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The mechanism is unclear for the reported protective effect of hyperbaric oxygen preconditioning against oxidative stress in tissues, and the distinct effects of hyperbaric oxygen applied after stress. The trained mice were divided into three groups: the control, hyperbaric oxygenation preconditioning, and hyperbaric oxygenation applied after mild (fasting) or hard (prolonged exercise) stress. After preconditioning, we observed a decrease in basal levels of nitric oxide, tetrahydrobiopterin, and catalase despite the drastic increase in inducible and endothelial nitric oxide synthases. Moreover, the basal levels of glutathione, related enzymes, and nitrosative stress only increased in the preconditioning group. The control and preconditioning groups showed a similar mild stress response of the endothelial and neuronal nitric oxide synthases. At the same time, the activity of all nitric oxide synthase, glutathione (GSH) in muscle, declined in the experimental groups but increased in control during hard stress. The results suggested that hyperbaric oxygen preconditioning provoked uncoupling of nitric oxide synthases and the elevated levels of GSH in muscle during this study, while hyperbaric oxygen applied after stress showed a lower level of GSH but higher recovery post-exercise levels in the majority of antioxidant enzymes. We discuss the possible mechanisms of the redox response and the role of the nitric oxide in this process.
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(-)-Epicatechin is a phenolic compound with antioxidant activity that is present in natural food and drinks, such as cocoa and red wine. Evidence suggests that (-)-epicatechin exhibits anticancer activity; however, its mechanism of action is poorly understood. Here, we investigated the anticancer effects of (-)-epicatechin and its mechanism of action in breast cancer cells. We assessed the anticancer activity by cell proliferation assays, apoptosis by DNA fragmentation and flow cytometry. The expression of proteins associated with apoptosis was analyzed by the human apoptosis array. MitoSOXTM Red and biomarkers of oxidative damage were used to measure the effect of (-)-epicatechin on mitochondrial reactive oxygen species (ROS) and cellular damage, respectively. (-)-Epicatechin treatment caused a decreasing in the viability of MDA-MB-231 and MCF-7 cells. This cell death was associated with DNA fragmentation and an apoptotic proteomic profile. Further, (-)-epicatechin in MDA-MB-231 cells upregulated death receptor (DR4/DR5), increased the ROS production, and modulated pro-apoptotic proteins. In MCF-7 cells, (-)-epicatechin did not involve death receptor; however, an increase in ROS and the upregulation of pro-apoptotic proteins (Bad and Bax) were observed. These changes were associated with the apoptosis activation through the intrinsic pathway. In conclusion, this study shows that (-)-epicatechin has anticancer activity in breast cancer cells and provides novel insight into the molecular mechanism of (-)-epicatechin to induce apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Catequina/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fragmentação do DNA/efeitos dos fármacos , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Espécies Reativas de Oxigênio/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genéticaRESUMO
BACKGROUND: The arrival of large quantities of Sargassum in the Mexican Caribbean Sea has generated major environmental, health and economic problems. Although Sargassum has been used in the generation of some commercial products, few studies have described its possible applications as a source of compounds with anticancer activity. OBJECTIVE: This study aimed to evaluate the antiproliferative effects of different Sargassum extracts on various cancer cell lines. Furthermore, LC/QTOF-MS was used to identify the compounds related to the antiproliferative effect. METHODS: First, determination of the seaweed was performed, and dichloromethane, chloroform and methanol extracts were obtained. The extracts were evaluated for their antiproliferative effects by MTT in breast (MDAMB- 231 and MCF-7), prostate (DU-145), lung (A549) and cervical (SiHa) cancer cell lines. Finally, LC/QTOFMS identified the compounds related to the antiproliferative effect. RESULTS: The authentication showed Sargassum fluitans as the predominant species. The extracts of dichloromethane and chloroform showed an antiproliferative effect. Interestingly, the fractionation of the chloroform extract showed two fractions (FC1 and FC2) with antiproliferative activity in MDA-MB-231, SiHa and A549 cancer cell lines. On the other hand, three fractions of dichloromethane extract (FD1, FD4 and FD5) also showed antiproliferative effects in the MDA-MB-231, MCF-7, SiHa and DU-145 cancer cell lines. Furthermore, LC/QTOF-MS revealed the presence of eight major compounds in FC2. Three compounds with evidence of anticancer activity were identified (D-linalool-3-glucoside, (3R,4S,6E,10Z)-3,4,7,11-tetramethyl-6,10-tridecadienal and alpha-tocotrienol). CONCLUSION: These findings showed that Sargassum fluitans extracts are a possible source of therapeutic agents against cancer and could act as scaffolds for new drug discovery.
Assuntos
Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Sargassum , Humanos , Sargassum/química , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Estrutura Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificaçãoRESUMO
For this study, procyanidins generated through the autoxidation of (-)-epicatechin (Flavan-3-ol) under mildly acidic conditions (pH = 6.0) were characterized with ultra high-performance liquid chromatography (UHPLC) coupled with tandem mass spectrometry (MS/MS). Two procyanidins (types A and B) and a mix of oligomers were generated through the autoxidation of (-)-epicatechin. The antiproliferative activity of this mixture of procyanidins on MDA-MB-231, MDA-MB-436, and MCF-7 breast cancer cells was evaluated. The results indicate that the procyanidin mixture inhibited the proliferation of breast cancer cells, where the activity of the procyanidin mixture was stronger than that of (-)-epicatechin. Moreover, the mechanism underlying the antiproliferative activity of procyanidins was investigated. The resulting data demonstrate that the procyanidins induced apoptotic cell death in a manner selective to cancerous cells. In particular, they caused the activation of intrinsic and extrinsic apoptotic pathways in the breast cancer cells. The findings obtained in this study demonstrate that the generation of procyanidins in vitro by the autoxidation of (-)-epicatechin has potential for the development of anti-breast cancer agents.
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BACKGROUND/OBJECTIVES: Cocoa consumption is associated with health benefits due to its high content of polyphenols. However, the effects of short-term cocoa consumption remain unclear. We aimed to determine the effects generated by cocoa consumption (for 7 days) in young adults in normoweight and class II obesity. SUBJECTS/METHODS: Before-and-after study was carried out in normoweight (NW) (n = 15) and class II obesity (CIIO) (n = 15) young adults. The NW and CIIO participants consumed 25 and 39 g of cocoa, respectively, per day for 7 days. The effect of cocoa consumption was evaluated on the lipid profile, insulin resistance (IR), and inflammation. Oxidative damage was also examined by assessing the biomarkers of oxidative damage in plasma. In addition, recombinant human insulin was incubated with blood obtained from the participants, and the molecular damage to the hormone was analyzed. RESULTS: Cocoa consumption resulted in decreased low-density lipoprotein-cholesterol in both groups (P = 0.04), while the total cholesterol, high-density lipoprotein cholesterol, and triglycerides were maintained at the recommended levels. Initially, IR was detected in the CIIO group (homeostasis model assessment [HOMA] = 4.78 ± 0.4), which is associated with molecular damage to insulin. Interestingly, intervention with cocoa resulted in improved IR (HOMA = 3.14 ± 0.31) (P = 0.0018) as well as molecular damage to insulin. Finally, cocoa consumption significant decreased the arginase activity (P = 0.0249) in the CIIO group; this is a critical enzymatic activity in the inflammatory process associated with obesity. CONCLUSIONS: The short-term consumption of cocoa improves the lipid profile, exerts anti-inflammatory effects, and protects against oxidative damage. Results of this study indicate that cocoa consumption can potentially improve IR and restore a healthy redox status.
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Breast cancer (BC) is the most frequently diagnosed cancer and is the second-most common cause of death in women worldwide. Because of this, the search for new drugs and targeted therapy to treat BC is an urgent and global need. Histone deacetylase 6 (HDAC6) is a promising anti-BC drug target associated with its development and progression. In the present work, the design and synthesis of a new family of dihydropyrazole-carbohydrazide derivatives (DPCH) derivatives focused on HDAC6 inhibitory activity is presented. Computational chemistry approaches were employed to rationalize the design and evaluate their physicochemical and toxic-biological properties. The new family of nine DPCH was synthesized and characterized. Compounds exhibited optimal physicochemical and toxicobiological properties for potential application as drugs to be used in humans. The in silico studies showed that compounds with -Br, -Cl, and -OH substituents had good affinity with the catalytic domain 2 of HDAC6 like the reference compounds. Nine DPCH derivatives were assayed on MCF-7 and MDA-MB-231 BC cell lines, showing antiproliferative activity with IC50 at µM range. Compound 2b showed, in vitro, an IC50 value of 12 ± 3 µM on human HDAC6. The antioxidant activity of DPCH derivatives showed that all the compounds exhibit antioxidant activity similar to that of ascorbic acid. In conclusion, the DPCH derivatives are promising drugs with therapeutic potential for the epigenetic treatment of BC, with low cytotoxicity towards healthy cells and important antioxidant activity.
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Natural compounds such as (-)-epicatechin show a variety of biological properties including anticancer activity. Nonetheless, (-)-epicatechin's therapeutic application is limited due to its low water solubility and sensitivity to oxygen and light. Additionally, previous studies have reported that the encapsulation of flavonoids in nanoparticles might generate stable deliverable forms, which improves the availability and solubility of the bioactive compounds. The aims of this study were to generate (-)-epicatechin-loaded lecithin-chitosan nanoparticles (EC-LCT-NPs) by molecular self-assembly and to assess their cytotoxic potential against breast cancer cells. Various parameters were measured to characterize the EC-LCT-NPs including size, polydispersity index (PdI), zeta potential, morphology and entrapment efficiency. The results showed that the mean particle size of the EC-CLT-NPs was 159 ± 2.23 nm (PdI, 0.189), and the loading and entrapment efficiencies of (-)-epicatechin were 3.42 ± 0.85% and 56.1 ± 3.9%, respectively. The cytotoxic effect of the EC-CLT-NPs was greater than that of free (-)-epicatechin on breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-436 and SK-Br3). Indeed, EC-LCT-NPs showed an IC50 that was four-fold lower (85 µM) than free (-)-epicatechin (350 µM) and showed selectivity to cancerous cells. This study demonstrated that encapsulating (-)-epicatechin into lecithin-chitosan nanoparticles opens new options for breast cancer treatment.
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The objectives of this study were (1) to evaluate the capacity of human plasma that had been obtained from healthy adult volunteers before and after they ingested vitamin E or C to inhibit induced lipoperoxidation in vitro (antioxidant capacity of plasma [ACP]), and (2) to compare the efficiency of these vitamins with that of a commercial mixture of antioxidant vitamins, cofactors, and minerals (MAOx). Seventy-nine healthy individuals between 19 and 23 y of age were randomly assigned to 1 of 4 groups. Each received a daily dose of antioxidants for 7 d: vitamin C (n=18; 500 mg), vitamin E (n=21; 400 IU), vitamins C and E (n=19), or MAOx (n=21; 1.2 g). ACP and plasma malondialdehyde were measured at 4 and 24 h and 7 d. ACP increased significantly (P<.05) in all 4 groups within 4 h of antioxidant intake, and this effect was sustained throughout supplementation. Plasma ACP increased significantly over basal values in the group taking MAOx; relative increases were 42%, 44%, and 55% at 4 h, 24 h, and 7 d, respectively (P<.001). Smaller increases in plasma ACP were observed in the vitamin C group (25%, 32%, and 36%) and, specifically, in the vitamin E group (17%, 24%, and 28%) (P<.05). The mixture of vitamins and minerals was comparatively more efficient than vitamin C or E alone, presumably because MAOx contains various antioxidant compounds with different redox potentials, leading to the possible development of chain reactions.
Assuntos
Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Vitamina E/uso terapêutico , Vitaminas/uso terapêutico , Administração Oral , Adulto , Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Vitamina E/administração & dosagem , Vitaminas/administração & dosagemRESUMO
Introducción: Patologías como asma, enfermedad pulmonar obstructiva crónica, diabetes mellitus, neuropatías y el síndrome de Alzheimer, entre otros, están asociados al estrés oxidante, condición metabóllca por la cual las personas que sufren estos padecimientos presentan modificaciones y rompimiento de biomoléculas en plasma; es importante conocer sus valores básales en personas sanas para poder interpretarlos adecuadamente. Objetivo: Determinar las concentraciones básales de algunos marcadores de estrés oxidante en adultos sanos (31-60 años). Método: A 67 personas sanas, divididas en tres grupos. Grupo 1 (31-40 años); grupo 2 (41-50 años) y grupo 3 (51-60 años), se les evaluaron los siguientes marcadores de estrés oxidante: Compuestos reactivos al ácido tiobarbitúrico (CRAT), predisposición al daño oxidante, determinación de grupos carbonilo, capacidad antioxidante total de plasma (CATP), y actividad enzimática de paraoxonasa. Los resultados se sometieron a pruebas estadísticas de ANOVA de una vía y post-hoc de Bonferroni, considerando una significancia de 0.05. Resultados: Se encontró un aumento significativo en CRAT en el grupo 2 y en el grupo 3 (8.462 ± 0.571 vs 10.34 ± 1.23µM CRAT, respectivamente). En la predisposición a la lipoperoxidación, el grupo 3 fue el más susceptible al daño, debido a que hubo un incremento en los niveles de CRAT (477.0 ± 16.71 µM) en comparación al grupo 2 (432.3 ± 25.71 µM) y al grupo 1 (320.6 ± 28.95µM). En la determinación de grupos carbonilo no existieron diferencias entre los grupos. La CATP disminuyó en el grupo 2 con respecto al grupo 1 (0.950 ± 0.071 vs 0.69 ± 0.068 unidades, respectivamente). La actividad de paraoxonasa presentó un aumento en el grupo 3 con respecto al grupo 1 (0.119 ± 0.004 vs 0.072 ± 0.007 nmol p-nitrofenol/ mg proteína, respectivamente). Conclusión: Las concentraciones de los marcadores de daño por estrés oxidante se ven modificadas por la edad del individuo. En el proceso natural de envejecimiento, el principal daño es a Iípidos.
Introduction: Patients with asthma, COPD, diabetes mellitus, kidney diseases and Alzheimer syndrome, conditions associated to oxidative stress, have modifications and rupture of certain plasma biomolecules. In order to explain properly this findings, basal values in normal individuals of such biomolecules should be known. Objective: To determine the basal values of some markers of oxidative stress in healthy 31 to 60 year old individuals. Method: Seventy seven healthy volunteers were classified into group 1, 31 to 40 years, group 2, 41 to 50 years and group 3, 51 to 60 years; the following oxidative stress markers were measured: reactive compounds to tiobarbituric acid (TBARs), predisposition to oxidative stress, determination of carbonil groups, total antioxidative capacity of plasma (TACP) and enzymatic activity of paraoxonase. ANOVA and Bonferroni tests were used; a level of 0.05 was considered significant. Results: Croup 2 and 3 showed significant increment in TBARs (8.462 ± 0.571 vs 10.34 ± 1.23µM TBARs, respectively). In the predisposition to lipoper oxidation, group 3 was more susceptible, due to an increase in RCTA levels (477.0 ± 16.71 µM) in comparison to group 2 (432.3 ± 25.71 µM) and 1 (320.6 ± 28.95 µM). There was no difference in the determination of carbonil groups between the groups. TACP is significantly diminished in group 2 in relation to group 1 (0.950 ± 0.071 vs 0.69 ± 0.068 units, respectively). Paraoxonase's activity showed a significant increase in group 3 in relation to group 1 (0.119 ± 0.004 vs 0.072 ± 0.007 nmol p-nitrophenol/mg protein, respectively). Conclusion: Advancing age modifies biomolecular markers of oxidative stress; during the natural aging process, the main damage is to lipids.
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Al tratarse de un proceso inflamatorio, en el asma hay participación e incremento en la generación de especies reactivas del oxígeno, dando lugar a un desequilibrio oxidante/antioxidante, fenómeno que se ha descrito como estrés oxidante, que causa daño a diferentes biomoléculas. La utilización de agentes antioxidantes exógenos o activadores de antioxidantes endógenos como coadyuvantes de la terapéutica del paciente asmático, es una posibilidad a discutir.
Oxidative stress seen in bronchial asthma can damage different kinds of biomolecules; this oxidant/antioxidant imbalance results from an increment in the production of oxygen reactive species. The utilization of exogenous antioxidant agents or promoters of endogenous antioxidants can be seen as an alternative therapy for asthma that is worth discussing.
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El asma es una enfermedad inflamatoria crónica del tracto respiratorio de etiología aún desconocida; sin embargo, nuevas evidencias han involucrado al estrés oxidante, en el que la participación e incremento en la generación de especies reactivas del oxígeno por diferentes sistemas bioquímicos, superan a los mecanismos antioxidantes en el ambiente de las vías respiratorias del asmático, lo cual es acompañado de alteraciones inducidas por radicales libres que involucran daño estructural y modificaciones metabólicas presentes, a nivel sistémico y en el tracto respiratorio.
Asthma is a chronic inflammatory disease of the airways: its precise etiology is still unknown. New evidence points to oxydative stress, in which the participation and increment of reactive species of oxygen by several biochemical systems overwhelms the anti oxidant mechanisms of the airways; this, in conjunction with changes induced by free radicals involving systemic and local respiratory structural damage and metabolic changes.
Assuntos
Antioxidantes/metabolismo , Antioxidantes/farmacologia , Adulto , Ácido Ascórbico/farmacologia , Química Farmacêutica , Ácidos Graxos Insaturados/metabolismo , Humanos , Radical Hidroxila , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/sangue , Minerais/farmacologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Vitamina E/farmacologia , Vitaminas/farmacologiaRESUMO
Las especies reactivas de oxígeno son moléculas (O2-, HO , NO ), muy reactivas debido a que en el último orbital tienen un electrón no pareado (radical libre), lo cual confiere inestabilidad física. Se incluyen en las especies reactivas de oxígeno a moléculas precursoras de los radicales libres (H2O2, HONO2-). Estas especies participan en procesos fisiológicos en el organismo. Cuando la generación de especies reactivas de oxígeno supera a los mecanismos de inactivación, se presenta el estado metabólico de estrés oxidante que se caracteriza por daños moleculares y celulares que conducen a predisposición o modificación de diversos padecimientos crónico-degenerativos. Entre las enfermedades pulmonares en que se ha demostrado la participación de las especies reactivas de oxígeno, destacan el síndrome de insuficiencia respiratoria progresiva, la enfermedad pulmonar obstructiva crónica y el asma. Se analizan las características del estrés oxidante en estos padecimientos.
Reactive Oxygen Species (ROS) are very reactive molecules (O2-, HO, NO ) since they have a single and unpaired electron in the last orbital (free radical) which confers them physical instability. Free radical precursors such as H2O2 , HONO2- are considered ROS. These species are important in the physiological processes. When ROS production exceeds the inactivation mechanisms, oxidative stress takes place. This stress is characterized by molecular and cellular damage which predisposes to or modifies chronic-degenerative diseases. Among pulmonary diseases in which ROS participation has been proved are ARDS, COPD and asthma. The aim of this paper was to analyze the mechanisms of oxidative stress that lead to those illnesses.
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En los organismos aeróbicos el oxígeno es esencial para la vida, pero puede ser tóxico cuando se presentan situaciones favorables en las que sí hay una producción exagerada de especies de oxígeno reactivas (ROS): anión superóxido (O2-) e hidroxilo (-OH), y por la generación del peróxido de hidrógeno (H2O2) que es una especie reactiva del O2 y puede ser precursora de los radicales libres. Las ROS contribuyen al daño molecular y estructural que se presenta en una serie de padecimientos en donde la capacidad antioxidante del organismo es rebasada y por lo tanto incapaz de inactivar las ROS, dando lugar al proceso llamado estrés oxidante. El daño provocado en la membrana celular es inducido por los radicales libres que llevan a la lipoperoxidación. El proceso de congelación y descongelación del semen reduce el porcentaje de espermatozoides vivos, afectando con la movilidad y la viabilidad, y por lo tanto la fertilidad del gameto, fenómeno atribuido a diversos factores, incluyendo los cambios de temperatura y al efecto de las ROS. Durante el metabolismo las mitocondrias del espermatozoide generan ROS que son inactivadas por los mecanismos antioxidantes. Para contrarrestar los efectos de la ROS generados por mecanismos no fisiológicos o en exceso se ha empleado una variedad de antioxidantes, pretendiendo anular o minimizar sus efectos. El objetivo de esta revisión es identificar las causas que dañan a las células espermáticas en la preservación de semen y los sistemas de defensa antioxidante enzimáticos y no enzimáticos