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1.
J Photochem Photobiol B ; 222: 112258, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34399205

RESUMO

Photodynamic therapy (PDT) is an approved therapeutic approach and an alternative to conventional chemotherapy for the treatment of several types of cancer with the advantages of reducing the side effects and developing resistance mechanisms. Here, was evaluated the photosensitization capabilities of 5,10,15,20-tetrakis[4-(pyridinium-1-yl-methyl)phenyl]porphyrin (3), its N-confused isomer (4) and of the neutral precursors (1) and (2) and the results were compared with the ones obtained with the cationic 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP). Both regular porphyrin derivatives 1 and 3 showed higher efficiency to generate singlet oxygen than TMPyP. The PDT assays towards MCF-7 cells under red light irradiation (λ > 640 nm, 23.7 mW cm-2) demonstrated that the cationic porphyrin 3 is an efficient photosensitizer to kill MCF-7 breast cancer cells. The study of the cell death mechanisms induced by the photodynamic process showed that the studied porphyrin 3 and TMPyP caused cell death by autophagic flux and necrosis.


Assuntos
Apoptose/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Apoptose/efeitos da radiação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Feminino , Humanos , Luz , Células MCF-7 , Microscopia Confocal , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Porfirinas/uso terapêutico , Oxigênio Singlete/metabolismo
2.
Theranostics ; 11(14): 6860-6872, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093858

RESUMO

Background: Immunotherapy has profoundly changed the landscape of cancer management and represented the most significant breakthrough. Yet, it is a formidable challenge that the majority of cancers - the so-called "cold" tumors - poorly respond to immunotherapy. To find a general immunoregulatory modality that can be applied to a broad spectrum of cancers is an urgent need. Methods: Magnetic hyperthermia (MHT) possesses promise in cancer therapy. We develop a safe and effective therapeutic strategy by using magnetism-mediated targeting MHT-immunotherapy in "cold" colon cancer. A magnetic liposomal system modified with cell-penetrating TAT peptide was developed for targeted delivery of a CSF1R inhibitor (BLZ945), which can block the CSF1-CSF1R pathway and reduce M2 macrophages. The targeted delivery strategy is characterized by its magnetic navigation and TAT-promoting intratumoral penetration. Results: The liposomes (termed TAT-BLZmlips) can induce ICD and cause excessive CRT exposure on the cell surface, which transmits an "eat-me" signal to DCs to elicit immunity. The combination of MHT and BLZ945 can repolarize M2 macrophages in the tumor microenvironment to relieve immunosuppression, normalize the tumor blood vessels, and promote T-lymphocyte infiltration. The antitumor effector CD8+ T cells were increased after treatment. Conclusion: This work demonstrated that TAT-BLZmlips with magnetic navigation and MHT can remodel tumor microenvironment and activate immune responses and memory, thus inhibiting tumor growth and recurrence.


Assuntos
Neoplasias do Colo/terapia , Terapia Combinada/métodos , Hipertermia , Imunoterapia/métodos , Lipossomos/química , Terapia de Campo Magnético/métodos , Nanopartículas de Magnetita/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Benzotiazóis/farmacocinética , Benzotiazóis/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/imunologia , Feminino , Humanos , Lipossomos/metabolismo , Lipossomos/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/terapia , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/farmacologia , Ratos , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074015

RESUMO

TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.


Assuntos
Adenocarcinoma/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Antineoplásicos/farmacologia , Apoptose/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Esofágicas/metabolismo , MicroRNAs/metabolismo , Estresse Oxidativo/genética , Proteína Supressora de Tumor p53/metabolismo , Adenocarcinoma/genética , Sistema y+ de Transporte de Aminoácidos/genética , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Neoplasias Esofágicas/genética , Estrogênios/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Técnicas de Inativação de Genes , Ontologia Genética , Glutationa/metabolismo , Humanos , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética
4.
J Med Chem ; 64(11): 7724-7734, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34018753

RESUMO

New thiophene-dipicolinato-based compounds, K2nTdpa (n = 1, 2), were isolated. Their anions are sensitizers of lanthanide ion (LnIII) luminescence and singlet oxygen generation (1O2). Emission in the visible and near-infrared regions was observed for the LnIII complexes with efficiencies (ϕLn) ϕEu = 33% and ϕYb = 0.31% for 1Tdpa2- and ϕYb = 0.07% for 2Tdpa2-. The latter does not sensitize EuIII emission. Fluorescence imaging of HeLa live cells incubated with K3[Eu(1Tdpa)3] indicates that the complex permeates the cell membrane and localizes in the mitochondria. All complexes generate 1O2 in solution with efficiencies (ϕO12) as high as 13 and 23% for the GdIII complexes of 1Tdpa2- and 2Tdpa2-, respectively. [Ln(nTdpa)3]3- (n = 1, 2) are phototoxic to HeLa cells when irradiated with UV light with IC50 values as low as 4.2 µM for [Gd(2Tdpa)3]3- and 91.8 µM for [Eu(1Tdpa)3]3-. Flow cytometric analyses indicate both apoptotic and necrotic cell death pathways.


Assuntos
Complexos de Coordenação/química , Elementos da Série dos Lantanídeos/química , Ácidos Picolínicos/química , Tiofenos/química , Raios Ultravioleta , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Európio/química , Gadolínio/química , Células HeLa , Humanos , Microscopia de Fluorescência , Mitocôndrias/metabolismo , Teoria Quântica , Oxigênio Singlete/metabolismo
5.
J Photochem Photobiol B ; 220: 112216, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34023595

RESUMO

Ultraviolet B (UVB) radiation induces mutagenic DNA photolesions in skin cells especially in form of cyclobutane pyrimidine dimers (CPDs). Protection mechanisms as DNA repair and apoptosis are of great importance in order to prevent skin carcinogenesis. In human skin, neural crest-derived precursors of melanocytes, the dermal stem cells (DSCs), are discussed to be at the origin of melanoma. Although they are constantly exposed to solar UV radiation, it is still not investigated how DSCs cope with UV-induced DNA damage. Here, we report a comparative study of the DNA damage response after irradiation with a physiological relevant UVB dose in DSCs in comparison to fibroblasts, melanocytes and keratinocytes isolated from human foreskin. Within our experimental settings, DSCs were able to repair DNA photolesions as efficient as the other skin cell types with solely keratinocytes repairing significantly faster. Interestingly, only fibroblasts showed significant alterations in cell cycle distribution in terms of a transient S phase arrest following irradiation. Moreover, with the applied UVB dose none of the examined cell types was prone to UVB-induced apoptosis. This may cause persistent genomic alterations and in case of DSCs it may have severe consequences for their daughter cells, the differentiated melanocytes. Altogether, this is the first study demonstrating a similar UV response in dermal stem cells compared to differentiated skin cells.


Assuntos
Prepúcio do Pênis/citologia , Queratinócitos/efeitos da radiação , Melanócitos/efeitos da radiação , Pele/efeitos da radiação , Células-Tronco/efeitos da radiação , Raios Ultravioleta , Apoptose/efeitos da radiação , Dano ao DNA , Reparo do DNA , Fibroblastos/efeitos da radiação , Humanos , Masculino , Pele/citologia
6.
Acta Biochim Biophys Sin (Shanghai) ; 53(6): 726-738, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33913495

RESUMO

The cellular response to DNA damage is crucial for maintaining the integrity and stability of molecular structure. To maintain genome stability, DNA-damaged cells should be arrested so that mutations can be repaired before replication. Although several key components required for this arrest have been discovered, the majority of the pathways are still unclear. Through a number of assays, including cell viability, colony formation, and apotheosis assay, we found that AKR1B10 protected cells from UVC-induced DNA damage. Surprisingly, UVC-induced γH2AX foci and DNA double-strand breaks in the AKR1B10-overexpressing cells were ∼4-5 folds lower than those in the control group. The expression levels of AKR1B10, p53, chk1, chk2, nuclear factor (NF)-κB, and p65 showed dynamic changes in response to UVC irradiation. Our results suggested that AKR1B10 is involved in the pathway of cell cycle checkpoint and NF-κB in DNA damage. Taken together, our results suggest that AKR1B10 is involved in the repair of the DNA double-strand break, which provides a new insight into the role of AKR1B10 in DNA damage repair and indicates a new trail in tumorigenesis and cancer drug resistance.


Assuntos
Aldo-Ceto Redutases/metabolismo , Neoplasias da Mama/metabolismo , Dano ao DNA/efeitos da radiação , Transdução de Sinais/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Aldo-Ceto Redutases/genética , Apoptose/efeitos da radiação , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Quinase 1 do Ponto de Checagem/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/genética , Feminino , Vetores Genéticos/genética , Histonas/metabolismo , Humanos , Células MCF-7 , NF-kappa B/metabolismo , Transfecção , Proteína Supressora de Tumor p53/metabolismo
7.
Mol Immunol ; 135: 21-27, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857815

RESUMO

Ultraviolet A (UVA) irradiation caused skin keratinocytes to accumulate reactive oxygen species (ROS) leading to the skin injury. Thymoquinone (TQ) was identified as the prominent bioactive ingredient in Nigella sativa seeds which was applied in therapying various human diseases. This study aimed to illustrate the role and mechanism of TQ in UVA-induced skin injury. We pre-treated HaCaT cells with TQ and irradiated them by UVA. MTT and Elisa assays were used to evaluate cell viability and apoptosis, as well as cytokine levels. To detect the related parameters of oxidative stress and mitochondrial function, colorimetry, spectrophotometry, bioluminescence, and dual-luciferase reporter methods were used. RT-qPCR and western blotting were performed for expressions of related mRNAs and proteins. TQ significantly improved the UVA-induced cytotoxicity on HaCaT cells. TQ treatment alleviated the oxidative stress and inflammation in UVA-irradiated keratinocytes. Besides, UVA irradiation promoted mitochondrial dysregulation in HaCaT cells leading to cell apoptosis, which could be reversed by TQ treatment. More importantly, NrF2/ARE pathway was activated in TQ-treated cells, while COX-2 was depressed, and inhibiting the pathway or activating COX-2 blocked the therapeutic effect of TQ on UVA-induced skin cell injury. Our study suggested that TQ treatment attenuated the UVA-induced oxidative and inflammatory responses, as well as mitochondrial apoptosis in keratinocytes by COX-2 inhibition via activating NrF2/ARE pathway. This might be a novel sight for preventing the solar radiation damage to the skin.


Assuntos
Benzoquinonas/farmacologia , Queratinócitos/efeitos da radiação , Mitocôndrias/efeitos da radiação , Nigella sativa/metabolismo , Substâncias Protetoras/farmacologia , Raios Ultravioleta/efeitos adversos , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Citocinas/metabolismo , Células HaCaT , Humanos , Inflamação/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos da radiação , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sementes/metabolismo , Pele/lesões
8.
J Photochem Photobiol B ; 218: 112183, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33831753

RESUMO

Photodynamic therapy is an attractive technique for various skin tumors and non-cancerous skin lesions. However, while the aim of photodynamic therapy is to target and damage only the malignant cells, it unavoidably affects some of the healthy cells surrounding the tumor as well. However, data on the effects of PDT to normal cells are scarce, and the characterization of the pathways activated after the photodamage of normal cells may help to improve clinical photodynamic therapy. In our study, primary human epidermal keratinocytes were used to evaluate photodynamic treatment effects of photosensitizers with different subcellular localization. We compared the response of keratinocytes to lysosomal photodamage induced by phthalocyanines, aluminum phthalocyanine disulfonate (AlPcS2a) or aluminum phthalocyanine tetrasulfonate (AlPcS4), and cellular membrane photodamage by m-tetra(3-hydroxyphenyl)-chlorin (mTHPC). Our data showed that mTHPC-PDT promoted autophagic flux, whereas lysosomal photodamage induced by aluminum phthalocyanines evoked differentiation and apoptosis. Photodamage by AlPcS2a, which is targeted to lysosomal membranes, induced keratinocyte differentiation and apoptosis more efficiently than AlPcS4, which is targeted to lysosomal lumen. Computational analysis of the interplay between these molecular pathways revealed that keratin 10 is the coordinating molecular hub of primary keratinocyte differentiation, apoptosis and autophagy.


Assuntos
Indóis/química , Lisossomos/metabolismo , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/química , Apoptose/efeitos da radiação , Autofagia/efeitos da radiação , Diferenciação Celular/efeitos da radiação , Simulação por Computador , Humanos , Queratinócitos/citologia , Cinética , Mesoporfirinas/química , Modelos Biológicos , Fotoquimioterapia
9.
Biochem Biophys Res Commun ; 555: 175-181, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33819748

RESUMO

Microgravity and radiation exposure-induced bone damage is one of the most significant alterations in astronauts after long-term spaceflight. However, the underlying mechanism is still largely unknown. Recent ground-based simulation studies have suggested that this impairment is likely mediated by increased production of reactive oxygen species (ROS) during spaceflight. The small Maf protein MafG is a basic-region leucine zipper-type transcription factor, and it globally contributes to regulation of antioxidant and metabolic networks. Our research investigated the role of MafG in the process of apoptosis induced by simulated microgravity and radiation in MC3T3-E1 cells. We found that simulated microgravity or radiation alone decreased MafG expression and elevated apoptosis in MC3T3-E1 cells, and combined simulated microgravity and radiation treatment aggravated apoptosis. Meanwhile, under normal conditions, increased ROS levels facilitated apoptosis and downregulated the expression of MafG in MC3T3-E1 cells. Overexpression of MafG decreased apoptosis induced by simulated microgravity and radiation. These findings provide new insight into the mechanism of bone damage induced by microgravity and radiation during space flight.


Assuntos
Apoptose/efeitos da radiação , Fator de Transcrição MafG/metabolismo , Osteoblastos/citologia , Osteoblastos/efeitos da radiação , Proteínas Repressoras/metabolismo , Apoptose/fisiologia , Linhagem Celular , Regulação para Baixo , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Fator de Transcrição MafG/genética , Osteoblastos/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/genética , Simulação de Ausência de Peso , Raios X
10.
ACS Appl Mater Interfaces ; 13(15): 17392-17403, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33829761

RESUMO

The integration of reactive oxygen species (ROS)-involved molecular dynamic therapy (MDT) and photodynamic therapy (PDT) holds great promise for enhanced anticancer effects. Herein, we report a biodegradable tumor microenvironment-responsive nanoplatform composed of sinoporphyrin sodium (SPS) photosensitizer-loaded zinc peroxide nanoparticles (SPS@ZnO2 NPs), which can enhance the action of ROS through the production of hydrogen peroxide (H2O2) and singlet oxygen (1O2) for MDT and PDT, respectively, and the depletion of glutathione (GSH). Under these conditions, SPS@ZnO2 NPs show excellent MDT/PDT synergistic therapeutic effects. We demonstrate that the SPS@ZnO2 NPs quickly degrade to H2O2 and endogenous Zn2+ in an acidic tumor environment and produce toxic 1O2 with 630 nm laser irradiation both in vitro and in vivo. Anticancer mechanistic studies show that excessive production of ROS damages lysosomes and mitochondria and induces cellular apoptosis. We show that SPS@ZnO2 NPs increase the uptake and penetration depth of photosensitizers in cells. In addition, the fluorescence of SPS is a powerful diagnostic tool for the treatment of tumors. The depletion of intracellular GSH through H2O2 production and the release of cathepsin B enhance the effectiveness of PDT. This theranostic nanoplatform provides a new avenue for tumor microenvironment-responsive and ROS-involved therapeutic strategies with synergistic enhancement of antitumor activity.


Assuntos
Simulação de Dinâmica Molecular , Fotoquimioterapia/métodos , Nanomedicina Teranóstica/métodos , Microambiente Tumoral/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio/metabolismo , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Oxigênio Singlete/metabolismo
11.
Toxicol Appl Pharmacol ; 421: 115545, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33894213

RESUMO

The present study elucidated mechanisms through which sulforaphane (SFN) protects retinal pigment epithelial (RPE) cells from blue light-induced impairment. SFN could activate the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increase the expression of the heme oxygenease-1 (HO-1) gene and production of glutathione. SFN reduced blue light-induced oxidative stress, and effectively activated cytoprotective components including Nrf-2, HO-1, thioredoxin-1, and glutathione. The protective effect of SFN on blue light-induced injury was blocked by the Nrf2 inhibitor ML385, suggesting that the SFN-induced Nrf2 pathway is involved in the cytoprotective effect of SFN. SFN inhibited intercellular adhesion molecule-1 expression induced by TNF-α or blue light, suggesting the anti-inflammatory activity of SFN. The inhibitory effect of SFN was associated with the blocking of NF-κB p65 nuclear translocation in blue light-exposed RPE cells. SFN protected RPE cells from blue light-induced interruption of the mitochondrial membrane potential and reduction of the Bcl-2/Bax ratio and cleaved caspase-3 and PARP-1 expression, suggesting the antiapoptotic activity of SFN. SFN alone or together with blue light exposure increased the expression of the autophagy-related proteins LC3BII and p62. An autophagy inhibitor, 3-MA, inhibited the protective effect of SFN on blue light-induced cell damage. SFN increased sirtuin-1 (SIRT1) expression; however, treatment with blue light induced peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) expression. Our study results demonstrated that SFN exerts its protective effect under blue light exposure by maintaining the Nrf2-related redox state and upregulating SIRT1 and PGC-1α expression and autophagy.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Sirtuína 1/metabolismo , Sulfóxidos/farmacologia , Apoptose/efeitos da radiação , Autofagia/efeitos da radiação , Técnicas de Cocultura , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Células Epiteliais/efeitos da radiação , Glutationa/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Luz , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/enzimologia , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/efeitos da radiação , Transdução de Sinais , Células THP-1 , Fator de Transcrição RelA/metabolismo
12.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916053

RESUMO

In this day and age, the expectation of cosmetic products to effectively slow down skin photoaging is constantly increasing. However, the detrimental effects of UVB on the skin are not easy to tackle as UVB dysregulates a wide range of molecular changes on the cellular level. In our research, irradiated keratinocyte cells not only experienced a compromise in their redox system, but processes from RNA translation to protein synthesis and folding were also affected. Aside from this, proteins involved in various other processes like DNA repair and maintenance, glycolysis, cell growth, proliferation, and migration were affected while the cells approached imminent cell death. Additionally, the collagen degradation pathway was also activated by UVB irradiation through the upregulation of inflammatory and collagen degrading markers. Nevertheless, with the treatment of Swietenia macrophylla (S. macrophylla) seed extract and fractions, the dysregulation of many genes and proteins by UVB was reversed. The reversal effects were particularly promising with the S. macrophylla hexane fraction (SMHF) and S. macrophylla ethyl acetate fraction (SMEAF). SMHF was able to oppose the detrimental effects of UVB in several different processes such as the redox system, DNA repair and maintenance, RNA transcription to translation, protein maintenance and synthesis, cell growth, migration and proliferation, and cell glycolysis, while SMEAF successfully suppressed markers related to skin inflammation, collagen degradation, and cell apoptosis. Thus, in summary, our research not only provided a deeper insight into the molecular changes within irradiated keratinocytes, but also serves as a model platform for future cosmetic research to build upon. Subsequently, both SMHF and SMEAF also displayed potential photoprotective properties that warrant further fractionation and in vivo clinical trials to investigate and obtain potential novel bioactive compounds against photoaging.


Assuntos
Meliaceae/química , Extratos Vegetais/farmacologia , Sementes/química , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Cromatografia Líquida , Cosméticos , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/efeitos da radiação , Perfilação da Expressão Gênica/métodos , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Espectrometria de Massas , Oxirredução/efeitos dos fármacos , Extratos Vegetais/química , Proteômica/métodos
13.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804163

RESUMO

Autophagy can play a double role in cancerogenesis: it can either inhibit further development of the disease or protect cells, causing stimulation of tumour growth. This phenomenon is called "autophagy paradox", and is characterised by the features that the autophagy process provides the necessary substrates for biosynthesis to meet the cell's energy needs, and that the over-programmed activity of this process can lead to cell death through apoptosis. The fight against cancer is a difficult process due to high levels of resistance to chemotherapy and radiotherapy. More and more research is indicating that autophagy may play a very important role in the development of resistance by protecting cancer cells, which is why autophagy in cancer therapy can act as a "double-edged sword". This paper attempts to analyse the influence of autophagy and cancer stem cells on tumour development, and to compare new therapeutic strategies based on the modulation of these processes.


Assuntos
Autofagia/genética , Carcinogênese/genética , Neoplasias/tratamento farmacológico , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/efeitos da radiação , Autofagia/efeitos dos fármacos , Autofagia/efeitos da radiação , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias/genética , Neoplasias/patologia , Neoplasias/radioterapia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
14.
J Photochem Photobiol B ; 217: 112171, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33711563

RESUMO

Dual phototherapy agents have attracted great interest in recent years as they offer enhanced cytotoxicity on cancer cells due to the synergistic effect of photodynamic and photothermal therapies (PDT/PTT). In this study, we demonstrate a brominated hemicyanine (HC-1), which is previously shown as mitochondria targeting PDT agent, can also serve as an effective photosensitizer for PTT for the first time under a single (640 nm or 808 nm) and dual laser (640 nm + 808 nm) irradiation. Generation of reactive oxygen species and photothermal conversion as a function of irradiation wavelength and power were studied. Both single wavelength irradiations caused significant phototoxicity in colon and cervical cancer cells after 5 min of irradiation. However, co-irradiation provided near-complete elimination of cancer cells due to synergistic action. This work introduces an easily accessible small molecule-based synergistic phototherapy agent, which holds a great promise towards the realization of local, rapid and highly efficient treatment modalities against cancer.


Assuntos
Apoptose/efeitos dos fármacos , Carbocianinas/farmacologia , Lasers , Fármacos Fotossensibilizantes/farmacologia , Apoptose/efeitos da radiação , Carbocianinas/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Citometria de Fluxo , Humanos , Neoplasias/patologia , Neoplasias/terapia , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Oxigênio Singlete/química , Oxigênio Singlete/metabolismo
15.
Radiat Res ; 195(5): 452-462, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33755170

RESUMO

The goals of this study were to determine whether curcumin can radiosensitize human urethral scar fibroblasts (HUSFs) and inhibit the synthesis of collagen, and to explore the molecular mechanism. Here, HUSFs were established and cultured in vitro and cell counting kit-8 (CCK-8) experiment and plate clone formation assay were performed to determine the appropriate concentration of curcumin and radiation dose. The radiosensitization of curcumin was confirmed by plate clone formation assay. Cell cycle distribution was determined by flow cytometry and apoptosis rate by TdT-mediated dUTP nick-end labeling (TUNEL). Western blot was used to detect the levels of collagen I, collagen III, Smad2, Smad3, Smad4, transforming growth factor-ß (TGF-ß1), Beclin1 and microtubule-associated protein light chain 3 (LC3), as a means of determining the mechanism. Our findings showed that curcumin enhanced radiosensitivity of HUSFs in vitro (sensitization enhancement ratio = 2.030). Furthermore, curcumin and radiation treatments promoted the apoptosis of HUSFs and blocked the cells in G2/M phase. In addition, curcumin combined with radiation inhibited the synthesis of collagen I and collagen III through Smad4 pathway, with possible involvement of autophagy. These results suggest that curcumin could be a radiosensitizer of HUSFs, inhibit the proliferation of HUSFs and suppress fibrosis by downregulation of Smad4 via autophagy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Cicatriz/patologia , Curcumina/farmacologia , Fibroblastos/efeitos dos fármacos , Proteína Smad4/metabolismo , Apoptose/efeitos da radiação , Autofagia/efeitos da radiação , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/efeitos da radiação , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/efeitos da radiação , Humanos , Radiossensibilizantes/farmacologia , Uretra/patologia
16.
Biochem Biophys Res Commun ; 552: 183-190, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33751936

RESUMO

Malignant melanoma is a critical and aggressive skin tumor with a steeply rising incidence and a less favorable prognosis due to the lack of efficient treatment. Photodynamic therapy (PDT) is a new promising treatment for this tumor through photosensitizers-mediated oxidative cytotoxicity. In this study, we explored the role of berberine-mediated PDT (BBR-PDT) in the anti-proliferative effect on human malignant melanoma cells (MMCs). We found that there were significant differences between MMCs with BBR-PDT and MMCs with BBR or PDT only. Further research showed that BBR-PDT induced apoptosis via up-regulating the expression of cleaved caspase-3 protein. We also observed that LC3-related autophagy level was upregulated in MMCs with BBR-PDT. Besides, it was also found that BBR-PDT activated endoplasmic reticulum (ER) stress, involving a dramatic increase in reactive oxygen species (ROS). Interestingly, the knockdown of CHOP protein expression inhibited apoptosis, autophagy and ER stress levels caused by BBR-PDT, suggesting that CHOP protein may be related to apoptosis, autophagy and ER stress in MMCs with BBR-PDT. Collectively, our results indicated that BBR-PDT had an essential impact on MMCs' growth inhibition, and therefore may reveal the possibility of developing BBR-PDT into human malignant melanoma.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Berberina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Melanoma/terapia , Fotoquimioterapia/métodos , Fator de Transcrição CHOP/metabolismo , Apoptose/efeitos da radiação , Autofagia/efeitos da radiação , Berberina/química , Western Blotting , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos da radiação , Humanos , Luz , Melanoma/metabolismo , Melanoma/patologia , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
17.
Biochem Biophys Res Commun ; 554: 49-55, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33774279

RESUMO

Radiation-induced rectal injury is one of the common side effects of pelvic radiation therapy. This study aimed to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in this process. In vivo, knockout (KO) of Nrf2 led to aggravated radiation-induced histological changes in the rectums. In vitro, interference or overexpression of Nrf2 resulted in enhanced or reduced radiosensitivity in human intestinal epithelial crypts (HIEC) cells, respectively. A potential relationship between Nrf2 and necroptosis was identified using RNA sequencing (RNA-seq) and western blotting (WB), which showed that necroptosis-related proteins were negatively correlated with Nrf2. Upon treatment with necrostatin-1 (Nec-1), the increased radiosensitivity, decreased cell viability, increased γH2AX foci formation, and decreased mitochondrial membrane potential (MMP) in Nrf2-interfered HIEC cells were alleviated. A significant recovery in morphological alterations was also observed in Nrf2 KO mice administered with Nec-1. Taken together, our results highlight the important protective effect of Nrf2 in radiation-induced rectal injury through the inhibition of necroptosis, and the physiological significance of necroptosis in radiation-induced rectal injury.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Reto/efeitos da radiação , Animais , Apoptose/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos da radiação , Dano ao DNA , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Necroptose , Tolerância a Radiação , Reto/metabolismo , Reto/patologia
18.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670592

RESUMO

In this study, we investigated the effects of blue light exposure on nucleotide-binding oligomerization domain 2 (NOD2) expression on the mouse ocular surface and evaluated the role of NOD2 activation in light-induced cell death. Mice were divided into wild-type (WT), NOD2-knock out (KO), WT + blue light (WT + BL), and NOD2-KO + blue light (NOD2-KO + BL) groups, and the mice in the WT+BL and NOD2-KO + BL groups were exposed to blue light for 10 days. After 10 days of blue light exposure, increased reactive oxygen species and malondialdehyde were observed in the WT + BL and NOD2-KO + BL groups, and the WT + BL group showed a higher expression of NOD2 and autophagy related 16 like 1. Although both WT+BL and NOD2-KO + BL groups showed an increase in the expression of light chain 3-II, NOD2-KO + BL mice had a significantly lower p62 expression than WT + BL mice. In addition, NOD2-KO+BL mice had significantly lower corneal epithelial damage and apoptosis than WT + BL mice. In conclusion, blue light exposure can induce impaired autophagy by activation of NOD2 on the ocular surface. In addition, the reactive oxygen species (ROS)-NOD2-autophagy related 16 like 1 (ATG16L) signaling pathway may be involved in the blue-light-induced autophagy responses, resulting in corneal epithelial apoptosis.


Assuntos
Autofagia/efeitos da radiação , Epitélio Corneano/efeitos da radiação , Luz , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Apoptose/genética , Apoptose/efeitos da radiação , Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Western Blotting , Túnica Conjuntiva/metabolismo , Túnica Conjuntiva/efeitos da radiação , Epitélio Corneano/metabolismo , Feminino , Malondialdeído/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/genética , Espécies Reativas de Oxigênio/metabolismo
19.
Arch Biochem Biophys ; 702: 108830, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33727039

RESUMO

Peroxiredoxin 6 (Prdx6) is a bifunctional enzyme with multi-substrate peroxidase and phospholipase activities that is involved in cell redox homeostasis and regulates intracellular processes. Previously, recombinant Prdx6 was shown to exert a radioprotective effect during whole-body exposure to a lethal dose of X-ray radiation. Moreover, a mutant form Prdx6-C47S, which lacks peroxidase activity, also had a radioprotective effect, and this indicates that the mechanism of radioprotection is unknown. The present study was aimed to test the hypothesis that the radioprotective effect of Prdx6 and Prdx6-C47S may be mediated through the TLR4/NF-κB signaling pathway. It was demonstrated that exogenously applied Prdx6 protected 3T3 fibroblast cells against LD50 X-ray radiation in vitro. Pretreatment with Prdx6 increased cell survival, stimulated proliferation, normalized the level of reactive oxygen species in culture, and suppressed apoptosis and necrosis. Wild-type Prdx6 and, to a lesser degree, the Prdx6-C47S mutant proteins promoted a significant increase in NF-κB activation in irradiated cells, which likely contributes to the antiapoptotic effect. Pretreatment with TLR4 inhibitors, especially those directed to the extracellular part of the receptor, significantly reduced the radioprotective effect, and this supports the role of TLR4 signaling in the protective effects of Prdx6. Therefore, the radioprotective effect of Prdx6 was related not only to its antioxidant properties, but also to its ability to trigger cellular defense mechanisms through interaction with the TLR4 receptor and subsequent activation of the NF-κB pathway. Recombinant Prdx6 may be useful for the development of a new class of safe radioprotective compounds that have a combination of antioxidant and immunomodulatory properties.


Assuntos
NF-kappa B/metabolismo , Peroxirredoxina VI/farmacologia , Protetores contra Radiação/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Células 3T3 , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Camundongos , Modelos Moleculares , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Peroxirredoxina VI/química , Peroxirredoxina VI/metabolismo , Conformação Proteica , Protetores contra Radiação/química , Protetores contra Radiação/metabolismo , Transdução de Sinais/efeitos da radiação , Receptor 4 Toll-Like/química
20.
Biochem Biophys Res Commun ; 550: 84-91, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33689884

RESUMO

The monopolar spindle 1 ((hMps1/TTK) is a serine/threonine kinase that plays an important role in spindle assembly checkpoint signaling. To explore the possible relationship between TTK inhibition and radiosensitivity, we examined whether TTK inhibition influences cellular susceptibility of radiation. And we further revealed its mechanisms. We found that the expression of TTK was obviously higher in liver cancer tissues compared to the normal liver tissues. Kaplan-Meier Plotter demonstrated that patients with low TTK expression levels had a longer overall survival than patients with high TTK expression levels. TTK inhibitor AZ3146 could simulated liver cancer cells to accumulate in the G2/M phase, which ultimately enhances DNA damage with more γ-H2AX foci and more apoptosis and necrosis induced by radiation, which prompted that TTK inhibition sensitized liver cancer cells to radiation. In addition, TTK inhibition altered cell-cycle progression and exacerbated centrosome abnormalities, resulting in enhanced mitotic catastrophe (MC) induced by radiation in a p21-mediated manner. In this study, we present evidences that the TTK inhibitor promotes the radiosensitivity of liver cancer cells through regulating cell cycle in p21-mediated manner in vitro, indicating that TTK inhibitor may be an attractive radiosensitizer for the patients with liver cancer.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Proteínas Oncogênicas/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Tolerância a Radiação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Centrossomo/efeitos dos fármacos , Centrossomo/metabolismo , Centrossomo/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Histonas/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos da radiação , Necrose/tratamento farmacológico , Necrose/radioterapia , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Análise de Sobrevida
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