RESUMO
Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, effective vaccines are essential to control the current coronavirus disease 2019 (COVID-19) pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here, we report the immunogenicity and protection induced in rhesus macaques by intramuscular injections of a VLP bearing a SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytidine-phospho-guanosine (CpG) 1018. Although a single dose of the unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after priming) and adjuvant administration significantly improved both responses, with higher immunogenicity and protection provided by the AS03-adjuvanted CoVLP. Fifteen micrograms of CoVLP adjuvanted with AS03 induced a polyfunctional interleukin-2 (IL-2)-driven response and IL-4 expression in CD4 T cells. Animals were challenged by multiple routes (i.e., intratracheal, intranasal, and ocular) with a total viral dose of 106 plaque-forming units of SARS-CoV-2. Lower viral replication in nasal swabs and bronchoalveolar lavage fluid (BALF) as well as fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of proinflammatory cytokines and chemotactic factors in the BALF were observed in animals immunized with the CoVLP adjuvanted with AS03. No clinical, pathologic, or virologic evidence of vaccine-associated enhanced disease was observed in vaccinated animals. The CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.
Assuntos
Adjuvantes Imunológicos/efeitos adversos , Vacinas contra COVID-19/efeitos adversos , COVID-19/imunologia , COVID-19/prevenção & controle , Imunogenicidade da Vacina/imunologia , Nicotiana/metabolismo , Pandemias/prevenção & controle , Polissorbatos/efeitos adversos , SARS-CoV-2/imunologia , Esqualeno/efeitos adversos , Vacinação/métodos , Vacinas de Partículas Semelhantes a Vírus/efeitos adversos , alfa-Tocoferol/efeitos adversos , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/epidemiologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Modelos Animais de Doenças , Combinação de Medicamentos , Composição de Medicamentos/métodos , Imunidade Humoral , Macaca mulatta , Masculino , Polissorbatos/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Esqualeno/administração & dosagem , Resultado do Tratamento , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , alfa-Tocoferol/administração & dosagemRESUMO
BACKGROUND: This is the second update of this Cochrane Review. Some studies have suggested a protective effect of antioxidant nutrients and higher dietary levels of fruits and vegetables on lung cancer. OBJECTIVES: To determine whether vitamins and minerals and other potential agents, alone or in combination, reduce lung cancer incidence and lung cancer mortality in healthy populations. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase from 1974 to May 2019 and screened references included in published studies and reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing vitamins or mineral supplements with placebo, administered to healthy people with the aim of preventing lung cancer. DATA COLLECTION AND ANALYSIS: Four review authors independently selected the trials to be included in the review, assessed their methodological quality and extracted data. For dichotomous outcomes we calculated risk ratios (RRs) and 95% confidence intervals (CIs) and pooled results using the random-effects model. We assessed the risk of bias using Cochrane's 'Risk of bias' assessment tool and certainty of evidence using the GRADE approach. MAIN RESULTS: In this update, we identified three new trials for a total of 12 studies. Six analysed vitamin A, three vitamin C, three combined vitamin D3 + calcium, four vitamin E combined with other products, one selenium supplements and nine studied combinations of two or more products. Four studies included only men and five only women. Vitamin A results in little to no difference in lung cancer incidence (RR 1.09, 95% CI 1.00 to 1.19; 5 RCTs, 212314 participants; high-certainty evidence) and lung cancer mortality (RR 1.06, 95% CI 0.81 to 1.38; 3 RCTs, 190118 participants; high-certainty evidence). But in smokers or asbestos workers vitamin A increases the risk of lung cancer incidence (RR 1.10, 95% CI 1.01 to 1.20; 3 RCTs, 43995 participants; high-certainty evidence), lung cancer mortality (RR 1.18, 95% CI 1.01 to 1.38; 2 RCTs, 29426 participants; high-certainty evidence) and all-cause mortality (RR 1.09, 95% CI 1.05 to 1.13; 2 RCTs, 32883 participants; high-certainty evidence). Vitamin A increases the risk of minor side effects, such as yellowing of the skin and minor gastrointestinal symptoms (high-certainty evidence). Vitamin C likely results in little to no difference in lung cancer incidence (RR 1.29, 95% CI 0.67 to 2.49; 2 RCTs, 14953 participants; moderate-certainty evidence). In women, vitamin C increases the risk of lung cancer incidence (RR 1.84, 95% CI 1.14 to 2.95; 1 RCT, 7627 participants; high-certainty evidence). In men, vitamin C results in little to no difference in mortality for lung cancer (RR 0.81, 95% CI 0.53 to 1.23; 1 RCT, 7326 participants; high-certainty evidence). Vitamin D + calcium may result in little to no difference in lung cancer incidence in postmenopausal women (RR 0.90, 95% CI 0.39 to 2.08; 3 RCTs, 37601 women; low-certainty evidence). Vitamin E results in little to no difference in lung cancer incidence (RR 1.01, 95% CI 0.90 to 1.14; 3 RCTs, 36841 participants; high-certainty evidence) or to lung cancer mortality (RR 0.96, 95% CI 0.77 to 1.18; 2 RCTs, 29214 participants; high-certainty evidence), but increases the risk of haemorrhagic strokes (hazard ratio (HR), 1.74, 95% CI 1.04 to 2.91; 1 RCT, 14641 participants; high-certainty evidence). Calcium results in little to no difference in lung cancer incidence in postmenopausal women (RR 0.65, 95% CI 0.13 to 3.18; 1 RCT, 733 participants) or in risk of renal calculi (RR 1.94, 95% CI 0.20 to 18.57; 1 RCT, 733 participants; low-certainty evidence). Selenium in men results in little to no difference in lung cancer incidence (RR 1.11, 95% CI 0.80 to 1.54; 1 RCT, 17448 participants; high-certainty evidence) and lung cancer mortality (RR 1.09, 95% CI 0.72 to 1.66; 1 RCT, 17448 participants; high-certainty evidence) and increases the risk for grade 1 to 2 dermatitis (RR 1.16, 95% CI 1.04 to 1.31; 1 RCT, 17448 participants; high-certainty evidence) and for alopecia (RR 1.28, 95% CI 1.07 to 1.53; 1 RCT, 17448 participants; high-certainty evidence). The combination of vitamins A, C, E + selenium + zinc results in little to no difference in lung cancer incidence (RR 0.64, 95% CI 0.28 to 1.48; 1 RCT, 12741 participants; high-certainty evidence). AUTHORS' CONCLUSIONS: Well-designed RCTs have shown no beneficial effect of supplements for the prevention of lung cancer and lung cancer mortality in healthy people. Vitamin A supplements increase lung cancer incidence and mortality in smokers or persons exposed to asbestos. Vitamin C increases lung cancer incidence in women. Vitamin E increases the risk of haemorrhagic strokes.
Assuntos
Suplementos Nutricionais , Nível de Saúde , Neoplasias Pulmonares/prevenção & controle , Minerais/uso terapêutico , Vitaminas/uso terapêutico , Ácido Ascórbico/uso terapêutico , Cálcio da Dieta/efeitos adversos , Cálcio da Dieta/uso terapêutico , Colecalciferol/uso terapêutico , Intervalos de Confiança , Feminino , Humanos , Incidência , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/mortalidade , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Selênio , Compostos de Selênio/uso terapêutico , Fatores Sexuais , Vitamina A/efeitos adversos , Vitamina A/uso terapêutico , Vitamina E/uso terapêutico , Vitaminas/efeitos adversos , alfa-Tocoferol/efeitos adversos , alfa-Tocoferol/uso terapêutico , beta Caroteno/uso terapêuticoRESUMO
BACKGROUND: Vitamins are among the most frequently used supplements (48% of US adults). However, little is known about contributions of genetic variation to their efficacy and safety. Multiple pathways link catechol-O-methyltransferase (COMT) to the vitamin E supplement, alpha-tocopherol, and cancer. METHODS: Here we determined if COMT exerted pharmacogenetic effects on cancer prevention in two randomized trials of alpha-tocopherol supplementation. Pharmacogenetic effects of common COMT rs4680 (val158met), which encodes a nonsynonymous valine-to-methionine substitution, were examined in the trial plus a 10-year post-trial follow-up (overall) period of The Women's Genome Health Study (WGHS, N = 23 294), a 10-year alpha-tocopherol and aspirin trial with 10 years post-trial follow-up. Results were validated in a case/control (N = 2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC, N = 29 133). The primary outcome was total cancers. Rates of cancer types prevalent in women (colorectal, breast, lung, uterine, and lymphoma/leukemia) were also examined. All statistical tests were two-sided. RESULTS: Random-effects meta-analysis of rs4680 genotype strata, in WGHS and ATBC overall periods, revealed differential alpha-tocopherol effects compared with placebo: met/met (hazard ratio [HR] = 0.88; 95% confidence interval [CI] = 0.80 to 0.97; P = .01), val/met (HR = 0.99; 95% CI = 0.92 to 1.06; P = .74), and val/val (HR = 1.18; 95% CI = 1.06 to 1.31; P = .002) with a statistically significant COMT by alpha-tocopherol interaction (Pinteraction <.001). Timing of effects differed, with stronger effects in WGHS trial and ATBC post-trial. CONCLUSION: Pharmacogenetic analysis of COMT and cancer prevention in two large randomized trials revealed statistically significant COMT by alpha-tocopherol interaction, such that alpha-tocopherol was beneficial among rs4680 met-allele (28.0%), but not val-allele (22.8%) homozygotes. These effects indicate the need for additional studies of genetic variation as a determinant of the benefits and possible harms of over-the-counter supplements, like alpha-tocopherol, used for health promotion.
Assuntos
Catecol O-Metiltransferase/genética , Estudos de Associação Genética , Neoplasias/genética , alfa-Tocoferol/uso terapêutico , Alelos , Suplementos Nutricionais/efeitos adversos , Feminino , Genótipo , Humanos , Masculino , Neoplasias/dietoterapia , Neoplasias/patologia , Neoplasias/prevenção & controle , Testes Farmacogenômicos , Ensaios Clínicos Controlados Aleatórios como Assunto , alfa-Tocoferol/efeitos adversos , beta Caroteno/uso terapêuticoRESUMO
α-Tocopherol (α-Toc) overload increases the risk of dying in humans (E.R. Miller III et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality Ann Int Med. 142 (2005) 37-46), and overload during early development leads to elevation of blood pressure at adult life, but the mechanism(s) remains unknown. We hypothesized that α-Toc overload during organogenesis affects the renal renin angiotensin system (RAS) components and renal Na+ handling, culminating with late elevated blood pressure. Pregnant Wistar rats received α-Toc or the superoxide dismutase mimetic tempol throughout pregnancy. We evaluated components of the intrarenal renin angiotensin system in neonate and juvenile offspring: Ang II-positive cells, Ang II receptors (AT1 and AT2), linked protein kinases, O2- production, NADPH oxidase abundance, lipid peroxidation and activity of Na+-transporting ATPases. In juvenile offspring we followed the evolution of arterial blood pressure. Neonates from α-Toc and tempol mothers presented with accentuated retardment in tubular development, pronounced decrease in glomerular Ang II-positive cells and AT1/AT2 ratio, intense production of O2- and upregulation of the α, ε and λ PKC isoforms. α-Toc decreased or augmented the abundance of renal (Na++K+)ATPase depending on the age and α-Toc dose. In juvenile rats the number of Ang II-positive cells returned to control values as well as PKCα, but co-existing with marked upregulation in the activity of (Na++K+) and Na+-ATPase and elevated arterial pressure at 30â¯days. We conclude that the mechanisms of these alterations rely on selective targeting of renal RAS components through genic and pro-oxidant effects of the vitamin.
Assuntos
Angiotensina II/metabolismo , Hipertensão , Rim , Transdução de Sinais/efeitos dos fármacos , alfa-Tocoferol/efeitos adversos , Animais , Animais Recém-Nascidos , Feminino , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Rim/crescimento & desenvolvimento , Rim/patologia , Rim/fisiopatologia , Proteína Quinase C/metabolismo , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismo , alfa-Tocoferol/farmacologiaRESUMO
The development of imaging-guided smart drug delivery systems for combinational photodynamic/chemotherapy of the tumor has become highly demanded in oncology. Herein, redox-responsive theranostic polymeric nanoparticles (NPs) were fabricated innovatively using low molecular weight heparin (LWMH) as the backbone. Chlorin e6 (Ce6) and alpha-tocopherol succinate (TOS) were conjugated to LMWH via cystamine as the redox-sensitive linker, forming amphiphilic Ce6-LMWH-TOS (CHT) polymer, which could self-assemble into NPs in water and encapsulate paclitaxel (PTX) inside the inner core (PTX/CHT NPs). The enhanced near-infrared (NIR) fluorescence intensity and reactive oxygen species (ROS) generation of Ce6 were observed in a reductive environment, suggesting the cystamine-switched "ON/OFF" of Ce6. Also, the in vitro release of PTX exhibited a redox-triggered profile. MCF-7 cells showed a dramatically higher uptake of Ce6 delivered by CHT NPs compared with free Ce6. The improved therapeutic effect of PTX/CHT NPs compared with mono-photodynamic or mono-chemotherapy was observed in vitro via MTT and apoptosis assays. Also, the PTX/CHT NPs exhibited a significantly better in anti-tumor efficiency upon NIR irradiation according to the results of in vivo combination therapy conducted on 4T1-tumor-bearing mice. The in vivo NIR fluorescence capacity of CHT NPs was also evaluated in tumor-bearing nude mice, implying that the CHT NPs could enhance the accumulation and retention of Ce6 in tumor foci compared with free Ce6. Interestingly, the anti-metastasis activity of CHT NPs was observed against MCF-7 cells by a wound healing assay, which was comparable to LMWH, suggesting LMWH was promising for construction of nanocarriers for cancer management.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Raios Infravermelhos/uso terapêutico , Nanopartículas/química , Paclitaxel/administração & dosagem , Fotoquimioterapia , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorofilídeos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/efeitos adversos , Feminino , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/química , Humanos , Raios Infravermelhos/efeitos adversos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Eletrônica de Transmissão , Nanopartículas/efeitos adversos , Nanopartículas/efeitos da radiação , Nanopartículas/ultraestrutura , Transplante de Neoplasias , Imagem Óptica , Paclitaxel/efeitos adversos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fotoquimioterapia/efeitos adversos , Porfirinas/efeitos adversos , Porfirinas/química , Distribuição Aleatória , Espécies Reativas de Oxigênio/efeitos adversos , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/química , Nanomedicina Teranóstica/métodos , Carga Tumoral/efeitos dos fármacos , Imagem Corporal Total , alfa-Tocoferol/efeitos adversos , alfa-Tocoferol/químicaRESUMO
BACKGROUND: The indications for a cochlear implant (CI) have been extended to include patients with some residual hearing. Shorter and thinner atraumatic electrodes have been designed to preserve the residual hearing in the implanted ear. However, the insertion of the electrode array into the cochlea, with potential mechanical trauma and the presence of this foreign body inside the cochlea, may lead to free radical formation and reduced blood perfusion of the cochlea which can result in the loss of residual hearing. METHODS/DESIGN: In this single-center, randomized, placebo-controlled, double-blind phase II clinical trial the effect of free radical scavengers and a vasodilator on the residual hearing of 140 CI patients will be evaluated. The formulation is composed of ß-carotene (vitamin A), ascorbic acid (vitamin C), dl-α-tocopherol acetate (vitamin E) and the vasodilator magnesium (Mg), or ACEMg. Medication is administered twice daily per os for approximately 3 months. The primary measure is based upon the reduction in postoperative low-frequency air-conducted pure-tone thresholds compared to preoperative thresholds in ACEMg-treated patients compared to those of a placebo group. Additionally, the effect of different electrode lengths (20, 24 and 28 mm) is analyzed. Study visits are scheduled 2 days before surgery, at first fitting, which is the adjustment and start of stimulation via CI 4 weeks after surgery and 3, 6, 9 and 12 months after first fitting. The primary endpoint is the air-conduction hearing loss at 500 Hz 3 months after first fitting. Additionally, speech recognition tests, hearing aid benefit in the implanted ear and electrophysiological measurements of implant function are assessed. Since this is a blinded clinical trial and recruitment is still ongoing, data continue to accrue and we cannot yet analyze the outcome of the ACEMg treatment. DISCUSSION: There is an unfulfilled need for new strategies to preserve acoustic hearing in CI patients. This study will provide first-in-man data on ACEMg-mediated protection of residual hearing in CI patients. Performing all surgeries and patient follow-up at one study site improves consistency in diagnosis and therapy and less variability in surgery, audiological test techniques and fitting. This approach will allow investigation of the influence of ACEMg on residual hearing in CI patients. TRIAL REGISTRATION: The German Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) application number 4039192, was registered on 6 December 2013 with protocol amendment version 3.0 from 19 August 2014. EudraCT number: 2012-005002-22 .
Assuntos
Ácido Ascórbico/uso terapêutico , Implante Coclear/instrumentação , Implantes Cocleares , Sequestradores de Radicais Livres/uso terapêutico , Audição/efeitos dos fármacos , Magnésio/uso terapêutico , Pessoas com Deficiência Auditiva/reabilitação , Percepção da Fala/efeitos dos fármacos , Vasodilatadores/uso terapêutico , alfa-Tocoferol/uso terapêutico , beta Caroteno/uso terapêutico , Ácido Ascórbico/efeitos adversos , Audiometria de Tons Puros , Audiometria da Fala , Limiar Auditivo/efeitos dos fármacos , Protocolos Clínicos , Método Duplo-Cego , Combinação de Medicamentos , Sequestradores de Radicais Livres/efeitos adversos , Alemanha , Humanos , Magnésio/efeitos adversos , Pessoas com Deficiência Auditiva/psicologia , Desenho de Prótese , Projetos de Pesquisa , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/efeitos adversos , alfa-Tocoferol/efeitos adversos , beta Caroteno/efeitos adversosRESUMO
BACKGROUND: Contrast medium-induced acute kidney injury (CIAKI) is a leading cause of acquired renal impairment. The effects of antioxidants have been conflicting regarding the prevention of CIAKI. We performed a study of vitamin E use to decrease CIAKI in patients undergoing elective coronary angiography. METHODS AND RESULTS: In a placebo-controlled randomized trial at 2 centers in Iran, 300 patients with chronic kidney disease-defined as estimated glomerular filtration rate <60 mL/min per 1.73 m(2)-were randomized 1:1 to receive 0.9% saline infusion 12 hours prior to and after intervention combined with 600 mg vitamin E 12 hours before plus 400 mg vitamin E 2 hours before coronary angiography or to receive placebo. The primary end point was the development of CIAKI, defined as an increase ≥0.5 mg/dL or ≥25% in serum creatinine that peaked within 72 hours. Based on an intention-to-treat analysis, CIAKI developed in 10 (6.7%) and 21 (14.1%) patients in the vitamin E and placebo groups, respectively (P=0.037). Change in white blood cell count from baseline to peak value was greater in the vitamin E group compared with the placebo group (-500 [-1500 to 200] versus 100 [-900 to 600]×10(3)/mL, P=0.001). In multivariate analysis, vitamin E (odds ratio 0.408, 95% CI 0.170-0.982, P=0.045) and baseline Mehran score (odds ratio 1.257, 95% CI 1.007-1.569; P=0.043) predicted CIAKI. CONCLUSIONS: Prophylactic short-term high-dose vitamin E combined with 0.9% saline infusion is superior to placebo for prevention of CIAKI in patients undergoing elective coronary angiography. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02070679.
Assuntos
Injúria Renal Aguda/prevenção & controle , Antioxidantes/administração & dosagem , Meios de Contraste/efeitos adversos , Angiografia Coronária/efeitos adversos , Insuficiência Renal Crônica/complicações , Ácidos Tri-Iodobenzoicos/efeitos adversos , Vitaminas/administração & dosagem , alfa-Tocoferol/administração & dosagem , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Idoso , Antioxidantes/efeitos adversos , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Meios de Contraste/administração & dosagem , Creatinina/sangue , Método Duplo-Cego , Feminino , Hidratação/métodos , Taxa de Filtração Glomerular , Humanos , Infusões Parenterais , Análise de Intenção de Tratamento , Irã (Geográfico) , Rim/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Cloreto de Sódio/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Ácidos Tri-Iodobenzoicos/administração & dosagem , Vitaminas/efeitos adversos , alfa-Tocoferol/efeitos adversosRESUMO
OBJECTIVES: The E vitamins are a class of lipophilic compounds including tocopherols, which have high antioxidative properties. Because of the elevated lipid peroxidation and increased reactive oxidative species in Alzheimer's disease (AD) many attempts have been made to slow down the progression of AD by utilizing the antioxidative action of vitamin E. Beside the mixed results of these studies nothing is known about the impact of vitamin E on the mechanisms leading to amyloid-ß production and degradation being responsible for the plaque formation, one of the characteristic pathological hallmarks in AD. Here we systematically investigate the influence of different tocopherols on Aß production and degradation in neuronal cell lines. MEASUREMENTS: Beside amyloid-ß level the mechanisms leading to Aß production and degradation are examined. RESULTS: Surprisingly, all tocopherols have shown to increase Aß level by enhancing the Aß production and decreasing the Aß degradation. Aß production is enhanced by an elevated activity of the involved enzymes, the ß- and γ-secretase. These secretases are not directly affected, but tocopherols increase their protein level and expression. We could identify significant differences between the single tocopherols; whereas α-tocopherol had only minor effects on Aß production, δ-tocopherol showed the highest potency to increase Aß generation. Beside Aß production, Aß clearance was decreased by affecting IDE, one of the major Aß degrading enzymes. CONCLUSIONS: Our results suggest that beside the beneficial antioxidative effects of vitamin E, tocopherol has in respect to AD also a potency to increase the amyloid-ß level, which differ for the analysed tocopherols. We therefore recommend that further studies are needed to clarify the potential role of these various vitamin E species in respect to AD and to identify the form which comprises an antioxidative property without having an amyloidogenic potential.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Neuroblastoma/metabolismo , Tocoferóis/metabolismo , Secretases da Proteína Precursora do Amiloide/biossíntese , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/biossíntese , Amiloidose/induzido quimicamente , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Humanos , Insulisina/metabolismo , Peroxidação de Lipídeos , Proteólise/efeitos dos fármacos , Tocoferóis/efeitos adversos , Tocoferóis/farmacologia , alfa-Tocoferol/efeitos adversos , alfa-Tocoferol/metabolismo , alfa-Tocoferol/farmacologia , gama-Tocoferol/efeitos adversos , gama-Tocoferol/metabolismo , gama-Tocoferol/farmacologiaRESUMO
BACKGROUND: Two chemoprevention trials found that supplementation with ß-carotene increased the risk of lung cancer and overall mortality. The biologic basis of these findings remains poorly understood. OBJECTIVE: The objective was to compare the on-study change in metabolomic profiles of men randomly assigned to receive or not receive ß-carotene supplements in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. DESIGN: The ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial; participants were Finnish male smokers assigned to 1 of 4 intervention groups: 1) α-tocopherol, 2) ß-carotene, 3) both, or 4) placebo. Fifty participants with both baseline and follow-up fasting serum samples were randomly selected from each of these groups. Metabolomic profiling was conducted by mass spectrometry. The association between change in each metabolite over time and trial assignment (ß-carotene or no ß-carotene) was estimated by linear regression. RESULTS: We measured 489 metabolites, and 17 changed significantly (P < 0.05) in response to ß-carotene supplementation. More of these 17 metabolites were of xenobiotic origin than would be expected by chance (9 of 60, or 15%; P = 0.00004). We also found a suggestive association with 1,5-anhydroglucitol-a marker of glycemic control (ß = -0.379, P = 0.0071). CONCLUSIONS: Male smokers supplemented with ß-carotene developed metabolomic profiles consistent with the induction of cytochrome P450 enzymes, the primary metabolizers of xenobiotics in humans. These findings may shed light on the increased mortality associated with ß-carotene supplementation in the ATBC Study and suggest the need to explore potential interactions between medication use and dietary supplements, particularly among smokers. This trial was registered at clinicaltrials.gov as NCT00342992.
Assuntos
Suplementos Nutricionais , Metaboloma , Fumar , alfa-Tocoferol/administração & dosagem , beta Caroteno/administração & dosagem , Idoso , Glicemia/análise , Cromatografia Líquida , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Desoxiglucose/administração & dosagem , Método Duplo-Cego , Jejum , Finlândia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Espectrometria de Massas em Tandem , alfa-Tocoferol/efeitos adversos , alfa-Tocoferol/sangue , beta Caroteno/efeitos adversos , beta Caroteno/sangueRESUMO
This study highlighted the pro-oxidative functions of α-tocopherol (αT) on the heart antioxidant system and tissue histopathology of oxidized sunflower oil (OSO)-exposed rats.Four groups of male Wistar rats were fed with different diets: 1) control diet containing FSO (fresh sunflower oil); 2) diet containing 5 % OSO; 3) diet containing 5 % OSO, supplemented with 600 mg αT kg-1; and 4) diet containing 5 % OSO, supplemented with 1200 mg αT kg-1. The hearts were then isolated, and the antioxidant enzymatic activities were assessed. Body weight and catalase (CAT), glutathione peroxidase (GPx) activities significantly decreased in groups fed with OSO, while the lipid peroxidation (LPO) level significantly increased. Administration of OSO with αT (600 mg · kg-1) returned the body weight values and LPO levels to similar values as the control group. The CAT and GPx activities increased but remained significantly lower compared to the control group. In the OSO group with αT (1200 mg · kg-1), the CAT and GPx activities also decreased, while LPO significantly increased. Heart tissue sections obtained from the groups revealed the presence of large areas of necrosis. This study suggested that OSO induced oxidative stress and that administration of a moderate dose of αT restored the antioxidant balance, but that high levels of αT supplementation result in a pro-oxidant effect.
Assuntos
Cardiotoxinas , Gorduras Insaturadas na Dieta/efeitos adversos , Óleos de Plantas/efeitos adversos , Óleos de Plantas/química , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/efeitos adversos , Animais , Antioxidantes/administração & dosagem , Catalase/antagonistas & inibidores , Gorduras Insaturadas na Dieta/administração & dosagem , Relação Dose-Resposta a Droga , Glutationa Peroxidase/antagonistas & inibidores , Glutationa Peroxidase/metabolismo , Coração/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Miocárdio/patologia , Oxidantes/administração & dosagem , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Óleo de GirassolRESUMO
BACKGROUND: The efficacy of a maintenance therapy in non-responder patients with chronic hepatitis C has been essentially evaluated by histological semiquantitative scores. AIM: The aim was to evaluate the efficiency of 2 years of treatment with peginterferon alpha-2a vs alpha-tocopherol in these patients by histology, morphometry and blood markers of fibrosis. METHOD: Hundred and five HCV patients with a Metavir fibrosis score > or = 2 were randomized to receive peginterferon alpha-2a 180 microg/week (PEG) (n=55) or alpha-tocopherol (TOCO) 1000 mg/day (n=50) for 96 weeks. The primary endpoint was improvement or stabilization of the Metavir fibrosis score by biopsy performed at week 96. Secondary endpoints included a quantitative assessment of fibrosis by morphometry and changes in blood markers of fibrosis. RESULTS: There was no difference at baseline between PEG and TOCO according to the metavir (83.3 vs 86.8%, P=0.751) stage. The median fibrosis rate, measured with morphometry was 2.72 and 2.86% at day 0, and 3.66 and 2.82% at week 96, in the PEG and TOCO groups (P=0.90) respectively. However, the percentage of patients with metavir activity grade improvement was significantly higher in the PEG group vs the TOCO group (52.8 vs 23.7%, P=0.016). Non-invasive markers analysis did not show any significant change in both groups. CONCLUSION: Long-term therapy with peginterferon alpha-2a did not reduce liver fibrosis degree assessed by morphometry and blood tests as compared with alpha-tocopherol. Blood tests could be useful to assess liver fibrosis changes in clinical trials.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Polietilenoglicóis/uso terapêutico , alfa-Tocoferol/uso terapêutico , Adulto , Antivirais/efeitos adversos , Biomarcadores/sangue , Biópsia , Progressão da Doença , Feminino , França , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Valor Preditivo dos Testes , RNA Viral/sangue , Proteínas Recombinantes , Fatores de Tempo , Resultado do Tratamento , alfa-Tocoferol/efeitos adversosRESUMO
Vitamin E, a micronutrient (comprising alpha-, beta-, gamma- and delta-tocopherols, alpha-, beta-, gamma- and delta-tocotrienols), has documented antioxidant and non-antioxidant effects, some of which inhibit inflammation and angiogenesis. We compared the abilities of alpha-, gamma- and delta-tocopherols to regulate human blood cytotoxicity (BEC) and lymphatic endothelial cytotoxicity (LEC), proliferation, invasiveness, permeability, capillary formation and suppression of TNF-alpha-induced VCAM-1 as in vitro models of inflammatory angiogenesis. alpha-, gamma- and delta-tocopherols were not toxic to either cell type up to 40 microM. In BEC, confluent cell density was decreased by all concentrations of delta- and gamma-tocopherol (10-40 microM) but not by alpha-tocopherol. LEC showed no change in cell density in response to tocopherols. delta-Tocopherol (40 microM), but not other isomers, decreased BEC invasiveness. In LEC, all doses of gamma-tocopherol, as well as the highest dose of alpha-tocopherol (40 microM), decreased cell invasiveness. delta-Tocopherol had no effect on LEC invasiveness at any molarity. delta-Tocopherol dose dependently increased cell permeability at 48 h in BEC and LEC; alpha- and gamma-tocopherols showed slight effects. Capillary tube formation was decreased by high dose (40 microM) concentrations of alpha-, gamma- and delta-tocopherol, but showed no effects with smaller doses (10-20 microM) in BEC. gamma-Tocopherol (10-20 microM) and alpha-tocopherol (10 microM), but not delta-tocopherol, increased LEC capillary tube formation. Lastly, in BEC, alpha-, gamma- and delta-tocopherol each dose-dependently reduced TNF-alpha-induced expression of VCAM-1. In LEC, there was no significant change to TNF-alpha-induced VCAM-1 expression with any concentration of alpha-, gamma- or delta-tocopherol. These data demonstrate that physiological levels (0-40 microM) of alpha-, gamma- and delta-tocopherols are nontoxic and dietary tocopherols, especially delta-tocopherol, can limit several BEC and LEC endothelial behaviors associated with angiogenesis. Tocopherols may therefore represent important nutrient-signals that limit cell behaviors related to inflammation/angiogenesis, which when deficient, may predispose individuals to risks associated with elevated angiogenesis such as inflammation and cancer; further differences seen from the tocopherols may be due to their blood or lymphatic cell origin.
Assuntos
Inibidores da Angiogênese/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Endotélio Linfático/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Tocoferóis/farmacologia , alfa-Tocoferol/farmacologia , gama-Tocoferol/farmacologia , Inibidores da Angiogênese/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Endotélio Linfático/citologia , Endotélio Linfático/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Humanos , Inflamação/prevenção & controle , Microvasos/citologia , Microvasos/efeitos dos fármacos , Microvasos/fisiologia , Neovascularização Patológica/prevenção & controle , Concentração Osmolar , Fatores de Tempo , Tocoferóis/efeitos adversos , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , alfa-Tocoferol/efeitos adversos , gama-Tocoferol/efeitos adversosRESUMO
Prior research shows that topical application of free, nonfatty acid-conjugated vitamin E (DL-alpha-tocopherol) prevents skin cancer in mice, as well as immunosuppression induced by UVB radiation. This study investigated the chemopreventive potential of DL-alpha-tocopherol in humans through monitoring surrogate end point biomarkers in sun-damaged skin. Contralateral arms of healthy human volunteers with actinic keratoses (AK) were randomly assigned to receive either 12.5% DL-alpha-tocopherol or placebo in a crème base for 6 months. Changes in number of AKs, levels of p53 protein expression, proliferating cell nuclear antigen, and polyamines were assessed along with skin and systemic vitamin E levels. Following treatment, plasma concentration levels of DL-alpha-tocopherol were unchanged, but skin levels were highly elevated (P < 0.001). Levels of p53 and proliferating cell nuclear antigen did not change significantly, whereas number of AKs declined insignificantly in both placebo and treatment arms. Regression models showed significant decreases in putrescine, spermidine, spermine, and total polyamine concentrations following treatment. Topically applied DL-alpha-tocopherol was substantially absorbed in skin, but the 6-month application did not significantly reduce numbers of preexisting AKs on moderately to severely sun-damaged forearms. Increases in polyamine synthesis are expected during tumor initiation and promotion; conversely, the significant reductions in polyamine levels resulting from the topical DL-alpha-tocopherol application are consistent with reductions in tumorigenesis potential. Topical tocopherol did not normalize established sun-induced lesions, but DL-alpha-tocopherol-induced reductions in polyamine metabolism are consistent with the inhibition of skin squamous cell carcinogenesis as seen in previous human trials and animal models.
Assuntos
Antioxidantes/administração & dosagem , Ceratose Actínica/prevenção & controle , alfa-Tocoferol/administração & dosagem , Administração Tópica , Idoso , Antioxidantes/efeitos adversos , Poliaminas Biogênicas/análise , Quimioprevenção , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Imuno-Histoquímica , Masculino , Antígeno Nuclear de Célula em Proliferação/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos , alfa-Tocoferol/efeitos adversosAssuntos
Antioxidantes/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Neoplasias/prevenção & controle , Antioxidantes/efeitos adversos , Humanos , Neoplasias/terapia , alfa-Tocoferol/efeitos adversos , alfa-Tocoferol/uso terapêutico , beta Caroteno/efeitos adversos , beta Caroteno/uso terapêuticoRESUMO
Combined use of pentoxifylline and vitamin E is reported to reduce radiation-induced toxicity in normal tissues at molecular level. We plan to evaluate the role of combined use of pentoxifylline (PTX) and alpha-tocopherol (vitamin E; Vit E) for minimizing radiation-induced lung toxicity. A total of 91 lung cancer patients were randomized. Among them, 44 received PTX (400 mg three times a day orally and Vit E 300 mg twice a day orally during the entire period of radiotherapy. PTX and Vit E were further administered at doses of 400 mg once a day and 300 mg once a day, respectively for 3 months after radiotherapy. A total of 47 patients were assigned as a control group. Radiation related acute and late toxicities are evaluated by radiation RTOG/EORTC toxicity scale. Median age was 59 (range, 41-75). Median follow-up was 13 months (range, 3-28 months). Radiation-induced lung toxicity was more frequent in control group for all phases than in pentoxifylline and alpha-tocopherol group (acute phase, P = 0.042, subacute phase P = 0.0001, late phase P = 0.256). PTX and Vit E combination might be considered especially in patients with lung cancer who receive concurrent chemo-radiotherapy, or have a poor respiratory function tests.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Pentoxifilina/uso terapêutico , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , alfa-Tocoferol/uso terapêutico , Adulto , Idoso , Carcinoma de Células Pequenas/radioterapia , Terapia Combinada , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Pulmão/efeitos da radiação , Pneumopatias/patologia , Pneumopatias/prevenção & controle , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Pentoxifilina/efeitos adversos , Lesões por Radiação/patologia , Protetores contra Radiação/efeitos adversos , Estatísticas não Paramétricas , Resultado do Tratamento , Vômito/induzido quimicamente , alfa-Tocoferol/efeitos adversosRESUMO
BACKGROUND: Although low dietary intakes of antioxidant vitamins and minerals have been associated with higher risks of cancer, results of trials testing antioxidant supplementation for cancer chemoprevention have been equivocal. We assessed whether supplementation with antioxidant vitamins could reduce the incidence of second primary cancers among patients with head and neck cancer. METHODS: We conducted a multicenter, double-blind, placebo-controlled, randomized chemoprevention trial among 540 patients with stage I or II head and neck cancer treated by radiation therapy between October 1, 1994, and June 6, 2000. Supplementation with alpha-tocopherol (400 IU/day) and beta-carotene (30 mg/day) or placebo began on the first day of radiation therapy and continued for 3 years after the end of radiation therapy. In the course of the trial, beta-carotene supplementation was discontinued after 156 patients had enrolled because of ethical concerns. The remaining patients received alpha-tocopherol or placebo only. Survival was evaluated by Kaplan-Meier analysis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: After a median follow-up of 52 months, second primary cancers and recurrences of the first tumor were diagnosed in 113 and 119 participants, respectively. The effect of supplementation on the incidence of second primary cancers varied over time. Compared with patients receiving placebo, patients receiving alpha-tocopherol supplements had a higher rate of second primary cancers during the supplementation period (HR = 2.88, 95% CI = 1.56 to 5.31) but a lower rate after supplementation was discontinued (HR = 0.41, 95% CI = 0.16 to 1.03). Similarly, the rate of having a recurrence or second primary cancer was higher during (HR = 1.86, 95% CI = 1.27 to 2.72) but lower after (HR = 0.71, 95% CI = 0.33 to 1.53) supplementation with alpha-tocopherol. The proportion of participants free of second primary cancer overall after 8 years of follow-up was similar in both arms. CONCLUSIONS: alpha-Tocopherol supplementation produced unexpected adverse effects on the occurrence of second primary cancers and on cancer-free survival.
Assuntos
Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias Induzidas por Radiação/prevenção & controle , Segunda Neoplasia Primária/prevenção & controle , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/efeitos adversos , beta Caroteno/administração & dosagem , beta Caroteno/efeitos adversos , Adulto , Idoso , Anticarcinógenos/administração & dosagem , Anticarcinógenos/efeitos adversos , Fatores de Confusão Epidemiológicos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Induzidas por Radiação/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Razão de Chances , Modelos de Riscos Proporcionais , Radioterapia/efeitos adversos , Análise de Sobrevida , Falha de TratamentoRESUMO
All-trans-retinoic acid (ATRA) alone or in combination with cytokines and vitamins has been shown to stimulate erythropoiesis in low-risk myelodysplastic syndromes (MDS). We performed a phase II study on 29 patients with MDS and isolated del(5q) including bands q31-q33 to determine the efficacy and safety of ATRA in combination with tocopherol-alpha. All patients had low/intermediate-1 risk MDS according to the international prognostic scoring system. They received 45 mg/m(2) ATRA on days 1 to 90, and 90 mg/m(2) on days 91 to 180. Tocopherol dosage was 600 IU three times daily. Twenty-four patients completed dose level I, and 12 patients dose level II. Eighty-six percent of patients experienced side effects. Thirty discontinued the drug treatment due to such events as skin reactions, cheilitis, conjunctivitis, joint pain, creatinine increase, or CNS symptoms. One patient (3%) achieved a major erythroid response resulting in transfusion independence throughout the study. Four patients (14%) achieved a minor erythroid response with >50% reduction of transfusion needs. None of the participants had a cytogenetic response. There was no significant improvement in quality of life among responding patients as measured by the European Organization for the Research and Treatment of Cancer (EORTC) quality of life questionnaire. Based on these results, the combination of ATRA and tocopherol-alpha is not recommended for the treatment of del(5q) MDS.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5/ultraestrutura , Síndromes Mielodisplásicas/tratamento farmacológico , Tretinoína/uso terapêutico , alfa-Tocoferol/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Bandeamento Cromossômico , Cromossomos Humanos Par 5/genética , Toxidermias/etiologia , Quimioterapia Combinada , Eritropoese/efeitos dos fármacos , Seguimentos , Hemoglobinas/análise , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Qualidade de Vida , Resultado do Tratamento , Tretinoína/administração & dosagem , Tretinoína/efeitos adversos , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/efeitos adversosRESUMO
AIMS/HYPOTHESIS: Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy. METHODS: Maternal diabetes-induced oxidative stress was blocked with alpha-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis. RESULTS: Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and alpha-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by alpha-tocopherol and GSH-ethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks. CONCLUSION/INTERPRETATION: Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress.
Assuntos
Desenvolvimento Embrionário e Fetal/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Defeitos do Tubo Neural/etiologia , Defeitos do Tubo Neural/genética , Oxidantes/farmacocinética , Gravidez em Diabéticas/complicações , Fatores de Transcrição , Animais , Antimicina A/efeitos adversos , Células Cultivadas , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Experimental/complicações , Embrião de Mamíferos/anormalidades , Células-Tronco de Carcinoma Embrionário , Feminino , Camundongos , Camundongos Endogâmicos ICR , Células-Tronco Neoplásicas , Defeitos do Tubo Neural/induzido quimicamente , Oxidantes/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados , Gravidez , RNA Mensageiro/genética , Espécies Reativas de Oxigênio , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/efeitos adversosAssuntos
Cosméticos/efeitos adversos , Cosméticos/química , Dermatite Alérgica de Contato/etiologia , alfa-Tocoferol/análogos & derivados , Adolescente , Óleo de Rícino/efeitos adversos , Óleo de Rícino/análise , Dimetilpolisiloxanos , Emolientes/efeitos adversos , Emolientes/análise , Humanos , Masculino , Palmitatos/efeitos adversos , Palmitatos/análise , Siloxanas/efeitos adversos , Siloxanas/análise , Simeticone/efeitos adversos , Simeticone/análogos & derivados , Simeticone/análise , Tensoativos/efeitos adversos , Tensoativos/análise , Tocoferóis , alfa-Tocoferol/efeitos adversos , alfa-Tocoferol/análiseRESUMO
Tissue ischaemia-reperfusion evokes toxic and harmful biochemical processes such as oxidative stress and inflammation. The aim of this study is to investigate the indices of tissue damage in rat liver and brain after ischaemia-reperfusion injury of these organs, and to study prospective cytoprotection of molecules such as the novel anti-inflammatory N-(2-thiolethyl)-2-(2-[N'-(2,6-dichlorophenyl)amino] phenyl)acetamide (compound 1) and alpha-tocopherol. Two experimental models were studied: firstly, 30 min liver ischaemia via hepatoduodenal ligament clamping followed by 60 min reperfusion; and secondly, 45 min cerebral ischaemia via bilateral common carotid artery occlusion followed by 90 min reperfusion. Compound 1 and alpha-tocopherol were administered intraperitoneally before induction of ischaemia. We hereby report that compound 1, a molecule that combines potent in-vitro antioxidant and in-vivo anti-inflammatory activity with low gastrointestinal toxicity, offered protection in-vivo against liver or brain ischaemia-reperfusion-induced damage. Both compound 1 and alpha-tocopherol prevented changes in lipid peroxidation in the rat liver and brain tissue and in tumour necrosis factor (TNF-alpha) levels in brain. Also compound 1 attenuated glutathione depletion, evoked by ischaemia-reperfusion, in the rat brain but not in the liver. These results could be explained on the basis of the antioxidant/anti-inflammatory properties of compound 1 and suggest its beneficial effect and potential therapeutic use in post-ischaemic injury.