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1.
J Photochem Photobiol B ; 204: 111791, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31981991

RESUMO

Photobiomodulation therapy (PBMT) is a curative technique that uses low intensity light to relegate pain and inflammation, and accelerate tissue repair. At a molecular level, the effects of photobiomodulation (PBM) are not fully established. The present study aimed to assess the impact of PBM on the alteration of genes linked to Janus kinase-Signal transducer and activator of transcription (JAK-STAT) signalling in wounded and diabetic wounded cells in vitro. Cells were irradiated using a diode laser at a wavelength of 660 nm and an energy density of 5 J/cm2. RNA was extracted from cells 48 h post-irradiation, and was used to synthesise complementary deoxyribonucleic acid (cDNA) that was used in PCR arrays to profile for 84 JAK/STAT signalling related genes. Irradiation at a wavelength of 660 nm and an energy density of 5 J/cm2 significantly regulated genes related to the JAK/STAT signalling pathway in wounded and diabetic wounded cells. In irradiated wounded cells, 19 genes were significantly regulated, of which two were up-regulated and 17 were down-regulated, while 73 genes were significantly regulated in irradiated diabetic wounded cells of which 46 were up-regulated and 27 were down-regulated. This data suggests that PBM modulates gene transcription for protein synthesis and activates cellular signalling, and may indeed be helpful in enhancing diabetic wound repair.


Assuntos
Expressão Gênica/efeitos da radiação , Lasers Semicondutores , Transdução de Sinais/efeitos da radiação , Linhagem Celular , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo
2.
Nucleic Acids Res ; 48(4): 1652-1668, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31930303

RESUMO

The excision of mutagenic DNA adducts by the nucleotide excision repair (NER) pathway is essential for genome stability, which is key to avoiding genetic diseases, premature aging, cancer and neurologic disorders. Due to the need to process an extraordinarily high damage density embedded in the nucleosome landscape of chromatin, NER activity provides a unique functional caliper to understand how histone modifiers modulate DNA damage responses. At least three distinct lysine methyltransferases (KMTs) targeting histones have been shown to facilitate the detection of ultraviolet (UV) light-induced DNA lesions in the difficult to access DNA wrapped around histones in nucleosomes. By methylating core histones, these KMTs generate docking sites for DNA damage recognition factors before the chromatin structure is ultimately relaxed and the offending lesions are effectively excised. In view of their function in priming nucleosomes for DNA repair, mutations of genes coding for these KMTs are expected to cause the accumulation of DNA damage promoting cancer and other chronic diseases. Research on the question of how KMTs modulate DNA repair might pave the way to the development of pharmacologic agents for novel therapeutic strategies.


Assuntos
Cromatina/genética , Dano ao DNA/genética , Histona Metiltransferases/genética , Histonas/genética , Cromatina/efeitos da radiação , Dano ao DNA/efeitos da radiação , Reparo do DNA/genética , Reparo do DNA/efeitos da radiação , Instabilidade Genômica/genética , Instabilidade Genômica/efeitos da radiação , Histona Metiltransferases/química , Metilação/efeitos da radiação , Nucleossomos/genética , Nucleossomos/efeitos da radiação , Saccharomyces cerevisiae/genética , Transdução de Sinais/efeitos da radiação , Raios Ultravioleta
3.
J Photochem Photobiol B ; 202: 111704, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31743829

RESUMO

Ultraviolet B (UVB) induces inflammation and causes skin aging. The signs of skin aging, such as wrinkles, discolored spots, loss of skin moisture, and disruption of the skin barrier, are mostly caused by inflammatory signaling among various skin layers. The cells on the outermost surface of the skin are keratinocytes; these cells protect the skin against environmental stress and play an important role in immunomodulation by secreting cytokines in response to environmental stress. In the present study, we found that UVB activates STAT1 to mediate inflammatory signaling, yet STAT1 (S272) and STAT (Y702) shows different responses against UVB exposure. Anhua drak tea is a post-fermented dark tea produced in Anhua and Xinhua country in Hunan province of China. Treatment with 2S,3R-6-methoxycarbonylgallocatechin (MCGE), an epigallocatechin gallate derivative isolated from black tea (Anhua dark tea), effectively suppresses STAT1 activation and inflammatory cytokines, and activates Nrf2 pathway to protect cells from reactive oxygen species production in UVB exposed keratinocyte cells (HaCaT). Interestingly, the effects of MCGE were independent on MAPK signaling pathway. Moreover, MCGE regulates inflammatory cytokines in monocyte-keratinocyte (THP-1, HaCaT) co-culture and macrophage differentiation models. These results suggest that MCGE potentially can be used as a photoprotective agent against UVB-induced inflammatory responses.


Assuntos
Catequina/farmacologia , Protetores contra Radiação/farmacologia , Transdução de Sinais/efeitos dos fármacos , Chá/química , Raios Ultravioleta , Sítios de Ligação , Catequina/análogos & derivados , Catequina/química , Catequina/isolamento & purificação , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Técnicas de Cocultura , Citocinas/metabolismo , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos da radiação , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estrutura Terciária de Proteína , Protetores contra Radiação/química , Protetores contra Radiação/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT1/química , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos da radiação , Chá/metabolismo
4.
Spine (Phila Pa 1976) ; 44(22): E1290-E1297, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31689248

RESUMO

STUDY DESIGN: This is an in vitro study of bovine disc cells exposed to pulsed electromagnetic fields. OBJECTIVE: The purpose of the present study was to investigate whether pulsed electromagnetic fields (PEMF) effects on the expression of interleukin-6 (IL-6) expression is mediated by two known inflammation regulators, nuclear factor-κB (NF-κß) and phosphorylated mitogen-activated protein kinase p38 (p38-MAPK) signaling pathways SUMMARY OF BACKGROUND DATA.: Inflammatory cytokines play a dominant role in the pathogenesis of disc degeneration. Increasing evidence showed that PEMF, a noninvasive biophysical stimulation, can have physiologically beneficial effects on inflammation and tissue repair. Our previous research shows that PEMF treatment can reduce IL-6 expression by intervertebral disc cells. However, the underlying mechanisms of PEMF action are yet to be uncovered. METHODS: Intervertebral disc nuclear pulposus cells were challenged with interleukin-1α (IL-1α) (for mimicking inflammatory microenvironment) and treated with PEMF simultaneously up to 4 hours. Cells were then collected for NF-κß and phosphorylated p38-MAPK protein detection with Western blot. Additionally, the RelA (p65) subunit of NF-κß was examined with immunostaining for assessment of NF-κß activation. RESULTS: As expected, Western blot results showed that both NF-κß and phosphorylated p38 expression were significantly increased by IL-1α treatment. This induction was significantly inhibited to control condition levels by PEMF treatment. Immunostaining demonstrated similar trends, that PEMF treatment reduced the NF-κß activation induced by IL-1α exposure. CONCLUSION: Our data indicate that the previously-reported inhibitory effect of PEMF treatment on disc inflammation is mediated by NF-κß and phosphorylated p38-MAPK signaling pathways. These results further establish PEMFs anti-inflammatory activity, and may inform potential future clinical uses for management of inflammation associated with disc degeneration. LEVEL OF EVIDENCE: N/A.


Assuntos
Campos Eletromagnéticos , Interleucina-6/metabolismo , Disco Intervertebral , NF-kappa B/metabolismo , Transdução de Sinais/efeitos da radiação , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Bovinos , Disco Intervertebral/citologia , Disco Intervertebral/metabolismo , Disco Intervertebral/efeitos da radiação
5.
Mutat Res ; 816-818: 111679, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31715522

RESUMO

Glioblastoma (GBM) is the most lethal type of primary brain tumor. Currently, even with optimal and multimodal cancer therapies, the survival rate of GBM patients remains poor. One reason for inadequate response of GBM tumors to radiotherapy is radioresistance (RR). Thus, there is a critical need for new insights about GBM treatment to increase the chance of treatment. microRNAs (miRNAs) are important regulatory molecules that can effectively control GBM radiosensitivity (RS) by affecting radiation-related signal transduction pathways such as apoptosis, proliferation, DNA repair and cell cycle regulation. miRNAs provide new clinical perspectives for developing effective GBM treatments. A growing body of literature has demonstrated that GBM RS can be modified by modulating the expression of miRNAs such as miR-7, miR-10b, miR-124, miR-128, miR-320, miR-21, miR-203, and miR-153. This paper highlights the miRNAs and the underlying molecular mechanisms that are involved in the RS of GBM. Besides highlighting the role of miRNAs in different signaling pathways, we explain the mechanisms that affect RS of GBM for modulating radiation response at the clinical level.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , MicroRNAs/genética , Tolerância a Radiação/genética , Transdução de Sinais/genética , Animais , Neoplasias Encefálicas/radioterapia , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioblastoma/radioterapia , Humanos , Tolerância a Radiação/efeitos da radiação , Transdução de Sinais/efeitos da radiação
6.
Int J Mol Sci ; 20(19)2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591311

RESUMO

Proton therapy offers a distinct physical advantage over conventional X-ray therapy, but its biological advantages remain understudied. In this study, we aimed to identify genetic factors that contribute to proton sensitivity in breast cancer (BC). Therefore, we screened relative biological effectiveness (RBE) of 230 MeV protons, compared to 6 MV X-rays, in ten human BC cell lines, including five triple-negative breast cancer (TNBC) cell lines. Clonogenic survival assays revealed a wide range of proton RBE across the BC cell lines, with one out of ten BC cell lines having an RBE significantly different from the traditional generic RBE of 1.1. An abundance of cyclin D1 was associated with proton RBE. Downregulation of RB1 by siRNA or a CDK4/6 inhibitor increased proton sensitivity but not proton RBE. Instead, the depletion of cyclin D1 increased proton RBE in two TNBC cell lines, including MDA-MB-231 and Hs578T cells. Conversely, overexpression of cyclin D1 decreased the proton RBE in cyclin D1-deficient BT-549 cells. The depletion of cyclin D1 impaired proton-induced RAD51 foci formation in MDA-MB-231 cells. Taken together, this study provides important clues about the cyclin D1-CDK4-RB1 pathway as a potential target for proton beam therapy in TNBC.


Assuntos
Ciclina D1/genética , Tolerância a Radiação , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Ciclina D1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Células MCF-7 , Terapia com Prótons , Eficiência Biológica Relativa , Transdução de Sinais/efeitos da radiação , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/radioterapia , Raios X
7.
BMC Cancer ; 19(1): 958, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619190

RESUMO

BACKGROUND: We analyzed the changes in permeability of endothelial cell layers after photon irradiation, with a focus on the metalloproteases ADAM10 and ADAM17, and on VE-cadherin, components crucial for the integrity of endothelial intercellular junctions, and their roles in the transmigration of cancer cells through endothelial cell monolayers. METHODS: Primary HUVEC were irradiated with 2 or 4 Gy photons at a dose rate of 5 Gy/min. The permeability of an irradiated endothelial monolayer for macromolecules and tumor cells was analyzed in the presence or absence of the ADAM10/17 inhibitors GI254023X and GW280264X. Expression of ADAM10, ADAM17 and VE-Cadherin in endothelial cells was quantified by immunoblotting and qRT. VE-Cadherin was additionally analyzed by immunofluorescence microscopy and ELISA. RESULTS: Ionizing radiation increased the permeability of endothelial monolayers and the transendothelial migration of tumor cells. This was effectively blocked by a selective inhibition (GI254023X) of ADAM10. Irradiation increased both, the expression and activity of ADAM10, which led to increased degradation of VE-cadherin, but also led to higher rates of VE-cadherin internalization. Increased degradation of VE-cadherin was also observed when endothelial monolayers were exposed to tumor-cell conditioned medium, similar to when exposed to recombinant VEGF. CONCLUSIONS: Our results suggest a mechanism of irradiation-induced increased permeability and transendothelial migration of tumor cells based on the activation of ADAM10 and the subsequent change of endothelial permeability through the degradation and internalization of VE-cadherin.


Assuntos
Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Células Endoteliais/efeitos da radiação , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Proteínas de Membrana/metabolismo , Proteólise/efeitos da radiação , Radiação Ionizante , Migração Transendotelial e Transepitelial/efeitos da radiação , Proteína ADAM10/antagonistas & inibidores , Proteína ADAM10/genética , Proteína ADAM17/antagonistas & inibidores , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Linhagem Celular Tumoral , Dipeptídeos/farmacologia , Células Endoteliais/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Permeabilidade/efeitos da radiação , Radioterapia/efeitos adversos , Transdução de Sinais/efeitos da radiação , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia
8.
Turk Neurosurg ; 29(6): 887-900, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31608966

RESUMO

AIM: To investigate the potential protective effects of melatonin on the chronic radiation emitted by third generation mobile phones on the brain. MATERIAL AND METHODS: A total of 24 male Wistar albino rats were divided into four equal groups. Throughout a 90-day experiment, no application was performed on the control group. The second group was exposed to 2100 MHz radiation for 30 minutes. Subcutaneous melatonin was injected into the third group. Subcutaneous melatonin injection was applied 40 minutes before radiation and then the fourth group was exposed to radiation for 30 minutes. At the end of the experiment, brain (cerebrum and cerebellum) tissues were taken from the subjects. Histochemical, immunohistochemical, ultrastructural and western blot analyses were applied. In addition to brain weight, Purkinje cells’ number, immunohistochemical H Score analyses and the results of the Western blot were examined statistically. RESULTS: With the application of radiation, neuronal edema, relatively-decreased numbers of neurons on hippocampal CA1 and CA3 regions, displacement of the Purkinje neurons and dark neurons findings were observed as a result of histochemical stainings. Radiation also activated the NMDA-receptor 2B/Calpain-1/Caspase-12 pathway, NMDA-receptor 2B and Calpain-1 with the findings being supported by western blot analyses. Pre-increased protein synthesis before apoptosis was identified by electron microscopy. CONCLUSION: Mobile phone radiation caused certain (ultra) structural changes on the brain and activated the NMDA-receptor 2B/ Calpain-1/Caspase-12 pathway; in addition, melatonin was found to be effective, but insufficient in demonstrating the protective effects.


Assuntos
Encéfalo/metabolismo , Calpaína/metabolismo , Caspase 12/metabolismo , Radiação Eletromagnética , Melatonina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Encéfalo/efeitos dos fármacos , Encéfalo/efeitos da radiação , Calpaína/efeitos da radiação , Caspase 12/efeitos da radiação , Telefone Celular , Masculino , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
9.
Oxid Med Cell Longev ; 2019: 3173745, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531182

RESUMO

Premature ovarian failure (POF) is a common cause of infertility in premenopausal women who are unavoidably exposed to cytotoxic therapy. Radiotherapy is one of the most effective cytotoxic treatments. However, the radiosensitivity of ovarian tissues limits its therapeutic outcome and results in the depletion of the primordial follicle and loss of fertility. Therefore, the need for an effective radioprotective therapy is evident especially when none of the current clinically used modalities for radioprotection succeeds efficiently. The present study investigated the potential radioprotective effect of carvacrol (CAR) (80 mg) or thymol (80 mg) on gamma- (γ-) irradiation-induced ovarian damage as well as their role in the cross-talk between IGF-1 and TNF-α signaling and antioxidative activity. In immature female Wister rats, a single dose of whole-body irradiation (3.2 Gy, LD20) produced considerable ovarian damage, which was evident by histopathological findings and hormonal changes. Interestingly, pretreatment with CAR or thymol significantly enhanced the follicular development and restored the anti-Mullerian hormone (AMH), E2, and FSH levels. Both essential oils improved the irradiation-mediated oxidative stress and reduction in proliferating cell nuclear antigen (PCNA) expression. Moreover, irradiated rats exhibited an inverse relationship between IGF-1 and TNF-α levels two days post irradiation, which was further inverted by the pretreatment with CAR and thymol and ought to contribute in their radioprotective mechanisms. In conclusion, CAR and thymol showed a radioprotective effect and rescued the ovarian reserve mainly through counteracting oxidative stress and the dysregulated cross-talk between IGF-1 and TNF-α.


Assuntos
/farmacologia , Raios gama/efeitos adversos , Fator de Crescimento Insulin-Like I/metabolismo , Insuficiência Ovariana Primária/sangue , Protetores contra Radiação/farmacologia , Transdução de Sinais , Timol/farmacologia , Fator de Necrose Tumoral alfa/sangue , Animais , Feminino , Insuficiência Ovariana Primária/etiologia , Radioterapia/efeitos adversos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
10.
Oxid Med Cell Longev ; 2019: 6435364, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531186

RESUMO

Commercially available white light-emitting diodes (LEDs) have an intense emission in the range of blue light, which has raised a range of public concerns about their potential risks as retinal hazards. Distinct from other visible light components, blue light is characterized by short wavelength, high energy, and strong penetration that can reach the retina with relatively little loss in damage potential. Mitochondria are abundant in retinal tissues, giving them relatively high access to blue light, and chromophores, which are enriched in the retina, have many mitochondria able to absorb blue light and induce photochemical effects. Therefore, excessive exposure of the retina to blue light tends to cause ROS accumulation and oxidative stress, which affect the structure and function of the retinal mitochondria and trigger mitochondria-involved death signaling pathways. In this review, we highlight the essential roles of mitochondria in blue light-induced photochemical damage and programmed cell death in the retina, indicate directions for future research and preventive targets in terms of the blue light hazard to the retina, and suggest applying LED devices in a rational way to prevent the blue light hazard.


Assuntos
Apoptose/efeitos da radiação , Luz/efeitos adversos , Retina/metabolismo , Doenças Retinianas/metabolismo , Transdução de Sinais/efeitos da radiação , Animais , Humanos , Espécies Reativas de Oxigênio/metabolismo , Retina/patologia , Doenças Retinianas/patologia , Doenças Retinianas/prevenção & controle
11.
Int J Radiat Biol ; 95(12): 1640-1647, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31525117

RESUMO

Purpose: Identifying the association between somatic mutations and the radiation response of tumor is essential for understanding the mechanisms and practicing personalized radiotherapy. The present study aimed to discover specific genes or pathways that are associated with radiation response using targeted next-generation DNA sequencing.Material and methods: Fifty-five patients with various solid tumors whose specimen were sequenced using institutional panel which includes 148 cancer-related genes and received radiotherapy for a measurable tumor were analyzed. Patients with irradiated tumors in complete or partial remission for more than 6 months were defined as responders. Association between mutations including pathogenic single nucleotide variants and insertions/deletions in the 148 genes and 39 molecular pathways and radiation response was investigated.Results: Analyzing 17 responders and 38 non-responders, biologically effective dose (BED), but not concurrent chemotherapy, was associated with radiation response. No single gene correlated with radiation response. Mutations in Notch signaling pathway were associated with radiosensitivity after correction for multiple comparison (adjusted p = .094). When BED and Notch signaling pathway mutation were tested with logistic regression, both variables were associated with radiation response.Conclusions: Our results suggest that somatic mutations in Notch signaling pathway may be related to sensitivity to radiation, although these results should be validated in a larger and more homogeneous cohort.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Mutação/efeitos da radiação , Receptores Notch/metabolismo , Análise de Sequência de DNA , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação , Adulto , Idoso , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia , Neoplasias/radioterapia , Resultado do Tratamento , Adulto Jovem
12.
Int J Mol Sci ; 20(19)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547113

RESUMO

Sphingosine 1 phosphate (S1P) is a bioactive lipid that regulates cellular activity, including proliferation, cytoskeletal organization, migration, and fibrosis. In this study, the potential relevance of S1P-Rho signaling in pterygium formation and the effects of ultraviolet (UV) irradiation on activation of the S1P/S1P receptor axis and fibrotic responses were investigated in vitro. Expressions of the S1P2, S1P4, and S1P5 receptors were significantly higher in pterygium tissue than in normal conjunctiva, and the concentration of S1P was significantly elevated in the lysate of normal conjunctival fibroblast cell (NCFC) irradiated with UV (UV-NCFCs). RhoA activity was significantly upregulated in pterygium fibroblast cells (PFCs) and UV-NCFCs, and myosin phosphatase-Rho interacting protein (MRIP) was upregulated, and myosin phosphatase target subunit 1 (MYPT1) was downregulated in PFCs. Fibrogenic changes were significantly upregulated in both PFCs and UV-NCFCs compared to NCFCs. We found that the activation of the S1P receptor-Rho cascade was observed in pterygium tissue. Additionally, in vitro examination showed S1P-rho activation and fibrogenic changes in PFCs and UV-NCFCs. S1P elevation and the resulting upregulation of the downstream Rho signaling pathway may be important in pterygium formation; this pathway offers a potential therapeutic target for suppressing pterygium generation.


Assuntos
Túnica Conjuntiva/metabolismo , Lisofosfolipídeos/metabolismo , Pterígio/metabolismo , Transdução de Sinais/efeitos da radiação , Esfingosina/análogos & derivados , Raios Ultravioleta , Proteínas rho de Ligação ao GTP/metabolismo , Túnica Conjuntiva/patologia , Proteínas do Olho/biossíntese , Feminino , Humanos , Masculino , Pterígio/patologia , Esfingosina/metabolismo , Regulação para Cima/efeitos da radiação
13.
BMC Cancer ; 19(1): 889, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488097

RESUMO

BACKGROUND: Capacitive-resistive electric transfer (CRET) is a non-invasive therapeutic strategy that applies radiofrequency electric currents within the 400-600 kHz range to tissue repair and regeneration. Previous studies by our group have shown that 48 h of intermittent exposure to a 570 kHz CRET signal at a subthermal density of 50 µA/mm2 causes significant changes in the expression and activation of cell cycle control proteins, leading to cycle arrest in human cancer cell cultures. The present study investigates the relevance of the signal frequency in the response of the human neuroblastoma cell line NB69 to subthermal electric treatment with four different signal frequency currents within the 350-650 kHz range. METHODS: Trypan blue assay, flow cytometry, immunofluorescence and immunoblot were used to study the effects of subthermal CRET currents on cell viability, cell cycle progression and the expression of several marker proteins involved in NB69 cell death and proliferation. RESULTS: The results reveal that among the frequencies tested, only a 448 kHz signal elicited both proapoptotic and antiproliferative, statistically significant responses. The apoptotic effect would be due, at least in part, to significant changes induced by the 448 kHz signal in the expression of p53, Bax and caspase-3. The cytostatic response was preceded by alterations in the kinetics of the cell cycle and in the expression of proteins p-ERK1/2, cyclin D1 and p27, which is consistent with a potential involvement of the EGF receptor in electrically induced changes in the ERK1/2 pathway. This receives additional support from results indicating that the proapototic and antiproliferative responses to CRET can be transiently blocked when the electric stimulus is applied in the presence of PD98059, a chemical inhibitor of the ERK1/2 pathway. CONCLUSION: The understanding of the mechanisms underlying the ability of slowing down cancer cell growth through electrically-induced changes in the expression of proteins involved in the control of cell proliferation and apoptosis might afford new insights in the field of oncology.


Assuntos
Crista Neural/efeitos da radiação , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Tratamento por Radiofrequência Pulsada/métodos , Apoptose/efeitos da radiação , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Receptores ErbB/metabolismo , Flavonoides/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Neuroblastoma/radioterapia , Transdução de Sinais/efeitos da radiação , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo
14.
Nucleic Acids Res ; 47(18): 9467-9479, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31396623

RESUMO

The DNA damage response (DDR) encompasses the cellular response to DNA double-stranded breaks (DSBs), and includes recognition of the DSB, recruitment of numerous factors to the DNA damage site, initiation of signaling cascades, chromatin remodeling, cell-cycle checkpoint activation, and repair of the DSB. Key drivers of the DDR are multiple members of the phosphatidylinositol 3-kinase-related kinase family, including ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). ATM and ATR modulate multiple portions of the DDR, but DNA-PKcs is believed to primarily function in the DSB repair pathway, non-homologous end joining. Utilizing a human cell line in which the kinase domain of DNA-PKcs is inactivated, we show here that DNA-PKcs kinase activity is required for the cellular response to DSBs immediately after their induction. Specifically, DNA-PKcs kinase activity initiates phosphorylation of the chromatin factors H2AX and KAP1 following ionizing radiation exposure and drives local chromatin decondensation near the DSB site. Furthermore, loss of DNA-PKcs kinase activity results in a marked decrease in the recruitment of numerous members of the DDR machinery to DSBs. Collectively, these results provide clear evidence that DNA-PKcs activity is pivotal for the initiation of the DDR.


Assuntos
Cromatina/genética , Dano ao DNA/genética , Reparo do DNA/genética , DNA/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Pontos de Checagem do Ciclo Celular/genética , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Dano ao DNA/efeitos da radiação , Proteína Quinase Ativada por DNA/genética , Humanos , Proteínas Nucleares/genética , Fosforilação/efeitos da radiação , Radiação Ionizante , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação
15.
Mar Drugs ; 17(8)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374828

RESUMO

Excessive exposure to ultraviolet (UV) radiation is the main risk factor to develop skin pathologies or cancer because it encourages oxidative condition and skin inflammation. In this sense, strategies for its prevention are currently being evaluated. Natural products such as carotenoids or polyphenols, which are abundant in the marine environment, have been used in the prevention of oxidative stress due to their demonstrated antioxidant activities. Nevertheless, the anti-inflammatory activity and its implication in photo-prevention have not been extensively studied. Thus, we aimed to evaluate the combination of fucoxanthin (FX) and rosmarinic acid (RA) on cell viability, apoptosis induction, inflammasome regulation, and anti-oxidative response activation in UVB-irradiated HaCaT keratinocytes. We demonstrated for the first time that the combination of FX and RA (5 µM RA plus 5 µM FX, designated as M2) improved antioxidant and anti-inflammatory profiles in comparison to compounds assayed individually, by reducing UVB-induced apoptosis and the consequent ROS production. Furthermore, the M2 combination modulated the inflammatory response through down-regulation of inflammasome components such as NLRP3, ASC, and Caspase-1, and the interleukin (IL)-1ß production. In addition, Nrf2 and HO-1 antioxidant genes expression increased in UVB-exposed HaCaT cells pre-treated with M2. These results suggest that this combination of natural products exerts photo-protective effects by down-regulating NRLP3-inflammasome and increasing Nrf2 signalling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Xantofilas/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Sinergismo Farmacológico , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/efeitos da radiação , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiação , Pele/citologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos
16.
Toxicol Lett ; 315: 23-30, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442584

RESUMO

Ulcerative colitis2 (UC) is an inflammatory bowel disease3 (IBD) that causes long-lasting inflammation and ulcers in the human digestive tract. The repair function of TLR4 in the intestinal epithelium is still unknown. Here, wild-type4 (WT) mice, TLR4-knockout mice5 (KO; TLR4-/-) and commensal-depleted mice were used as dextran sulfate sodium6 (DSS)-induced or radiation-induced colitis and injury models to explore the role of TLR4 signaling in intestinal injury. Exogenous lipopolysaccharide7 (LPS) promoted DSS-induced inflammatory cytokines and aggravated intestinal damage. TLR4 deficiency and commensal bacterial depletion inhibited the toxic effects of LPS, but these mice were more susceptible to DSS-induced and radiation-induced intestinal damage. Compared with WT mice, neither DSS nor radiation promoted production of more inflammatory cytokines in the guts of TLR4-KO and commensal-depleted mice. Introducing the cytokine repair factors, PGE2 and GM-CSF, increased the cytokine levels in the guts of DSS-induced colitis mice. We hypothesized that TLR4 and its ligands repaired the epithelium after DSS-induced and radiation-induced intestinal damage by upregulating PGE2 and GM-CSF. Transwell migration assays suggested that LPS, IL6, TNF, PGE2 and GM-CSF promoted intestinal cell migration, and cell viability analysis suggested that these factors protected against radiation-induced intestinal damage. Our data underscore the importance of the balancing role of TLR4 in intestinal injury and repair.


Assuntos
Linhagem Celular/efeitos da radiação , Colite/induzido quimicamente , Colite/fisiopatologia , Sulfato de Dextrana/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos da radiação , Receptor 4 Toll-Like/efeitos da radiação , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
17.
Life Sci ; 234: 116781, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430455

RESUMO

Cancer stem cells (CSCs) are a population of self-renewal cells with high tumorigenic potency. CSCs can adopt easily with changes in the nearby milieu, and are more resistant to conventional therapies than other cells within a tumor. CSC resistance can be induced secondary to radio- and chemotherapy, or even after chemotherapy secession. A combination of both intrinsic and extrinsic factors is contributed to CSC-mediated therapy resistance. CSCs represent protective autophagy and efficient cell cycling, along with highly qualified epithelial-mesenchymal transition (EMT) regulators, reactive oxygen species (ROS) scavengers, drug transporters, and anti-apoptotic and DNA repairing systems. In addition, CSCs develop cross-talking and share some characteristics with other cells within the tumor microenvironment (TME) being more intense in higher stage tumors, and thereby sophisticating tumor-targeted therapies. TME, in fact, is a nest for aggravating resistance mechanisms in CSCs. TME is exposed constantly to the nutritional, metabolic and oxygen deprivation; these conditions promote CSC adaptation. This review is aimed to discuss main (intrinsic and extrinsic) mechanisms of CSC resistance and suggest some strategies to revoke this important promoter of therapy failure.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Células-Tronco Neoplásicas/patologia , Animais , Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação
18.
Technol Cancer Res Treat ; 18: 1533033819868225, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401938

RESUMO

OBJECTIVE: Tumor-treating fields are currently used to successfully treat various cancers; however, the specific pathways associated with its efficacy remain unknown in the immune responses. Here, we evaluated tumor-treating fields-mediated initiation of the macrophage-specific immune response. MATERIALS AND METHODS: We subjected RAW 264.7 mouse macrophages to clinically relevant levels of tumor-treating fields (0.9 V/cm, 150 kHz) and evaluated alterations in cytokine expression and release, as well as cell viability. Additionally, we investigated the status of immunomodulatory pathways to determine their roles in tumor-treating fields-mediated immune activation. RESULTS AND DISCUSSION: Our results indicated that tumor-treating fields treatment at 0.9 V/cm decreased cell viability and increased cytokine messenger RNA/protein levels, as well as levels of nitric oxide and reactive oxygen species, relative to controls. The levels of tumor necrosis factor α, interleukin 1ß, and interleukin 6 were markedly increased in tumor-treating fields-treated RAW 264.7 cells cocultured with 4T1 murine mammary carcinoma cells compared with those in 4T1 or RAW 264.7 cells with or without tumor-treating fields treatment. Moreover, the viability of 4T1 cells treated with the conditioned medium of tumor-treating fields-stimulated RAW 264.7 cells decreased, indicating that macrophage activation by tumor-treating fields effectively killed the tumor cells. Moreover, tumor-treating fields treatment activated the nuclear factor κB and mitogen-activated protein kinase pathways involved in immunomodulatory signaling. CONCLUSION: These results provide critical insights into the mechanisms through which tumor-treating fields affect macrophage-specific immune responses and the efficacy of this method for cancer treatment.


Assuntos
Antígenos de Histocompatibilidade Classe II/imunologia , Ativação de Macrófagos/imunologia , Terapia de Campo Magnético , Neoplasias/radioterapia , Animais , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/efeitos da radiação , Humanos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Ativação de Macrófagos/genética , Ativação de Macrófagos/efeitos da radiação , Macrófagos/imunologia , Macrófagos/efeitos da radiação , Camundongos , NF-kappa B/genética , Neoplasias/imunologia , Neoplasias/patologia , Células RAW 264.7 , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiação
19.
Nat Commun ; 10(1): 2904, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266952

RESUMO

Plant survival necessitates constant monitoring of fluctuating light and balancing growth demands with adaptive responses, tasks mediated via interconnected sensing and signaling networks. Photoreceptor phytochrome B (phyB) and plastidial retrograde signaling metabolite methylerythritol cyclodiphosphate (MEcPP) are evolutionarily conserved sensing and signaling components eliciting responses through unknown connection(s). Here, via a suppressor screen, we identify two phyB mutant alleles that revert the dwarf and high salicylic acid phenotypes of the high MEcPP containing mutant ceh1. Biochemical analyses show high phyB protein levels in MEcPP-accumulating plants resulting from reduced expression of phyB antagonists and decreased auxin levels. We show that auxin treatment negatively regulates phyB abundance. Additional studies identify CAMTA3, a MEcPP-activated calcium-dependent transcriptional regulator, as critical for maintaining phyB abundance. These studies provide insights into biological organization fundamentals whereby a signal from a single plastidial metabolite is transduced into an ensemble of regulatory networks controlling the abundance of phyB, positioning plastids at the information apex directing adaptive responses.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Fitocromo B/metabolismo , Plastídeos/metabolismo , Arabidopsis/genética , Arabidopsis/efeitos da radiação , Proteínas de Arabidopsis/genética , Eritritol/análogos & derivados , Eritritol/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Ácidos Indolacéticos/metabolismo , Luz , Fitocromo B/genética , Plastídeos/genética , Transdução de Sinais/efeitos da radiação , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
20.
Plant Cell Physiol ; 60(10): 2307-2318, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31290959

RESUMO

Chlorophyll biosynthesis plays essential roles in photosynthesis and plant growth in response to environmental conditions. The accumulation of excess chlorophyll biosynthesis intermediates under light results in the production of reactive oxygen species and oxidative stress. In this study, we identified a rice (Oryza sativa) mutant, oxidation under photoperiod (oxp), that displayed photobleached lesions on its leaves, reduced growth and decreased chlorophyll content during light/dark cycles or following a dark-to-light transition. The oxp mutant accumulated more chlorophyll precursors (5-aminolevulinic acid and protochlorophyllide) than the wild type in the dark, and more singlet oxygen following light exposure. Several singlet-oxygen-responsive genes were greatly upregulated in oxp, whereas the expression patterns of OsPORA and OsPORB, two genes encoding the chlorophyll biosynthesis enzyme NADPH:protochlorop hyllide oxidoreductase, were altered in de-etiolated oxp seedlings. Molecular and complementation studies revealed that oxp is a loss-of-function mutant in LOC_Os01g32730, a homolog of FLUORESCENT (FLU) in Arabidopsis thaliana. Rice PHYTOCHROME-INTERACTING FACTOR-LIKE14 (OsPIL14) transcription factor directly bound to the OsFLU1 promoter and activated its expression. Dark-grown transgenic rice seedlings overexpressing OsPIL14 accumulated more chlorophyll and turned green faster than the wild type upon light illumination. Thus, OsFLU1 is an important regulator of chlorophyll biosynthesis in rice.


Assuntos
Proteínas de Arabidopsis/genética , Oryza/genética , Proteínas de Plantas/metabolismo , Transdução de Sinais/efeitos da radiação , Ácido Aminolevulínico/metabolismo , Clorofila/biossíntese , Estiolamento , Luz , Mutação , Oryza/fisiologia , Oryza/efeitos da radiação , Estresse Oxidativo , Fotoperíodo , Fotossíntese , Folhas de Planta/genética , Folhas de Planta/fisiologia , Folhas de Planta/efeitos da radiação , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas/genética , Protoclorifilida/metabolismo , Plântula/genética , Plântula/fisiologia , Plântula/efeitos da radiação , Oxigênio Singlete/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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