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1.
Ecotoxicol Environ Saf ; 208: 111579, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396102

RESUMO

Studies about radiation damage in vivo are very significant for healthy risk assessment as well as cancer radiotherapy. Ceramide as a second messenger has been found to be related to radiation-induced apoptosis. However, the detailed mechanisms in living systems are still not fully understood. In the present study, the effects of ceramide in gamma radiation-induced response were investigated using Caenorhabditis elegans. Our results indicated that ceramide was required for gamma radiation-induced whole-body germ cell apoptosis by the production of radical oxygen species and decrease of mitochondrial transmembrane potential. Using genetic ceramide synthase-related mutated strains and exogenous C16-ceramide, we illustrated that ceramide could regulate DNA damage response (DDR) pathway to mediate radiation-induced germ cell apoptosis. Moreover, ceramide was found to function epistatic to pmk-1 and mpk-1 in MAPK pathway to promote radiation-induced apoptosis in Caenorhabditis elegans. These results demonstrated ceramide could potentially mediated gamma radiation-induced apoptosis through regulating mitochondrial function, DDR pathway and MAPK pathway.


Assuntos
Caenorhabditis elegans/fisiologia , Ceramidas/farmacologia , Protetores contra Radiação/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos da radiação , Proteínas de Caenorhabditis elegans/genética , Ceramidas/metabolismo , Dano ao DNA , Células Germinativas/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Radiação , Espécies Reativas de Oxigênio/metabolismo
2.
Biochim Biophys Acta Gen Subj ; 1865(1): 129768, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33148501

RESUMO

BACKGROUND: Extensive research is being carried out globally to design and develop new selenium compounds for various biological applications such as antioxidants, radio-protectors, anti-carcinogenic agents, biocides, etc. In this pursuit, 3,3'-diselenodipropionic acid (DSePA), a synthetic organoselenium compound, has received considerable attention for its biological activities. SCOPE OF REVIEW: This review intends to give a comprehensive account of research on DSePA so as to facilitate further research activities on this organoselenium compound and to realize its full potential in different areas of biological and pharmacological sciences. MAJOR CONCLUSIONS: It is an interesting diselenide structurally related to selenocystine. It shows moderate glutathione peroxidase (GPx)-like activity and is an excellent scavenger of reactive oxygen species (ROS). Exposure to radiation, as envisaged during radiation therapy, has been associated with normal tissue side effects and also with the decrease in selenium levels in the body. In vitro and in vivo evaluation of DSePA has confirmed its ability to reduce radiation induced side effects into normal tissues. Administration of DSePA through intraperitoneal (IP) or oral route to mice in a dose range of 2 to 2.5 mg/kg body weight has shown survival advantage against whole body irradiation and a significant protection to lung tissue against thoracic irradiation. Pharmacokinetic profiling of DSePA suggests its maximum absorption in the lung. GENERAL SIGNIFICANCE: Research work on DSePA reported in fifteen years or so indicates that it is a promising multifunctional organoselenium compound exhibiting many important activities of biological relevance apart from radioprotection.


Assuntos
Antioxidantes/farmacologia , Propionatos/farmacologia , Protetores contra Radiação/farmacologia , Compostos de Selênio/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/farmacocinética , Antioxidantes/toxicidade , Humanos , Oxirredução/efeitos dos fármacos , Propionatos/síntese química , Propionatos/farmacocinética , Propionatos/toxicidade , Protetores contra Radiação/síntese química , Protetores contra Radiação/farmacocinética , Protetores contra Radiação/toxicidade , Espécies Reativas de Oxigênio/metabolismo , S-Nitrosotióis/metabolismo , Compostos de Selênio/síntese química , Compostos de Selênio/farmacocinética , Compostos de Selênio/toxicidade
3.
Adv Gerontol ; 33(4): 646-656, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33342093

RESUMO

Radiation-protective and anti-aging properties are often combined. Combination of this properties is linked to the common mechanisms of action such as direct and indirect antioxidant activities, inhibition of free radicals formation, increase resistance to stress impacts at the cellular level, acceleration of DNA reparation, prevention of chronic diseases linked to abnormalities in regeneration processes, activation of immune inflammatory processes and carcinogenesis. Regulation of cell cycle and apoptosis can often be considered as an implementing driver of radiation-protective and anti-aging activities. On the one hand, against the background of stopping the cell cycle and blockade of apoptosis increases the time required to repair the defects of a DNA. Antiapoptotic effects enhances survival chances at the early stage after irradiation in a particular range of doses. On the other hand, activation of apoptosis of altered cells can be seen as one of the mechanisms to delay aging processes and prevention of isolated effects of exposure to ionizing radiation. Formation of radiation-induced and age-related alterations are characterized by multiple factors and a variety of manifestations. Nevertheless, similarity of individual links of the pathogenesis of disease related to radiation exposure and aging of the body is striking. It could be stated that radiation-protective property defines an increase in life expectancy by short-term exposure in sub-lethal and lethal doses. However anti-aging activities prevent the development of remote effects of ionizing radiation by prolonged low doses or fractionated exposure to radiation.


Assuntos
Protetores contra Radiação , Apoptose , Dano ao DNA , Relação Dose-Resposta à Radiação , Radiação Ionizante , Protetores contra Radiação/farmacologia
4.
Mutat Res ; 856-857: 503220, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32928367

RESUMO

We assessed the radioprotective and mitigative actions of sodium diclofenac, a non-steroidal anti-inflammatory drug using cultured human peripheral blood as a model. Both pre- and post-irradiation treatments with the drug reduced gamma radiation-induced formation of dicentric chromosome, cytochalasin-blocked micronuclei and γ-H2AX foci in human peripheral blood lymphocytes. This work supports the concept that sodium diclofenac may be a useful radiation countermeasure agent.


Assuntos
Diclofenaco/farmacologia , Relação Dose-Resposta à Radiação , Histonas/genética , Protetores contra Radiação/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Aberrações Cromossômicas/efeitos dos fármacos , Aberrações Cromossômicas/efeitos da radiação , Análise Citogenética/métodos , Reposicionamento de Medicamentos , Raios gama/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos da radiação , Linfócitos/efeitos dos fármacos , Linfócitos/efeitos da radiação
5.
Ecotoxicol Environ Saf ; 206: 111190, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32871518

RESUMO

Radiotherapy represents a critical component in cancer treatment. However, premature ovarian failure (POF) is a major hurdle of deleterious off-target effects in young females, which, therefore, call for an effective radioprotective agent. The present study aimed to explore the molecular mechanism underlying the protective effects of N-acetyl-L-cysteine (NAC) against γ-radiation-provoked POF. Immature female Sprague-Dawley rats were orally-administered NAC (50 mg/kg) and were exposed to a single whole-body dose of 3.2 Gy ϒ-radiation. NAC administration remarkably reversed abnormal serum estradiol and anti-Müllerian hormone levels by 73% and 40%, respectively while ameliorating the histopathological and ultrastructural alterations-triggered by γ-radiation. Mechanistically, NAC alleviated radiation-induced oxidative damage through significantly increased glutathione peroxidase activity by 102% alongside with decreasing NADPH oxidase subunits (p22 and NOX4) gene expressions by 48% and 38%, respectively compared to the irradiated untreated group. Moreover, NAC administration achieved its therapeutic effect by inhibiting ovarian apoptosis-induced by radiation through downregulating p53 and Bax levels by 33% and 16%, respectively while increasing the Bcl-2 mRNA expression by 135%. Hence, the Bax/Bcl2 ratio and cytochrome c expression were subsequently reduced leading to decreased caspase 3 activity by 43%. Importantly, the anti-apoptotic property of NAC could be attributed to inactivation of MAPK signaling molecules; p38 and JNK, and enhancement of the ovarian vascular endothelial growth factor (VEGF) expression. Taken together, our results suggest that NAC can inhibit radiotherapy-induced POF while preserving ovarian function and structure through upregulating VEGF expression and suppressing NOX4/MAPK/p53 apoptotic signaling.


Assuntos
Acetilcisteína/farmacologia , Raios gama/efeitos adversos , Ovário/efeitos dos fármacos , Insuficiência Ovariana Primária/prevenção & controle , Protetores contra Radiação/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , NADPH Oxidase 4/metabolismo , Ovário/metabolismo , Ovário/efeitos da radiação , Ovário/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/patologia , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
J Environ Pathol Toxicol Oncol ; 39(2): 191-199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749127

RESUMO

We have proven that naringin, a phytonutrient, diminishes oxidative damage and inflammatory responses by modulating PPAR-γ expressions in ultraviolet-B radiation (UVB)-induced NIH-3T3 cells. However, the role of naringin against DNA damage, photoaging, and apoptosis in NIH-3T3 cells has yet to be studied, necessitating investigation. We show that Naringin pretreatment significantly reduces UVB-induced alkaline DNA damage and potentially modulates NER gene (XPC, TFIIH, XPE, ERCC1, and GAPDH) expression, thereby augmenting DNA repair. We determined experimentally that naringin pretreatment prevents UVB-induced nuclear fragmentation in NIH-3T3 cells, as well as altering UVB-induced apoptotic marker (Bax, BCl-2, Caspase-9, and Caspase-3) expression in them. In addition, naringin pretreatment inhibits UVB-stimulated matrix metalloproteinase (MMP-2, MMP-9 and MMP-13) expression in these 3T3 cells. Therefore, we report that naringin can effectively avert UVB-mediated DNA damage, photoaging, and apoptosis in NIH-3T3 cells.


Assuntos
Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Flavanonas/farmacologia , Raios Ultravioleta/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Apoptose/efeitos da radiação , Reparo do DNA/efeitos da radiação , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Camundongos , Células NIH 3T3 , Protetores contra Radiação/farmacologia , Envelhecimento da Pele/efeitos dos fármacos
7.
Free Radic Res ; 54(7): 497-516, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32746646

RESUMO

The present study was conceptualized to delineate radioprotective efficacy of a formulation G-003M (a combination of podophyllotoxin and rutin) against radiation-induced damage to the lymphohematopoietic system of mice. C57BL/6J mice, treated with G-003M 1 h prior to 9 Gy lethal dose, were assessed for reactive oxygen species (ROS)/nitric oxide (NO) generation, antioxidant alterations, Annexin V/PI and TUNEL staining for apoptosis, modulation of apoptotic proteins, cell proliferation, histological alterations in thymus and cell cycle arrest in bone marrow cells. Induction of granulocyte colony-stimulating factor (G-CSF), granulocytes macrophage colony-stimulating factor (GM-CSF), interleukin-IL-6, IL-10, IL-1α, and IL-1ß in response to G-003M was also evaluated in different groups of mice. Haematopoietic reconstitution with G-003M was explored by examining endogenous spleen colony-forming units (CFU-S) in irradiated animals. G-003M significantly inhibited ROS/NO, malondialdehyde (MDA) and restored cellular antioxidant glutathione in the thymus of irradiated animals. G-003M pre-treatment significantly (p < 0.001) restrained apoptosis in thymocytes via upregulation of Bcl2 and down-regulation of Bax, p53 and caspase-3. Stimulation of cell proliferation and inhibition of apoptosis by G-003M, restored architecture of thymus in irradiated animals within 30 days as evaluated by histological analysis. G-003M arrested cells at the G2/M phase by inducing reversible cell cycle arrest. Peak expression of G-CSF (45-fold) and IL-6 (60-fold) as well as moderate induction of GM-CSF, IL-10, IL-1α by G-003M helped in haematopoietic recovery of irradiated mice. A higher number of endogenous CFU-S in G-003M pre-treated irradiated mice suggested haematopoietic recovery. Data obtained from the current study affirms that G-003M can be proved as a potential radioprotective agent against radiation damage.


Assuntos
Citocinas/metabolismo , Sistema Hematopoético/efeitos dos fármacos , Sistema Hematopoético/efeitos da radiação , Podofilotoxina/farmacologia , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , Rutina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Combinação de Medicamentos , Sistema Hematopoético/metabolismo , Sistema Hematopoético/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Distribuição Aleatória , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
PLoS One ; 15(7): e0235515, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692781

RESUMO

BACKGROUND: The skin provides a predominant barrier against chemical, physical and microbial incursion. The intemperate exposure to ultraviolet A (UVA) radiation can cause excessive cellular oxidative stress, leading to skin damage, proteins damage and mitochondrial dysfunction. There is sufficient evidences supporting the proposal that mitochondria is highly implicated in skin photo-damage. METHODS: In the present study, a polysaccharide isolated from Astragalus membranaceus was further purified to be an α-glucan, which was further investigated its beneficial influence on UVA-induced photo-damage in HaCaT cells. RESULTS: Our results showed that the purified Astragalus membranaceus polysaccharide (AP) can protect HaCaT cells from UVA-induced photo-damage through reducing UVA-induced intracellular ROS production and mitochondrial membrane potential, thereby altering ATP content. It was found that the UVA induced damage in HaCaT cells could be effectively restored by co-treatment with AP. CONCLUSIONS: AP exhibited promising potential for advanced application as multifunctional skin care products and drugs.


Assuntos
Astragalus propinquus/química , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Polissacarídeos/farmacologia , Protetores contra Radiação/farmacologia , Raios Ultravioleta/efeitos adversos , Trifosfato de Adenosina/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/química , Protetores contra Radiação/química , Espécies Reativas de Oxigênio/metabolismo
9.
Clin Interv Aging ; 15: 897-905, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606631

RESUMO

Introduction: Skin, as the outermost organ, is exposed to a wide range of environmental risk factors including ultraviolet (UV) and all kinds of pollutants. Excessive UV exposure contributes to many disorders, such as photoaging, skin inflammation, and carcinogenesis. Methods: To determine the effects of bamboo extract (BEX) from our local plant, Acidosasa longiligula, on UV-irritated human skin, we conducted a variety of studies, including Western blot, apoptosis assays, reactive oxygen species (ROS) detection, and thioredoxin (TXN) and thioredoxin reductase (TXNRD) activity assays in primary skin keratinocytes. Results: We first determined that BEX protects human skin keratinocytes against UV radiation-induced apoptosis and ROS production. UV radiation can robustly impair TXN and TXNRD activity which can, in turn, be significantly rescued by BEX treatment. Moreover, BEX regulates TXN1 levels in primary skin keratinocytes and TXN1 is proved to be required for the protective function of BEX. Last, we found that the NF-κB/p65 pathway mediates the protective function of BEX against UV. Discussion: Collectively, our work delineates the beneficial role of BEX in UV-induced skin cell damage and provides a novel therapeutic reagent to prevent or alleviate the progress of photoaging and other UV-provoked skin diseases.


Assuntos
Queratinócitos/metabolismo , Extratos Vegetais/farmacologia , Protetores contra Radiação/farmacologia , Pele/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Humanos , Poaceae , Espécies Reativas de Oxigênio/metabolismo , Raios Ultravioleta/efeitos adversos
10.
Life Sci ; 255: 117743, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32371064

RESUMO

AIMS: Radiation-induced lung injury (RILI) is a serious complication of radiation therapy. Development of an effective drug that selectively protects normal lung tissues and sensitizes tumor cells to radiotherapy is an unmet need. 2-Methoxyestradiol (2ME2) possesses polypharmacological properties, which qualifies it as an effective radioprotector. Our aim is to explore the potential protective effects of 2ME2 against early and late stages of RILI and the underlying mechanisms. MAIN METHODS: BALB/c mice were either treated with 2ME2 (50 mg/kg/day i.p., for 4 weeks); or received a single dose of 10 Gy ionizing radiation (IR) delivered to the lungs; or 10 Gy IR and 2ME2. Animal survival and pulmonary functions were evaluated. Immune-phenotyping of alveolar macrophages (AM) in the broncho-alveolar lavage fluids (BALF) was determined by flow cytometry. ELISA was used to evaluate the expression levels of TNF-α, TGF-ß; and IL-10 in BALF. Lung tissues were used for histopathological examination or immunofluorescence staining for CD68 (pan-macrophage marker), Arginase-1 (Arg1, M2-specific marker), inducible nitric oxide synthase (iNOS, M1-specific marker) and HIF-1α. VEGF and γH2AX expression in lung tissues were detected by western blot. KEY FINDINGS: The results demonstrated that 2ME2 improved the survival, lung functions and histopathological parameters of irradiated mice. Additionally, it attenuated the radiation-induced AM polarization and reduced the pneumonitis and fibrosis markers in lung tissues. Significant reduction of TNF-α and TGF-ß with concomitant increase in IL-10 concentrations were observed. Moreover, the expression of HIF-1α, VEGF and γH2AX declined. SIGNIFICANCE: 2ME2 is a promising radioprotectant with fewer anticipated side effects.


Assuntos
2-Metoxiestradiol/farmacologia , Lesão Pulmonar/prevenção & controle , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , 2-Metoxiestradiol/toxicidade , Animais , Líquido da Lavagem Broncoalveolar , Feminino , Interleucina-10/metabolismo , Lesão Pulmonar/etiologia , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Protetores contra Radiação/toxicidade , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Eur J Med Chem ; 197: 112333, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32361176

RESUMO

In order to discover new antioxidants, fifteen novel quinazolinone derivatives bearing benzenesulfonamide moiety with variable heterocyclic tail, were synthesized and their structures were established on the basis of spectral data. All the synthesized compounds were screened for their antioxidant potential using DPPH assay in comparison to ascorbic acid. The N-(pyrazin-2-yl)-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide 16 was the most active scaffold in this series with greater scavenging activity than that of ascorbic acid. In vivo acute toxicity study of compound 16 indicates its relative safety with a median lethal dose of 200 mg/kg. The possible antioxidant and hepatoprotective activities of compound 16 were evaluated in irradiated mice. Compound 16 caused mitigation of gamma radiation-induced oxidative stress verified by the decline in MDA, ROS and NF-κB levels. Moreover, SOD and PON1 activities, as well as Zn2+ levels, were improved in liver tissues. Furthermore, molecular docking of compound 16 inside the active site of SOD and PON1 demonstrated the same binding interactions as that of the co-crystallized ligands considering the binding possibilities and energy scores. These findings support that compound 16 may represent a structural lead for developing new antioxidants and hepatoprotective agents.


Assuntos
Depuradores de Radicais Livres/farmacologia , Fígado/efeitos dos fármacos , Quinazolinonas/farmacologia , Protetores contra Radiação/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Arildialquilfosfatase/química , Arildialquilfosfatase/metabolismo , Domínio Catalítico , Depuradores de Radicais Livres/síntese química , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Subunidade p50 de NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Quinazolinonas/síntese química , Protetores contra Radiação/síntese química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Superóxido Dismutase/química , Superóxido Dismutase/metabolismo
12.
Int J Radiat Biol ; 96(7): 919-928, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32159411

RESUMO

Purpose: To evaluate the effects of polyethylene glycol (PEG) 6000 pretreatment on growth and physiological responses of eukaryotic microalga Chlorella vulgaris exposed to ionizing irradiation.Materials and methods: The microalgal cells pretreated with different PEG concentrations (0, 5, 10 and 20%) and then exposed to 300 Gray gamma irradiation at a dose rate of 0.5 Gy s-1. The various growth and physiological parameters including algal growth, cell size, the degree of electrolyte leakage (EL) and lipid peroxidation, the content of pigments and proline and the activity of antioxidant enzymes under gamma-free or 300 Gray gamma irradiation conditions were examined.Results: The results showed that PEG stimulated a higher growth and cell size under both stress-free and gamma-stress conditions. The maximum growth and cell size was reported when the algae was pretreated with 10% PEG. A relative increase of catalase activity was observed in all samples after exposing to gamma irradiation. However, the highest value was recorded for the gamma-radiated algae pretreated with 10% PEG. In the absence of PEG, gamma irradiation induced a significant reduction in ascorbate peroxidase activity, but with PEG pretreatment, the enzyme activity remained constant or even increased after gamma irradiation. On the other hand, although gamma irradiation stress generally suppressed the activity of superoxide dismutase in all cells, pretreating the algae with PEG could diminish this suppressing effect at all applied concentrations. Compared to the PEG-free controls, a lower rate of chlorophylls and membrane integrity loss was shown in the PEG-treated algae when exposed to gamma stress. Total carotenoid content in PEG-treated algae was also similar under both gamma-free and gamma-radiated conditions. A PEG-independent increase in proline accumulation was reported under gamma-irradiation treatment.Conclusions: Overall, the results suggested that PEG pretreatment could improve gamma-irradiation tolerance in C. vulgaris probably by stimulating a range of enzymatic and non-enzymatic reactive oxygen species scavenging systems. The microalgae may also consume PEG to break down and use it as an alternative source of carbon during stress which should be further studied in detail.


Assuntos
Chlorella vulgaris/efeitos dos fármacos , Chlorella vulgaris/efeitos da radiação , Raios gama/efeitos adversos , Polietilenoglicóis/farmacologia , Protetores contra Radiação/farmacologia , Carotenoides/metabolismo , Chlorella vulgaris/crescimento & desenvolvimento , Chlorella vulgaris/metabolismo , Clorofila/metabolismo , Relação Dose-Resposta a Droga , Eletrólitos/metabolismo , Malondialdeído/metabolismo , Prolina/metabolismo
13.
Int J Radiat Biol ; 96(6): 709-717, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32149561

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by interstitial remodeling, leading to compromised lung function. Extra vascular fibrin deposition and abnormalities in the fibrinolysis are the major clinical manifestations of lung diseases such as acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS). ALI progresses to pulmonary fibrosis (PF) and makes patient's life miserable. Anti-fibrinolysis and apoptosis are involved in the progression of PF. Apoptotic markers are detectable within IPF lung tissue and senescent cell deletion can rejuvenate pulmonary health. Enhanced expression of p53 due to DNA damage is seen in irradiated lung tissue. The role of fibrinolytic components such as Urokinase Plasminogen activator (uPA), uPA receptor (uPAR) and Plasminogen activator inhibitor-1 (PAI-1) has been detailed in I. Curcumin is known to possess anti-inflammatory and anti-fibrotic effects. Radioprotective effect of curcumin enables it to attenuate radiation-induced inflammation and fibrosis. Understanding the mechanism of radioprotective effect of curcumin in radiation-induced PF and apoptosis can lead to the development of an effective therapeutic to combat acute lung injury and fibrosis.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Curcumina/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Lesões por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Animais , Curcumina/uso terapêutico , Humanos , Fibrose Pulmonar/etiologia , Lesões por Radiação/etiologia , Protetores contra Radiação/uso terapêutico
14.
J Photochem Photobiol B ; 205: 111824, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32126496

RESUMO

Excessive exposure to UVB radiation can lead to oxidative and inflammatory damage that compromises the cutaneous integrity. The application on the skin of photochemoprotective products is considered a relevant approach for the prevention of oxidative damage. In this study the in vitro and in vivo photochemoprotective effects of antioxidant plant materials obtained from the leaves of Nectandra cuspidata Nees following UVB irradiation were evaluated. The cytoprotective effect, reactive oxygen species (ROS) production and lipid peroxidation (LPO) were assessed in L-929 fibroblasts treated with the ethyl acetate fraction (EAF) or isolated compounds (epicatechin, isovitexin and vitexin) before or after irradiation with UVB (500 mJ/cm2). EAF substantially reduced the dead of cells and inhibited the UVB-induced ROS production and LPO in both treatments, compared with the irradiated untreated fibroblasts, presenting effects similar or better than pure compounds. The in vivo photochemoprotective effects of a topical emulsion containing 1% EAF (F2) were evaluated in hairless mice exposed to UVB. F2 improved all evaluated parameters in the skin of animals, inhibited ROS production, increased antioxidant defenses by decreasing reduced glutathione (GSH) and catalase depletion, reduced the activities of metalloproteinases (MMP-2 and MMP-9) and myeloperoxidase, decreased epidermal thickness and skin edema, and inhibited the appearance of sunburn cells as well as the recruitment of neutrophils and mast cell inflammatory infiltrates. These findings show that EAF presents high photochemoprotective effects, and that a topical formulation containing it may have potential for skin care.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Fibroblastos/efeitos dos fármacos , Lauraceae , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Protetores contra Radiação/farmacologia , Pele/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Feminino , Fibroblastos/efeitos da radiação , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Pelados , Folhas de Planta , Espécies Reativas de Oxigênio/metabolismo , Pele/metabolismo , Pele/patologia , Pele/efeitos da radiação
15.
Int J Radiat Biol ; 96(7): 879-893, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32167845

RESUMO

Purpose: Gastrointestinal (GI) injuries post ionizing radiation (IR) becomes a crucial factor in survival. Thus, the current study was aimed to explore the molecular mechanisms behind IR produced GI proteome alterations and their amelioration by a safe radioprotective formulation candidate, G-003M (podophyllotoxin+rutin).Materials and method: C57BL/6 mice were administered with G-003M 1 h before 9 Gy whole body γ irradiation. 2DE-MS analysis was conducted to identify differential expression of jejunum proteins with fold change >1.5 (p < .05) at various time-points. Results: G-003M pre-administration decreased total number of differential proteins. It mediated protection to cytoskeleton, modulated stress, apoptosis and inflammatory proteins. Direct effect on eukaryotic translation initiation factor 4H (Eif4h), thioredoxin domain-containing protein 17 (Txndc17) and interferon-induced protein 35 (Ifi35) was observed. Bioinformatics depicted transcription factor-MYC, was also positively modulated by G-003M. Further, it also enhanced level of citrulline (ELISA analysis), and restored crypts and villi lengths (histological analysis) against severe damage caused by lethal irradiation.Conclusion: Current findings reveal that G-003M may be an efficient candidate in protecting key proteins of metabolic and biochemical pathways assisting in the rapid recovery of GI proteome. This fairly improved the chances of animal survival exposed to lethal doses of whole body radiation.


Assuntos
Jejuno/efeitos dos fármacos , Jejuno/efeitos da radiação , Podofilotoxina/farmacologia , Proteoma/metabolismo , Protetores contra Radiação/farmacologia , Rutina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Raios gama/efeitos adversos , Jejuno/citologia , Jejuno/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Irradiação Corporal Total
16.
Radiat Res ; 193(6): 513-519, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32216711

RESUMO

D-methionine (D-met), a dextrorotatory isoform of the amino acid L-methionine (L-met), can prevent oral mucositis and salivary hypofunction in mice exposed to radiation. However, the mechanism of its radioprotection is unclear, especially with regard to the stereospecific functions of D-met. Radiation is known to cause injury to normal tissue by triggering DNA damage in cells. Thus, in this study we sought to determine whether the chirality of D-/L-met affects radiation-induced events at the DNA level. We selected plasmid DNA assays to examine this effect in vitro, since these assays are highly sensitive and allow easy detection of DNA damage. Samples of supercoiled pBR322 plasmid DNA mixed with D-met, L-met or dimethylsulfoxide (DMSO) were prepared and irradiated with a Bragg peak beam of carbon ions (∼290 MeV/u) with a 6-cm spread. DNA strand breaks were indicated by the change in the form of the plasmid and were subsequently quantified using agarose gel electrophoresis. We found that D-met yielded approximately equivalent protection from carbon-ion-induced DNA damage as DMSO. Thus, we propose that the protective functions of methionine against plasmid DNA damage could be explained by the same mechanism as that for DMSO, namely, hydroxyl radical scavenging. This stereospecific radioprotective mechanism occurred at a level other than the DNA level. There was no significant difference between the radioprotective effect of D-met and L-met on DNA.


Assuntos
Dano ao DNA , Radioterapia com Íons Pesados/efeitos adversos , Metionina/farmacologia , Plasmídeos/genética , Protetores contra Radiação/farmacologia , Relação Dose-Resposta a Droga
17.
Radiat Res ; 193(5): 435-450, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134361

RESUMO

Mitigation of total-body irradiation (TBI) in C57BL/6 mice by two drugs, which target apoptosis and necroptosis respectively, increases survival compared to one drug alone. Here we investigated whether the biomarker (signature)directed addition of a third anti-ferroptosis drug further mitigated TBI effects. C57BL/6NTac female mice (30-33 g) received 9.25 Gy TBI, and 24 h or later received JP4-039 (20 mg/kg), necrostatin-1 (1.65 mg/kg) and/or lipoxygenase-15 inhibitor (baicalein) (50 mg/kg) in single-, dual- or three-drug regimens. Some animals were sacrificed at days 0, 1, 2, 3, 4 or 7 postirradiation, while the majority in each group were maintained beyond 30 days. For those mice sacrificed at the early time points, femur bone marrow, intestine (ileum), lung and blood plasma were collected and analyzed for radiation-induced and mitigator-modified levels of 33 pro-inflammatory and stress response proteins. Each single mitigator administered [JP4-039 (24 h), necrostatin-1 (48 h) or baicalein (24 h)] improved survival at day 30 after TBI to 25% (P = 0.0432, 0.2816 or 0.1120, respectively) compared to 5% survival of 9.25 Gy TBI controls. Mice were administered the drug individually based on weight (mg/kg). Drug vehicles comprised 30% cyclodextrin for JP4-039 and baicalein, and 10% Cremphor-EL/10% ethanol/80% water for necrostatin-1; thus, dual-vehicle controls were also tested. The dual-drug combinations further enhanced survival: necrostatin-1 (delayed to 72 h) with baicalein 40% (P = 0.0359); JP4-039 with necrostatin-1 50% (P = 0.0062); and JP4-039 with baicalein 60% (P = 0.0064). The three-drug regimen, timed to signature directed evidence of onset after TBI of each death pathway in marrow and intestine, further increased the 30-day survival to 75% (P = 0.0002), and there was optimal normalization to preirradiation levels of inflammatory cytokine and stress response protein levels in plasma, intestine and marrow. In contrast, lung protein levels were minimally altered by 9.25 Gy TBI or mitigators over 7 days. Significantly, elevated intestinal proteins at day 7 after TBI were reduced by necrostatin-1-containing regimens; however, normalization of plasma protein levels at day 7 required the addition of JP4-039 and baicalein. These findings indicate that mitigator targeting to three distinct cell death pathways increases survival after TBI.


Assuntos
Apoptose/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Protetores contra Radiação/farmacologia , Irradiação Corporal Total/efeitos adversos , Animais , Apoptose/efeitos da radiação , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/efeitos da radiação , Citocinas/metabolismo , Interações Medicamentosas , Feminino , Ferroptose/efeitos da radiação , Íleo/efeitos dos fármacos , Íleo/metabolismo , Íleo/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Necroptose/efeitos da radiação , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/prevenção & controle , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Tempo
18.
Cancer Immunol Res ; 8(4): 451-464, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32127391

RESUMO

Colorectal cancer is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor colorectal cancer clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiotherapy in colorectal cancer. We used human and mouse colorectal cancer cell lines, organoids, mouse syngeneic colorectal cancer tumor graft models, and colorectal cancer tissues from patients who received radiotherapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation induced IDO1 overexpression in colorectal cancer through type I and II IFN signaling. IDO1 enzymatic activity directly influenced colorectal cancer radiation sensitivity. IDO1 inhibition sensitized colorectal cancer to radiation-induced cell death, whereas the IDO1 metabolite kynurenine promoted radioprotection. IDO1 inhibition also potentiated Th1 cytokines and myeloid cell-modulating factors in the tumor microenvironment and promoted an abscopal effect on tumors outside the radiation field. Conversely, IDO1 blockade protected the normal small intestinal epithelium from radiation toxicity and accelerated recovery from radiation-induced weight loss, indicating a role in limiting side effects. These data demonstrated that IDO1 inhibition potentiates radiotherapy effectiveness in colorectal cancer. The findings also provide rationale and mechanistic insight for the study of IDO1 inhibitors as adjuvant therapy to radiation in patients with locally advanced sporadic and colitis-associated colorectal cancer.


Assuntos
Neoplasias Colorretais/radioterapia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Interferons/farmacologia , Oximas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Sulfonamidas/farmacologia , Microambiente Tumoral , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Mucosa Intestinal/efeitos da radiação , Cinurenina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Protetores contra Radiação/farmacologia
19.
Eur J Med Chem ; 189: 112087, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007667

RESUMO

Based on the definite therapeutic benefits, such as neuroprotective, cardioprotective, anticancer, anti-diabetic and so on, the Panax genus which contains many valuable plants, including ginseng (Panax ginseng C.A. Meyer), notoginseng (Panax notoginseng) and American ginseng (Panax quinquefolius L.), attracts research focus. Actually, the biological and pharmacological effects of the Panax genus are mainly attributed to the abundant ginsenosides. However, the low membrane permeability and the gastrointestinal tract influence seriously limit the absorption and bioavailability of ginsenosides. The acid or base hydrolysates of ginsenosides, 20 (R,S)-panaxadiol and 20 (R,S)-protopanaxadiol showed improved bioavailability and diverse pharmacological activities. Moreover, relative stable skeletons and active hydroxyl group at C-3 position and other reactive sites are suitable for structural modification to improve biological activities. In this review, the pharmacological activities of panaxadiol, protopanaxadiol and their structurally modified derivatives are comprehensively summarized.


Assuntos
Descoberta de Drogas , Ginsenosídeos/farmacologia , Panax/química , Compostos Fitoquímicos/química , Sapogeninas/farmacologia , Triterpenos/química , Antineoplásicos/farmacologia , Ginsenosídeos/química , Humanos , Fármacos Neuroprotetores/farmacologia , Protetores contra Radiação/farmacologia , Sapogeninas/química
20.
Mar Drugs ; 18(2)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013063

RESUMO

Skin is an important barrier to protect the body from environmental stress. However, exposure to ultraviolet radiation (UV) and various environmental oxidative stresses can cause skin inflammation. Cyclooxygenase-2 (COX-2) is an inducible enzyme that mediates the formation of prostaglandin E2 (PGE2) against internal and external inflammatory stimulations. Therefore, the inhibition of COX-2 is an important approach to maintain skin health and prevent skin inflammation and carcinogenesis. Topsentin, a bis(indolyl)imidazole alkaloid isolated from the marine sponge Spongosorites genitrix, has been reported to exhibit anti-tumor and anti-microbial activities. However, the effect of topsentin on skin inflammation and its underlying molecular mechanism has not been elucidated. In the present study, we identified the photoprotective effects of topsentin on UVB irradiated human epidermal keratinocyte HaCaT cells. Topsentin suppresses COX-2 expression and its upstream signaling pathways, AP-1 and MAPK. Furthermore, topsentin inhibits miR-4485, a new biomarker selected from a microarray, and its target gene tumor necrosis factor alpha induced protein 2 (TNF-α IP2). The photoprotective effect of topsentin was also confirmed in a reconstructed human skin model. These findings suggest that topsentin may serve as a potential candidate for cosmetic formulations with skin inflammatory-mediated disorder.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Imidazóis/farmacologia , Indóis/farmacologia , Poríferos , Protetores contra Radiação/farmacologia , Animais , Células Epidérmicas , Queratinócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Pele , Raios Ultravioleta
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