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1.
Chemosphere ; 250: 126416, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32380589

RESUMEN

The flavonoid metal-insecticide magnesium-hesperidin complex (MgHP) has recently been considered as a novel insecticide to replace some persistent pesticides. However, it is important to evaluate its action on non-target species, mainly those living in an aquatic environment, as these ecosystems are the final receptors of most chemicals. Reactive oxygen species, antioxidant and oxidative stress biomarkers, genotoxicity as well as cell cycle was evaluated in the liver cell line from zebrafish (Danio rerio; ZF-L) exposed to 0, 0.1, 1, 10, 100 and 1000 ng mL-1 MgHP. MgHP affected cell stability by increasing reactive oxygen species (ROS) in both exposure times (24 and 96 h) at high concentrations. Catalase (CAT) activity decreased after 24 h exposure, and glutathione and metallothionein values increased, avoiding the lipid peroxidation. Genotoxicity increased as MgHP concentration increased, after 24 h exposure, exhibiting nuclear abnormalities; it was recovered after 96 h exposure, evidencing possible stimulation of DNA repair mechanisms. The alteration in the cell cycle (increasing in the Sub-G1 phase and decreasing in the S-phase) was associated with chromosomal instability. In conclusion, the responses of ROS and the antioxidant defense system depended on MgHP concentration and time exposure, while DNA exhibited some instability after 24 h exposure, which was recovered after 96 h.


Asunto(s)
Ciclo Celular/efectos de los fármacos , Insecticidas/toxicidad , Hígado/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Antioxidantes/metabolismo , Línea Celular , Daño del ADN , Relación Dosis-Respuesta a Droga , Ecotoxicología/métodos , Biomarcadores Ambientales/efectos de los fármacos , Glutatión/metabolismo , Hesperidina/química , Hesperidina/toxicidad , Insecticidas/administración & dosificación , Insecticidas/química , Peroxidación de Lípido/efectos de los fármacos , Hígado/citología , Hígado/metabolismo , Magnesio/química , Pruebas de Mutagenicidad/métodos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Contaminantes Químicos del Agua/química , Pez Cebra
2.
Environ Pollut ; 260: 113873, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32369892

RESUMEN

Cadmium (Cd), a heavy metal contaminant, exists in humans and animals throughout life and closely associate with severe hepatotoxicity. Selenium (Se) has been recognized as an effective chemo-protectant of Cd, but the underlying mechanisms remain unclear. The objective of the present study is to illustrate the antagonistic effect of Se against Cd-induced hepatotoxicity. Primary hepatocytes were cultured in the presence of 5 µM Cd, 1 µM Se and the mixture of 1 µM Se and 5 µM Cd for 24 h. Cell viability and morphology, antioxidant status, endoplasmic reticulum (ER) stress response and selenotranscriptome were assessed. It was observed that Se treatment dramatically alleviated Cd-induced hepatocytes death and morphological change. Simultaneously, Se mitigated Cd-induced oxidative stress by reducing ROS production, increasing reduced glutathione (GSH) level and increasing selenoenzyme (glutathione peroxidase, GPX) activity. Cd induced hepatotoxicity via disordering ER-resident selenoproteins transcription and triggering ER stress and unfolded protein response. Supplementary Se evidently relieved hepatocytes injury via modulating ER-resident selenoproteins transcription to inhibit ER stress. Collectively, our findings showed a potential protection of Se against Cd-induced hepatotoxicity via suppressing ER stress response.


Asunto(s)
Cadmio/toxicidad , Retículo Endoplásmico/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Selenio/farmacología , Selenoproteínas/biosíntesis , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico
3.
Phys Chem Chem Phys ; 22(15): 7942-7951, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32232288

RESUMEN

A pharmacophoric motif decorated with supramolecular functionalities (TZT) was designed for potential interaction with biological targets. Main insights of this work include the correlation of supra functionalities of TZT with its binding ability to proteins leading to the modulation of their structure and bioactivity as a promising perspective in the field of cellular protection from oxidative stress. To investigate the role of TZT in obliterating oxidative stress at a molecular level, its binding propensity with bovine serum albumin (BSA) and bovine liver catalase (BLC) was characterized using various biophysical methods. The binding constants of TZT with BSA (Kb = 2.09 × 105 M-1) and BLC (Kb = 2.349 × 105 M-1) indicate its considerable interaction with these proteins. TZT efficiently triggers favourable structural changes in BLC, thereby enhancing its enzyme activity in a dose dependent manner. The enzyme kinetics parameters of TZT binding to BLC were quantified using the Michaelis-Menten model. Both in silico and experimental results suggest that an increased substrate availability could be the reason for enhanced BLC activity. Furthermore, physiological relevance of this interaction was demonstrated by investigating the ability of TZT to attenuate oxidative stress. Treatment with TZT was found to mitigate the inhibition of A549 cell proliferation in the presence of high concentrations of vitamin C. This finding was confirmed at a molecular level by PARP cleavage status, demonstrating that TZT inhibits apoptotic cell death induced by oxidative stress.


Asunto(s)
Catalasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Tiazolidinas/farmacología , Células A549 , Animales , Antioxidantes/farmacología , Bovinos , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos
4.
An Acad Bras Cienc ; 92(1): e20180596, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32267305

RESUMEN

Red cabbage (Brassica oleracea L. var. capitata f. rubra DC.) extract has been demonstrated hypolipidemic and antioxidant capacity. Herein, we investigated the effect of red cabbage aqueous extract (RC) or fenofibrate (FF) in oxidative stress induced by Triton WR-1339 in rats. The antioxidant capacity was evaluated through the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities and, thiobarbituric reactive species (TBARS) and protein carbonyl (PC) levels in erythrocytes, liver, kidneys, cerebral cortex and hippocampus of male rats. The alterations promoted by Triton WR-1339 in enzymatic antioxidant defense in the liver, kidneys and hippocampus were reversed by RC or FF treatments. The TBARS and PC levels increased in the liver, cerebral cortex and hippocampus of hyperlipidemic rats were decreased by the treatments with RC or FF. These findings demonstrated that RC is a potential therapy to treat diseases not only involving dyslipidemic condition but also oxidative stress.


Asunto(s)
Antioxidantes/farmacología , Brassica/química , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Catalasa/efectos de los fármacos , Glutatión Peroxidasa/efectos de los fármacos , Masculino , Oxidación-Reducción , Ratas , Ratas Wistar , Superóxido Dismutasa , Sustancias Reactivas al Ácido Tiobarbitúrico
5.
Mutat Res ; 850-851: 503136, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32247553

RESUMEN

Tumorigenesis induced by oxidative stress is thought to be initiated by mutagenesis, but via an indirect mechanism. The dose-response curves for agents that act by this route usually show a threshold, for unknown reasons. To gain insight into these phenomena, we have analyzed the dose response for mutagenesis induced by the oral administration of potassium bromate, a typical oxidative-stress-generating agent, to gpt delta mice. The agent was given orally for 90 d to either Nrf2+ or Nrf2-knockout (KO) mice and mutants induced in the small intestine were analyzed. In Nrf2+mice, the mutant frequency was significantly greater than in the vehicle controls at a dose of 0.6 g/L but not at 0.2 g/L, indicating that a practical threshold for mutagenesis lies between these doses. At 0.6 g/L, the frequencies of G-to-T transversions (landmark mutations for oxidative stress) and G-to-A transitions were significantly elevated. In Nrf2-KO mice, too, the total mutant frequency was increased only at 0.6 g/L. G-to-T transversions are likely to have driven tumorigenesis in the small intestine. A site-specific G-to-T transversion at guanine (nucleotide 406) in a 5'-TGAA-3' sequence in gpt, and our primer extension reaction showed that formation of the oxidative DNA base modification 8-oxo-deoxyguanosine (8-oxo-dG) at nucleotide 406 was significantly increased at doses of 0.6 and 2 g/L in the gpt delta mice. In the Apc oncogene, guanine residues in the same or similar sequences (TGAA or AGAA) are highly substituted by thymine (G-to-T transversions) in potassium bromate-induced tumors. We propose that formation of 8-oxo-dG in the T(A)GAA sequence is an initiating event in tumor formation in the small intestine in response to oxidative stress.


Asunto(s)
Bromatos/toxicidad , Mutagénesis/genética , Estrés Oxidativo/genética , Pentosiltransferasa/genética , 8-Hidroxi-2'-Desoxicoguanosina/genética , Administración Oral , Animales , Bromatos/farmacología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , ADN/efectos de los fármacos , ADN/genética , Relación Dosis-Respuesta a Droga , Intestino Delgado/efectos de los fármacos , Intestino Delgado/patología , Ratones , Ratones Noqueados , Mutagénesis/efectos de los fármacos , Mutación , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos
6.
Life Sci ; 250: 117596, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32240678

RESUMEN

AIMS: ß-Estradiol (ß-E), one of the chemical forms of female gonad hormone exhibited antioxidant efficacy in biochemical system, in vitro. The aim of the study was to investigate whether any other mechanism of protection by ß-E to hepatic mitochondria in presence of stressor agent i.e.,a combination of Cu2+ and ascorbic acid is involved. MAIN METHODS: Freshly prepared goat liver mitochondria was incubated with stressors and 1 µM ß-E and post incubated with the same concentration at 37 °C at pH 7.4. Mitochondrial viability, biomarkers of oxidative stress, activities of Krebs cycle enzymes, mitochondrial membrane potential, Ca2+ permeability were measured. Mitochondrial morphology and binding pattern of ß-E with stressors were also studied. KEY FINDINGS: Upon incubation of mitochondria with Cu, ascorbic acid and their combination there is a significant decline in activities of four of Krebs cycle enzymes in an uncompetitive manner with a concomitant increase in Ca2+ permeability and membrane potential of inner mitochondrial membrane, which is withdrawn during co-incubation with ß-E, but was not reversed during post incubation with the ß-E. The final studies on mitochondrial membrane morphology using scanning electron microscope also exhibited damage. Isothermal titration calorimetry data also showed the negative heat change in the mixture of ß-E with ascorbic acid and also its combination with Cu2+. SIGNIFICANCE: Our results for the first time demonstrated that ß-E protects againstCu2+-ascorbate induced oxidative stress by binding with ascorbic acid. The new mechanism of binding of ß-E with stress agents may have a future therapeutic relevance.


Asunto(s)
Ácido Ascórbico/efectos adversos , Cobre/efectos adversos , Estradiol/farmacología , Mitocondrias Hepáticas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Femenino , Glutatión/metabolismo , Cabras , Técnicas In Vitro , Peroxidación de Lípido , Potencial de la Membrana Mitocondrial , Mitocondrias Hepáticas/enzimología , Oxidación-Reducción , Permeabilidad , Unión Proteica
7.
Rev Soc Bras Med Trop ; 53: e20200016, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32348434

RESUMEN

INTRODUCTION: Sepsis is an important cause of mortality and morbidity, and inflammatory response and oxidative stress play major roles underlying its pathophysiology. Here, we evaluated the effect of intraperitoneal etanercept administration on oxidative stress and inflammation indicators in the kidney and blood of experimental sepsis-induced rats. METHODS: Twenty-eight adult Sprague Dawley rats were classified into Control (Group 1), Sepsis (Group 2), Sepsis+Cefazolin (Group 3), and Sepsis+Cefazolin+Etanercept (Group 4) groups. Kidney tissue and serum samples were obtained for biochemical and histopathological investigations and examined for the C reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), triggering receptor expressed on myeloid cells (TREM), and malondialdehyde (MDA) levels. RESULTS: The levels of TNF-α, TREM, and MDA in serum and kidney samples were significantly higher in rats from sepsis group than in rats from control group (p < 0.05). Group 3 showed a significant reduction in serum levels of TNF-α, CRP, and TREM as compared with Group 2 (p < 0.05). Serum TNF-α, CRP, TREM, and MDA levels and kidney TNF-α and TREM levels were significantly lower in Group 4 than in Group 2 (p < 0.05). Serum TNF-α and TREM levels in Group 4 were significantly lower than those in Group 3, and histopathological scores were significantly lower in Group 3 and Group 4 than in Group 2 (p < 0.05). Histopathological scores of Group 4 were significantly lower than those of Group 3 (p < 0.05). CONCLUSIONS: Etanercept, a TNF-α inhibitor, may ameliorate sepsis-induced oxidative stress, inflammation, and histopathological damage.


Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Etanercept/administración & dosificación , Inflamación/prevención & control , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sepsis/patología , Factor de Necrosis Tumoral alfa/sangre , Animales , Antiinflamatorios no Esteroideos/farmacología , Modelos Animales de Enfermedad , Etanercept/farmacología , Inflamación/patología , Inyecciones Intraperitoneales , Ratas , Ratas Sprague-Dawley , Sepsis/sangre
8.
Acta Cir Bras ; 35(2): e202000203, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32348402

RESUMEN

Purpose To evaluate the effect of remote ischemic conditioning associated to N-acetylcysteine (NAC) on testicular ischemia∕reperfusion (I∕R) injury in rats. Methods Twenty-five adult male Wistar rats were randomly distributed into five experimental groups (n=5), as follows: Sham, I∕R, Perconditioning (PER), NAC and PER+NAC. Two-hour ischemia was induced by rotating the left testis 720° to clockwise direction, followed by 4 hours of reperfusion. Perconditioning was performed by three I/R cycles of 10 min each on the left limb, 30 min before reperfusion. N-acetylcysteine (150 mg∕kg) was administered 30 min before reperfusion. Results Statistical differences were observed in MDA levels between I/R group with all groups (p<0.01), in addition there was statistical difference between PER and Sham, and PER+ NAC groups (p<0.05) in plasma. Conclusions The protective effect of perconditioning isolated in the reduction of lipid peroxidation related to oxidative stress was demonstrated. However, when Perconditioning was associated with NAC, there was no protective effect against testicular injury of ischemia and reperfusion.


Asunto(s)
Acetilcisteína/farmacología , Depuradores de Radicales Libres/farmacología , Precondicionamiento Isquémico/métodos , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión , Testículo/irrigación sanguínea , Animales , Evaluación Preclínica de Medicamentos , Masculino , Capacidad de Absorbancia de Radicales de Oxígeno , Distribución Aleatoria , Ratas , Ratas Wistar , Testículo/efectos de los fármacos
9.
Tumour Biol ; 42(4): 1010428320914477, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32342732

RESUMEN

Triple-negative breast cancers are the most aggressive subtypes with poor prognosis due to lack of targeted cancer therapy. Recently, we reported an association of A-kinase anchor protein 4 expression with various clinico-pathological parameters of breast cancer patients. In this context, we examined the effect of knockdown of A-kinase anchor protein 4 on cell cycle, apoptosis, cellular proliferation, colony formation, migration, and invasion in triple-negative breast cancer cells. We also examined the synergistic cytotoxic effect of paclitaxel on A-kinase anchor protein 4 downregulated triple-negative breast cancer cells. Knockdown of A-kinase anchor protein 4 resulted in significant reduction in cellular growth and migratory abilities. Interestingly, we also observed enhanced cell death in A-kinase anchor protein 4 downregulated cells treated with paclitaxel. Knockdown of A-kinase anchor protein 4 in cell cycle resulted in G0/G1 phase arrest. Knockdown of A-kinase anchor protein 4 also led to increased reactive oxygen species generation as a result of upregulation of NOXA and CHOP. In addition, levels of cyclins, cyclin-dependent kinases, anti-apoptotic molecules, and mesenchymal markers were reduced in A-kinase anchor protein 4 downregulated cells. Moreover, downregulation of A-kinase anchor protein 4 also caused tumor growth reduction in in vivo studies. These data together suggest that A-kinase anchor protein 4 downregulation inhibits various malignant properties and enhances the cytotoxic effect of paclitaxel, and this combinatorial approach could be useful for triple-negative breast cancer treatment.


Asunto(s)
Proteínas de Anclaje a la Quinasa A/deficiencia , Neoplasias de la Mama Triple Negativas/genética , Proteínas de Anclaje a la Quinasa A/genética , Proteínas de Anclaje a la Quinasa A/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Humanos , Inmunofenotipificación , Ratones , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Paclitaxel/farmacología , Especies Reactivas de Oxígeno/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Chem Biol Interact ; 324: 109085, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32275922

RESUMEN

Herbal medicines and their bioactive compounds are increasingly being recognized as useful drugs for cancer treatments. The parasitic fungus Cordyceps militaris is an attractive anticancer herbal since it shows very powerful anticancer activity due to its phytocompound cordycepin. We previously discovered and reported that a high amount of xylitol is present in Cordyceps militaris extract, and that xylitol unexpectedly showed anticancer activity in a cancer-selective manner. We thus hypothesized that xylitol could become a useful supplement to help prevent various cancers, if we can clarify the specific machinery by which xylitol induces cancer cell death. It is also unclear whether xylitol acts on cancer suppression in vivo as well as in vitro. Here we show for the first time that induction of the glutathione-degrading enzyme CHAC1 is the main cause of xylitol-induced apoptotic cell death in cancer cells. The induction of CHAC1 is required for the endoplasmic reticulum (ER) stress that is triggered by xylitol in cancer cells, and is linked to a second induction of oxidative stress in the treated cells, and eventually leads to apoptotic cell death. Our in vivo approach also demonstrated that an intravenous injection of xylitol had a tumor-suppressing effect in mice, to which the xylitol-triggered ER stress also greatly contributed. We also observed that xylitol efficiently sensitized cancer cells to chemotherapeutic drugs. Based on our findings, a chemotherapeutic strategy combined with xylitol might improve the outcomes of patients facing cancer.


Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Glutatión/metabolismo , Neoplasias/tratamiento farmacológico , Xilitol/uso terapéutico , Animales , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Células HEK293 , Humanos , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , gamma-Glutamilciclotransferasa/metabolismo
11.
Chem Biol Interact ; 324: 109086, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32275923

RESUMEN

Oxidative stress-induced apoptosis of retinal ganglion cells (RGCs) contributes to the development and progression of glaucoma. Sestrin2 (Sesn2), a stress-inducible protein, has a potent antioxidant capacity that can provide cytoprotection against various noxious stimuli. However, whether Sesn2 is involved in protecting RGCs from oxidative stress remains unexplored. The purpose of this study was to evaluate the role of Sesn2 in regulating hydrogen peroxide (H2O2)-induced oxidative stress of RGCs. Here, we showed that Sesn2 expression was induced in RGCs following H2O2 exposure. Sesn2 depletion markedly exacerbated H2O2-induced apoptosis and reactive oxygen species (ROS) generation in RGCs. Notably, upregulation of Sesn2 significantly decreased H2O2-induced apoptosis and ROS generation. Moreover, Sesn2 overexpression increased the nuclear translocation of nuclear factor erythroid-derived 2-like 2 (Nrf2), elevated Nrf2/antioxidant response element (ARE)-mediated transcriptional activity and upregulated the expression of Nrf2 target genes in H2O2-stimulated RGCs. Interestingly, we found that Sesn2 promoted Nrf2/ARE activation through downregulation of kelch-like ECH-associated protein 1 (Keap1). Restoration of Keap1 or inhibition of Nrf2 significantly reversed the Sesn2-mediated protective effect in H2O2-stimulated RGCs. In conclusion, these results elucidated that Sesn2 confers a protective effect in RGCs against H2O2-induced oxidative stress by reinforcing Nrf2/ARE activation via downregulation of Keap1. Our study suggests that the Sesn2/Keap1/Nrf2 axis may play an important role in retinal degeneration in glaucoma.


Asunto(s)
Apoptosis/fisiología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Nucleares/metabolismo , Estrés Oxidativo/fisiología , Células Ganglionares de la Retina/metabolismo , Animales , Elementos de Respuesta Antioxidante/fisiología , Apoptosis/efectos de los fármacos , Regulación hacia Abajo , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas , Células Ganglionares de la Retina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba
12.
Chem Biol Interact ; 324: 109091, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32283069

RESUMEN

Folate and alcohol are dietary factors affecting the risk of cancer development in humans. The interaction between folate status and alcohol consumption in carcinogenesis involves multiple mechanisms. Alcoholism is typically associated with folate deficiency due to reduced dietary folate intake. Heavy alcohol consumption also decreases folate absorption, enhances urinary folate excretion and inhibits enzymes pivotal for one-carbon metabolism. While folate metabolism is involved in several key biochemical pathways, aberrant DNA methylation, due to the deficiency of methyl donors, is considered as a common downstream target of the folate-mediated effects of ethanol. The negative effects of low intakes of nutrients that provide dietary methyl groups, with high intakes of alcohol are additive in general. For example, low methionine, low-folate diets coupled with alcohol consumption could increase the risk for colorectal cancer in men. To counteract the negative effects of alcohol consumption, increased intake of nutrients, such as folate, providing dietary methyl groups is generally recommended. Here mechanisms involving dietary folate and folate metabolism in cancer disease, as well as links between these mechanisms and alcohol effects, are discussed. These mechanisms include direct effects on folate pathways and indirect mediation by oxidative stress, hypoxia, and microRNAs.


Asunto(s)
Carcinogénesis/efectos de los fármacos , Etanol/farmacología , Ácido Fólico/metabolismo , Neoplasias/etiología , Animales , Dieta , Deficiencia de Ácido Fólico/inducido químicamente , Humanos , MicroARNs/metabolismo , Estrés Oxidativo/efectos de los fármacos , Factores de Riesgo
13.
Chem Biol Interact ; 324: 109084, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32289290

RESUMEN

INTRODUCTION: An imbalance between oxidants and antioxidants in favour of oxidants, potentially leading to damage, is termed oxidative stress. Antioxidants (AO), either enzymatic or non-enzymatic, are the ones that can reduce diverse effects of pro-oxidants such as DNA, proteins and lipids damage. Chalcones (1,3-diaryl-2-propen-1-ones) are open chain flavonoids that are widely biosynthesized in plants. Aim of this study was to test antioxidative potency of 15 chalcones (Chs) in in vitro model in serum (native conditions), so as with exogenously induced oxidative stress. MATERIAL AND METHODS: Oxidative stress was induced in serum samples of healthy individuals with 0.25 mmol/L terc-buthyl-hydroperoxide (TBH), and then we monitored the effects of various concentrations of chalcones on oxidative stress parameters: total antioxidative status (TAS), total oxidative status (TOS), total concentration of sulfhydryl group (SHG) and prooxidative-antioxidative balance (PAB), and calculated prooxidative score, antioxidative score, and oxy score (OS). Nonparametric repeated measures ANOVA (Friedman's test) was used for comparison of antioxidative potency of samples with 15 different chalcones, in a native state and upon TBH influence. Spearman's nonparametric correlation analysis was used for estimation of relation between different parameters. RESULTS: Negative Oxy Score (OS) values for Chs11-15 showed significantly stronger antioxidative potency compared to other investigated chalcones (p < 0.05). Ch11, Ch13 and Ch14 remained with negative OS even after TBH addition, whereas OS of Ch12 and Ch15 became positive, with small nominal values. Samples with Ch11 and Ch13 showed significant negative correlation between TAS and TOS (p < 0.05 for both), but in Ch14 sample the negative correlation existed between TAS and PAB (p < 0.05). CONCLUSION: Lower value of OS (i.e. better antioxidative potency) was noticed in samples with Ch11-Ch15. Electron-donor effects of substituent groups as a structural part of these chalcones could explain its antioxidative capability. Phenolic and methyl groups are responsible for antioxidative ability enhancement of five chalcones with the best activity.


Asunto(s)
Antioxidantes/farmacología , Sangre/metabolismo , Chalconas/farmacología , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/síntesis química , Antioxidantes/química , Sangre/efectos de los fármacos , Chalconas/síntesis química , Chalconas/química , Humanos , Estructura Molecular , Relación Estructura-Actividad , terc-Butilhidroperóxido/farmacología
14.
Gene ; 747: 144653, 2020 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-32259630

RESUMEN

Diabetic retinopathy (DR) is a frequent complication of diabetes and it can lead to visual impairment and blindness. However, the mechanism of their regulation remains little known. circRNAs can function as crucial competing endogenous RNA, which can sponge corresponding miRNAs and affect mRNA expression in various diseases, including DR. In our current research, we observed that circRNA_0084043 was elevated in high glucose (HG)-incubated ARPE-19 cells. Then, we focused on whether and how circRNA_0084043 participated in retinal vascular dysfunction under conditions diabetes. Apoptosis, inflammation and oxidative stress are hallmark of DR progression. This work was aimed to investigate the signaling mechanisms of circRNA_0084043 in these pathogenesis of DR. We discovered loss of circRNA_0084043 significantly increased cell survival and repressed HG-triggered apoptosis. In addition, knockdown of circRNA_0084043 remarkably reduced oxidative stress as evidenced by the down-regulated malondialdehyde (MDA) content, enhanced activities of Super Oxide Dismutase (SOD) and Glutathione peroxidase (GSH-PX). Addition, silence of circRNA_0084043 effectively restrained HG-stimulated inflammation as proved by repressing inflammatory cytokines Tumor Necrosis Factor α (TNF-α), Interleukin 6 (IL-6) and Cox-2 in ARPE-19 cells. Subsequently, we successfully predicted that miR-140-3p was a downstream target of circRNA_0084043, which could be negatively regulated by circRNA_0084043. Mechanistically, loss of miR-140-3p abrogated the beneficial effects of circRNA_0084043 siRNA on ARPE-19 cells. Transforming Growth Factor alpha (TGFA) can exhibit a role in multiple diseases. Taken these together, these data demonstrated that loss of circRNA_0084043 depressed HG-induced damage via sponging miR-140-3p and regulating TGFA.


Asunto(s)
Retinopatía Diabética/genética , Progresión de la Enfermedad , Células Epiteliales/metabolismo , Regulación de la Expresión Génica , MicroARNs/metabolismo , ARN Circular/genética , Epitelio Pigmentado de la Retina/patología , Factor de Crecimiento Transformador alfa/genética , Apoptosis/efectos de los fármacos , Secuencia de Bases , Línea Celular , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/toxicidad , Humanos , Inflamación/patología , MicroARNs/genética , Modelos Biológicos , Estrés Oxidativo/efectos de los fármacos , ARN Circular/metabolismo , Factor de Crecimiento Transformador alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética
15.
Med Sci Monit ; 26: e921905, 2020 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-32245940

RESUMEN

BACKGROUND Type 2 diabetes mellitus (T2DM) and its comorbidities, including obesity, hypertension, and hyperlipidemia, are commonly associated with non-alcoholic fatty liver disease (NAFLD). Ganoderma lucidum polysaccharide (GDLP) is one of the central bioactive components in Ganoderma lucidum with anti-inflammatory, antioxidant, and hepatoprotective properties. However, the effect and mechanisms of GDLP in hepatic steatosis remain largely unknown. In the present study, we aimed to investigate the function of GDLP in hepatic steatosis and the underlying mechanism. MATERIAL AND METHODS In this study, male db/db mice were received with a high-fat diet (HFD) to investigate the effect of GDLP in T2DM-induced hepatic steatosis. The biological characteristics of the hepatic steatosis were evaluated through the detection of clinical indicators, including biochemical parameters, histopathology, and related cytokine levels. Additionally, the protein expression levels of Nrf2 (nuclear factor E2 (erythroid-derived 2)-related factor-2) signaling pathway were investigated by using western blotting and immunohistochemical staining. RESULTS The levels of food/water intake, body weight, fasting blood glucose, plasma lipids, urinary biomarkers, hepatic lipid accumulation, and tumor necrosis factor (TNF)-alpha were observably decreased in GDLP-treated db/db mice. Additionally, administration of GDLP increased the expression of various antioxidases, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), whereas it reduced the level of malonaldehyde (MDA). Furthermore, GDLP was significantly promoted protein expression level of Nrf2 and its downstream target gene HO-1 (heme oxygenase-1) while decreased TNF-alpha expression. CONCLUSIONS These results indicate that GDLP against T2DM-induced hepatic steatosis, oxidative stress, and inflammation by improving the Nrf2/HO-1 signaling pathway in db/db mice, suggesting the GDLP may serve as an effective strategy for in fatty liver treatment.


Asunto(s)
Hígado Graso/tratamiento farmacológico , Hemo-Oxigenasa 1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Reishi/química , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Ratones , Polisacáridos
16.
Anticancer Res ; 40(4): 1963-1972, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234885

RESUMEN

BACKGROUND/AIM: The menadione/ascorbate (M/A) combination has attracted attention due to the unusual ability of pro-vitamin/vitamin combination to kill cancer cells without affecting the viability of normal cells. The aim of this study was to elucidate the role of M/A in targeting cancerous mitochondria. MATERIALS AND METHODS: Several cancer and normal cell lines of the same origin were used. Cells were treated with different concentrations of M/A for 24 h. The cell viability, mitochondrial superoxide, mitochondrial membrane potential, and succinate were analyzed using conventional analytical tests. RESULTS: M/A exhibited a highly specific suppression on cancer cell growth and viability, without adversely affecting the viability of normal cells at concentrations attainable by oral or parenteral administration in vivo. This effect was accompanied by: (i) an extremely high production of mitochondrial superoxide in cancer cells, but not in normal cells; (ii) a significant dose-dependent depolarization of mitochondrial membrane and depletion of oncometabolite succinate in cancer cells. CONCLUSION: The anticancer effect of M/A is related to the induction of severe mitochondrial oxidative stress in cancer cells only. Thus, M/A has a potential to increase the sensitivity and vulnerability of cancer cells to conventional anticancer therapy and immune system.


Asunto(s)
Ácido Ascórbico/farmacología , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Vitamina K 3/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/patología , Neoplasias/genética , Neoplasias/patología , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa/genética , Superóxidos/metabolismo
17.
Medicine (Baltimore) ; 99(17): e18704, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32332593

RESUMEN

BACKGROUND: Hypoxic ischemic encephalopathy (HIE) is brain injury caused by different reasons and the most common diagnosed is neonatal HIE. Most of the existing treatments have their own shortcomings or there are still some unexplained mechanisms in it. Topiramate (TPM) is a new drug for the treatment for seizures in neonates with HIE, but is currently used off-label. Our protocol aims to access the efficiency and safety of TPM for HIE. METHODS AND ANALYSIS: Eight databases will be searched by 2 independent researchers for the article on the topic of using TPM as treatment for HIE, including PubMed, the Cochrane Central Register of Controlled Trials (Cochrane Library), Embase, and Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wang Fang Database and Chinese Science and Technology Periodical database (VIP). The included papers are those published from the established date of the databases to 2019. The therapeutic effects based on the grade of neonatal behavioral neurological assessment will be regarded as the primary outcomes. RevMan V5.3 will be used to compute the data synthesis and carry out meta-analysis. The risk of bias will be appraised by the Cochrane risk of bias tool. Rare ratio for dichotomous outcomes and mean different for continuous data will be expressed with 95% confidence intervals (CI) for analysis. A random effects model or a fixed effects model will be employed, when heterogeneity is found or not. Subgroup analysis and sensitivity analysis will be applied if the heterogeneity is obvious. RESULTS: This study will provide the recent evidence of TPM for HIE from reducing seizure acticity. CONCLUSION: The conclusion of this study will provide proof to evaluate if TPM is effective and safe in the treatment of HIE.PROSPERO registration number: PROSPERO CRD42018117981.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Topiramato/uso terapéutico , Anticonvulsivantes/efectos adversos , Humanos , Hipoxia-Isquemia Encefálica/complicaciones , Hipoxia-Isquemia Encefálica/mortalidad , Recién Nacido , Estrés Oxidativo/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Índice de Severidad de la Enfermedad , Topiramato/efectos adversos
18.
Chemosphere ; 249: 126481, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32209501

RESUMEN

Dechlorane Plus (DP) is a widely used chlorinated flame retardant, which has been extensively detected in the environment. Although DP content in the surface water is low, it can pose a continuous exposure risk to aquatic organisms due to its strong bioaccumulation. Considering that the related studies on the toxicity mechanism of DP exposure are limited, the effect of DP on carp embryo development was evaluated. In the present work, carp embryos were exposed to different concentrations (0, 30, 60, and 120 µg/L) of DP at 3 h post-fertilization (hpf). The expression levels of neural and skeletal development-associated genes, such as sox2, sox19a, Mef2c and BMP4, were detected with quantitative PCR, and the changes in different developmental toxicity endpoints were observed. Our results demonstrated that the expression levels of sox2, sox19a, Mef2c and BMP4 were significantly altered and several developmental abnormalities were found in DP-exposed carp embryos, such as DNA damage, increased mortality rate, delayed hatching time, reduced hatching rate, decreased body length, and increased morphological deformities. In addition, the activities of reactive oxygen species and malondialdehyde were remarkably higher in 60 and 120 µg/L DP exposure groups than in control group. These results suggest that DP can exhibit a unique modes of action, which lead to aberration occurrence in the early development stage of common carps, which may be related to some gene damage and oxidative stress. Besides, the parameters evaluated here can be used as tools to access the environmental risk for biota and humans exposed to DP.


Asunto(s)
Carpas/fisiología , Retardadores de Llama/toxicidad , Hidrocarburos Clorados/toxicidad , Compuestos Policíclicos/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Carpas/metabolismo , Daño del ADN , Desarrollo Embrionario/efectos de los fármacos , Retardadores de Llama/análisis , Halogenación , Malondialdehído/metabolismo , Sistema Nervioso , Estrés Oxidativo/efectos de los fármacos , Contaminantes Químicos del Agua/análisis
19.
Life Sci ; 250: 117531, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32151691

RESUMEN

AIMS: To investigate the protective effects and mechanism of semaglutide on exercise-induced myocardial injury. MAIN METHODS: Effects of semaglutide on lipopolysaccharide (LPS)-induced oxidative stress injuries and inflammatory response were assessed in H9c2 cell via MTT assay and Western blot. Quiet control group, over training group and three doses of semaglutide treated overtraining groups were subjected to the swimming training with increasing load for consecutive 10 weeks. Immediately after the last training, the body weight, myocardial morphological changes, injury markers and inflammatory response related proteins of the model rats were analyzed. KEY FINDINGS: Semaglutide at three concentrations in LPS treated H9c2 cells significantly increased the survival rate and inhibited the apoptosis of cardiomyocytes. Moreover, semaglutide activated AMPK pathway, improve autophagy and inhibited reactive oxygen species production in LPS treated H9C2 cells. In vivo results further revealed that chronic treatment of semaglutide induced significant increase in myocardial injury markers. The pathological histology analysis results showed that semaglutide ameliorated myocardial morphological changes, reduced area of lipid accumulation and significantly decreased the expression levels of NF-κB, TNF-α and IL-1ß. SIGNIFICANCE: Semaglutide exert the protective effects on exercise-induced cardiomyopathy by activating AMPK pathway, increasing autophagy, reducing the production of ROS and inflammation-related proteins.


Asunto(s)
Péptidos Similares al Glucagón/farmacología , Lesiones Cardíacas/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Condicionamiento Físico Animal/efectos adversos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis , Línea Celular , Supervivencia Celular , Citocinas/metabolismo , Lesiones Cardíacas/prevención & control , Interleucina-1beta/metabolismo , Lípidos/química , Lipopolisacáridos , Masculino , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
20.
Bratisl Lek Listy ; 121(3): 192-198, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32115976

RESUMEN

AIM: The study was designed to evaluate the possible adverse effects and consequences of metal oxide nanoparticles used on some major body organ functions and health parameters. MATERIALS AND METHODS: Thirty albino rats, allocated randomly into three groups for experimental period of 20 days post-administration were used. Different effects of metal oxide nanoparticles were targeted including, thyroid, parathyroid, kidney, calcium, phosphate, hematological parameters and indices, as well as oxidative stress markers of the red blood cells and their membranes as alpha tocopherol and GSH, by using different analytical methods. RESULTS: Data revealed thyroid and parathyroid hormonal disturbances; kidney dysfunction in the form of accumulation of some waste products as BUN, creatinine, and uric acid. A decrease in the calcium and phosphate and an increase in the potassium and phosphate concentrations was recorded.  A marked decrease in the indices of anemia and diminished oxidative stress indicators were also evident, associated with marked increase in the total leukocyte count. CONCLUSION: The present study confirmed the health risks of the use of metal oxide nanoparticles in the medical field without precautions and supervision; and may encourage application of nanoparticles from alternative origins, such as plants, algae, or microorganisms instead (Tab. 5, Fig. 4, Ref. 30) Keywords: nanoparticles, thyroid, parathyroid, kidney, oxidative stress, blood, green, alternative.


Asunto(s)
Nanopartículas del Metal , Estrés Oxidativo , Animales , Nanopartículas del Metal/toxicidad , Metales , Estrés Oxidativo/efectos de los fármacos , Óxidos , Ratas , Distribución Tisular
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