RESUMEN
In this paper, we demonstrated the biological effects of acute low-dose neutrons on the whole body of rats and investigated the impact of that level of neutron dose to induce an in vivo radio-adaptive response. To understand the radio-adaptive response, the examined animals were exposed to acute neutron radiation doses of 5 and 10 mSv, followed by a 50 mSv challenge dose after 14 days. After irradiation, all groups receiving single and double doses were kept in cages for one day before sampling. The electron paramagnetic resonance (EPR) method was used to estimate the radiation-induced radicals in the blood, and some hematological parameters and lipid peroxidation (MDA) were determined. A comet assay was performed beside some of the antioxidant enzymes [catalase enzyme (CAT), superoxide dismutase (SOD), and glutathione (GSH)]. Seven groups of adult male rats were classified according to their dose of neutron exposure. Measurements of all studied markers are taken one week after harvesting, except for hematological markers, within 2 h. The results indicated lower production of antioxidant enzymes (CAT by 1.18-5.83%, SOD by 1.47-17.8%, and GSH by 11.3-82.1%). Additionally, there was an increase in red cell distribution width (RDW) (from 4.61 to 25.19%) and in comet assay parameters such as Tail Length, (from 6.16 to 10.81 µm), Tail Moment, (from 1.17 to 2.46 µm), and percentage of DNA in tail length (DNA%) (from 9.58 to 17.32%) in all groups exposed to acute doses of radiation ranging from 5 to 50 mSv, respectively. This emphasizes the ascending harmful effect with the increased acute thermal neutron doses. The values of the introduced factor of radio adaptive response for all markers under study reveal that the lower priming dose promotes a higher adaptation response and vice versa. Ultimately, the results indicate significant variations in DNA%, SOD enzyme levels, EPR intensity, total Hb concentration, and RDWs, suggesting their potential use as biomarkers for acute thermal neutron dosimetry. Further research is necessary to validate these measurements as biodosimetry for radiation exposure, including investigations involving the response impact of RAR with varied challenge doses and post-irradiation behavior.
Asunto(s)
Biomarcadores , Neutrones , Animales , Ratas , Masculino , Biomarcadores/metabolismo , Superóxido Dismutasa/metabolismo , Peroxidación de Lípido/efectos de la radiación , Radiometría/métodos , Relación Dosis-Respuesta en la Radiación , Daño del ADN/efectos de la radiación , Adaptación Fisiológica/efectos de la radiación , Catalasa/metabolismo , Glutatión/metabolismo , Glutatión/sangre , Ensayo Cometa , Estrés Oxidativo/efectos de la radiación , Espectroscopía de Resonancia por Spin del Electrón/métodosRESUMEN
Naturally Occurring Radioactive Materials (NORM) contribute to everyone's natural background radiation dose. The technologically advanced activities of the gas and oil sectors produce considerable amounts of radioactive materials as industrial by-products or waste products. The goal of the current study is to estimate the danger of long-term liability to Technologically Enhanced Naturally Occurring Radioactive Materials (TE-NORM) on blood indices, neurotransmitters, oxidative stress markers, and ß-amyloid in the cerebral cortex of rats' brains. Twenty adult male albino rats were divided into two equal groups (n = 10): control and irradiated. Irradiated rats were exposed to a total dose of 0.016 Gy of TE-NORM as a whole-body chronic exposure over a period of two months. It should be ''The results showed no significant changes in RBC count, Hb concentration, hematocrit percentage (HCT%), and Mean Corpuscular Hemoglobin Concentration (MCHC). However, there was a significant increase in the Mean Corpuscular Volume of RBCs (MCV) and a significant decrease in cell distribution width (RDW%) compared to the control. Alteration in neurotransmitters is noticeable by a significant increase in glutamic acid and significant decreases in serotonin and dopamine. Increased lipid peroxidation, decreased glutathione content, superoxide dismutase, catalase, and glutathione peroxidase activities indicating oxidative stress were accompanied by increased ß-amyloid in the cerebral cortex of rats' brains. The findings of the present study showed that chronic radiation liability has some harmful effects, that may predict the risks of future health problems in occupational radiation exposure in the oil industries. Therefore, the control of exposure and application of sample dosimetry is recommended for health and safety.
Asunto(s)
Estrés Oxidativo , Animales , Masculino , Ratas , Estrés Oxidativo/efectos de la radiación , Radiación de Fondo , Neurotransmisores/metabolismo , Neurotransmisores/sangre , Encéfalo/efectos de la radiación , Encéfalo/metabolismo , Peroxidación de Lípido/efectos de la radiación , Péptidos beta-Amiloides/metabolismoRESUMEN
UVA exposure disturbs the metabolism of skin cells, often inducing oxidative stress and inflammation. Therefore, there is a need for bioactive compounds that limit such consequences without causing undesirable side effects. The aim of this study was to analyse in vitro the effects of the phytocannabinoids cannabigerol (CBG) and cannabidiol (CBD), which differ in terms of biological effects. Furthermore, the combined use of both compounds (CBG+CBD) has been analysed in order to increase their effectiveness in human skin fibroblasts and keratinocytes protection against UVA-induced alternation. The results obtained indicate that the effects of CBG and CBD on the redox balance might indeed be enhanced when both phytocannabinoids are applied concurrently. Those effects include a reduction in NOX activity, ROS levels, and a modification of thioredoxin-dependent antioxidant systems. The reduction in the UVA-induced lipid peroxidation and protein modification has been confirmed through lower levels of 4-HNE-protein adducts and protein carbonyl groups as well as through the recovery of collagen expression. Modification of antioxidant signalling (Nrf2/HO-1) through the administration of CBG+CBD has been proven to be associated with reduced proinflammatory signalling (NFκB/TNFα). Differential metabolic responses of keratinocytes and fibroblasts to the effects of the UVA and phytocannabinoids have indicated possible beneficial protective and regenerative effects of the phytocannabinoids, suggesting their possible application for the purpose of limiting the harmful impact of the UVA on skin cells.
Asunto(s)
Cannabidiol , Cannabinoides , Fibroblastos , Inflamación , Queratinocitos , Oxidación-Reducción , Transducción de Señal , Piel , Rayos Ultravioleta , Humanos , Oxidación-Reducción/efectos de los fármacos , Piel/efectos de los fármacos , Piel/efectos de la radiación , Piel/metabolismo , Piel/patología , Rayos Ultravioleta/efectos adversos , Cannabinoides/farmacología , Transducción de Señal/efectos de los fármacos , Cannabidiol/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de la radiación , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Queratinocitos/metabolismo , Inflamación/patología , Inflamación/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Antioxidantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiaciónRESUMEN
BACKGROUND: Exposure to environmental stressors like particulate matter (PM) and ultraviolet radiation (UV) induces cutaneous oxidative stress and inflammation and leads to skin barrier dysfunction and premature aging. Metals like iron or copper are abundant in PM and are known to contribute to reactive oxygen species (ROS) production. AIMS: Although it has been suggested that topical antioxidants may be able to help in preventing and/or reducing outdoor skin damage, limited clinical evidence under real-life exposure conditions have been reported. The aim of the present study was to evaluate the ability of a topical serum containing 15% ascorbic acid, 0.5% ferulic acid, and 1% tocopherol (CF Mix) to prevent oxinflammatory skin damage and premature aging induced by PM + UV in a human clinical trial. METHODS: A 4-day single-blinded, clinical study was conducted on the back of 15 females (18-40 years old). During the 4 consecutive days, the back test zones were treated daily with or without the CF Mix, followed by with/without 2 h of PM and 5 min of UV daily exposure. RESULTS: Application of the CF Mix prevented PM + UV-induced skin barrier perturbation (Involucrin and Loricrin), lipid peroxidation (4HNE), inflammatory markers (COX2, NLRP1, and AhR), and MMP9 activation. In addition, CF Mix was able to prevent Type I Collagen loss. CONCLUSION: This is the first human study confirming multipollutant cutaneous damage and suggesting the utility of a daily antioxidant topical application to prevent pollution induced skin damage.
Asunto(s)
Antioxidantes , Estrés Oxidativo , Material Particulado , Piel , Rayos Ultravioleta , Humanos , Femenino , Rayos Ultravioleta/efectos adversos , Adulto , Antioxidantes/administración & dosificación , Método Simple Ciego , Adulto Joven , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Material Particulado/efectos adversos , Material Particulado/administración & dosificación , Piel/efectos de la radiación , Piel/efectos de los fármacos , Piel/metabolismo , Adolescente , Envejecimiento de la Piel/efectos de los fármacos , Envejecimiento de la Piel/efectos de la radiación , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/farmacología , Administración Cutánea , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiación , Ácidos CumáricosRESUMEN
The prevalence of Light-emitting diodes (LEDs) has exposed us to an excessive amount of blue light (BL) which causes various ophthalmic diseases. Previous studies have shown that conjunctiva is vulnerable to BL. In this study, we aimed to investigate the underlying mechanism of BL-induced injury in conjunctiva. We placed C57BL/6 mice and human conjunctival epithelial cell lines (HCECs) under BL (440 nm ± 15 nm, 0.2 mW/cm2) to establish a BL injury model in vivo and in vitro. Immunohistochemistry and MDA assay were used to identify lipid peroxidation (LPO) in vivo. HE staining was applied to detect morphological damage of conjunctival epithelium. DCFH-DA, C11-BODIPY 581/591, Calcein-AM, and FeRhoNox™-1 probes were performed to identify ferroptosis levels in vitro. Real-time qPCR and Western blotting techniques were employed to uncover signaling pathways of blue light-induced ferroptosis. Our findings demonstrated that BL affected tear film instability and induced conjunctival epithelium injury in vivo. Ferrostatin-1 significantly alleviated blue light-induced ferroptosis in vivo and in vitro. BL downregulates the levels of solute carrier family 7 member 11 (SLC7A11), Ferritin heavy chain (FTH1), and glutathione peroxidase (GPX4) by inhibiting the activation and translocation of the Signal transducer and activator of transcription 3 (STAT3) from inducing Fe2+ burst, ROS and LPO accumulation, ultimately resulting in ferroptosis. This study will offer new insight into BL-induced conjunctival injury and LED-induced dry eye.
Asunto(s)
Luz Azul , Conjuntiva , Ferroptosis , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Factor de Transcripción STAT3 , Animales , Humanos , Ratones , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Línea Celular , Conjuntiva/metabolismo , Conjuntiva/efectos de la radiación , Conjuntiva/patología , Ciclohexilaminas , Células Epiteliales/metabolismo , Células Epiteliales/efectos de la radiación , Células Epiteliales/patología , Epitelio/efectos de la radiación , Epitelio/metabolismo , Epitelio/patología , Ferroptosis/efectos de la radiación , Peroxidación de Lípido/efectos de la radiación , Ratones Endogámicos C57BL , Fenilendiaminas/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de la radiación , Factor de Transcripción STAT3/metabolismoRESUMEN
UV irradiation significantly alters nanoplastics (NPs) physicochemical properties, thus affecting their biological toxicity. This study is the first to assess the influence of virgin and UV-aged polystyrene NPs (v-PS NPs, a-PS NPs) on the intestinal barrier of ICR mice. We found that a-PS NPs can cause more severe intestinal barrier damage compared with v-PS NPs. The reason may be attributed to that a-PS NPs produced more ROS in intestinal tissue. Moreover, the strong oxidizing property of hydroxyl radicals (·OH) generated from the a-PS NPs can damage cell membranes through lipid peroxidation, thereby leading to a low clearance rate of ·OH due to the impaired intestinal tissue function, in turn, causing more ROS to accumulate and inducing severe oxidative damage. This research underscores the crucial role of ·OH in mediating oxidative damage from UV-aged nanoparticles, emphasizing the need to consider environmental factors in assessing NPs toxicity.
Asunto(s)
Mucosa Intestinal , Ratones Endogámicos ICR , Nanopartículas , Poliestirenos , Especies Reactivas de Oxígeno , Rayos Ultravioleta , Animales , Poliestirenos/toxicidad , Rayos Ultravioleta/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de la radiación , Nanopartículas/toxicidad , Masculino , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiación , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Radical Hidroxilo/metabolismo , Ratones , Microplásticos/toxicidadRESUMEN
PURPOSE: The products of lipid peroxidation have been implicated in human diseases and aging. This prompted us to investigate the response to conventional (CONV) versus FLASH irradiation of oxylipins, a family of bioactive lipid metabolites derived from omega-3 or omega-6 polyunsaturated fatty acids through oxygen-dependent non-enzymatic as well as dioxygenase-mediated free radical reactions. METHODS AND MATERIALS: Ultrahigh performance liquid chromatography coupled to tandem mass spectrometry was used to quantify the expression of 37 oxylipins derived from eicosatetraenoic, eicosapentaenoic and docosahexaenoic acid in mouse lung and in normal or cancer cells exposed to either radiation modality under precise monitoring of the temperature and oxygenation. Among the 37 isomers assayed, 14-16 were present in high enough amount to enable quantitative analysis. The endpoints were the expression of oxylipins as a function of the dose of radiation, normoxia versus hypoxia, temperature and post-irradiation time. RESULTS: In normal, normoxic cells at 37°C radiation elicited destruction and neosynthesis of oxylipins acting antagonistically on a background subject to rapid remodeling by oxygenases. Neosynthesis was observed in the CONV mode only, in such a way that the level of oxylipins at 5 minutes after FLASH irradiation was 20-50% lower than in non-irradiated and CONV-irradiated cells. Hypoxia mitigated the differential CONV versus FLASH response in some oxylipins. These patterns were not reproduced in tumor cells. Depression of specific oxylipins following FLASH irradiation was observed in mouse lung at 5 min following irradiation, with near complete recovery in 24 hours and further remodeling at one week and two months post-irradiation. CONCLUSIONS: Down-regulation of oxylipins was a hallmark of FLASH irradiation specific of normal cells. Temperature effects suggest that this process occurs via diffusion-controlled, bimolecular recombination of a primary radical species upstream from peroxyl radical formation and evoke a major role of the membrane composition and fluidity in response to the FLASH modality.
Asunto(s)
Oxilipinas , Oxilipinas/metabolismo , Animales , Ratones , Peroxidación de Lípido/efectos de la radiación , Humanos , Pulmón/efectos de la radiación , Pulmón/metabolismo , Temperatura , Cromatografía Líquida de Alta Presión , Espectrometría de Masas en Tándem , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ácido Eicosapentaenoico/metabolismo , Ratones Endogámicos C57BL , Ácidos Docosahexaenoicos/metabolismoRESUMEN
BACKGROUND: This work was carried out to compare the modifying roles of ascorbic and metformin during Ehrlich (ESC) tumor-bearing mice irradiation. METHODS: Fifty Swiss albino male mice were segmented into seven groups, including one control group and six Ehrlich induced tumors treated with ascorbic, ascorbic plus radiation, metformin, metformin plus radiation, and radiation only. Many tests, including behavioral, biochemical, immunohistochemistry, gene expression, DNA fragmentation, oxidative stress markers, and EPR, were performed to interrogate the modifying effects on tumor and liver tissues. RESULTS: Remarkable apoptosis was found in metformin irradiated animals compared to irradiated ascorbic counterparts. The irradiated metformin mice showed the greatest reduction in PCNA. There was a significant reduction of DNA fragmentation in the liver tissues of the irradiated metformin group. Irradiated metformin and irradiated ascorbic acid animals showed a reduced signal of ERK as well as c-Fos genes. There was a tendency of metformin and metformin irradiated animals to reduce MDA levels in liver tissues. ESC-bearing mice treated with ascorbic or metformin showed an improvement in the spontaneous alternation percentage (SAP%) and improved short-term memory. There was also an improvement in long memory tests. CONCLUSIONS: The study added more preclinical evidence on the utility of metformin in cancer treatment during radiotherapy. Metformin was shown to reduce lipid peroxidation in irradiated healthy tissues, increase tumor cytotoxicity, downregulate critical pathways involved in tumor progression and proliferation, and enhance tumor apoptosis. Controlled clinical trials using metformin are highly warranted.
Asunto(s)
Carcinoma de Ehrlich , Metformina , Neoplasias , Animales , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/radioterapia , Peroxidación de Lípido/efectos de la radiación , Metformina/uso terapéutico , RatonesRESUMEN
Oxidative stress and lipid peroxidation are major causes of skin injury induced by ultraviolet (UV) irradiation. Ferroptosis is a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids and contributes to kinds of tissue injuries. However, it remains unclear whether the accumulation of lipid peroxides in UV irradiation-induced skin injury could lead to ferroptosis. We generated UV irradiation-induced skin injury mice model to examine the accumulation of the lipid peroxides and iron. Lipid peroxides 4-HNE, the oxidative enzyme COX2, the oxidative DNA damage biomarker 8-OHdG, and the iron level were increased in UV irradiation-induced skin. The accumulation of iron and lipid peroxidation was also observed in UVB-irradiated epidermal keratinocytes without actual ongoing ferroptotic cell death. Ferroptosis was triggered in UV-irradiated keratinocytes stimulated with ferric ammonium citrate (FAC) to mimic the iron overload. Although GPX4 protected UVB-injured keratinocytes against ferroptotic cell death resulted from dysregulation of iron metabolism and the subsequent increase of lipid ROS, keratinocytes enduring constant UVB treatment were markedly sensitized to ferroptosis. Nicotinamide mononucleotide (NMN) which is a direct and potent NAD+ precursor supplement, rescued the imbalanced NAD+/NADH ratio, recruited the production of GSH and promoted resistance to lipid peroxidation in a GPX4-dependent manner. Taken together, our data suggest that NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation-induced skin injury and inhibits oxidative skin damage. NMN or ferroptosis inhibitor might become promising therapeutic approaches for treating oxidative stress-induced skin diseases or disorders.
Asunto(s)
Glutatión/genética , Hierro/metabolismo , Estrés Oxidativo/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Piel/metabolismo , 8-Hidroxi-2'-Desoxicoguanosina/farmacología , Aldehídos/farmacología , Animales , Ciclooxigenasa 2/genética , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Compuestos Férricos/farmacología , Ferroptosis/efectos de los fármacos , Ferroptosis/efectos de la radiación , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiación , Peróxidos Lipídicos/farmacología , Ratones , Mononucleótido de Nicotinamida/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Compuestos de Amonio Cuaternario/farmacología , Piel/efectos de los fármacos , Piel/lesiones , Piel/patología , Rayos Ultravioleta/efectos adversosRESUMEN
Radiotherapy promotes tumor cell death and senescence through the induction of oxidative damage. Recent work has highlighted the importance of lipid peroxidation for radiotherapy efficacy. Excessive lipid peroxidation can promote ferroptosis, a regulated form of cell death. In this review, we address the evidence supporting a role of ferroptosis in response to radiotherapy and discuss the molecular regulators that underlie this interaction. Finally, we postulate on the clinical implications for the intersection of ferroptosis and radiotherapy.
Asunto(s)
Metabolismo de los Lípidos/efectos de la radiación , Peroxidación de Lípido/efectos de la radiación , Neoplasias/radioterapia , Muerte Celular/efectos de la radiación , Senescencia Celular/genética , Senescencia Celular/efectos de la radiación , Ferroptosis/genética , Ferroptosis/efectos de la radiación , Humanos , Metabolismo de los Lípidos/genética , Neoplasias/genética , Neoplasias/patología , Estrés Oxidativo/efectos de la radiaciónRESUMEN
In recent decades, atmospheric pollution led to a progressive reduction of the ozone layer with a consequent increase in UV-B radiation. Despite the high adaptation of olive trees to the Mediterranean environment, the progressive increase of UV-B radiation is a risk factor for olive tree cultivation. It is therefore necessary to understand how high levels of UV-B radiation affect olive plants and to identify olive varieties which are better adapted. In this study we analyzed two Italian olive varieties subjected to chronic UV-B stress. We focused on the effects of UV-B radiation on RubisCO, in terms of quantity, enzymatic activity and isoform composition. In addition, we also analyzed changes in the activity of antioxidant enzymes (SOD, CAT, GPox) to get a comprehensive picture of the antioxidant system. We also evaluated the effects of UV-B on the enzyme sucrose synthase. The overall damage at biochemical level was also assessed by analyzing changes in Hsp70, a protein triggered under stress conditions. The results of this work indicate that the varieties (Giarraffa and Olivastra Seggianese) differ significantly in the use of specific antioxidant defense systems, as well as in the activity and isoform composition of RubisCO. Combined with a different use of sucrose synthase, the overall picture shows that Giarraffa optimized the use of GPox and opted for a targeted choice of RubisCO isoforms, in addition to managing the content of sucrose synthase, thereby saving energy during critical stress points.
Asunto(s)
Antioxidantes/metabolismo , Olea/metabolismo , Olea/efectos de la radiación , Proteínas de Plantas/metabolismo , Ribulosa-Bifosfato Carboxilasa/metabolismo , Enzimas/metabolismo , Glucosiltransferasas/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Italia , Peroxidación de Lípido/efectos de la radiación , Malondialdehído/metabolismo , Microscopía Electrónica de Transmisión , Olea/citología , Hojas de la Planta/citología , Hojas de la Planta/efectos de la radiación , Rayos UltravioletaRESUMEN
UV radiation is known to induce a multiple changes in the metabolism of skin-building cells, what can affect the functioning not only neighboring cells, but also, following signal transduction releasing into the blood vessels, the entire body. Therefore, the aim of this study was to analyze the proteomic disturbances occurred in plasma of chronically UVA/UVB irradiated rats and define the effect on these changes of skin topically applied cannabidiol (CBD). Obtained results showed significant changes in the expression of numerous anti-inflammatory and signaling proteins including: NFκB inhibitor, 14-3-3 protein, protein kinase C, keratin, and protein S100 after UV irradiation and CBD treatment. Moreover, the effects of UVA and UVB were manifested by increased level of lipid peroxidation products-protein adducts formation. CBD partially prevented all of these changes, but in a various degree depending on the UV radiation type. Moreover, topical treatment with CBD resulted in the penetration of CBD into the blood and, as a consequence, in direct modifications to the plasma protein structure by creating CBD adducts with molecules, such as proline-rich protein 30, transcription factor 19, or N-acetylglucosamine-6-sulfatase, what significantly changed the activity of these proteins. In conclusion, it may be suggested that CBD applied topically may be an effective compound against systemic UV-induced oxidative stress, but its effectiveness requires careful analysis of CBD's effects on other tissues of the living organism.
Asunto(s)
Cannabidiol/administración & dosificación , Proteoma/efectos de la radiación , Piel/efectos de los fármacos , Piel/efectos de la radiación , Administración Tópica , Animales , Antiinflamatorios/farmacología , Antioxidantes/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiación , Masculino , Ratones Desnudos , Proteoma/metabolismo , Proteómica/métodos , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Piel/metabolismo , Rayos UltravioletaRESUMEN
Lipid oxidation is ubiquitous in cell life under oxygen and essential for photodynamic therapy (PDT) of carcinomas. However, the mechanisms underlying lipid oxidation in rather complex systems such as plasma membranes remain elusive. Herein, Langmuir monolayers were assembled with the lipid extract of glandular breast cancer (MCF7) cells and used to probe the molecular interactions allowing adsorption of the photosensitizer (PS) erythrosine B and subsequent photooxidation outcomes. Surface pressure (π) versus area (cm2/mL) isotherms of MCF7 lipid extract shifted to larger areas upon erythrosine incorporation, driven by secondary interactions that affected the orientation of the carbonyl groups and lipid chain organization. Light-irradiation increased the surface area of the MCF7 lipid extract monolayer containing erythrosine owing to the lipid hydroperoxidation, which may further undergo decomposition, resulting in the chain cleavage of phospholipids and membrane permeabilization. Incorporation of erythrosine by MCF7 cells induced slight toxic effects on in vitro assays, differently of the severe phototoxicity caused by light-irradiation, which significantly decreased cell viability by more than 75% at 2.5 × 10-6 mol/L of erythrosine incubated for 3 and 24 h, reaching nearly 90% at 48 h of incubation. The origin of the phototoxic effects is in the rupture of the plasma membrane shown by the frontal (FSC) and side (SSC) light scattering of flow cytometry. Consistent with hydroperoxide decomposition, membrane permeabilization was also confirmed by cleaved lipids detected in mass spectrometry and subsidizes the necrotic pathway of cell death.
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Membrana Celular/efectos de los fármacos , Eritrosina/farmacología , Luz , Fármacos Fotosensibilizantes/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Membrana Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Elasticidad , Eritrosina/química , Femenino , Humanos , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiación , Lípidos/análisis , Lípidos/química , Microscopía Confocal , Fármacos Fotosensibilizantes/química , Análisis de Componente Principal , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Radon inhalation decreases the level of lipid peroxide (LPO); this is attributed to the activation of antioxidative functions. This activation contributes to the beneficial effects of radon therapy, but there are no studies on the risks of radon therapy, such as DNA damage. We evaluated the effect of radon inhalation on DNA damage caused by oxidative stress and explored the underlying mechanisms. Mice were exposed to radon inhalation at concentrations of 2 or 20 kBq/m3 (for one, three, or 10 days). The 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels decreased in the brains of mice that inhaled 20 kBq/m3 radon for three days and in the kidneys of mice that inhaled 2 or 20 kBq/m3 radon for one, three or 10 days. The 8-OHdG levels in the small intestine decreased by approximately 20-40% (2 kBq/m3 for three days or 20 kBq/m3 for one, three or 10 days), but there were no significant differences in the 8-OHdG levels between mice that inhaled a sham treatment and those that inhaled radon. There was no significant change in the levels of 8-oxoguanine DNA glycosylase, which plays an important role in DNA repair. However, the level of Mn-superoxide dismutase (SOD) increased by 15-60% and 15-45% in the small intestine and kidney, respectively, following radon inhalation. These results suggest that Mn-SOD probably plays an important role in the inhibition of oxidative DNA damage.
Asunto(s)
Daño del ADN/efectos de la radiación , Estrés Oxidativo/efectos de la radiación , Radón/farmacología , Superóxido Dismutasa/fisiología , 8-Hidroxi-2'-Desoxicoguanosina/análisis , Administración por Inhalación , Animales , Química Encefálica/efectos de la radiación , ADN Glicosilasas/análisis , Inducción Enzimática/efectos de la radiación , Intestino Delgado/química , Intestino Delgado/efectos de la radiación , Riñón/química , Riñón/efectos de la radiación , Peroxidación de Lípido/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos BALB C , Especificidad de Órganos , Oxidación-Reducción , Radón/administración & dosificación , Radón/uso terapéutico , Superóxido Dismutasa/biosíntesis , Superóxido Dismutasa/genéticaRESUMEN
The mammalian target of rapamycin (mTOR) is a sensor of nutrient status and plays an important role in cell growth and metabolism. Although inhibition of mTOR signaling promotes tumor cell death and several mTOR inhibitors have been used clinically, recent reports have shown that co-treatment with MHY1485, an mTOR activator, enhances the anti-cancer effects of anti-PD-1 antibody and 5-fluorouracil. However, it remains unclear whether MHY1485 treatment alters the effects of radiation on tumor cells. In this study, the radiosensitizing effects of MHY1485 were investigated using murine CT26 and LLC cell lines. We examined mTOR signaling, tumor cell growth, colony formation, apoptosis, senescence, oxidative stress, p21 accumulation and endoplasmic reticulum (ER) stress levels in cells treated with MHY1485 and radiation, either alone or together. We found that MHY1485 treatment inhibited growth and colony formation in both cell lines under irradiation and no-irradiation conditions, results that were not fully consistent with MHY1485's known role in activating mTOR signaling. Furthermore, we found that combined treatment with MHY1485 and radiation significantly increased apoptosis and senescence in tumor cells in association with oxidative stress, ER stress and p21 stabilization, compared to radiation treatment alone. Our results suggested that MHY1485 enhances the radiosensitivity of tumor cells by a mechanism that may differ from MHY1485's role in mTOR activation.
Asunto(s)
Apoptosis/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Morfolinas/farmacología , Proteínas de Neoplasias/agonistas , Serina-Treonina Quinasas TOR/efectos de los fármacos , Triazinas/farmacología , Animales , Apoptosis/efectos de la radiación , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Línea Celular Tumoral , Senescencia Celular/efectos de la radiación , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Ensayos de Selección de Medicamentos Antitumorales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de la radiación , Genes p53 , Genes ras , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiación , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/efectos de la radiación , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Ensayo de Tumor de Célula MadreRESUMEN
Ultraviolet (UV) irradiation is an important risk factor in cataractogenesis. Lens epithelial cells (LECs), which are a highly metabolically active part of the lens, play an important role in UV-induced cataractogenesis. The purpose of this study was to characterize cell compounds such as nucleic acids, proteins, and lipids in human UV C-irradiated anterior lens capsules (LCs) with LECs, as well as to compare them with the control, non-irradiated LCs of patients without cataract, by using synchrotron radiation-based Fourier transform infrared (SR-FTIR) micro-spectroscopy. In order to understand the effect of the UV C on the LC bio-macromolecules in a context of cataractogenesis, we used the SR-FTIR micro-spectroscopy setup installed on the beamline MIRAS at the Spanish synchrotron light source ALBA, where measurements were set to achieve a single-cell resolution with high spectral stability and high photon flux. UV C irradiation of LCs resulted in a significant effect on protein conformation with protein formation of intramolecular parallel ß-sheet structure, lower phosphate and carboxyl bands in fatty acids and amino acids, and oxidative stress markers with significant increase of lipid peroxidation and diminishment of the asymmetric CH3 band.
Asunto(s)
Cápsula del Cristalino/química , Cápsula del Cristalino/efectos de la radiación , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Rayos Ultravioleta/efectos adversos , Anciano , Carbohidratos/química , Catarata/etiología , Células Epiteliales/química , Células Epiteliales/efectos de la radiación , Ésteres/química , Humanos , Cápsula del Cristalino/diagnóstico por imagen , Peroxidación de Lípido/efectos de la radiación , Masculino , Ácidos Nucleicos/química , Estrés Oxidativo/efectos de la radiación , Conformación Proteica , Proteínas/química , SincrotronesRESUMEN
Photobiomodulation with 808 nm laser light electively stimulates Complexes III and IV of the mitochondrial respiratory chain, while Complexes I and II are not affected. At the wavelength of 1064 nm, Complexes I, III, and IV are excited, while Complex II and some mitochondrial matrix enzymes seem to be not receptive to photons at that wavelength. Complex IV was also activated by 633 nm. The mechanism of action of wavelengths in the range 900-1000 nm on mitochondria is less understood or not described. Oxidative stress from reactive oxygen species (ROS) generated by mitochondrial activity is an inescapable consequence of aerobic metabolism. The antioxidant enzyme system for ROS scavenging can keep them under control. However, alterations in mitochondrial activity can cause an increment of ROS production. ROS and ATP can play a role in cell death, cell proliferation, and cell cycle arrest. In our work, bovine liver isolated mitochondria were irradiated for 60 sec, in continuous wave mode with 980 nm and powers from 0.1 to 1.4 W (0.1 W increment at every step) to generate energies from 6 to 84 J, fluences from 7.7 to 107.7 J/cm2, power densities from 0.13 to 1.79 W/cm2, and spot size 0.78 cm2. The control was equal to 0 W. The activity of the mitochondria's complexes, Krebs cycle enzymes, ATP production, oxygen consumption, generation of ROS, and oxidative stress were detected. Lower powers (0.1-0.2 W) showed an inhibitory effect; those that were intermediate (0.3-0.7 W) did not display an effect, and the higher powers (0.8-1.1 W) induced an increment of ATP synthesis. Increasing the power (1.2-1.4 W) recovered the ATP production to the control level. The interaction occurred on Complexes III and IV, as well as ATP production and oxygen consumption. Results showed that 0.1 W uncoupled the respiratory chain and induced higher oxidative stress and drastic inhibition of ATP production. Conversely, 0.8 W kept mitochondria coupled and induced an increase of ATP production by increments of Complex III and IV activities. An augmentation of oxidative stress was also observed, probably as a consequence of the increased oxygen consumption and mitochondrial isolation experimental conditions. No effect was observed using 0.5 W, and no effect was observed on the enzymes of the Krebs cycle.
Asunto(s)
Láseres de Semiconductores , Terapia por Luz de Baja Intensidad , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Animales , Bovinos , Respiración de la Célula/efectos de la radiación , Complejo III de Transporte de Electrones/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Isocitrato Deshidrogenasa/metabolismo , Peroxidación de Lípido/efectos de la radiación , Malato Deshidrogenasa/metabolismo , Masculino , Fosforilación Oxidativa/efectos de la radiación , Estrés Oxidativo/efectos de la radiación , ATPasas de Translocación de Protón/metabolismo , Superóxidos/metabolismo , TemperaturaRESUMEN
Exposure to reactive oxygen species can easily result in serious diseases, such as hyperproliferative skin disorders or skin cancer. Herbal extracts are widely used as antioxidant sources in different compositions. The importance of antioxidant therapy in inflammatory conditions has increased. Innovative formulations can be used to improve the effects of these phytopharmacons. The bioactive compounds of Plantago lanceolata (PL) possess different effects, such as anti-inflammatory, antioxidant, and bactericidal pharmacological effects. The objective of this study was to formulate novel liquid crystal (LC) compositions to protect Plantago lanceolata extract from hydrolysis and to improve its effect. Since safety is an important aspect of pharmaceutical formulations, the biological properties of applied excipients and blends were evaluated using assorted in vitro methods on HaCaT cells. According to the antecedent toxicity screening evaluation, three surfactants were selected (Gelucire 44/14, Labrasol, and Lauroglycol 90) for the formulation. The dissolution rate of PL from the PL-LC systems was evaluated using a Franz diffusion chamber apparatus. The antioxidant properties of the PL-LC systems were evaluated with 2,2-diphenyl-1-picrylhydrazyl (DPPH) and malondialdehyde (MDA) assessments. Our results suggest that these compositions use a nontraditional, rapid-permeation pathway for the delivery of drugs, as the applied penetration enhancers reversibly alter the barrier properties of the outer stratum corneum. These excipients can be safe and highly tolerable thus, they could improve the patient's experience and promote adherence.
Asunto(s)
Composición de Medicamentos , Cristales Líquidos/química , Extractos Vegetales/farmacología , Plantago/química , Piel/efectos de los fármacos , Compuestos de Bifenilo/química , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Impedancia Eléctrica , Depuradores de Radicales Libres/farmacología , Células HaCaT , Humanos , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiación , Malondialdehído/metabolismo , Permeabilidad , Picratos/química , Piel/efectos de la radiación , Rayos UltravioletaRESUMEN
Ultra-violet (UV) radiation (UVR) causes significant oxidative injury to retinal pigment epithelium (RPE) cells. Obacunone is a highly oxygenated triterpenoid limonoid compound with various pharmacological properties. Its potential effect in RPE cells has not been studied thus far. Here in ARPE-19 cells and primary murine RPE cells, obacunone potently inhibited UVR-induced reactive oxygen species accumulation, mitochondrial depolarization, lipid peroxidation and single strand DNA accumulation. UVR-induced RPE cell death and apoptosis were largely alleviated by obacunone. Obacunone activated Nrf2 signaling cascade in RPE cells, causing Keap1-Nrf2 disassociation, Nrf2 protein stabilization and nuclear translocation. It promoted transcription and expression of antioxidant responsive element-dependent genes. Nrf2 silencing or CRISPR/Cas9-induced Nrf2 knockout almost reversed obacunone-induced RPE cytoprotection against UVR. Forced activation of Nrf2 cascade, by Keap1 knockout, similarly protected RPE cells from UVR. Importantly, obacunone failed to offer further RPE cytoprotection against UVR in Keap1-knockout cells. In vivo, intravitreal injection of obacunone largely inhibited light-induced retinal damage. Collectively, obacunone protects RPE cells from UVR-induced oxidative injury through activation of Nrf2 signaling cascade.
Asunto(s)
Benzoxepinas/farmacología , Limoninas/farmacología , Degeneración Macular/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Epitelio Pigmentado de la Retina/efectos de los fármacos , Rayos Ultravioleta/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Benzoxepinas/uso terapéutico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , ADN de Cadena Simple/efectos de los fármacos , ADN de Cadena Simple/efectos de la radiación , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Humanos , Inyecciones Intravítreas , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Limoninas/uso terapéutico , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiación , Degeneración Macular/etiología , Degeneración Macular/patología , Ratones , Membranas Mitocondriales/efectos de los fármacos , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/genética , Estrés Oxidativo/efectos de la radiación , Cultivo Primario de Células , Especies Reactivas de Oxígeno/metabolismo , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/efectos de la radiación , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/efectos de la radiaciónRESUMEN
Ultraviolet B (UVB) light corresponds to 5% of ultraviolet radiation. It is more genotoxic and mutagenic than UVA and causes direct and indirect cellular damage through the generation of reactive oxygen species (ROS). Even after radiation, ROS generation may continue through activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) enzyme. Long-term exposure can progress to premature skin aging and photocarcinogenesis. To prevent damage that is caused by UVB radiation, several studies have focused on the topical administration of compounds that have antioxidant properties. 2-Acetylphenothiazine (ML171) is a potent and selective inhibitor of NOX1. The present study investigated the antioxidant potential and photoprotective ability of ML171 in UVB-irradiated L929 fibroblasts. ML171 had considerable antioxidant activity in both the DPPH⢠and xanthine/luminol/xanthine oxidase assays. ML171 did not induce cytotoxicity in L929 fibroblasts and increased the viability of UVB-irradiated cells. ML171 also inhibited ROS production, the enzymatic activity of NOX, depolarization of the mitochondrial membrane, and DNA damage. Additionally, ML171 protected cell membrane integrity and induced fibroblast migration. These results suggest that the incorporation of ML171 in topical administration systems may be a promising strategy to mitigate UVB-induced oxidative damage in L929 fibroblasts.