoptosis and anti-angiogenesis. Conclusion: Taken together, our findings validated that the strategy of using NB and TMZ could be a highly efficient way to achieve anticancer synergism.

20.
Neurochem Res ; 43(7): 1317-1327, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29804240

RESUMO

Radioactive 125I seeds-based radiotherapy has achieved great success in treatment of human cancers. However, radioresistance and severe side effects badly limited its clinic application. Recently, chemoradiotherapy as a superior strategy has been rapidly developed and widely used in clinic. However, the underlying mechanism remains elusive. Herein, in the present study, a combined chemoradiation model of 125I seeds and salinomycin (SAL) in vitro and in vivo was designed, and the enhanced anticancer efficiency and mechanism were also evaluated in human glioma. The results showed that combined treatment of 125I seeds and SAL induced enhanced growth inhibition against human glioma cells through induction of cell apoptosis. Further investigation revealed that combined treatment of 125I seeds and SAL triggered enhanced DNA damage through inducing reactive oxide species (ROS) generation. Additionally, enhanced dysfunction of MAPKs and AKT pathways both contributed to combined treatment-induced growth inhibition against human glioma cells. Importantly, the U251 human glioma xenograft growth was effectively inhibited by combined treatment of 125I seeds and SAL by induction of cell apoptosis with involvement of inhibiting cell proliferation and angiogenesis. Taken together, our results indicated that combined treatment of 125I seeds and SAL achieved enhanced growth inhibition and apoptosis in human glioma in vitro and in vivo through triggering ROS-mediated DNA damage and regulation of MAPKs and AKT pathways, which validated that the combined strategy of using 125I seeds and SAL could be a highly efficient way to achieve enhanced glioma chemo-radiotherapy.


Assuntos
Apoptose/fisiologia , Quimiorradioterapia/métodos , Glioma/metabolismo , Radioisótopos do Iodo/administração & dosagem , Piranos/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Animais , Antibacterianos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Doses de Radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos da radiação
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