Comparative effects of thymol and vitamin E on nonalcoholic fatty liver disease in male Wistar rats / Efeitos comparativos de timol e de vitamina E em doença hepática gordurosa não alcoólica em ratos Wistar machos

Following the obesity epidemics, nonalcoholic fatty liver disease (NAFLD) has grown in prevalence and become a main cause of morbidity and death, intimately linked to cardiovascular disease, cancer, and cirrhosis. The key factor in the evolution of NAFLD is thought to be oxidative stress. Because most patients cannot change their lifestyle or dietary habits, a pharmaceutical strategy is now required to treat NAFLD. Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis, is treated with vitamin E. (NASH). Vitamin E is also a powerful antioxidant that has been demonstrated to lower oxidative stress in people with NAFLD. Thymol is a monoterpene phenol with a variety of pharmacological effects, however its anti-fatty liver properties have yet to be investigated. Despite the fact that oxidative stress is thought to have a role in the etiology of nonalcoholic steatohepatitis, antioxidant therapies have not been well studied in the treatment of nonalcoholic steatohepatitis. The goal was to learn more about vitamin E and thymol's biological activities, with a particular emphasis on their therapeutic effectiveness in NAFLD. Four groups of thirty-two adult male rats were formed (healthy control, thymol, Vit E, and fatty liver). For 28 days, rats were given either oral vitamin E (200 mg/kg) or thymol (50 mg/kg) randomly. The levels of ALT, AST, TNF- α, Ferritin, CK-MB enzymes, and MAPK gene expression were then determined in the serum. Based on a random effect model analysis, at the end of 28 days of therapy, ALT (41.43 U/L), AST (47.91 U/L), Ferritin (1.13 pg/dl), CK-MB (251.22 IU/L), TNF-α (95.39 pg/mL) (p≤0.001), and MAPK gene expression levels (p≤0.05) significantly reduced in both experimental groups compared with the fatty liver group. Vitamin E and thymol therapy is a safe, affordable, and effective therapeutic option in the fatty liver group. Patients with fatty liver disease should be encouraged to take vitamin E and Thymol supplements, which are both safe and affordable, because more effective new therapeutic options are lacking.

Após a epidemia de obesidade, a doença hepática gordurosa não alcoólica (DHGNA) cresceu em prevalência e se tornou a principal causa de morbidade e morte, intimamente ligada a doenças cardiovasculares, como câncer e cirrose. Acredita-se que o fator chave na evolução da DHGNA seja o estresse oxidativo. Como a maioria dos pacientes não pode mudar seu estilo de vida ou hábitos alimentares, uma estratégia farmacêutica para tratar a DHGNA se fez necessária. A doença hepática gordurosa não alcoólica (DHGNA), incluindo esteatohepatite não alcoólica, é tratada com vitamina E. (NASH). A vitamina E também é considerada um poderoso antioxidante que demonstrou reduzir o estresse oxidativo em pessoas com DHGNA. O timol é um fenol monoterpeno com uma variedade de efeitos farmacológicos, porém suas propriedades antigorduras no fígado ainda não foram investigadas. Apesar de se pensar que o estresse oxidativo tem um papel na etiologia da esteatohepatite não alcoólica, as terapias antioxidantes não foram ainda bem estudadas no tratamento da esteatohepatite não alcoólica. O objetivo deste trabalho foi investigar sobre as possíveis atividades biológicas da vitamina E e do timol, com ênfase particular na sua eficácia terapêutica na DHGNA. Foram formados quatro grupos de trinta e dois ratos machos adultos (controle saudável, timol, vitamina E e fígado gorduroso). Durante 28 dias, os ratos receberam vitamina E oral (200 mg/kg) ou timol (50 mg/kg) aleatoriamente. Os níveis de ALT, AST, TNF-α, Ferritina, enzimas CK-MB e expressão do gene MAPK foram então determinados no soro. Com base em uma análise de modelo de efeito aleatório, ao final de 28 dias de terapia, ALT (41,43 U/L), AST (47,91 U/L), Ferritina (1,13 pg/dl), CK-MB (251,22 IU/L), TNF-α (95,39 pg/mL) (p ≤ 0,001) e os níveis de expressão do gene MAPK (p ≤ 0,05) reduziram significativamente em ambos os grupos experimentais em comparação com o grupo fígado gorduroso. A terapia com vitamina E e timol é uma opção terapêutica segura, acessível e eficaz no grupo de fígado gorduroso. Pacientes com doença hepática gordurosa devem ser encorajados a tomar suplementos de vitamina E e Timol, que são seguros e acessíveis, dado que faltam novas opções terapêuticas mais eficazes.

Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects.

Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1ß, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFß), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NO3- and NO2-), glutathione reductase, and superoxide dismutase decreased after treatment with Vit C, Vit E, NAC, and MT. The levels of thiols recovered with the use of Vit E, and all patients treated with antioxidants maintained their selenium levels, in contrast with controls (p = 0.04). The findings regarding oxidative stress markers and cytokines after treatment with antioxidants allow us to consider to future the combined use of antioxidants in a randomized clinical trial with a larger sample to demonstrate the reproducibility of these beneficial effects.

Vitamin E and Its Molecular Effects in Experimental Models of Neurodegenerative Diseases.

With the advancement of in vivo studies and clinical trials, the pathogenesis of neurodegenerative diseases has been better understood. However, gaps still need to be better elucidated, which justifies the publication of reviews that explore the mechanisms related to the development of these diseases. Studies show that vitamin E supplementation can protect neurons from the damage caused by oxidative stress, with a positive impact on the prevention and progression of neurodegenerative diseases. Thus, this review aims to summarize the scientific evidence of the effects of vitamin E supplementation on neuroprotection and on neurodegeneration markers in experimental models. A search for studies published between 2000 and 2023 was carried out in the PubMed, Web of Science, Virtual Health Library (BVS), and Embase databases, in which the effects of vitamin E in experimental models of neurodegeneration were investigated. A total of 5669 potentially eligible studies were identified. After excluding the duplicates, 5373 remained, of which 5253 were excluded after checking the titles, 90 articles after reading the abstracts, and 11 after fully reviewing the manuscripts, leaving 19 publications to be included in this review. Experiments with in vivo models of neurodegenerative diseases demonstrated that vitamin E supplementation significantly improved memory, cognition, learning, motor function, and brain markers associated with neuroregeneration and neuroprotection. Vitamin E supplementation reduced beta-amyloid (Aß) deposition and toxicity in experimental models of Alzheimer's disease. In addition, it decreased tau-protein hyperphosphorylation and increased superoxide dismutase and brain-derived neurotrophic factor (BDNF) levels in rodents, which seems to indicate the potential use of vitamin E in preventing and delaying the progress of degenerative lesions in the central nervous system.

Randomized Clinical Trial of Antioxidant Therapy Patients with Septic Shock and Organ Dysfunction in the ICU: SOFA Score Reduction by Improvement of the Enzymatic and Non-Enzymatic Antioxidant System.

BACKGROUND AND AIM: Here, we assess the effect of adjuvant antioxidant therapies in septic shock patients with organ dysfunction and their effect on the enzymatic and non-enzymatic antioxidant systems. METHODS: Randomized clinical trial run between 2018 and 2022. One hundred and thirty-one patients with septic shock were included in five groups with 25, 27, 24, 26 and 29 patients each. Group 1 received vitamin C (Vit C), Group 2 vitamin E (Vit E), Group 3 n-acetylcysteine (NAC), Group 4 melatonin (MT) and group 5 no treatment. All antioxidants were administered orally or through a nasogastric tube for 5 days as an adjuvant to standard therapy. RESULTS: All patients had multiple organ failure (MOF) and low Vit C levels. Vit C therapy decreased CRP, PCT and NO3-/NO2- but increased Vit C levels. The SOFA score decreased with MT in 75%, Vit C 63% and NAC 50% vs. controls 33% (p = 0.0001, p = 0.03 and p = 0.001 respectively). MT diminished lipid peroxidation (LPO) (p = 0.01) and improved total antioxidant capacity (TAC) (p = 0.04). Vit E increased thiol levels (p = 0.02) and tended to decrease LPO (p = 0.06). Selenium levels were decreased in the control group (p = 0.04). CONCLUSIONS: Antioxidants used as an adjuvant therapy in the standard treatment of septic shock decrease MOF and oxidative stress markers. They increase the TAC and thiols, and maintain selenium levels.

Comparative effects of thymol and vitamin E on nonalcoholic fatty liver disease in male Wistar rats.

Following the obesity epidemics, nonalcoholic fatty liver disease (NAFLD) has grown in prevalence and become a main cause of morbidity and death, intimately linked to cardiovascular disease, cancer, and cirrhosis. The key factor in the evolution of NAFLD is thought to be oxidative stress. Because most patients cannot change their lifestyle or dietary habits, a pharmaceutical strategy is now required to treat NAFLD. Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis, is treated with vitamin E. (NASH). Vitamin E is also a powerful antioxidant that has been demonstrated to lower oxidative stress in people with NAFLD. Thymol is a monoterpene phenol with a variety of pharmacological effects, however its anti-fatty liver properties have yet to be investigated. Despite the fact that oxidative stress is thought to have a role in the etiology of nonalcoholic steatohepatitis, antioxidant therapies have not been well studied in the treatment of nonalcoholic steatohepatitis. The goal was to learn more about vitamin E and thymol's biological activities, with a particular emphasis on their therapeutic effectiveness in NAFLD. Four groups of thirty-two adult male rats were formed (healthy control, thymol, Vit E, and fatty liver). For 28 days, rats were given either oral vitamin E (200 mg/kg) or thymol (50 mg/kg) randomly. The levels of ALT, AST, TNF- α, Ferritin, CK-MB enzymes, and MAPK gene expression were then determined in the serum. Based on a random effect model analysis, at the end of 28 days of therapy, ALT (41.43 U/L), AST (47.91 U/L), Ferritin (1.13 pg/dl), CK-MB (251.22 IU/L), TNF-α (95.39 pg/mL) (p≤0.001), and MAPK gene expression levels (p≤0.05) significantly reduced in both experimental groups compared with the fatty liver group. Vitamin E and thymol therapy is a safe, affordable, and effective therapeutic option in the fatty liver group. Patients with fatty liver disease should be encouraged to take vitamin E and Thymol supplements, which are both safe and affordable, because more effective new therapeutic options are lacking.

Vitamin E protective effects on genomic and cellular damage caused by paediatric preventive supplementation for anaemia: an experimental model.

Iron deficiency is the leading cause of anaemia. In Argentina, the prevalence of anaemia and iron deficiency is very high; for that reason, the Argentine Society of Pediatrics recommends daily ferrous sulphate supplementation as a preventive treatment strategy. Alternatively, weekly ferrous sulphate supplementation has also been shown to be effective for anaemia prevention. Excess iron could be related to oxidative stress, which may in turn cause cytomolecular damage. Both can be prevented with vitamin E supplementation. We evaluated the effect of both daily and weekly ferrous sulphate supplementation combined with two doses of vitamin E on cell viability, oxidative stress and cytomolecular damage in peripheral blood cultured in vitro. The experimental design included the following groups: untreated negative control, two vitamin E controls (8·3 and 16·6 µg/ml), weekly ferrous sulphate supplementation (0·55 mg/ml) with each vitamin E dose, daily ferrous sulphate supplementation (0·14 mg/ml) with each vitamin E dose and a positive control. Daily ferrous sulphate supplementation decreased cell viability and increased the levels of reactive oxygen species, lipid peroxidation and cytomolecular damage (P < 0·5) compared with the weekly supplementation, probably due to the excess iron observed in the former. Vitamin E seemed to reduce ferrous sulphate-induced oxidative stress and genomic damage.

Estado nutricional de vitamina E e fatores de risco cardiovascular em adultos e idosos: estudo Brazuca Natal / Nutritional status of vitamin E and cardiovascular risk factors in adults and elderly people: Brazuca Natal study

Introdução: As doenças cardiovasculares (DCV) são a principal causa de morbimortalidade no mundo. Diante disso, são estudadas estratégias de prevenção e tratamento de eventos cardiovasculares. Dentre elas, a vitamina E destaca-se por suas propriedades antioxidantes e anti-inflamatórias, apoiado por descobertas de que maior ingestão dietética de vitamina E e maiores concentrações de α-tocoferol (α-TOH) sérico estão associados com menor risco de eventos cardiovasculares. Com isso, dados sobre o estado nutricional de vitamina E da população e a sua relação com os fatores de risco cardiovascular são estratégias importantes para subsidiar programas e políticas públicas voltadas a prevenção e tratamento das DCV. Objetivo: Avaliar o estado nutricional de vitamina E e a relação com fatores de risco cardiovascular em adultos e idosos do Estudo Brazuca Natal. Métodos: Trata-se de um estudo de diferentes métodos. 1) A revisão narrativa que investigou na literatura estudos populacionais sobre a relação da vitamina E e as DCV, buscando compreender se a deficiência de vitamina E (DVE) também deve ser considerada um problema de saúde pública. 2) Estudo transversal que se decompõe, a partir das variáveis dependentes, em dois artigos científicos. O primeiro artigo desse estudo buscou avaliar a prevalência de DVE e os fatores de risco cardiovascular que estão associados ao status do α-TOH sérico em adultos e idosos do estudo Brazuca Natal. Análise de regressão linear múltipla foi realizada entre o αTOH sérico (variável dependente) e fatores de risco cardiovascular. O segundo artigo do estudo transversal objetivou avaliar o consumo de vitamina E, e identificar as principais fontes alimentares consumidas do micronutriente pela população avaliada. Para tanto, foram analisadas as condições socioeconômicas e demográficas (sexo, idade, cor/raça, escolaridade, renda per capita e distrito sanitário de moradia) e o consumo alimentar de vitamina E (variável dependente). Resultados: Na revisão narrativa foi observado que a DVE pode ser um problema de saúde pública, por ocorrer uma variação de 0,6% a 55,5% de DVE em todo o mundo, com percentuais mais elevados na Ásia e na Europa, onde se destacam as elevadas taxas de mortalidade por DCV. Estudos populacionais sugerem efeitos protetores da vitamina E nas DCV, porém, estudos de intervenção com suplementação de α-TOH não confirmaram a sua ação cardioprotetora. No artigo 2 do estudo transversal foi observado que 24,8% dos adultos e idosos de Natal apresentavam DVE e 89% apresentaram baixas concentrações de αTOH circulante (abaixo de 30 µmol/L). Verificamos que as pessoas do sexo feminino tinham maiores valores médios de α-TOH sérico. Além disso, o índice de adiposidade visceral elevado e maiores valores do escore de risco global foram associados a maiores concentrações de α-TOH sérico. O artigo 3 demonstrou que 95,7% dos indivíduos apresentavam baixa ingestão de vitamina E, considerando a Estimated Average Requirement (EAR) de 12 mg/dia, com menores valores de ingestão em indivíduos acima de 40 anos, mulheres, naqueles com renda per capita menor que um salário-mínimo e com menor escolaridade. O óleo de soja, polpa de açaí e carne vermelha forneceram o maior teor de vitamina E ingerida. Conclusão: A partir da revisão narrativa, foi demonstrado que a DVE pode ser um problema de saúde pública. O estudo transversal observou uma elevada prevalência de DVE na população estudada, em que o sexo, o índice de adiposidade visceral e o escore de risco global estão associados ao α-TOH sérico. Além disso, foi observado um baixo consumo de vitamina E, principalmente, em indivíduos mais velhos, mulheres e com baixa condição socioeconômica. A maior parte da vitamina E consumida era proveniente do óleo de soja, polpa de açaí e carne vermelha, destacando-se também a vitamina E proveniente de alimentos ultraprocessados, principalmente, na população de menor renda (AU).

Introduction: Cardiovascular diseases (CVD) are the principal cause of morbidity and mortality in the world. Therefore, experts have studied strategies for preventing and treating cardiovascular events. One of this knowledge is vitamin E stands out for its antioxidant and anti-inflammatory properties, supported by findings that higher dietary intake of vitamin E and higher concentrations of serum α-tocopherol (α-TOH) are associated with a lower risk of cardiovascular events. Therefore, data on the nutritional status of vitamin E in the population and its relationship with cardiovascular risk factors are relevant strategies to support programs and public policies aimed at preventing and treating CVD. Objective: To evaluate the nutritional status of vitamin E and its association with cardiovascular risk factors in adults and older adults in the Brazuca Natal Study. Methods: This is a study of different methodological strategies. 1) The narrative review aimed to verify if surveys could demonstrate an association between serum vitamin E and the occurrence of CVD. Moreover, we would like to understand whether vitamin E deficiency (VED) should also be considered a public health problem. 2) Cross-sectional study, divided into two scientific articles. The first article of this study sought to evaluate the prevalence of VED and cardiovascular risk factors that are associated with serum α-TOH status in adults and elderly people from the Brazuca Natal study. We performed a multiple linear regression analysis between serum α-TOH (dependent variable) and cardiovascular risk factors. The second article aimed to evaluate vitamin E intake, and we would like to identify the principal food sources of this micronutrient intake. To this end, we analyzed socioeconomic and demographic conditions (sex, age, color/race, education, per capita income, and health district of residence), and vitamin E intake (dependent variable). Results: In the narrative review, we observed that VED could be a public health problem. The prevalence of VED varies from 0.6% to 55.5% in the world, with higher percentages in Asia and Europe, where the high mortality rates from CVD stand out. Population studies suggest the protective effects of vitamin E on CVD. However, intervention studies with α-TOH supplementation have not confirmed its cardioprotective action. In article 2 of the crosssectional study, we observed that 24.8% of adults and older adults in Natal had VED, and 89% had low concentrations of circulating α-TOH (below 30 µmol/L). Furthermore, high visceral adiposity index and higher global risk score values were associated with higher serum α-TOH concentrations. Article 3 demonstrated that 95.7% of individuals had a low intake of vitamin E, considering the Estimated Average Requirement (EAR) of 12 mg/day, with lower intake values in individuals over 40 years of age, women, those who have a per capita income of less than the minimum wage and with less education. Soybean oil, açaí pulp, and red meat provided the highest content of ingested vitamin E. Conclusion: From the narrative review, it was demonstrated that VED can be a public health problem. The cross-sectional study observed a high prevalence of VED in the studied population, in which sex, visceral adiposity index and global risk score are associated with serum α-TOH. Furthermore, a low consumption of vitamin E was observed, mainly in older individuals, women and those with low socioeconomic status. Most of the vitamin E consumed came from soybean oil, açaí pulp and red meat, with vitamin E also coming from ultra-processed foods, especially in the lowerincome population (AU).

Ornithine Aspartate and Vitamin-E Combination Has Beneficial Effects on Cardiovascular Risk Factors in an Animal Model of Nonalcoholic Fatty Liver Disease in Rats.

Cardiovascular (CV) disease is the main cause of death in nonalcoholic fatty liver disease (NAFLD), a clinical condition without any approved pharmacological therapy. Thus, we investigated the effects of ornithine aspartate (LOLA) and/or Vitamin E (VitE) on CV parameters in a steatohepatitis experimental model. Adult Sprague Dawley rats were randomly assigned (10 animals each) and treated from 16 to 28 weeks with gavage as follows: controls (standard diet plus distilled water (DW)), NAFLD (high-fat choline-deficient diet (HFCD) plus DW), NAFLD+LOLA (HFCD plus LOLA (200 mg/kg/day)), NAFLD+VitE (HFCD plus VitE (150 mg twice a week)) or NAFLD+LOLA+VitE in the same doses. Atherogenic ratios were higher in NAFLD when compared with NAFLD+LOLA+VitE and controls (p < 0.05). Serum concentration of IL-1ß, IL-6, TNF-α, MCP-1, e-selectin, ICAM-1, and PAI-1 were not different in intervention groups and controls (p > 0.05). NAFLD+LOLA decreased miR-122, miR-33a, and miR-186 (p < 0.05, for all) in relation to NAFLD. NAFLD+LOLA+VitE decreased miR-122, miR-33a and miR-186, and increased miR-126 (p < 0.05, for all) in comparison to NAFLD and NAFLD+VitE. NAFLD+LOLA and NAFLD+LOLA+VitE prevented liver collagen deposition (p = 0.006) in comparison to NAFLD. Normal cardiac fibers (size and shape) were lower in NAFLD in relation to the others; and the inverse was reported for the percentage of regular hypertrophic cardiomyocytes. NAFLD+LOLA+VitE promoted a significant improvement in atherogenic dyslipidemia, liver fibrosis, and paracrine signaling of lipid metabolism and endothelial dysfunction. This association should be further explored in the treatment of NAFLD-associated CV risk factors.

Vitamin E supplementation improves testosterone, glucose- and lipid-related metabolism in women with polycystic ovary syndrome: a meta-analysis of randomized clinical trials.

AIM: This systematic review and meta-analysis assessed the effect of vitamin E supplementation on testosterone, glucose, lipid profile, pregnancy rate, hirsutism, and body mass index (BMI) in women with polycystic ovary syndrome (PCOS). METHODS: A multi-database search was performed from inception to January 2022 for randomized controlled trials (RCTs) reporting the effects of vitamin E supplementation with or without another nutritional supplement on women with PCOS. A random-effects model was used to obtain mean differences (MDs) and its 95% confidence intervals (95%CI). Evidence certainty was assessed with GRADE methodology. RESULTS: We meta-analyzed eight RCTs reporting vitamin E supplementation alone or combined with other individual substances like omega-3, vitamin D3, or magnesium oxide in adult women ≤40 years old with PCOS. Vitamin E supplementation reduced fasting glucose (MD: -1.92 mg/dL, 95%CI: -3.80 to -0.05), fasting insulin (MD: -2.24 µIU/mL, 95%CI: -3.34 to -1.14), HOMA-IR (MD: -0.42, 95%CI: -0.65 to -0.19), total cholesterol (MD: -18.12 mg/dL, 95%CI: -34.37 to -1.86), LDL-cholesterol (MD: -15.92 mg/dL, 95%CI: -29.93 to -1.90), triglycerides (MD: -20.95 mg/dL, 95%CI: -37.31 to -4.58), total testosterone (MD: -0.42 ng/mL, 95%CI: -0.55 to -0.29), and increased sex hormone-binding globulin (MD: 7.44 nmol/L, 95%CI: 2.68 to 12.20). However, it had no impact on female sex hormones, HDL-cholesterol, BMI, and hirsutism. Two RCTs assessed pregnancy and implantation rates with inconsistent results. The certainty of the evidence was very low to moderate. CONCLUSION: Vitamin E supplementation improves glucose, lipid, and androgenic-related biomarkers in women with PCOS.

Delta-tocotrienol enhances the anti-tumor effects of interferon alpha through reactive oxygen species and Erk/MAPK signaling pathways in hepatocellular carcinoma cells.

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN-α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN-α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared with single therapies. Combining δ-tocotrienol and IFN-α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase (MMP) 7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and reactive oxygen species (ROS) generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anti-cancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN-α therapy showed promising results for HCC cell treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.

Vitamin E for the management of major depressive disorder: possible role of the anti-inflammatory and antioxidant systems.

OBJECTIVES: Vitamin E has various functions in humans, including antioxidant, anti-inflammatory, anti-cancer, and anti-atherogenic actions, as well as direct effects on enzymatic activities and modulation of gene transcription. In addition to these functions, vitamin E is also important for the central nervous system, and its role in the prevention and/or treatment of some neurological diseases has been suggested. In particular, the role of vitamin E in the modulation of major depressive disorder (MDD) is an issue that has emerged in recent studies. Many factors have been implicated in the pathophysiology of this disorder, including inflammation, oxidative, and nitrosative stress. METHODS: This narrative review discusses the involvement of inflammation, oxidative, and nitrosative stress in the pathophysiology of MDD and presents clinical and preclinical studies that correlate vitamin E with this psychiatric disorder. RESULTS: We gathered evidence from clinical studies that demonstrated the relationship between low vitamin E status and MDD symptoms. Vitamin E has been reported to exert a beneficial influence on the oxidative and inflammatory status of individuals, factors that may account for the attenuation of depressive symptoms. Preclinical studies have reinforced the antidepressant-like response of vitamin E, and the mechanisms underlying its effect seem to be related to the modulation of oxidative stress and neuroinflammation. CONCLUSION: We suggest that vitamin E has potential to be used as an adjuvant for the management of MDD, but more studies are clearly needed to ascertain the efficacy of vitamin E for alleviating depressive symptoms.

Application of natural antioxidants in animal reproduction / Aplicação de antioxidantes naturais na reprodução animal

Antioxidants are natural or synthetic substances that delay oxidation through one or more mechanisms, such as scavenging free radicals, inhibiting lipid peroxidation, and complexing with metals, inhibiting tissue destruction via oxidation. Antioxidants are commonly used in animal feed and the food industry to prevent the oxidation of animal-origin products. Moreover, natural oxidants are used increasingly in animal reproduction, especially for semen preservation. In this context, this study aimed to review the applications of natural antioxidants in animal reproduction. We observed that the bulk of the natural antioxidants, approximately 80.4%, were commercially acquired and used mainly for semen cooling/freezing (72%) with promising results (90%) in Sus scrofa (boar), Capra aegagrus hircus (goat), Gallus gallus domesticus (rooster), and Ovis aries (ram). However, further studies are needed to help determine the appropriate dosage of natural antioxidants for applications.

Antioxidantes são substâncias naturais ou sintéticas que facilitam o retardo da oxidação por um ou mais mecanismos, como sequestrar radicais livres, inibir a peroxidação lipídica e complexar com metais, inibindo a destruição tecidual via oxidação. Antioxidantes são comumente usados na alimentação animal e na indústria alimentícia para prevenir a oxidação de produtos de origem animal. Além disso, os oxidantes naturais estão sendo cada vez mais aplicados na reprodução animal, principalmente na preservação do sêmen. Nesse contexto, este trabalho teve como objetivo revisar a aplicação de antioxidantes naturais na reprodução animal. Observamos que os antioxidantes naturais foram geralmente adquiridos comercialmente (80,4%) e utilizados principalmente no resfriamento/congelamento de sêmen (72%) com resultados promissores (90%) em Sus scrofa (javali), Capra aegagrus hircus (cabra), Gallus gallus domesticus (galo) e Ovis aries (carneiro). No entanto, mais estudos devem ser realizados para ajudar a regular a dosagem de antioxidantes naturais para sua aplicação.

Relationship of Enhanced Liver Fibrosis Score with Pediatric Nonalcoholic Fatty Liver Disease Histology and Response to Vitamin E or Metformin.

OBJECTIVES: To study the diagnostic performance of the enhanced liver fibrosis score (ELF) for detecting different stages of fibrosis and its usefulness in detecting histologic response to vitamin E or metformin in children with nonalcoholic fatty liver disease who participated in the Vitamin E or Metformin for the Treatment Of NAFLD In Children (TONIC) trial. STUDY DESIGN: ELF was measured at baseline and weeks 24, 48, and 96 on sera from 166 TONIC participants. Associations between ELF with baseline and end of trial (EOT) fibrosis stages and other histologic features were assessed using χ2 tests and logistic regression models. RESULTS: ELF was significantly associated with severity of fibrosis at baseline and EOT. ELF areas under the curve for discriminating patients with clinically significant and advanced fibrosis were 0.70 (95% CI, 0.60-0.80) and 0.79 (95% CI, 0.69-0.89), respectively. A 1-unit decrease in ELF at EOT was associated with overall histologic improvement (OR, 1.86; 95% CI, 1.11-3.14; P = .02), resolution of steatohepatitis (OR, 1.88; 95% CI, 1.09-3.25; P = .02), improvement in steatosis grade (OR, 1.76; 95% CI, 1.06-2.82; P = .03), and hepatocellular ballooning (OR, 1.79; 95% CI, 1.06-3.00; P = .03), but not with improvement in fibrosis stage (OR, 1.26; 95% CI, 0.78-2.03; P = .34). CONCLUSIONS: ELF was associated with fibrosis stage in children who participated in TONIC. Although not associated with improvement in fibrosis, a decrease in ELF at EOT was associated with Nonalcoholic Steatohepatitis resolution and improvement in nonalcoholic fatty liver disease histology. ELF may be a useful noninvasive test to monitor treatment response in children with nonalcoholic fatty liver disease.

Topical cream containing nanoparticles with vitamin E to prevent radiodermatitis in women with breast cancer: a clinical trial protocol.

OBJECTIVE: Little is known about the efficacy of products aiming to prevent radiodermatitis, which affects between 90-95% of women with breast cancer. The use of antioxidants is promising, however, there is a lack of evidenceon their effectiveness. Here, the authors present a clinical trial protocol to evaluate the effects of applying a cream containing nanoparticles with vitamin E to prevent radiodermatitis in patients with breast cancer. METHOD: The protocol recommends that 108 women with breast cancer, receiving radiotherapy, are included in this triple-blinded, randomized, controlled study at an oncology hospital. Patients will be divided in three groups of 36 individuals each: group A will receive a cream with lipid nanoparticles and vitamin E, group B will receive a cream without nanoparticles nor vitamin E, and group C will receive a cream with nanoparticles without vitamin E. The primary endpoints will evaluate the incidence, degree, and time of onset of radiodermatitis. The secondary endpoints will focus on the quality of life, symptoms, and local temperature. Patients will be assessed three times a week, from the start of their radiotherapy treatment to two weeks after the last session. This protocol was approved by the research ethics committee of the institutions involved and registered on an international trials database.

Beneficial effects of natural compounds on experimental liver ischemia-reperfusion injury.

Liver ischemia-reperfusion injury (IRI) is a phenomenon inherent to hepatic surgery that severely compromises the organ functionality, whose underlying mechanisms involve cellular and molecular interrelated processes leading to the development of an excessive inflammatory response. Liver resident cells and those recruited in response to injury generate pro-inflammatory signals such as reactive oxygen species, cytokines, chemokines, proteases and lipid mediators that contribute to hepatocellular necrosis and apoptosis. Besides, dying hepatocytes release damage-associated molecular patterns that actívate inflammasomes to further stimulate inflammatory responses leading to massive cell death. Since liver IRI is a complication of hepatic surgery in man, extensive preclinical studies have assessed potential protective strategies, including the supplementation with natural compounds, with the objective to downregulate nuclear factor-κB functioning, the main effector of inflammatory responses. This can be accomplished by either the activation of peroxisome proliferator-activated receptor-α, G protein-coupled receptor 120 or antioxidant signaling pathways, the synthesis of specific pro-resolving mediators, downregulation of Toll-like receptor 4 activity or additional contributory mechanisms that are beginning to be understood. The latter aspect is a crucial issue to be accomplished in preclinical studies, in order to establish adequate conditions for the supplementation with natural products before major liver surgeries in man involving warm IR, such as hepatic trauma or resection of large intrahepatic tumors.

Usefulness of Antioxidants as Adjuvant Therapy for Septic Shock: A Randomized Clinical Trial.

Background and objectives: Oxidative stress (OS) participates in the pathophysiology of septic shock, which leads to multiple organ failure (MOF), ischemia-reperfusion injury, and acute respiratory distress syndrome. Therefore, antioxidants have been proposed as therapy. Here, we evaluated the effect of antioxidant treatments in patients with septic shock with MOF and determined levels OS before and after treatment. This study was a randomized, controlled, triple-masked, and with parallel assignment clinical trial with a control group without treatment. Materials and Methods: It included 97 patients of either sex with septic shock. 5 treatments were used each in an independent group of 18 patients. Group 1 received vitamin C (Vit C), group 2 vitamin E (Vit E), group 3 n-acetylcysteine (NAC), group 4 melatonin (MT), and group 5 served as control. All antioxidants were administered orally or through a nasogastric tube for five days as an adjuvant to the standard therapy. Results: The results showed that all patients presented MOF due to sepsis upon admission and that the treatment decreased it (p = 0.007). The antioxidant treatment with NAC increased the total antioxidant capacity (p < 0.05). The patients that received Vit C had decreased levels of the nitrate and nitrite ratio (p < 0.01) and C-reactive protein levels (p = 0.04). Procalcitonin levels were reduced by Vit E (p = 0.04), NAC (p = 0.001), and MT (p = 0.04). Lipid-peroxidation was reduced in patients that received MT (p = 0.04). Conclusions: In conclusion, antioxidant therapy associated with standard therapy reduces MOF, OS, and inflammation in patients with septic shock.

Topical cream containing nanoparticles with vitamin E to prevent radiodermatitis in women with breast cancer: a clinical trial protocol.

OBJECTIVE: Little is known about the efficacy of products aiming to prevent radiodermatitis, which affects between 90-95% of women with breast cancer. The use of antioxidants is promising, however, there is a lack of evidenceon their effectiveness. Here, the authors present a clinical trial protocol to evaluate the effects of applying a cream containing nanoparticles with vitamin E to prevent radiodermatitis in patients with breast cancer. METHOD: The protocol recommends that 108 women with breast cancer, receiving radiotherapy, are included in this triple-blinded, randomized, controlled study at an oncology hospital. Patients will be divided in three groups of 36 individuals each: group A will receive a cream with lipid nanoparticles and vitamin E, group B will receive a cream without nanoparticles nor vitamin E, and group C will receive a cream with nanoparticles without vitamin E. The primary endpoints will evaluate the incidence, degree, and time of onset of radiodermatitis. The secondary endpoints will focus on the quality of life, symptoms, and local temperature. Patients will be assessed three times a week, from the start of their radiotherapy treatment to two weeks after the last session. This protocol was approved by the research ethics committee of the institutions involved and registered on an international trials database.

Oxidative Stress Biomarkers, Nut-Related Antioxidants, and Cardiovascular Disease.

Atherosclerosis is related to fat accumulation in the arterial walls and vascular stiffening, and results in acute coronary syndrome which is commonly associated with acute myocardial infarction. Oxidative stress participates in the pathogenesis of atherosclerosis. Thus, the inclusion of food sources of dietary antioxidants, such as different kinds of nuts, may improve biomarkers related to oxidative stress, contributing to a possible reduction in atherosclerosis progression. This article has briefly highlighted the interaction between oxidative stress, atherosclerosis, and cardiovascular disease, in addition to the effect of the consumption of different nuts and related dietary antioxidants-like polyphenols and vitamin E-on biomarkers of oxidative stress in primary and secondary cardiovascular prevention. Studies in vitro suggest that nuts may exert antioxidant effects by DNA repair mechanisms, lipid peroxidation prevention, modulation of the signaling pathways, and inhibition of the MAPK pathways through the suppression of NF-κB and activation of the Nrf2 pathways. Studies conducted in animal models showed the ability of dietary nuts in improving biomarkers of oxidative stress, such as oxLDL and GPx. However, clinical trials in humans have not been conclusive, especially with regards to the secondary prevention of cardiovascular disease.

Drugs for preventing lung cancer in healthy people.

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.