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1.
Georgian Med News ; (295): 141-145, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31804217

RESUMO

Aim - to assess the effects of doxycycline on the state of lipid peroxidation processes and the activity of the antioxidant system. The study was performed on 144 rats of the WAG population weighing 200-250 g (6 rats in each group). Animals with thermal burns were injected with the test drug doxycycline, as well as reference drugs - thiotriazolin and methyluracil orally in starch suspensionafter thermal exposure and daily during the entire experiment period (28 days). Animals were removed from the experiment in accordance with the rules of bioethics on the 7th, 14th, 21st and 28th day. As a result of the research, the most intense influence of doxycycline on the processes of lipid peroxidation in the blood serum of rats was found - a decrease in DC activity by the end of the experiment (regardless of dose) and TBA-AP starting from the 14th day of observation reaching the value of intact rats (at a dose of 30 mg/kg). At the same time, an increase in the activity of enzymes of the antioxidant system was noted - the level of catalase from the 14th day (significantly higher than the control group regardless of dose) and the level of ceruloplasmin (from the second week of observation the indicator reached intact values ​​at a dose of 30 mg/kg). Reference drugs were inferior to doxycycline in their effectiveness. The data obtained may indicate the possibility of reducing the healing time of a thermal burn due to the suppression of excessive free radical oxidation activity and activation of antioxidant protection.


Assuntos
Antioxidantes , Queimaduras , Peróxidos Lipídicos , Metaloproteinases da Matriz , Animais , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Queimaduras/tratamento farmacológico , Queimaduras/metabolismo , Doxiciclina/farmacologia , Peroxidação de Lipídeos , Peróxidos Lipídicos/metabolismo , Metaloproteinases da Matriz/metabolismo , Oxirredução , Cicatrização
2.
Chem Biol Interact ; 314: 108847, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610155

RESUMO

Lead (Pb) is one of the toxic heavy metals that have several toxicological implications including cytotoxicities and oxidative stress. The release of reactive oxygen species (ROS) usually initiates lipid peroxidation and resulting in inflammation and tissue injury. However, the detailed identification of the Pb-produced lipid hydroperoxides has received little attention. Furthermore, the mechanisms behind such effects are less informed. Therefore, this study firstly investigated Pb-produced lipid hydroperoxides in human HepG2 cells using LC/MS. The effects of Pb on the antioxidant enzymes were additionally examined using qPCR and their dependent activities. As a protection trial, the ameliorative effects of rosmarinic (RMA) and ascorbic (ASA) acids on Pb-induced cytotoxicity and oxidative stress and their regulatory effects on Nrf2/Keap1 pathway were investigated. The achieved results confirmed cytotoxicity and oxidative damage of Pb on HepG2 cells. In addition, 20 lipid hydroperoxides (LOOH) were identified including 11 phosphatidylcholine hydroperoxides (PCOOH), 5 triacylglycerol hydroperoxides (TGOOH) and 4 cholesteryl ester hydroperoxides (CEOOH). The most dominant LOOH species were PCOOH 34:2, PCOOH 34:3, PCOOH 38:7, TGOOH 60:14, TGOOH 60:15, CEOOH 18:3 and CEOOH 20:4. Pb significantly downregulated Nrf2-regulated antioxidant enzymes at both the pretranscriptional and functional levels. Co-exposure of HepG2 cells to RMA and ASA significantly reduced Pb-produced adverse outcomes. This protection occurred via activation Nrf2-Keap1 antioxidant pathway.


Assuntos
Antioxidantes/metabolismo , Ácido Ascórbico/química , Cinamatos/química , Depsídeos/química , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Chumbo/química , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Ascórbico/farmacologia , Cromatografia Líquida de Alta Pressão , Cinamatos/farmacologia , Depsídeos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Células Hep G2 , Humanos , Chumbo/toxicidade , Peróxidos Lipídicos/análise , Peróxidos Lipídicos/metabolismo , Espectrometria de Massas , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
3.
ACS Appl Mater Interfaces ; 11(33): 29655-29666, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31359759

RESUMO

Ferroptosis is an iron-dependent cell death pathway that can eradicate certain apoptosis-insensitive cancer cells. The ferroptosis-inducing molecules are tailored lipid peroxides whose efficacy is compromised in hypoxic solid tumor and lack of tumor selectivity. It has been demonstrated that ascorbate (Asc) in pharmacological concentrations can selectively kill cancer cells via accumulating hydrogen peroxide (H2O2) only in tumor extracellular fluids. It was hypothesized that Asc-induced, selective enrichment of H2O2 in tumor coupled with Fe3+ codelivery could simultaneously address the above two problems via boosting the levels of hydroxyl radicals and oxygen in the tumor site to ease peroxidation initiation and propagation, respectively. The aim of this work was to synergize the action of Asc with lipid-coated calcium phosphate (CaP) hybrid nanocarrier that can concurrently load polar Fe3+ and nonpolar RSL3, a ferroptosis inducer with the mechanism of inhibiting lipid peroxide repair enzyme (GPX4). The hybrid nanocarriers showed accelerated cargo release at acidic conditions (pH 5.0). The combinational approach (Asc plus nanocarrier) produced significantly elevated levels of hydroxyl radicals, lipid peroxides, and depleted glutathione under hypoxia, which was accompanied with the strong cytotoxicity (IC50 = 1.2 ± 0.2 µM) in the model 4 T1 cells. In the 4 T1 tumor-bearing xenograft mouse model, the intravenous nanocarrier delivery plus intraperitoneal Asc administration resulted in a superior antitumor performance in terms of tumor suppression, which did not produce supplementary adverse effects to the healthy organs. This work provides a novel approach to enhance the potency of ferroptotic nanomedicine against solid tumors without inducing additional side effects.


Assuntos
Antineoplásicos/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Fosfatos de Cálcio , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Peróxidos Lipídicos/química , Peróxidos Lipídicos/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Eur J Pharm Biopharm ; 142: 1-7, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31176725

RESUMO

Recent studies using 3D scaffolds have emphasized the importance of the surrounding stroma on chemoresistance in drug efficacy screenings. Since 15-lipoxygenase (15-LOX) metabolites reduced growth of breast, colon, prostate, lung and leukemia cancer cells in 2D cell culture, we were intrigued by the direct comparison of 15-LOX metabolite efficacy in 2D and 3D culture including a stroma equivalent. Herein, we studied the effects of 15-LOX metabolites 13-HpOTrE, 13-HpODE, and 15-HpETE on cutaneous squamous cell carcinoma cells. All metabolites reduced the viability of cancer cells in 2D culture below 10% at 100 µM of each substance. 13-HpOTrE, being the most active agent with respect to cytotoxicity and apoptosis was selected for further experiments. Other than with the 2D culture, we did not obverse cell death, neither from lactate dehydrogenase release, nor from morphology when applying 13-HpOTrE onto the surface of the 3D tumor constructs for one week. Next, we investigated the protein expression of peroxisome proliferator activated receptor gamma, for which the ligand is 13-HpOTrE, and Bcl-2 protein, an apoptosis regulator, but did not find any change following 13-HpOTrE administration. However, 13-HpOTrE treatment reduced the release of interleukin-6, bringing it closer to the level of tumor-free constructs. In conclusion, 13-HpOTrE reduces viability of skin cancer cells in 2D cultures only but modulates inflammatory cytokine levels in the corresponding 3D tumor constructs, too. These studies highlight the need for screening of anticancer drugs employing 3D tumors and including tumor microenvironment in the screening process to increase the low success rate of clinical trials in oncology.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Araquidonato 15-Lipoxigenase/metabolismo , Leucotrienos/metabolismo , Ácidos Linoleicos/metabolismo , Peróxidos Lipídicos/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo
5.
Environ Pollut ; 252(Pt A): 51-61, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146238

RESUMO

Melatonin (Mel) serves as an important signalling molecule in various aspects of stress tolerance in plants. However, the function of Mel in pesticide metabolism remains unknown. Here, selecting the widely used fungicide carbendazim (MBC) as the model, we found that exogenous Mel had the ability to alleviate pesticide phytotoxicity and residues in tomato as well as in some other vegetables. Additionally, overexpression of the Mel biosynthetic gene caffeic acid O-methyltransferase 1 (COMT1) significantly enhanced the capacity of the tomato to reduce MBC phytotoxicity and residue. This outcome was mainly because of the Mel-induced antioxidant capability, as well as the key detoxification process. Indeed, levels of reactive oxygen species (ROS) and lipid peroxides significantly decreased after applying exogenous Mel or overexpressing COMT1, which resulted from direct ROS scavenging, and increased Mel levels significantly enhanced antioxidant enzymatic activity. More importantly, Mel activated the ascorbate-glutathione cycle to participate in glutathione S-transferase-mediated pesticide detoxification. A grafting experiment showed that rootstocks from COMT1 transgenic plants increased the Mel accumulation of wild-type scions, resulting in MBC metabolism in the scions. To our knowledge, this is the first report providing evidence of Mel-induced pesticide metabolism, which provides a novel approach for minimizing pesticide residues in crops by exploiting plant self-detoxification mechanisms.


Assuntos
Benzimidazóis/metabolismo , Carbamatos/metabolismo , Fungicidas Industriais/metabolismo , Inativação Metabólica/fisiologia , Lycopersicon esculentum/metabolismo , Melatonina/metabolismo , Metiltransferases/metabolismo , Benzimidazóis/toxicidade , Carbamatos/toxicidade , Fungicidas Industriais/toxicidade , Glutationa Transferase/metabolismo , Peróxidos Lipídicos/metabolismo , Melatonina/biossíntese , Metiltransferases/biossíntese , Plantas Geneticamente Modificadas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
6.
Lipids Health Dis ; 18(1): 125, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31138221

RESUMO

BACKGROUND: Exercise has proved effective in attenuating the unfavourable response normally associated with postprandial hypertriglyceridemia (PHTG) and accompanying oxidative stress. Yet, the acute effects of prior exercise and PHTG on DNA damage remains unknown. The purpose of this study was to examine if walking alters PHTG-induced oxidative damage and the interrelated inflammatory mechanisms. METHODS: Twelve apparently healthy, recreationally active, male participants (22.4 ± 4.1 years; 179.2 ± 6 cm; 84.2 ± 14.7 kg; 51.3 ± 8.6 ml·kg- 1·min- 1) completed a randomised, crossover study consisting of two trials: (1) a high-fat meal alone (resting control) or (2) a high-fat meal immediately following 1 h of moderate exercise (65% maximal heart rate). Venous blood samples were collected at baseline, immediately post-exercise or rest, as well as at 2, 4 and 6 h post-meal. Biomarkers of oxidative damage (DNA single-strand breaks, lipid peroxidation and free radical metabolism) and inflammation were determined using conventional biochemistry techniques. RESULTS: DNA damage, lipid peroxidation, free radical metabolism and triglycerides increased postprandially (main effect for time, p < 0.05), regardless of completing 1 h of preceding moderate intensity exercise. Plasma antioxidants (α-tocopherol and γ-tocopherol) also mobilised in response to the high-fat meal (main effect for time, p < 0.05), but no changes were detected for retinol-binding protein-4. CONCLUSION: The ingestion of a high fat meal induces postprandial oxidative stress, inflammation and a rise in DNA damage that remains unaltered by one hour of preceding exercise.


Assuntos
Vasos Sanguíneos/patologia , Dano ao DNA , Exercício/fisiologia , Hipertrigliceridemia/sangue , Inflamação/sangue , Linfócitos/patologia , Período Pós-Prandial , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Sedimentação Sanguínea , Quebras de DNA de Cadeia Simples , Humanos , Peróxidos Lipídicos/metabolismo , Masculino , Solubilidade , Adulto Jovem
7.
Proc Natl Acad Sci U S A ; 116(8): 2996-3005, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30718432

RESUMO

Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis. We found that HSP90 defined a common regulatory nodal between necroptosis and ferroptosis. We showed that inhibition of HSP90 by CDDO blocked necroptosis by inhibiting the activation of RIPK1 kinase. Furthermore, we showed that the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation of GPX4. Importantly, inhibition of CMA stabilized GPX4 and reduced ferroptosis. Our results suggest that activation of CMA is involved in the execution of ferroptosis.


Assuntos
Autofagia/genética , Glutationa Peroxidase/genética , Proteína 2 de Membrana Associada ao Lisossomo/genética , Chaperonas Moleculares/genética , Necrose/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Caspases/genética , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/genética , Humanos , Ferro/metabolismo , Ligantes , Peróxidos Lipídicos/genética , Peróxidos Lipídicos/metabolismo , Chaperonas Moleculares/metabolismo , Piperazinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fator de Necrose Tumoral alfa/genética
8.
Cells ; 8(2)2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30709034

RESUMO

The electron-transfer flavoprotein dehydrogenase gene (ETFDH) that encodes the ETF-ubiquinone oxidoreductase (ETF-QO) has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). ETF-QO is an electron carrier that mainly functions in mitochondrial fatty acid ß-oxidation and the delivery of electrons to the ubiquinone pool in the mitochondrial respiratory chain. A high frequency of c.250G>A has been found in Taiwanese patients with late-onset MADD. We postulated that the ETFDH c.250G>A mutation may concomitantly impair fatty acid ß-oxidation and mitochondrial function. Using MADD patient-derived lymphoblastoid cells and specifically overexpressed ETFDH c.92C>T, c.250G>A, or coexisted c.92C>T and c.250G>A (c.92C>T + c.250G>A) mutated lymphoblastoid cells, we addressed the genotype-phenotype relationship of ETFDH variation in the pathogenesis of MADD. The decreased adenosine triphosphate synthesis, dissipated mitochondrial membrane potentials, reduced mitochondrial bioenergetics, and increased neutral lipid droplets and lipid peroxides were found in the MADD patient-derived lymphoblastoid cells. Riboflavin and/or coenzyme Q10 supplementation rescued cells from lipid droplet accumulation. All three mutant types, c.92C>T, c.250G>A, or c.92C>T + c.250G>A, had increased lipid droplet accumulation after treatment with palmitic acid. These results help to clarify the molecular pathogenesis of MADD as a result of the high frequency of the ETFDH c.250G>A and c.92C>T mutations.


Assuntos
Complexo I de Transporte de Elétrons/metabolismo , Flavoproteínas Transferidoras de Elétrons/metabolismo , Metabolismo Energético , Ácidos Graxos/metabolismo , Lipídeos/química , Mitocôndrias/metabolismo , Mutação/genética , Adolescente , Sequência de Bases , Carnitina/análogos & derivados , Carnitina/metabolismo , Linhagem Celular Tumoral , Flavoproteínas Transferidoras de Elétrons/genética , Ácidos Graxos/sangue , Humanos , Gotículas Lipídicas/metabolismo , Peróxidos Lipídicos/metabolismo , Masculino , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Músculos/metabolismo , Músculos/ultraestrutura , Oxirredução , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Riboflavina/metabolismo , Sarcolema/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/metabolismo
9.
Appl Biochem Biotechnol ; 188(1): 208-224, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30417318

RESUMO

Despite advances in the management of cardiovascular diseases, acute coronary syndrome (ACS) remains the leading cause of death worldwide. ACS is associated with an imbalance between coronary blood supply and metabolic requirements. Lipid peroxidation and production of reactive oxygen species (ROS) damage the cardiac cell membrane. A total of 130 subjects, 65 ACS patients (45 with ST segment elevation (STE-ACS), 20 non-STE-ACS), and 65 healthy controls were recruited. Measurement of serum zinc, total antioxidant capacity (TAC) and malondialdehyde (MDA) by spectrophotometric methods 24 h after onset of ACS, and relations between the studied biochemical parameters and risk factors were performed. MDA levels were significantly increased; TAC and zinc levels were significantly decreased in ACS patients compared to the controls (P < 0.001 for each). No significant difference was detected between the different types of ACS and each of the oxidative stress parameters, cardiac biomarkers, lipogram, and risk factors. Only serum zinc in STE-ACS patients was significantly lower compared with NSTE-ACS patients (P < 0.001). Serum zinc showed the greatest AUC (area under the ROC curve) of 0.926 with 76.92% sensitivity and 95.38% specificity. Negative and positive correlations between MDA and zinc and between TAC and zinc levels respectively (P < 0.01) were found in ACS. Week negative correlation was observed between serum zinc and SYNTAX score (r = - 0.434, P = 0.049). Our results indicate that deficient serum zinc concentration strongly associated with the etiopathogenesis of ACS.


Assuntos
Síndrome Coronariana Aguda/metabolismo , Antioxidantes/metabolismo , Peróxidos Lipídicos/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Zinco/sangue , Síndrome Coronariana Aguda/sangue , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Peroxidação de Lipídeos , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Prognóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue
10.
Colloids Surf B Biointerfaces ; 175: 384-391, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30554017

RESUMO

Linoleic and linolenic acid hydroperoxides (HPOs) constitute key intermediate oxylipins playing an important role as signaling molecules during plant defense processes in response to biotic or abiotic stress. They have also been demonstrated in vitro as antimicrobial agents against plant fungi and bacteria. To reach the phytopathogens in vivo, the HPOs biosynthesized in the plant cells must cross the plant plasma membrane (PPM) where they can also interact with plasma membrane lipids and have an effect on their organization. In the present study, we have investigated the interaction properties of HPOs with PPM at a molecular level using biophysical tools combining in vitro and in silico approaches and using plant biomimetic lipid systems. Our results have shown that HPOs are able to interact with PPM lipids and perturb their lateral organization. Glucosylceramide (GluCer) is a privileged partner, sitosterol lessens their binding and the presence of both GluCer and sitosterol further reduces their interaction. Hydrophobic effect and polar interactions are involved in the binding. The chemical structure of HPOs influences their affinity for PPM lipids. The presence of three double bonds in the HPO molecule gives rise to a higher affinity comparatively to two double bonds, which can be explained by their differential interaction with the lipid polar headgroups.


Assuntos
Biomimética , Membrana Celular/metabolismo , Ácidos Linolênicos/metabolismo , Peróxidos Lipídicos/metabolismo , Plantas/metabolismo
11.
BMC Pharmacol Toxicol ; 19(1): 74, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30446004

RESUMO

BACKGROUND: Oxidative stress is one potential mechanism that explain the direct effects of smoking on cardiac remodeling process. However, no study has compared different myocardial products of macromolecule oxidation after tobacco smoke exposure. Thus, the aim of this study was to investigate the lipid hydroperoxide (LH) levels, protein carbonyl concentrations and DNA damage in cardiac tissue of rats exposed to tobacco smoke. METHODS: Male Wistar rats were divided into two groups: group C (control, n = 14) composed of animals not exposed to cigarette smoke; group ETS (exposed to tobacco smoke, n = 14) composed by animals exposed to cigarette smoke. The animals were exposed to 2 month of ETS and morphological, biochemical and functional analyses were performed. RESULTS: Cardiac cotinine levels were elevated in the ETS group. In addition, the myocyte cross-sectional area was higher in the ETS group. (C = 266.6 ± 23.2 µm2 and ETS = 347.5 ± 15.1 µm2, p <  0.001). Cardiac LH was higher in the ETS group than in group C (C = 196.4 ± 51.5 nmol/g and ETS = 331.9 ± 52.9 nmol/g, p <  0.001). However, there were no between-group differences in cardiac protein carbonyl concentration or DNA damage. CONCLUSIONS: Therefore, our results suggest that, in this model, lipid damage is a good marker of oxidative damage during the cardiac remodeling process induced by 2 months of exposure to tobacco smoke.


Assuntos
Peróxidos Lipídicos/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fumaça/efeitos adversos , Tabaco , Remodelação Ventricular/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Ensaio Cometa , Cotinina/metabolismo , Masculino , Carbonilação Proteica , Ratos Wistar , Remodelação Ventricular/fisiologia
12.
Cell Rep ; 25(7): 1708-1717.e5, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30428342

RESUMO

Autophagy is a homeostatic cellular process involved in the degradation of long-lived or damaged cellular components. The role of autophagy in adipogenesis is well recognized, but its role in mature adipocyte function is largely unknown. We show that the autophagy proteins Atg3 and Atg16L1 are required for proper mitochondrial function in mature adipocytes. In contrast to previous studies, we found that post-developmental ablation of autophagy causes peripheral insulin resistance independently of diet or adiposity. Finally, lack of adipocyte autophagy reveals cross talk between fat and liver, mediated by lipid peroxide-induced Nrf2 signaling. Our data reveal a role for autophagy in preventing lipid peroxide formation and its transfer in insulin-sensitive peripheral tissues.


Assuntos
Adipócitos/citologia , Tecido Adiposo/metabolismo , Autofagia , Resistência à Insulina , Peróxidos Lipídicos/metabolismo , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Adiposidade , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Composição Corporal , Peso Corporal , Humanos , Inflamação/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipoproteínas HDL/metabolismo , Camundongos Knockout , Mitocôndrias/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo
13.
Biochemistry ; 57(48): 6726-6734, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30407793

RESUMO

The reaction of 5 S,15 S-dihydroperoxyeicosatetraenoic acid (5,15-diHpETE) with human 5-lipoxygenase (LOX), human platelet 12-LOX, and human reticulocyte 15-LOX-1 was investigated to determine the reactivity and relative rates of producing lipoxins (LXs). 5-LOX does not react with 5,15-diHpETE, although it can produce LXA4 when 15-HpETE is the substrate. In contrast, both 12-LOX and 15-LOX-1 react with 5,15-diHpETE, forming specifically LXB4. For 12-LOX and 5,15-diHpETE, the kinetic parameters are kcat = 0.17 s-1 and kcat/ KM = 0.011 µM-1 s-1 [106- and 1600-fold lower than those for 12-LOX oxygenation of arachidonic acid (AA), respectively]. On the other hand, for 15-LOX-1 the equivalent parameters are kcat = 4.6 s-1 and kcat/ KM = 0.21 µM-1 s-1 (3-fold higher and similar to those for 12-HpETE formation by 15-LOX-1 from AA, respectively). This contrasts with the complete lack of reaction of 15-LOX-2 with 5,15-diHpETE [Green, A. R., et al. (2016) Biochemistry 55, 2832-2840]. Our data indicate that 12-LOX is markedly inferior to 15-LOX-1 in catalyzing the production of LXB4 from 5,15-diHpETE. Platelet aggregation was inhibited by the addition of 5,15-diHpETE, with an IC50 of 1.3 µM; however, LXB4 did not significantly inhibit collagen-mediated platelet activation up to 10 µM. In summary, LXB4 is the primary product of 12-LOX and 15-LOX-1 catalysis, if 5,15-diHpETE is the substrate, with 15-LOX-1 being 20-fold more efficient than 12-LOX. LXA4 is the primary product with 5-LOX but only if 15-HpETE is the substrate. Approximately equal proportions of LXA4 and LXB4 are produced by 12-LOX but only if LTA4 is the substrate, as described previously [Sheppard, K. A., et al. (1992) Biochim. Biophys. Acta 1133, 223-234].


Assuntos
Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Araquidonato 5-Lipoxigenase/metabolismo , Leucotrienos/metabolismo , Peróxidos Lipídicos/metabolismo , Lipoxinas/biossíntese , Biocatálise , Vias Biossintéticas , Plaquetas/metabolismo , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Cinética , Leucócitos/metabolismo , Reticulócitos/metabolismo , Especificidade por Substrato
14.
Int J Nanomedicine ; 13: 5685-5699, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30288041

RESUMO

Introduction: Graphene oxide nanoparticles have been widely used in industry and biomedical fields due to their unique physicochemical properties. However, comparative cytotoxicity of silver-doped reduced graphene oxide (rGO-Ag) nanoparticles on normal and cancerous liver cells has not been well studied yet. Materials and methods: This study aimed at determining the toxic potential of rGO-Ag nanocomposite on human liver normal (CHANG) and cancer (HepG2) cells. The rGO-Ag nanocomposite was characterized by using different advanced instruments, namely, dynamic light scattering, scanning electron microscope, and transmission electron microscope. Results: The rGO-Ag nanocomposite reduced cell viability and impaired cell membrane integrity of CHANG and HepG2 cells in a dose-dependent manner. Additionally, it induced reactive oxygen species generation and reduced mitochondrial membrane potential in both cells in a dose-dependent manner. Moreover, the activity of oxidative enzymes such as lipid peroxide, superoxide dismutase, and catalase were increased and glutathione was reduced in both cells exposed to rGO-Ag nanocomposite. Pretreatment with N-acetylcysteine inhibited cytotoxicity and reactive oxygen species generation in CHANG and HepG2 cells exposed to rGO-Ag nanocomposite (50 µg/mL). DNA damage was determined by Comet assay and maximum DNA damage occurred at rGO-Ag nanocomposite (25 µg/mL) for 24 h. It is also valuable to inform that HepG2 cells appear to be slightly more susceptible to rGO-Ag nanocomposite exposure than CHANG cells. Conclusion: This result provides a basic comparative toxic effect of rGO-Ag nanocomposite on hepatic normal and cancerous liver cells.


Assuntos
Apoptose , Grafite/química , Neoplasias Hepáticas/patologia , Fígado/patologia , Nanocompostos/química , Prata/química , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Catalase/metabolismo , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Glutationa/metabolismo , Células Hep G2 , Humanos , Peróxidos Lipídicos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanopartículas Metálicas/química , Nanocompostos/ultraestrutura , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
15.
Biomed Pharmacother ; 107: 292-302, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30098547

RESUMO

Therapeutic approaches based on dietary compounds obtained from food products to handle diabetes involving oxidative stress and inflammation. Garlic is a common spice and has a long history as a folk remedy. Allyl methyl sulfide (AMS) is a potential garlic-derived organosulfur compound displaying a substantial range of optimistic actions in various diseases. Herein, we investigated the potential role of AMS in ameliorating the effects of oxidative stress and inflammation in the liver of streptozotocin (STZ)-induced experimental rats. Diabetes was induced by single intraperitoneal (i.p.) injection of STZ (40 mg/kg/b.w). STZ-induced hyperglycemic rats received daily intragastric doses of 50, 100 and 200 mg/kg/b.w of the AMS for 30 days. Dietary intervention of AMS (100 mg/kg b.w) resulted in significant attenuation in blood glucose and expression of pro-inflammatory markers TNF-α, IL-6, NF-κB p65 unit and significant elevation in the plasma insulin level. Moreover, AMS instigated a marked enhance in the levels of hepatic tissue non enzymatic antioxidants and the activities enzymatic antioxidants of diabetic rats with significant decline in lipid peroxides and hydroperoxides formation, serum biomarkers of liver damage, thus representing the protecting efficacy of AMS in hyperglycemic state. The pathological abnormalities in hepatic tissues of diabetic rats were significantly ameliorated by AMS supplementation and offered great support to the biochemical findings. These conclusions explicate the prospective use of AMS as a promising compound against glucotoxicity mediated hepatic oxidative dysfunction in rats. Clinical trials in validating this benefit for optimizing the AMS nutrition are however warranted.


Assuntos
Compostos Alílicos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Hiperglicemia/tratamento farmacológico , Hiperglicemia/patologia , Inflamação/patologia , Estresse Oxidativo , Sulfetos/uso terapêutico , Compostos Alílicos/farmacologia , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Experimental/sangue , Ingestão de Líquidos , Comportamento Alimentar/efeitos dos fármacos , Hiperglicemia/sangue , Insulina/sangue , Peróxidos Lipídicos/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Estreptozocina , Sulfetos/farmacologia
16.
World J Gastroenterol ; 24(27): 2984-2994, 2018 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-30038465

RESUMO

Aldehyde dehydrogenase 2 (ALDH2) is best known for its critical detoxifying role in liver alcohol metabolism. However, ALDH2 dysfunction is also involved in a wide range of human pathophysiological situations and is associated with complications such as cardiovascular diseases, diabetes mellitus, neurodegenerative diseases and aging. A growing body of research has shown that ALDH2 provides important protection against oxidative stress and the subsequent loading of toxic aldehydes such as 4-hydroxy-2-nonenal and adducts that occur in human diseases, including ischemia reperfusion injury (IRI). There is increasing evidence of its role in IRI pathophysiology in organs such as heart, brain, small intestine and kidney; however, surprisingly few studies have been carried out in the liver, where ALDH2 is found in abundance. This study reviews the role of ALDH2 in modulating the pathways involved in the pathophysiology of IRI associated with oxidative stress, autophagy and apoptosis. Special emphasis is placed on the role of ALDH2 in different organs, on therapeutic "preconditioning" strategies, and on the use of ALDH2 agonists such as Alda-1, which may become a useful therapeutic tool for preventing the deleterious effects of IRI in organ transplantation.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Transplante de Órgãos/efeitos adversos , Traumatismo por Reperfusão/patologia , Aldeídos/metabolismo , Aldeídos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Ativadores de Enzimas/farmacologia , Ativadores de Enzimas/uso terapêutico , Humanos , Peróxidos Lipídicos/metabolismo , Peróxidos Lipídicos/toxicidade , Fígado/metabolismo , Taxa de Depuração Metabólica , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle
17.
Toxicol Sci ; 165(2): 462-474, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29939353

RESUMO

Supplemental oxygen is a life-saving intervention administered to individuals suffering from respiratory distress, including adults with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Despite the clinical benefit, supplemental oxygen can create a hyperoxic environment that increases reactive oxygen species, oxidative stress, and lung injury. We have previously shown that cytochrome P450 (CYP)1A enzymes decrease susceptibility to hyperoxia-induced lung injury. In this investigation, we determined the role of CYP1B1 in hyperoxic lung injury in vivo. Eight- to ten-week old C57BL/6 wild type (WT) and Cyp1b1-/- mice were exposed to hyperoxia (>95% O2) for 24-72 h or maintained in room air (21% O2). Lung injury was assessed by histology and lung weight to body weight (LW/BW) ratios. Extent of inflammation was determined by assessing pulmonary neutrophil infiltration and cytokine levels. Lipid peroxidation markers were quantified by gas chromatography mass spectrometry, and oxidative DNA adducts were quantified by 32P-postlabeling as markers of oxidative stress. We found that Cyp1b1-/- mice displayed attenuation of lung weight and pulmonary edema, particularly after 48-72 h of hyperoxia compared with WT controls. Further, Cyp1b1-/- mice displayed decreased levels of pulmonary oxidative DNA adducts and pulmonary isofurans after 24 h of hyperoxia. Cyp1b1-/- mice also showed increased pulmonary CYP1A1 and 1A2 and mRNA expression. In summary, our results support the hypothesis that Cyp1b1-/- mice display decreased hyperoxic lung injury than wild type counterparts and that CYP1B1 may act as a pro-oxidant during hyperoxia exposure, contributing to increases in oxidative DNA damage and accumulation of lipid hydroperoxides.


Assuntos
Lesão Pulmonar Aguda/etiologia , Citocromo P-450 CYP1B1/genética , Dano ao DNA , Hiperóxia/complicações , Estresse Oxidativo , Lesão Pulmonar Aguda/enzimologia , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Hiperóxia/enzimologia , Hiperóxia/patologia , Peroxidação de Lipídeos/genética , Peróxidos Lipídicos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/genética
18.
Free Radic Biol Med ; 124: 104-113, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-29859345

RESUMO

This study examined to what extent the human cerebral and femoral circulation contribute to free radical formation during basal and exercise-induced responses to hypoxia. Healthy participants (5♂, 5♀) were randomly assigned single-blinded to normoxic (21% O2) and hypoxic (10% O2) trials with measurements taken at rest and 30 min after cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled from the brachial artery (a), internal jugular and femoral veins (v) for non-enzymatic antioxidants (HPLC), ascorbate radical (A•-, electron paramagnetic resonance spectroscopy), lipid hydroperoxides (LOOH) and low density lipoprotein (LDL) oxidation (spectrophotometry). Cerebral and femoral venous blood flow was evaluated by transcranial Doppler ultrasound (CBF) and constant infusion thermodilution (FBF). With 3 participants lost to follow up (final n = 4♂, 3♀), hypoxia increased CBF and FBF (P = 0.041 vs. normoxia) with further elevations in FBF during exercise (P = 0.002 vs. rest). Cerebral and femoral ascorbate and α-tocopherol consumption (v < a) was accompanied by A•-/LOOH formation (v > a) and increased LDL oxidation during hypoxia (P < 0.043-0.049 vs. normoxia) implying free radical-mediated lipid peroxidation subsequent to inadequate antioxidant defense. This was pronounced during exercise across the femoral circulation in proportion to the increase in local O2 uptake (r = -0.397 to -0.459, P = 0.037-0.045) but unrelated to any reduction in PO2. These findings highlight considerable regional heterogeneity in the oxidative stress response to hypoxia that may be more attributable to local differences in O2 flux than to O2 tension.


Assuntos
Circulação Cerebrovascular/fisiologia , Exercício/fisiologia , Artéria Femoral/fisiologia , Radicais Livres/metabolismo , Hipóxia , Consumo de Oxigênio , Adulto , Antioxidantes/metabolismo , Ácido Ascórbico/metabolismo , Feminino , Humanos , Peroxidação de Lipídeos , Peróxidos Lipídicos/metabolismo , Masculino , Oxirredução , Estresse Oxidativo , Adulto Jovem
19.
J Cell Biochem ; 119(10): 8359-8367, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29932247

RESUMO

Huperzine A (HupA), derived from Huperzia Serrata, has exhibited a variety of biological actions, in particular neuroprotective effect. However, the protective activities of HupA on murine embryonic fibroblast NIH3T3 cells after X-rays radiation have not been fully elucidated. Herein, HupA treatment dramatically promoted cell viability, abated a G0/G1 peak accumulation, and ameliorated increase of cell apoptosis in NIH3T3 cells after X-rays radiation. Simultaneously, HupA notably enhanced activities of anti-oxidant enzymes, inhibited activity of lipid peroxide, and efficiently eliminated production of reactive oxygen species in NIH3T3 cells after X-rays radiation. Dose-dependent increase of antioxidant genes by HupA were associated with up-regulated Nrf2 and down-regulated Keap-1 expression, which was confirmed by increasing nuclear accumulation, and inhibiting of degradation of Nrf2. Notably, augmented luciferase activity of ARE may explained Nrf2/ARE-mediated signaling pathways behind HupA protective properties. Moreover, expression of Nrf2 HupA-mediated was significant attenuated by AKT inhibitor (LY294002), p38 MAPK inhibitor (SB202190) and ERK inhibitor (PD98059). Besides, HupA-mediated cell viability, and ROS production were dramatically bated by LY294002, SB202190, and PD98059. Taken together, HupA effectively ameliorated X-rays radiation-induced damage Nrf2-ARE-mediated transcriptional response via activation AKT, p38, and ERK signaling in NIH3T3 cells.


Assuntos
Alcaloides/farmacologia , Elementos de Resposta Antioxidante , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Protetores contra Radiação/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Sesquiterpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/efeitos da radiação , Catalase/genética , Catalase/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Ciclo Celular/efeitos da radiação , Cromonas/farmacologia , Flavonoides/farmacologia , Regulação da Expressão Gênica , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Imidazóis/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Peróxidos Lipídicos/antagonistas & inibidores , Peróxidos Lipídicos/metabolismo , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Morfolinas/farmacologia , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Células NIH 3T3 , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Raios X , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Georgian Med News ; (278): 50-55, 2018 May.
Artigo em Russo | MEDLINE | ID: mdl-29905545

RESUMO

The purpose of our study was a comparative analysis of the effect of dentures from various materials on the immunological and redox-dependent homeostasis of the oral cavity. We studied 60 patients with removable dentures made based on plastics Prothyl Hot, Vertex BasiQ 20 (differing by polymerization regime) and elastic thermoplastic polymer Perflex Flexi Nylon. The control group consisted of 15 volunteers with a practically healthy oral cavity, who did not use dentures. Saliva collected on an empty stomach in a glass tube without the use of a stimulator before the establishment of a denture and 3 days and 1 month after. The content of the protein P-53 in saliva determined by immunoenzymatic assay with use of "Cusabio" reagent. The cytokines (IL1ß, IL10) content in saliva was determined immunoenzymatic assay. To determine the redox balance in the saliva of patients, the lipoperoxydradicals content (LOO.) content (by EPR method, using the spin-labeled α-phenyl-tertbutylnitron (PBN) (SIGMA)) and the activity of antioxidant enzymes (catalase and SOD) (by spectrophotometry) studied. Statistical processing of the results was carried out using the software package SPSS (version 10.0). Results of analysis show that defects associated with a lack of teeth do not affect the immune and oxidative balance of the oral cavity, but contribute to the development of destructive changes in the oral cavity's soft tissues, which manifested by an increase in the content of the proapoptotic protein P-53 in the saliva. After establishment of a denture, the intensity of apoptosis in the oral cavity tissues reduced. Establishment of a denture induced development of an inflammatory reaction during the first days, the intensity of which gradually decreased and completely disappeared at the end of the first month of the observation (manifested by the normalization of the parameters of the immune balance and antioxidant system). Minimal traumatic effects observed during establishment of a denture made based on Perflex Flexi Nylon.


Assuntos
Materiais Dentários/uso terapêutico , Prótese Parcial Removível , Regulação da Expressão Gênica/efeitos dos fármacos , Resinas Sintéticas/uso terapêutico , Saliva/efeitos dos fármacos , Estudos de Casos e Controles , Catalase/genética , Catalase/metabolismo , Planejamento de Dentadura , Humanos , Interleucina-10/agonistas , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/agonistas , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Peróxidos Lipídicos/agonistas , Peróxidos Lipídicos/metabolismo , Boca/metabolismo , Boca/cirurgia , Oxirredução/efeitos dos fármacos , Saliva/química , Saliva/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/agonistas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
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