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1.
Einstein (Sao Paulo) ; 18: eAO5022, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32215468

RESUMO

OBJECTIVE: To evaluate the effects of oxidative stress on insulin signaling in cardiac tissue of obese mice. METHODS: Thirty Swiss mice were equally divided (n=10) into three groups: Control Group, Obese Group, and Obese Group Treated with N-acetylcysteine. After obesity and insulin resistance were established, the obese mice were treated with N-acetylcysteine at a dose of 50mg/kg daily for 15 days via oral gavage. RESULTS: Higher blood glucose levels and nitrite and carbonyl contents, and lower protein levels of glutathione peroxidase and phosphorylated protein kinase B were observed in the obese group when compared with their respective control. On the other hand, treatment with N-acetylcysteine was effective in reducing blood glucose levels and nitrite and carbonyl contents, and significantly increased protein levels of glutathione peroxidase and phosphorylated protein kinase B compared to the Obese Group. CONCLUSION: Obesity and/or a high-lipid diet may result in oxidative stress and insulin resistance in the heart tissue of obese mice, and the use of N-acetylcysteine as a methodological and therapeutic strategy suggested there is a relation between them.


Assuntos
Acetilcisteína/farmacologia , Dieta Hiperlipídica , Depuradores de Radicais Livres/farmacologia , Resistência à Insulina/fisiologia , Miocárdio/metabolismo , Obesidade/metabolismo , Estresse Oxidativo/fisiologia , Animais , Glicemia/análise , Western Blotting , Peso Corporal , Fluoresceínas/análise , Humanos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica , Espécies Reativas de Oxigênio/análise , Valores de Referência , Espectrofotometria
2.
Life Sci ; 250: 117554, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32184123

RESUMO

BACKGROUND: Mental stress (MS) is related to endothelial dysfunction in overweight/obese men. It is believed that the pro-oxidant profile, associated with an imbalance in the vascular remodeling process, may contribute to deleterious effects of MS on endothelial function. However, it is unknown whether administration of ascorbic acid (AA), a potent antioxidant, can prevent oxidative and remodeling dysfunction during MS in these subjects. METHODS: Fourteen overweight/obese grade I men (27 ± 7 years; 29.7 ± 2.6 kg·m-2) underwent the Stroop Color Word Test for 5 min to induce MS after AA (3 g) or placebo (PL, 0.9% NaCl) intravenous infusions. Venous blood samples were collected at baseline and the last minute of MS to measure nitrite concentration (chemiluminescence), protein carbonylation, thiobarbituric acid reactive substances (TBARS) and catalase activity (colorimetric assays), superoxide dismutase (SOD; immunoenzymatic assay), activities of active/inactive (pro) forms of metalloproteinases-9 and -2 (MMP; zymography) and its respective tissue inhibitors concentration (TIMP-1 and TIMP-2; immunoenzymatic assays). RESULTS: At baseline, MMP-9 activity (p < 0.01), the MMP-9/proMMP-9 ratio (p = 0.02) and TIMP-1 concentration (p = 0.05) were reduced, whereas proMPP-9 activity was increased (p = 0.02) after AA compared to PL infusion. After PL infusion, MS increased protein carbonylation (p < 0.01), catalase (p < 0.01), and the MMP-9/proMMP-9 ratio (p = 0.04) when compared to baseline. AA infusion reduced protein carbonylation (p = 0.02), MMP-9 activity (p < 0.01), and MMP-9/pro-MMP-9 ratio (p < 0.01), while SOD (p = 0.04 vs baseline), proMPP-9 (p < 0.01 vs PL), MMP-2 (p < 0.01 vs PL) and TIMP-2 (p = 0.02 vs baseline) remained elevated during MS. CONCLUSIONS: AA appears to minimize the oxidative imbalance and vascular remodeling induced by MS.


Assuntos
Ácido Ascórbico/farmacologia , Obesidade/psicologia , Sobrepeso/psicologia , Estresse Psicológico , Remodelação Vascular/efeitos dos fármacos , Adulto , Antioxidantes/metabolismo , Catalase/metabolismo , Estudos Cross-Over , Endotélio Vascular/patologia , Humanos , Luminescência , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Oxidantes/metabolismo , Carbonilação Proteica , Fatores de Risco , Teste de Stroop , Superóxido Dismutase/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Adulto Jovem
3.
PLoS One ; 15(2): e0218228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32032358

RESUMO

Systemic and central cardiovascular adaptations may vary in response to chronic exercise performed with different intensities and volumes. This study compared the effects of aerobic training with different intensities but equivalent volume upon microvascular reactivity in cremaster muscle and myocardial biomarkers of oxidative stress in Wistar rats. After peak oxygen uptake (VO2peak) assessment, rats (n = 24) were assigned into three groups: moderate-intensity exercise training (MI); high-intensity exercise training (HI); sedentary control (SC). Treadmill training occurred during 4 weeks, with exercise bouts matched by the energy expenditure (3.0-3.5 Kcal). Microvascular reactivity was assessed in vivo by intravital microscopy in cremaster muscle arterioles, while biomarkers of oxidative stress and eNOS expression were quantified at left ventricle and at aorta, respectively. Similar increasing vs. sedentary control group (SC) occurred in moderate intensity training group (MI) and high-intensity training group (HI) for endothelium-dependent vasodilation (10-4M: MI: 168.7%, HI: 164.6% vs. SC: 146.6%, P = 0.0004). Superoxide dismutase (SOD) (HI: 0.13 U/mg vs. MI: 0.09 U/mg and SC: 0.06 U/mg; P = 0.02), glutathione peroxidase (GPX) (HI: 0.00038 U/mg vs. MI: 0.00034 U/mg and SC: 0.00024 U/mg; P = 0.04), and carbonyl protein content (HI: 0.04 U/mg vs. MI: 0.03 U/mg and SC: 0.01 U/mg; P = 0.003) increased only in HI. No difference across groups was detected for catalase (CAT) (P = 0.12), Thiobarbituric acid reactive substances (TBARS) (P = 0.38) or eNOS expression in aorta (P = 0.44). In conclusion, higher exercise intensity induced greater improvements in myocardium antioxidant defenses, while gains in microvascular reactivity appeared to rely more on exercise volume than intensity.


Assuntos
Terapia por Exercício/métodos , Isquemia Miocárdica/terapia , Estresse Oxidativo , Condicionamento Físico Animal/métodos , Vasodilatação , Animais , Aorta/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Ventrículos do Coração/metabolismo , Masculino , Microvasos/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Consumo de Oxigênio , Carbonilação Proteica , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
4.
PLoS One ; 15(2): e0229282, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084205

RESUMO

We aimed to study the physiological effects of diet supplemented with copper (Cu) nanoparticles (NPs). During the eight weeks of the experiment, young Wistar rats (at seven weeks of age, n = 9) were supplemented with 6.5 mg of Cu either as NPs or carbonate salt (Cu6.5). A diet that was not supplemented with Cu served as a negative control (Cu0). The impact of nano Cu supplementation on lipid (reflected as thiobarbituric acid reactive substances-TBARS) and protein peroxidation (thiol and carbonyl groups) in blood plasma as well as the influence on the vasodilatory mechanism(s) of isolated rat thoracic arteries were studied. Supplementation with Cu enhanced lipid peroxidation (TBARS) in NP6.5 (x2.4) and in Cu6.5 (x1.9) compared to the negative control. Significant increase in TBARS was also observed in NP6.5 (x1.3) compared to the Cu6.5 group. The level of thiol groups increased in NP6.5 (x1.6) compared to Cu6.5. Meanwhile, significant (x0.6) decrease was observed in the Cu6.5 group compared to the negative control. Another marker of protein oxidation, carbonyl groups increased in NP6.5 (x1.4) and Cu6.5 (x2.3) compared to the negative control. However significant difference (x0.6) was observed between NP6.5 and Cu6.5. Arteries from Cu supplemented rats exhibited an enhanced vasodilation to gasotransmitters: nitric oxide (NO) and carbon monoxide (CO). An enhanced vasodilation to NO was reflected in the increased response to acetylcholine (ACh) and calcium ionophore A23187. The observed responses to ACh and CO releasing molecule (CORM-2) were more pronounced in NP6.5. The activator of cGMP-dependent protein kinases (8-bromo-cGMP) induced similar vasodilation of thoracic arteries in NP6.5 and Cu0 groups, while an increased response was observed in the Cu6.5 group. Preincubation with the inducible nitric oxide (iNOS) synthase inhibitor- 1400W, decreased the ACh-induced vasodilation in NP6.5, exclusively. Meanwhile the eicosanoid metabolite of arachidonic acid (20-HETE) synthesis inhibitor-HET0016, enhanced vasodilation of arteries from Cu0 group. In conclusion, this study demonstrates that supplementation with nano Cu influences oxidative stress, which further has modified the vascular response.


Assuntos
Cobre/química , Cobre/farmacologia , Suplementos Nutricionais/análise , Nanopartículas Metálicas , Estresse Oxidativo/efeitos dos fármacos , Artérias Torácicas/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Artérias Torácicas/fisiologia
5.
Chem Biol Interact ; 317: 108941, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926916

RESUMO

m-Trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] is an organoselenium molecule that displays multiple pharmacological actions, including the antinociceptive effect. The current study investigated the (m-CF3-PhSe)2 restorative properties in models of acute and chronic inflammatory pain induced by complete Freund's adjuvant (CFA). Male adult Swiss mice received an intraplantar injection of CFA in the hindpaw and 24 h (acute) or 14 days (subchronic) later they were treated with a single or repeated (m-CF3-PhSe)2 schedule via intragastric route, respectively. The mechanical and thermal hypernociceptive behaviors were assessed by von Frey hair and hot plate tests. Samples of injected paw were collected to evaluate the tissue edema and myeloperoxidase (MPO) activity while cerebral contralateral cortex samples were used to determine the inflammatory proteins content (subchronic protocol). The acute (m-CF3-PhSe)2 administration (1 and 10 mg/kg) reduced the hypernociceptive behavior and both paw thickness and MPO activity induced by CFA injection. In the subchronic protocol, the repeated administration with a low effective dosage of (m-CF3-PhSe)2 reduced the mechanical and thermal hypernociception as well as restored the edema and MPO activity in paw samples. In addition, the repeated treatment schedule mitigated the increase in TNF-α, IL-1ß and COX-2 content in cerebral contralateral cortex induced by CFA injection. Collectively, these data showed that (m-CF3-PhSe)2 presents anti-inflammatory properties, which could be mediated by an interplay between peripheral and central mechanisms of action, reinforcing the potential biological properties of the compound.


Assuntos
Inflamação/induzido quimicamente , Compostos de Organossilício/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Diclofenaco/administração & dosagem , Diclofenaco/farmacologia , Adjuvante de Freund/toxicidade , Inflamação/tratamento farmacológico , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Compostos de Organossilício/administração & dosagem , Medição da Dor , Sintase do Porfobilinogênio/metabolismo , Carbonilação Proteica , Compostos de Sulfidrila/metabolismo
6.
Chemistry ; 26(8): 1871-1879, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31804737

RESUMO

Mounting evidence supports the role of amyloidogenesis, oxidative stress, and metal dyshomeostasis in the development of neurodegenerative disorders. Parkinson's Disease is characterized by α-synuclein (αSyn) accumulation and aggregation in brain regions, also promoted by Cu2+ . αSyn is modified by reactive carbonyl species, including acrolein (ACR). Notwithstanding these findings, the interplay between ACR, copper, and αSyn has never been investigated. Therefore, we explored more thoroughly the effects of ACR on αSyn using an approach based on LC-MS/MS analysis. We also evaluated the influence of Cu2+ on the protein carbonylation and how the ACR modification impacts the Cu2+ binding and the production of Reactive Oxygen Species (ROS). Finally, we investigated the effects of ACR and Cu2+ ions on the αSyn aggregation by dynamic light scattering and fluorescence assays. Cu2+ regioselectively inhibits the modification of His50 by ACR, the carbonylation lowers the affinity of His50 for Cu2+ and ACR inhibits αSyn aggregation both in the presence and in the absence of Cu2+ .


Assuntos
Acroleína/química , Cobre/química , alfa-Sinucleína/química , Acroleína/farmacologia , Cromatografia Líquida de Alta Pressão , Cobre/farmacologia , Difusão Dinâmica da Luz , Humanos , Estresse Oxidativo/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Massas em Tandem , alfa-Sinucleína/análise , alfa-Sinucleína/metabolismo
7.
Artigo em Inglês | MEDLINE | ID: mdl-31654830

RESUMO

Cadmium (Cd) occurs naturally; however, its concentration can increase with anthropogenic activities. Excess Cd increases reactive oxygen species (ROS) production and oxidative damage, which can lead to pathological conditions. Marine mammals accumulate Cd in the liver and the kidney; yet, there are no reports of Cd-associated tissue damage in whales, seals or dolphins. Response to Cd exposure (0-5.0 µM CdCl2 for 1-12 h) was analyzed and compared in primary skeletal muscle cells isolated from northern elephant seals (Mirounga angustirostris) and humans (Homo sapiens). Antioxidant enzyme activities (glutathione S-transferase, glutathione reductase, glutathione peroxidase), glutathione concentration, and protein carbonyl levels (an indicator of oxidative damage) were quantified. Glutathione levels were higher in northern elephant seal than in human cells. Protein carbonyl content in cells exposed to Cd was lower and had a smaller variability range in elephant seals than in humans. Generalized linear models (GLIM) identified Cd exposure and antioxidant defenses as significant contributors to protein carbonyl variability in human but not in elephant seal cells. These results suggest that the previously observed differences in circulating and tissue glutathione levels between marine and terrestrial mammals are maintained under cell culture conditions and that northern elephant seal and human muscle cells respond differently to Cd exposure. The results also suggest that the observed differences could potentially be associated with the protective mechanisms that allow northern elephant seals to tolerate extreme conditions that result in increased ROS generation (e.g. diving, sleep apnea, fasting) with no oxidative damage.


Assuntos
Cádmio/toxicidade , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/citologia , Focas Verdadeiras/fisiologia , Animais , Antioxidantes/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Carbonilação Proteica
8.
Toxicol Lett ; 322: 1-11, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31884112

RESUMO

Chloropicrin (CP), a warfare agent now majorly used as a soil pesticide, is a strong irritating and lacrimating compound with devastating toxic effects. To elucidate the mechanism of its ocular toxicity, toxic effects of CP (0-100 µM) were studied in primary human corneal epithelial (HCE) cells. CP exposure resulted in reduced HCE cell viability and increased apoptotic cell death with an up-regulation of cleaved caspase-3 and poly ADP ribose polymerase indicating their contribution in CP-induced apoptotic cell death. Following CP exposure, cells exhibited increased expression of heme oxygenase-1, and phosphorylation of H2A.X and p53 as well as 4-hydroxynonenal adduct formation, suggesting oxidative stress, DNA damage and lipid peroxidation. CP also caused increases in mitogen activated protein kinase-c-Jun N-terminal kinase and inflammatory mediator cyclooxygenase-2. Proteomic analysis revealed an increase in the carbonylation of 179 proteins and enrichment of pathways (including proteasome pathway and catabolic process) in HCE cells following CP exposure. CP-induced oxidative stress and lipid peroxidation can enhance protein carbonylation, prompting alterations in corneal epithelial proteins as well as perturbing signaling pathways resulting in toxic effects. Pathways and major processes identified following CP exposure could be lead-hit targets for further biochemical and molecular characterization as well as therapeutic intervention.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Epitélio Anterior/efeitos dos fármacos , Hidrocarbonetos Clorados/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/toxicidade , Carbonilação Proteica/efeitos dos fármacos , Caspase 3/metabolismo , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Dano ao DNA , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Epitélio Anterior/metabolismo , Epitélio Anterior/patologia , Heme Oxigenase-1/metabolismo , Histonas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Peroxidação de Lipídeos , Fosforilação , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
9.
BMC Pharmacol Toxicol ; 20(Suppl 1): 75, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31852532

RESUMO

BACKGROUND: Gasoline is a complex mixture of saturated and unsaturated hydrocarbons, in which aromatic compounds, such as BTX (benzene, toluene, and xylene) feature as the main constituents. Simultaneous exposure to these aromatic hydrocarbons causes a significant impact on benzene toxicity. In order to detect early alterations caused in gasoline station attendants exposed to BTX compounds, immunological, inflammatory, and oxidative stress biomarkers were evaluated. METHODS: A total of 66 male subjects participated in this study. The gasoline station attendants (GSA) group consisted of 38 gasoline station attendants from Rio Grande do Sul, Brazil. The non-exposed group consisted of 28 subjects who were non-smokers and who had no history of occupational exposure. Environmental and biological monitoring of BTX exposure was performed using blood and urine. RESULTS: The GSA group showed increased BTX concentrations in relation to the non-exposed group (p < 0.001). The GSA group showed elevated protein carbonyl (PCO) levels and pro-inflammatory cytokines, decreased expression of CD80 and CD86 in monocytes, and reduced glutathione S-transferase (GST) activity compared to the non-exposed group (p < 0.05). BTX levels and trans,trans-muconic acid levels were positively correlated with pro-inflammatory cytokines and negatively correlated with interleukin-10 contents (p < 0.001). Increased levels of pro-inflammatory cytokines were accompanied by increased PCO contents and decreased GST activity (p < 0.001). Furthermore, according to the multiple linear regression analysis, benzene exposure was the only factor that significantly contributed to the increased pro-inflammatory cytokines (p < 0.05). CONCLUSIONS: Taken together, these findings show the influence of exposure to BTX compounds, especially benzene, on the immunological, inflammatory, and oxidative stress biomarkers evaluated. Furthermore, the data suggest the relationship among the evaluated biomarkers of effect, which could contribute to providing early signs of damage to biomolecules in subjects occupationally exposed to BTX compounds.


Assuntos
Poluentes Ocupacionais do Ar/análise , Derivados de Benzeno/urina , Monitoramento Biológico/métodos , Citocinas/urina , Biomarcadores Ambientais/imunologia , Exposição Ocupacional/análise , Estresse Oxidativo/efeitos dos fármacos , Adulto , Poluentes Ocupacionais do Ar/efeitos adversos , Antígeno B7-1/sangue , Antígeno B7-1/urina , Antígeno B7-2/sangue , Antígeno B7-2/urina , Derivados de Benzeno/toxicidade , Brasil , Citocinas/sangue , Biomarcadores Ambientais/efeitos dos fármacos , Humanos , Masculino , Exposição Ocupacional/efeitos adversos , Estresse Oxidativo/imunologia , Carbonilação Proteica/efeitos dos fármacos
10.
Int J Nanomedicine ; 14: 6073-6101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686803

RESUMO

Background: Amphotericin B (AmB) as a liposomal formulation of AmBisome is the first line of treatment for the disease, visceral leishmaniasis, caused by the parasite Leishmania donovani. However, nephrotoxicity is very common due to poor water solubility and aggregation of AmB. This study aimed to develop a water-soluble covalent conjugate of gold nanoparticle (GNP) with AmB for improved antileishmanial efficacy and reduced cytotoxicity. Methods: Citrate-reduced GNPs (~39 nm) were functionalized with lipoic acid (LA), and the product GNP-LA (GL ~46 nm) was covalently conjugated with AmB using carboxyl-to-amine coupling chemistry to produce GNP-LA-AmB (GL-AmB ~48 nm). The nanoparticles were characterized by dynamic light scattering, transmission electron microscopy (TEM), and spectroscopic (ultraviolet-visible and infrared) methods. Experiments on AmB uptake of macrophages, ergosterol depletion of drug-treated parasites, cytokine ELISA, fluorescence anisotropy, flow cytometry, and gene expression studies established efficacy of GL-AmB over standard AmB. Results: Infrared spectroscopy confirmed the presence of a covalent amide bond in the conjugate. TEM images showed uniform size with smooth surfaces of GL-AmB nanoparticles. Efficiency of AmB conjugation was ~78%. Incubation in serum for 72 h showed <7% AmB release, indicating high stability of conjugate GL-AmB. GL-AmB with AmB equivalents showed ~5-fold enhanced antileishmanial activity compared with AmB against parasite-infected macrophages ex vivo. Macrophages treated with GL-AmB showed increased immunostimulatory Th1 (IL-12 and interferon-γ) response compared with standard AmB. In parallel, AmB uptake was ~5.5 and ~3.7-fold higher for GL-AmB-treated (P<0.001) macrophages within 1 and 2 h of treatment, respectively. The ergosterol content in GL-AmB-treated parasites was ~2-fold reduced compared with AmB-treated parasites. Moreover, GL-AmB was significantly less cytotoxic and hemolytic than AmB (P<0.01). Conclusion: GNP-based delivery of AmB can be a better, cheaper, and safer alternative than available AmB formulations.


Assuntos
Anfotericina B/síntese química , Antiprotozoários/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Anfotericina B/química , Anfotericina B/farmacologia , Animais , Antiprotozoários/química , Candida albicans/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Difusão Dinâmica da Luz , Ergosterol/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/crescimento & desenvolvimento , Estágios do Ciclo de Vida/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Nanopartículas Metálicas/ultraestrutura , Camundongos , Carbonilação Proteica/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Ácido Tióctico/química , Resultado do Tratamento
11.
Elife ; 82019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610847

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aß)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aß peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Aß-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aß expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed Aß-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Aß-induced pathology and a promising target for intervention.


Assuntos
Peptídeos beta-Amiloides/genética , Caenorhabditis elegans/metabolismo , Ciclo do Ácido Cítrico/genética , Mitocôndrias/metabolismo , Neurônios/metabolismo , Estresse Fisiológico/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Ciclo do Ácido Cítrico/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hipoglicemiantes/farmacologia , Complexo Cetoglutarato Desidrogenase/genética , Complexo Cetoglutarato Desidrogenase/metabolismo , Análise do Fluxo Metabólico , Metformina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Neurônios/efeitos dos fármacos , Neurônios/patologia , Agregados Proteicos/efeitos dos fármacos , Carbonilação Proteica , Estresse Fisiológico/efeitos dos fármacos
12.
Bratisl Lek Listy ; 120(7): 516-522, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31602987

RESUMO

OBJECTIVES: The aim of this study was to evaluate the toxic effect of AlNPs on rat brain mitochondria and compare it with that of aluminium's ionic form. METHODS: Mitochondria were isolated from rat brain. Isolated mitochondria were treated with normal saline (Control) and different concentrations of aluminium ions (AlIs) and AlNPs (50, 100 and 200 µM). Then, the effect of AlNPs on electron transport chain complexes as well as various endpoints such as mitochondrial oxidative damage (reactive oxygen species, lipid peroxidation, glutathione, and protein carbonyl) and mitochondrial function were assessed. Also, apoptosis was evaluated by cytochrome c release, mitochondrial membrane potential and swelling. RESULTS: When compared to the control group, the exposure to AlNPs showed a marked elevation in oxidative stress markers and inhibition of complex III which was accompanied by disturbance in mitochondrial function. Also, AlNPs induced a significant collapse of mitochondrial membrane potential, mitochondrial swelling, and cytochrome c release. CONCLUSIONS: The comparison of mitochondrial toxicity markers between both forms of aluminium revealed that the toxic effect of AlNPs on isolated brain mitochondria was substantially greater than that that caused by AlIs, which can probably be ascribed to its higher reactivity (Tab. 1, Fig. 8, Ref. 45).


Assuntos
Alumínio/toxicidade , Encéfalo/diagnóstico por imagem , Mitocôndrias/efeitos dos fármacos , Nanopartículas/toxicidade , Animais , Apoptose , Citocromos c/metabolismo , Glutationa/metabolismo , Íons , Peroxidação de Lipídeos , Potencial da Membrana Mitocondrial , Estresse Oxidativo , Carbonilação Proteica , Ratos , Espécies Reativas de Oxigênio/metabolismo
13.
Int J Mol Sci ; 20(18)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547461

RESUMO

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by defects in the ATPase gene (ATP7B). The various clinical features result from the massive accumulation of copper in the liver, cornea and basal ganglia. Although WD can be effectively treated with proper medicine, this disease is difficult to clearly diagnose due to its indefinite symptoms. In the current study, we achieved a positive correlation between clinical symptoms and the enzymatic activity of ceruloplasmin in WD patients. Furthermore, proteome profiles of plasma as well as network analysis demonstrated that fibrinogen is a critical indicator which is significantly unregulated in WD subjects in comparison to healthy donors and closely linked to pathogenesis of WD. Here, we applied 2DE-immunoblots and immunohistochemistry to verify the protein level and localization in situ. The enhanced expression of fibrinogen in the plasma of WD subjects with respect to that of healthy controls and patients with distinct disorders was also confirmed by utilizing clinical samples. As expected, application of high dose of copper induced expression of fibrinogen, while knockdown of ceruloplasmin also resulted in upregulation of fibrinogen as well as elimination of superoxide dismutase (SOD), leading to increased oxidative stress in cells. In summary, the liver injury or oxidative stress induced by the progression of WD may account for the obvious increase of fibrinogen, which in turn triggers inflammatory responses and interferes coagulation cascades; this finding sheds light on the early detection and diagnosis of WD.


Assuntos
Fibrinogênio/metabolismo , Degeneração Hepatolenticular/metabolismo , Estresse Oxidativo , Ceruloplasmina/análise , Ceruloplasmina/metabolismo , Fibrinogênio/análise , Células Hep G2 , Degeneração Hepatolenticular/sangue , Humanos , Carbonilação Proteica , Mapas de Interação de Proteínas , Proteômica
14.
Aquat Toxicol ; 216: 105291, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31525644

RESUMO

Most pesticides used in agriculture end up in the aquatic environment through runoff and leaching of treated crops. One of the most commonly used herbicides is glyphosate. This compound or its metabolites are frequently detected in surface water in Europe. In the present study, in vivo and in vitro studies were carried out using the early life stages of rainbow trout (Oncorhynchus mykiss) and the cell line RTL-W1 (a liver cell line from rainbow trout) to characterize the toxic effects of glyphosate at environmentally-realistic concentrations. Both studies were performed using the commercial formulation Roundup® GT Max, and technical-grade glyphosate for the in vitro study. Eyed-stage embryos were exposed for 3 weeks to sub-lethal concentrations (0.1 and 1 mg/L) of glyphosate using Roundup. Numerous toxicity endpoints were recorded such as survival, hatching success, larval biometry, developmental abnormalities, swimming activity, genotoxicity (formamidopyrimidine DNA-glycosylase Fpg-modified comet assay), lipid peroxidation (TBARS), protein carbonyls and target gene transcription. Concentrations neither affected embryonic or larval survival nor increased developmental abnormalities. However, a significant decrease was observed in the head size of larvae exposed to 1 mg/L of glyphosate. In addition, a significant increase in mobility was observed for larvae exposed to glyphosate at 0.1 mg/L. TBARS levels were significantly decreased on larvae exposed to 1 mg/L (a.i.), and cat and cox1 genes were differently transcribed from controls. DNA damage was detected by the Fpg-modified comet assay in RTL-W1 cell line exposed to the technical-grade glyphosate and Roundup formulation. The results suggest that chronic exposure to glyphosate, at environmental concentrations, could represent a potential risk for early life stages of fish.


Assuntos
Glicina/análogos & derivados , Herbicidas/toxicidade , Estágios do Ciclo de Vida/efeitos dos fármacos , Fígado/citologia , Oncorhynchus mykiss/crescimento & desenvolvimento , Animais , Células Sanguíneas/metabolismo , Gatos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Ensaio Cometa , Dano ao DNA , Embrião não Mamífero/efeitos dos fármacos , Exposição Ambiental , Regulação da Expressão Gênica/efeitos dos fármacos , Glicina/toxicidade , Larva/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Mutagênicos/toxicidade , Oncorhynchus mykiss/sangue , Oncorhynchus mykiss/embriologia , Carbonilação Proteica/efeitos dos fármacos , Natação , Poluentes Químicos da Água/toxicidade
15.
Toxicol Lett ; 317: 24-44, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31541690

RESUMO

Exposure of humans to xenobiotic mixtures is a continuous state during their everyday routine. However, the majority of toxicological studies assess the in vivo effects of individual substances rather than mixtures. Therefore, our main objective was to evaluate the impact of the 12- and 18-month exposure of rats to a mixture containing 13 pesticides, food, and life-style additives in three dosage levels (i.e. 0.0025 × NOAEL, 0.01 × NOAEL, and 0.05 × NOAEL), on redox biomarkers in blood and tissues. Our results indicate that the exposure to the mixture induces physiological adaptations by enhancing the blood antioxidant mechanism (i.e., increased glutathione, catalase and total antioxidant capacity and decreased protein carbonyls and TBARS) at 12 months of exposure. On the contrary, exposure to the 0.05 × NOAEL dose for 18 months induces significant perturbations in blood and tissue redox profile (i.e., increased carbonyls and TBARS). This study simulates a scenario of real-life risk exposure to mixtures of xenobiotics through a long-term low-dose administration regimen in rats. The results obtained could support, at least in part, the necessity of introducing testing of combined stimuli at reference doses and long term for the evaluation of the risk from exposure to chemicals.


Assuntos
Aditivos Alimentares/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/toxicidade , Xenobióticos/toxicidade , Animais , Biomarcadores/sangue , Catalase/sangue , Relação Dose-Resposta a Droga , Exposição Ambiental/efeitos adversos , Feminino , Glutationa/sangue , Masculino , Nível de Efeito Adverso não Observado , Oxirredução , Carbonilação Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Medição de Risco , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fatores de Tempo
16.
Toxicol Lett ; 316: 60-72, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520699

RESUMO

Cholestasis is a significant decrease in bile flow. The liver is the primary organ affected by cholestasis. Chronic cholestasis could entail to tissue fibrotic changes and liver cirrhosis. Other organs, including heart, kidneys, nervous system, skeletal muscles, as well as the reproductive system, might also be affected during cholestasis. Although the cholestasis-associated pathological and biochemical alterations in organs such as liver have been widely investigated, there is little information about complications such as cholestasis-induced reproductive toxicity. The current study aimed to evaluate the pathologic effects of cholestasis on reproductive organs in both male and female animals. Rats underwent bile duct ligation (BDL) surgery. Markers of reproductive toxicity, including serum hormonal changes, tissue histopathological alterations, biomarkers of oxidative stress, and markers of mitochondrial impairment, were evaluated. Increased serum markers of liver injury and elevated level of cytotoxic molecules such as bile acids and bilirubin were evident in BDL animals. On the other hand, the serum level of hormones such as testosterone was suppressed in BDL rats. Significant histopathological alterations were also evident in the testis and ovary of BDL animals. A significant increase in oxidative stress markers, including ROS formation, lipid peroxidation, protein carbonylation, and depleted glutathione and antioxidant reservoirs were also detected in BDL rats. Moreover, mitochondrial depolarization decreased dehydrogenases activity, and depleted ATP content was detected in sperm isolated from the BDL group. These data indicate that cholestasis-associated reproductive toxicity in male and female rats is restrictedly coupled with severe oxidative stress and mitochondrial impairment.


Assuntos
Colestase/metabolismo , Mitocôndrias/metabolismo , Ovário/metabolismo , Estresse Oxidativo , Reprodução , Espermatozoides/metabolismo , Testículo/metabolismo , Animais , Colestase/etiologia , Colestase/fisiopatologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Feminino , Ligadura , Peroxidação de Lipídeos , Masculino , Mitocôndrias/patologia , Ovário/patologia , Ovário/fisiopatologia , Carbonilação Proteica , Ratos Sprague-Dawley , Medição de Risco , Testículo/patologia , Testículo/fisiopatologia
17.
Oxid Med Cell Longev ; 2019: 6528106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396304

RESUMO

In the cold environments of the interstellar medium, a variety of molecules in which a hydrogen (H) atom has been replaced by its heavier isotope deuterium (D) can be found. From its emergence, life had to counteract the toxic action of many agents, which posed a constant threat to its development and propagation. Oxygen-reactive species are archaic toxicants that lead to protein damage and genomic instability. Most of the oxidative lesions involve cleavage of C-H bonds and H abstraction. According to free radical chemistry principles, the substitution of D for H in oxidation-sensitive positions of cellular components should confer protection against the oxidative attack without compromising the chemical identity of the compounds. Here, we show that deuterated nucleosides and proteins protect from oxidative damage. Our data suggest a new, subtle but likely role of D in terrestrial life's evolution in that its inclusion in critical biomolecules might have facilitated their resistance during the infinite generations of life entities, cells, and organisms.


Assuntos
Deutério/química , Estresse Oxidativo , Sobrevivência Celular/efeitos dos fármacos , Sistema Livre de Células , Dano ao DNA/efeitos dos fármacos , Radicais Livres/química , Produtos Finais de Glicação Avançada/análise , Humanos , Células Jurkat , Nucleosídeos/química , Nucleosídeos/metabolismo , Nucleosídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica , Proteínas/química , Proteínas/metabolismo
18.
Nutrients ; 11(8)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31443235

RESUMO

The increase in consumption of "ultra-processed" foods has raised attention because of the possible adverse effects deriving from the Maillard reaction leading to the formation of toxic advanced glycation end-products (AGEs) during food processing. Additionally, the increasing trend and consumption of sugar-added foods and sweetened beverages is related to the endogenous formation of the same toxic compounds. However, ultra-processing in the context of food technology can bring challenges as well as a wealth of opportunities. Indeed, re-processing of grape pomace, a by-product of winemaking, can yield phenolic-rich fractions that efficiently counteract the effects of AGEs. In this review, the process of endogenous and exogenous AGE formation is illustrated. Then, the ability of grape phenolics to act as inhibitors of AGE formation is presented, including the efficacy ranking of various individual compounds measured in vitro and the outcome of in vivo double-blinded randomized crossover trials designed to prove the efficacy of grape phenolics as inhibitors of protein carbonylation. Finally, a survey of model functional foods added with grape phenolics, either to lower the dietary load of AGEs or to deliver antiglycation agents in vivo is listed in order to highlight the opportunity to develop safe and tailor-made "anti-AGEs" food applications.


Assuntos
Suplementos Nutricionais , Manipulação de Alimentos , Frutas , Produtos Finais de Glicação Avançada/metabolismo , Hipoglicemiantes/uso terapêutico , Fenóis/uso terapêutico , Extratos Vegetais/uso terapêutico , Carbonilação Proteica/efeitos dos fármacos , Vitis , Animais , Frutas/química , Humanos , Hipoglicemiantes/isolamento & purificação , Reação de Maillard , Fenóis/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Vitis/química
19.
Eur J Appl Physiol ; 119(10): 2301-2312, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31451954

RESUMO

PURPOSE: To compare concentric and eccentric cycling performed by older adults for metabolic demand and post-exercise oxidative stress, inflammation and muscle damage. METHODS: Eight male and two female healthy older adults (60.4 ± 6.8 years) performed 30 min of moderate-intensity concentric (CONC-M: 50% maximum power output; POmax) and eccentric cycling (ECC-M: 50% POmax) and high-intensity eccentric cycling (ECC-H: 100% POmax) in a randomized order. Average power output (PO), oxygen consumption (VO2), heart rate (HR) and rate of perceived exertion were recorded during cycling. Some indirect markers of muscle damage were assessed before, and immediately, 24 and 48 h after cycling. Markers of oxidative stress (malondialdehyde: MDA, protein carbonyl), antioxidant (total antioxidant capacity, glutathione peroxidase activity: GPx) and inflammation (IL-6, TNF-α) were measured before and 5 min after cycling. RESULTS: PO in ECC-H (202.6 ± 78.5 W) was > 50% greater (P < 0.05) than that of CONC-M (98.6 ± 33.1 W) and ECC-M (112.0 ± 42.1 W). VO2 and HR were also greater (P < 0.05) for ECC-H than CONC-M (50% and 17%, respectively) and ECC-M (40% and 23%, respectively). Muscle strength loss at 1 day post-exercise (8-22%), peak soreness (10-62 mm) and creatine kinase activity (30-250 IU/L) after ECC-H were greater (P < 0.05) than those after ECC-M and CONC-M. MDA decreased (P < 0.05) after CONC-M (- 28%) and ECC-M (- 22%), but not after ECC-H. GPx activity increased after all exercises similarly (20-27%). IL-6 increased (P < 0.05) only after ECC-H (18%). CONCLUSION: Oxidative stress was minimal after eccentric cycling, but high-intensity eccentric cycling induced moderate muscle damage and inflammation, which is not desirable for older individuals.


Assuntos
Mialgia/etiologia , Estresse Oxidativo , Condicionamento Físico Humano/métodos , Idoso , Feminino , Glutationa Peroxidase/sangue , Frequência Cardíaca , Humanos , Interleucina-6/sangue , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Contração Muscular , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Mialgia/sangue , Consumo de Oxigênio , Condicionamento Físico Humano/efeitos adversos , Esforço Físico , Carbonilação Proteica , Distribuição Aleatória , Fator de Necrose Tumoral alfa/sangue
20.
Rev. ADM ; 76(4): 203-208, jul.-ago 2019. ilus, tab
Artigo em Espanhol | LILACS | ID: biblio-1023314

RESUMO

Objetivo: Comparar las concentraciones de proteínas carboniladas y capacidad antioxidante total (CAT) en fluido crevicular gingival (FCG) de pacientes con recién diagnóstico de diabetes mellitus tipo 2 (DM2) con periodontitis crónica (PC), sujetos con PC y sujetos con gingivitis (G). Material y métodos: Estudio transversal en sujetos de ambos sexos (35-55 años). Se formaron tres grupos: DM2+PC, PC y G. Se incluyeron sujetos con ≤ 1.6 años de DM2 con PC. Se evaluaron parámetros clínicos y periodontales. Los marcadores de estrés oxidativo (OxS) se determinaron por colorimetría y se cuantificaron por espectrofotometría. Se utilizó ANOVA/Kruskal-Wallis para observar diferencias entre los grupos y se analizaron las correlaciones con Pearson/Spearman. Resultados: El grupo DM2 + PC mostró un incremento significativo en la edad, índice de masa corporal y glucosa en comparación con los grupos PC y G. La profundidad de la bolsa (PD), pérdida de inserción, sangrado e índice gingival fueron mayores en el grupo DM2 + PC versus grupos PC y G (p < 0.001). No se encontró diferencia entre los grupos en CAT. El grupo DM2 + PC mostró mayor concentración de proteínas carboniladas versus grupo G (p = 0.03). PD correlacionó directamente con LDL en el grupo DM2 + PC (p = 0.04). Conclusión: Las proteínas carboniladas en el grupo DM2 + PC presentaron una diferencia significativa, indicando el daño oxidativo sinérgico de ambas patologías. La concentración de CAT tiende a elevarse en el grupo DM2 + PC, probablemente como un mecanismo compensatorio en busca del restablecimiento de homeostasis (AU)


Objective: To compare the concentrations of carbonylated proteins and total antioxidant capacity (TAC) in gingival crevicular fluid (GCF) of patients with newly diagnosed type 2 diabetes mellitus (DM2) with chronic periodontitis (CP), subjects with CP and subjects with gingivitis (G). Material and methods: Cross-sectional study in subjects of both sexes (35-55 years). Three groups were formed: DM2 + CP, CP and G. Subjects with ≤ 1.6 years of DM2 with CP were included. Clinical and periodontal parameters were evaluated. OxS markers were determined by colorimetry and quantified by spectrophotometry. ANOVA/Kruskal Wallis was used to observe differences between the groups and the correlations were analyzed with Pearson/Spearman tests. Results: The DM2 + CP group showed a significant increase in age, body mass index and glucose in comparison with groups CP and G. The depth of the pocket (DP), insertion loss, bleeding and gingival index were higher in the group DM2 + CP versus groups CP and G (p < 0.001). No difference was found between the groups in TAC. The DM2 + CP group showed a higher concentration of carbonylated proteins versus group G (p = 0.03). DP correlated directly with LDL in the DM2 + CP group (p = 0.04). Conclusion: The carbonylated proteins in the DM2 + CP group showed a significant difference, indicating the synergistic oxidative damage of both pathologies. The concentration of TAC tends to rise in the DM2 + CP group, probably as a compensatory mechanism in search of the restoration of homeostasis (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Periodontite , Diabetes Mellitus Tipo 2 , Carbonilação Proteica , Capacidade de Absorbância de Radicais de Oxigênio , Estudos Transversais , Análise Estatística , Análise de Variância , Estudo Observacional , México
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