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1.
Int J Radiat Biol ; 93(5): 470-476, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28110593

RESUMEN

PURPOSE: To investigate alterations of mitochondria in irradiated endothelial cells to further elucidate the mechanism underlying radiation-induced heart disease. MATERIALS AND METHODS: Experiments were performed using human umbilical vein endothelial cells (HUVECs). HUVECs were irradiated with single gamma ray dose of 0, 5, 10 and 20 Gy, respectively. Apoptosis was assessed by flow cytometry at 24, 48 and 72 h post-irradiation, respectively. The intracellular reactive oxygen species (ROS) was measured with 2',7'-dichlorofluorescein-diacetate (DCFH-DA) at 24 h post-irradiation. Mitochondrial membrane potential (ΔΨm) by JC-1 and the opening of mitochondrial permeability transition pore (mPTP) by a calcein-cobalt quenching method were detected at 24 h post-irradiation in order to measure changes of mitochondria induced by gamma ray irradiation. RESULTS: Gamma ray irradiation increased HUVECs apoptosis in a dose-dependent and time-dependent manner. Irradiation also promoted ROS production in HUVECs in a dose-dependent manner. At 24 h post-irradiation, the results showed that irradiation decreases ΔΨm, however, paradoxically, flow cytometry showed green fluorescence instensity higher in irradiated HUVECs than in control HUVECs in an irradiation dose-dependent manner which indicated gamma ray irradiation inhibited mPTP opening in HUVECs. CONCLUSIONS: Gamma ray irradiation induces apoptosis and ROS production of endothelial cells, and decreases ΔΨm meanwhile contradictorily inhibiting the opening of mPTP.


Asunto(s)
Apoptosis/fisiología , Células Endoteliales/fisiología , Rayos gamma , Potencial de la Membrana Mitocondrial/fisiología , Mitocondrias/fisiología , Proteínas de Transporte de Membrana Mitocondrial/fisiología , Apoptosis/efectos de la radiación , Células Cultivadas , Relación Dosis-Respuesta en la Radiación , Células Endoteliales/efectos de la radiación , Células Endoteliales/ultraestructura , Humanos , Potencial de la Membrana Mitocondrial/efectos de la radiación , Mitocondrias/efectos de la radiación , Mitocondrias/ultraestructura , Proteínas de Transporte de Membrana Mitocondrial/efectos de la radiación , Proteínas de Transporte de Membrana Mitocondrial/ultraestructura , Poro de Transición de la Permeabilidad Mitocondrial , Dosis de Radiación , Especies Reactivas de Oxígeno/metabolismo
2.
Radiother Oncol ; 119(2): 259-64, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27072940

RESUMEN

BACKGROUND AND PURPOSE: Thoracic (chemo)radiation therapy is increasingly administered with tyrosine kinase inhibitors (TKI). While TKI have adverse effects on the heart, it is unknown whether combination with other cancer therapies causes enhanced toxicity. We used an animal model to investigate whether radiation and sunitinib interact in their effects on the heart. MATERIAL AND METHODS: Male Sprague-Dawley rats received local heart irradiation (9Gy per day, 5days). Oral sunitinib (8 or 15mg/kg bodyweight per day) started on day 1 of irradiation and continued for 2weeks. Cardiac function was examined with echocardiography. Cardiac remodeling, cell death, left ventricular (LV) oxidative stress markers, mitochondrial morphology and mitochondrial permeability transition pore (mPTP) opening were assessed. RESULTS: Cardiac diameter, stroke volume, and LV volume, mass and anterior wall thickness increased in time, but only in the vehicle group. Sunitinib reduced LV inner diameter and volume in systole, which were counteracted by radiation. Sunitinib and radiation showed enhanced effects on mitochondrial morphology and mPTP opening, but not on cardiac troponin I, mast cell numbers or markers of oxidative stress. CONCLUSIONS: This study found no early enhanced effects of radiation and sunitinib on cardiac function or structure. Long-term effects remain to be determined.


Asunto(s)
Corazón/efectos de la radiación , Indoles/farmacología , Mitocondrias Cardíacas/efectos de la radiación , Estrés Oxidativo , Pirroles/farmacología , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/efectos de la radiación , Corazón/efectos de los fármacos , Corazón/fisiología , Masculino , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/efectos de la radiación , Poro de Transición de la Permeabilidad Mitocondrial , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Ratas , Ratas Sprague-Dawley , Sunitinib , Remodelación Ventricular/efectos de los fármacos , Remodelación Ventricular/efectos de la radiación
3.
PLoS One ; 9(11): e114090, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25423172

RESUMEN

Opening of the mitochondrial permeability transition pore (mPTP) is involved in various cellular processes including apoptosis induction. Two distinct states of mPTP opening have been identified allowing the transfer of molecules with a molecular weight <1500 Da or <300 Da. The latter state is considered to be reversible and suggested to play a role in normal cell physiology. Here we present a strategy combining live-cell imaging and computer-assisted image processing allowing spatial visualization and quantitative analysis of reversible mPTP openings ("ΔΨ flickering") in primary mouse myotubes. The latter were stained with the photosensitive cation TMRM, which partitions between the cytosol and mitochondrial matrix as a function of mitochondrial membrane potential (ΔΨ). Controlled illumination of TMRM-stained primary mouse myotubes induced ΔΨ flickering in particular parts of the cell ("flickering domains"). A novel quantitative automated analysis was developed and validated to detect and quantify the frequency, size, and location of individual ΔΨ flickering events in myotubes.


Asunto(s)
Luz , Proteínas de Transporte de Membrana Mitocondrial/efectos de la radiación , Fibras Musculares Esqueléticas/efectos de la radiación , Animales , Ciclosporina/farmacología , Femenino , Ratones , Ratones Endogámicos C57BL , Proteínas de Transporte de Membrana Mitocondrial/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/fisiología , Poro de Transición de la Permeabilidad Mitocondrial , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/fisiología , Oligomicinas/farmacología
4.
Exp Cell Res ; 319(5): 750-60, 2013 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-23220213

RESUMEN

The CyP40 protein encoded by PPID gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. The CyP40 protein has been shown to possess PPIase activity and, similar to other family members, can bind to the immunosuppressant drug cyclosporin A (CsA). In this study, we created keratinocyte cell lines with CyP40 being stably knocked down using viral particles containing shRNA for CyP40 which knocked down the expression level of CyP40 transcripts by 90-99%. The proliferation rates of the cell lines with silenced CyP40 were decreased compared to the control cells. After UVA irradiation, the rate of apoptosis was found to be significantly lower in CyP40 silenced cell lines than it was in control cells. Moreover, mitochondrial membrane potential (MMP) was found to be less dissipated and mitochondrial permeability transition pore (MPTP) less active in cells with knocked down CyP40 than in control cells after UVA irradiation. Also, less mitochondrial superoxide was detected in the cells with silenced CyP40 compared to control cells after UVA exposure. Moreover, silencing of CyP40 partially modulates expression of key genes involved in mitochondrial pore formation including CyPD, ANTs and VDAC family members. The ability of CyP40 to regulate UV induced apoptosis implicates this protein as a potential target for therapy in cancer cells.


Asunto(s)
Apoptosis/efectos de la radiación , Ciclofilinas/metabolismo , Queratinocitos/patología , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rayos Ultravioleta/efectos adversos , Western Blotting , Proliferación Celular/efectos de la radiación , Células Cultivadas , Peptidil-Prolil Isomerasa F , Ciclofilinas/antagonistas & inhibidores , Ciclofilinas/genética , Citometría de Flujo , Humanos , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Mitocondrias/efectos de la radiación , Proteínas de Transporte de Membrana Mitocondrial/efectos de la radiación , Poro de Transición de la Permeabilidad Mitocondrial , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
5.
J Photochem Photobiol B ; 113: 42-50, 2012 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-22673012

RESUMEN

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a polyphenol compound, is derived from natural products such as the skin of red grapes, blueberries and cranberries. Resveratrol not only exhibits antioxidant, cardioprotection, and anti-aging properties, but can also inhibit cancer cell growth and induce apoptosis. It has been shown that resveratrol inhibits the activation of Nf-κB and subsequently down regulates the expression of Nf-κB regulated genes such as interleukin-2 and Bcl-2, leading to cell cycle arrest and increased apoptosis in multiple myeloma cells. In the skin, resveratrol has been reported to sensitize keratinocytes to UVA induced apoptosis. However, the effect of resveratrol on opening of the mitochondrial permeability transition pore has not been previously examined. Our data show that UVA (14 J/cm(2)) along with resveratrol causes massive oxidative stress in mitochondria. As a consequence of oxidative stress, the mitochondrial membrane potential decreases which results in opening of the mitochondrial pores ultimately leading to apoptosis in human keratinocytes. These results may have clinical implications for development of future chemotherapeutic treatment for tumors of the skin.


Asunto(s)
Apoptosis/efectos de la radiación , Queratinocitos/efectos de la radiación , Mitocondrias/efectos de la radiación , Proteínas de Transporte de Membrana Mitocondrial/efectos de la radiación , Estrés Oxidativo/efectos de la radiación , Estilbenos/farmacología , Rayos Ultravioleta , Apoptosis/efectos de los fármacos , Células HEK293 , Humanos , Queratinocitos/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/efectos de los fármacos , Poro de Transición de la Permeabilidad Mitocondrial , Estrés Oxidativo/efectos de los fármacos , Resveratrol
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