Poly(2-ethyl-2-oxazoline)-IR780 conjugate nanoparticles for breast cancer phototherapy.

Aims: To address the limitations of IR780 by preparing hydrophilic polymer-IR780 conjugates and to employ these conjugates in the assembly of nanoparticles (NPs) intended for cancer photothermal therapy. Materials & methods: The cyclohexenyl ring of IR780 was conjugated for the first time with thiol-terminated poly(2-ethyl-2-oxazoline) (PEtOx). This novel poly(2-ethyl-2-oxazoline)-IR780 (PEtOx-IR) conjugate was combined with D-α-tocopheryl succinate (TOS), leading to the assembly of mixed NPs (PEtOx-IR/TOS NPs). Results: PEtOx-IR/TOS NPs displayed optimal colloidal stability as well as cytocompatibility in healthy cells at doses within the therapeutic range. In turn, the combination of PEtOx-IR/TOS NPs and near-infrared light reduced heterotypic breast cancer spheroid viability to just 15%. Conclusion: PEtOx-IR/TOS NPs are promising agents for breast cancer photothermal therapy.

Conventional anticancer approaches are often associated with severe side effects. Herein, the authors assembled a novel nanoparticle whose therapeutic effect is triggered by laser light. In in vitro assays, the produced nanomaterial was able to, after interacting with laser light, reduce the viability of classic and advanced cancer models. In these conditions, but in the absence of laser light, no cytotoxicity was observed. In this way, the on-demand effect (triggered by laser light) may contribute to reduced side effects. Moreover, the produced nanoparticle revealed good stability, which is important for its future translation.

The Vitamin E Isoform α-Tocopherol is Not Effective as a Complementary Treatment in Cancer Treatment: A Systematic Review.

The term vitamin E describes tocopherols and tocotrienols, whose chemical variations result in different biological activities including antioxidants. Neuroprotective effects of alpha-tocopherol against different toxins are assumed, therefore, it is discussed as a possible protective factor for adverse effects in cancer treatment. In July 2020, a systematic search was conducted searching five databases (Embase, Cochrane, PsychInfo, Cinahl, Medline) to find studies concerning the impact of α-tocopherol application and its potential harm on cancer patients. From 7546 search results, 22 publications referring to 20 studies with 1941 patients were included. Included patients were diagnosed with various cancer types and stages. Outcome variables were overall survival of cancer, symptom management of mucositis and chemotherapy-induced peripheral neuropathy (CIPN). The studies had different methodological qualities (mainly acceptable) and reported heterogeneous results: some reported significant improvement of mucositis and CIPN while others did not find changes concerning these endpoints. Due to heterogeneous results and methodical limitations of the included studies, a clear statement regarding the effectiveness of α-tocopherol as complementary treatment for cancer patients is not possible. Despite findings regarding reduction of oral side effects, usage of α-tocopherol during therapy must be discouraged because of potential negative influence on survival rates.

Açaí (Euterpe oleracea Mart.) reduces the inflammatory response triggered in vitro by the antipsychotic drug olanzapine in RAW 264.7 macrophage cells.

BACKGROUND: Açaí (Euterpe oleracea Mart), a Brazilian fruit, is considered a "superfruit" due its energetic properties and bioactive compounds. The açai's anti-inflammatory effects could attenuate the undesirable metabolic and pro-inflammatory side effects triggered by some antipsychotic drugs, such as Olanzapine (OLZ). It is possible to infer that açai supplement could potentially minimize the adverse effects of OLZ. Aim. This study tested the potential in vitro effects of açai hydroalcoholic extract on the inflammatory activation of the RAW 264.7 macrophage line triggered by OLZ antipsychotic drugs. METHODS: An in vitro protocol was performed using commercial RAW 264.7 macrophages, cultured under sterile conditions at 37°C with 5% CO2 saturation. Initially, a pharmacological curve was defined to determine the concentration of Olanzapine to be used. After this, the cells were supplemented with different concentrations of hydroalcoholic extract of açaí, which had been previously chemically characterized. After 24 and 72 hours of treatment, oxidative and inflammatory tests were performed. Therefore, the aim of this study was to verify whether the hydroalcoholic extract of açaí can modulate the oxy-inflammatory response of olanzapine in vitro. RESULTS: From a preliminary analysis, the açai extract at 5 mg/mL presented higher activity against inflammation triggered by OLZ (0.03 µg/mL). At this concentration, açai was able to reduce several oxidative and inflammatory markers triggered by OLZ (0.03 µg/mL) exposure, such as nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory cytokine levels (IL-1b, IL-6, TNF-a, IFN-g) caused by OLZ (0.03 µg/mL). Moreover, açaí reverted the levels of anti-inflammatory cytokine IL-10 that had been dropped by OLZ exposure to their pre-exposure treatments. CONCLUSIONS: The results suggest that açai extract could be useful in attenuating the peripheral inflammatory states triggered by OLZ. Additional pre-clinical and clinical investigations could be useful in testing therapeutic açai extract supplements.

Treatment of Non-Alcoholic Steatosis: Preclinical Study of a New Nutraceutical Multitarget Formulation.

Multifactorial pathogenesis of non-alcoholic steatohepatitis (NASH) disease, a wide-spread liver pathology associated with metabolic alterations triggered by hepatic steatosis, should be hit by multitarget therapeutics. We tested a multicomponent food supplement mixture (AP-NHm), whose components have anti-dislipidemic, antioxidant and anti-inflammatory effects, on in vitro and in vivo models of NASH. In vitro, hepatic cells cultures were treated for 24 h with 0.5 mM oleic acid (OA): in the co-treatment set cells were co-treated with AP-NH mixtures (AP-NHm, 1:3:10 ratio) and in the post-injury set AP-NHm was added for 48 h after OA damage. In vivo, C57BL/6 mice were fed with high-fat diet (HFD) for 12 weeks, inducing NASH at 7th week, and treated with AP-NHm at two dosages (1:3 ratio) in co-treatment or post-injury protocols, while a control group was fed with a standard diet. In in vitro co-treatment protocol, alterations of redox balance, proinflammatory cytokines release and glucose uptake were restored in a dose-dependent manner, at highest dosages also in post-injury regimen. In both regimens, pathologic dyslipidemias were also ameliorated by AP-NHm. In vivo, high-dose-AP-NHm-co-treated-HFD mice dose-dependently gained less body weight, were protected from dyslipidemia, and showed a lower liver weight. Dose-dependently, AP-NHm treatment lowered hepatic LDL, HDL, triglycerides levels and oxidative damage; co-treatment regimen was anti-inflammatory, reducing TNF-α and IL-8 levels. Hepatic lipidic infiltration significantly decreased in co-treated and post-injury-AP-NHm-HFD animals. The multitarget approach with AP-NHm was effective in preventing and reducing NASH-related pathologic features, warranting for the clinical development of this compound.

The effect of vitamin E supplementation on biomarkers of endothelial function and inflammation among hemodialysis patients: A double-blinded randomized clinical trial.

OBJECTIVES: The present study was aimed to investigate the effect of alpha-tocopherol supplementation on biomarkers of endothelial function (Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Protein 1) and inflammatory markers (Interleukin 6 and high-sensitivity C-reactive protein) among the hemodialysis patients. METHODS: To conduct this randomized, double-blinded, and placebo-controlled clinical trial, 49 hemodialysis patients, aged 20-60 years, were recruited and randomly divided into the intervention and control groups. The intervention group (n = 25) received 600 IU alpha-tocopherol soft gels (200 IU three times daily), while the controls (n = 24) consumed the identical placebo soft gels for 10 weeks. At the baseline and end of the study, 7 ml pre-dialysis blood samples were taken from all participants to measure their serum concentrations of ICAM-1, VCAM-1, IL-6, and hs-CRP. RESULTS: Alpha-tocopherol supplementation reduced the serum levels of ICAM-1 and VCAM-1 significantly (-140.67 ± 57.25 ng/ml vs. -15.97 ± 79.19 ng/ml, P = 0.001 for ICAM-1 and --6.79 ± 4.76 ng/ml vs. 1.02 ± 3.22 ng/ml, P = 0.019 for VCAM-1). However, no significant difference was observed between the two groups regarding the serum levels of hs-CRP (-0.15 ± 0.19 mg/l vs. 0.02 ± 0.12 mg/l; P = 0.32) and IL-6 (-0.03 ± 0.1 pg/ml vs. - 0.06 ± 0.11 pg/ml; P = 0.65). CONCLUSIONS: Our results showed that 10 weeks of supplementation with 600 IU alpha-tocopherol improved ICAM-1 and VCAM-1 levels, but did not have any effect on the serum concentration of IL-6 and hs-CRP in hemodialysis patients. Further studies are required to confirm these findings.

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.

Alpha- and gamma-tocopherol levels in human semen and their potential functional implications.

Vitamin E is a potent antioxidant that has been considered involved in fertility, but studies have mostly focused on α-tocopherol. Our study aimed at measuring, by an isotope dilution gas chromatography-mass spectrometry method, α- and γ-tocopherol concentration in human semen in a large and well-characterised population (134 men with different semen parameters and in varicocele patients), as well as their potential role in male fertility. We carried out freeze/thaw experiments in 15 samples with the two isomers in the cryoprotective medium. Moreover, our study included 10 subjects supplemented in vivo with α-tocopherol for 90 days. In seminal plasma, γ-tocopherol concentration was significantly lower in the varicocele group than in the normozoospermic group. We observed that γ-tocopherol, supplemented to cryopreservation medium, induced a higher post-thaw human sperm viability and motility than α-tocopherol. The results of in vivo α-tocopherol supplementation showed a decrease in γ-tocopherol concentration with increasing α-tocopherol level in blood. This is the first report related to γ-tocopherol distribution in human semen analysed by gas chromatography-mass spectrometry. γ-tocopherol would not seem to be related to semen parameters but to cellular oxidative condition. This tocopherol may contribute to human health in a yet unexplored way.

Alpha-tocopherol in intravenous lipid emulsions imparts hepatic protection in a murine model of hepatosteatosis induced by the enteral administration of a parenteral nutrition solution.

Intestinal failure-associated liver disease (IFALD) is a risk of parenteral nutrition (PN)-dependence. Intravenous soybean oil-based parenteral fat can exacerbate the risk of IFALD while intravenous fish oil can minimize its progression, yet the mechanisms by which soybean oil harms and fish oil protects the liver are uncertain. Properties that differentiate soybean and fish oils include α-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little α-tocopherol. Fish oil contains abundant α-tocopherol and little phytosterols. This study tested whether α-tocopherol confers hepatoprotective properties while phytosterols confer hepatotoxicity to intravenous fat emulsions. Utilizing emulsions formulated in the laboratory, a soybean oil emulsion (SO) failed to protect from hepatosteatosis in mice administered a PN solution enterally. An emulsion of soybean oil containing α-tocopherol (SO+AT) preserved normal hepatic architecture. A fish oil emulsion (FO) and an emulsion of fish oil containing phytosterols (FO+P) protected from steatosis in this model. Expression of hepatic acetyl CoA carboxylase (ACC) and peroxisome proliferator-activated receptor gamma (PPARγ), was increased in animals administered SO. ACC and PPARγ levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for α-tocopherol in liver injury induced by the enteral administration of a parenteral nutrition solution. Phytosterols do not appear to compromise the hepatoprotective effects of fish oil.

Anticancer effects of methotrexate in combination with α­tocopherol and α­tocopherol succinate on triple­negative breast cancer.

Triple­negative breast cancers (TNBCs) lack the estrogen receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Therefore, hormone or targeted therapies are not effective in the treatment of TNBC and thus the development of novel therapeutic strategies is crucial. Methotrexate (MTX), a folate antagonist, has been used in the treatment of various types of cancer; however, the anticancer effects of MTX treatment on breast cancer have thus far been ineffective. Vitamin E variants and derivatives have been applied for cancer therapy. Previous studies have indicated that vitamin E variants and derivatives exert distinct anticancer effects on different types of cancer. However, whether MTX plus vitamin E variants or its derivatives can inhibit TNBC remains unclear. The aim of the present study was to examine the anticancer effects and mechanisms of action of MTX in combination with vitamin E variants (α­tocopherol) and derivatives (α­tocopherol succinate) on TNBC. In the present study, MTT assay and western blot analysis were used to determine the cell survival rates and protein levels. The results demonstrated that combination treatment with MTX and α­tocopherol suppressed TNBC cell proliferation. In addition, various concentrations of MTX exerted distinct cytotoxic effects on α­tocopherol succinate­treated cells. Furthermore, high­dose MTX enhanced α­tocopherol succinate­induced anticancer activity; however, low­dose MTX inhibited α­tocopherol succinate­induced anticancer activity. The present study also demonstrated that caspase­3 activation and poly(adenosine diphosphate­ribose) polymerase cleavage were observed in the α­tocopherol succinate/MTX­treated cells. In conclusion, the findings of the present study demonstrated that high­dose MTX enhanced anticancer activity in α­TOS­treated TNBC, while low­dose MTX reduced anticancer activity in α­TOS­treated TNBC.

COMT and Alpha-Tocopherol Effects in Cancer Prevention: Gene-Supplement Interactions in Two Randomized Clinical Trials.

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.

α-Tocopherol Ameliorates Redox Equilibrium and Reduces Inflammatory Response Caused by Chronic Variable Stress.

Chronic exposure to stress factors contributes to the development of depression by generating excess of reactive oxygen species which leads to oxidative stress and inflammatory processes. The aim of the study was to assess the potential protective properties of α-tocopherol supplementation on the rats exposed to chronic variable stress (CVS). Male Wistar rats (50-55 days old, weighing 200-250 g) were divided into three groups (n=10): control, stressed, and stressed and receiving (+)-α-tocopherol solution in a dose of 100 mg/kg/day. Rats in the stressed groups were exposed to CVS for 40 days. Markers of redox disorders (glutathione reduced and oxidized levels, GSH/GSSG ratio, glutathione peroxidase, glutathione reductase activities, total antioxidant status, and lipid peroxidation) and inflammatory response (IL-1ß, IL6, and TNF-α) were determined in the blood. Additionally, molecular biomarkers of depression (expression of Fkbp5 and Tph2) were studied in hippocampus. The biochemical analysis was inconclusive about the presence of oxidative stress in the blood of rats exposed to CVS. However, changes in all parameters suggest presence of redox equilibrium disorders. Similarly, activation of inflammatory processes was observed as a result of CVS. Molecular effects of environmental stress in hippocampus were also observed. Generally, α-tocopherol ameliorated redox equilibrium disorders, tempered inflammatory response, and protected from changes in determined molecular markers of depression.

Role of Borage Seed Oil and Fish Oil with or without Turmeric and Alpha- Tocopherol in Prevention of Cardiovascular Disease and Fatty Liver in Rats.

The aim of the present research was to Study the prevention of dyslipidemia, oxidative stress, inflammation and fatty liver as risk factors for cardiovascular disease via intervention by borage oil (B) and fish oil (F) with or without turmeric (T) and alpha-tocopherols (TC). Fatty acids were assessed in both oils while curcuminoids were determined in turmeric. Rats were divided into; first group fed on balanced diet and designated as normal control (NC), second fed on dyslipidemic and steatohepatitis (DS) inducer diet which represented the DS control group and groups 3-6 fed on DS inducer diet with daily oral administration of B, B+T+TC, F and F+T+TC; respectively for 5 weeks. Liver fat and plasma lipid profile, oxidative stress and inflammatory biomarker and liver and heart histopathology were assessed. Results showed gamma linolenic to be 21.01% in B. F contained eicosapentaenoic as 22.768% and docosahexaenoic acid as 13.574%.Total curcuminoids were 4.63 mg/g turmeric. The DS control group showed significant dyslipidemia, elevated malondialdehyde (MDA), tumor necrosis factor-alpha and liver fat with significant reduction in total antioxidant capacity (TAC) compared to NC. The different treatments produced significant improvement in all the parameters and histopathology. F was superior to B in ameliorating liver histopathological changes while B was more efficient in elevating TAC. B was more promising in improving lipid profile and liver fat compared to B + T + TC, while the latter was superior in improving MDA and liver histopathology. Fish oil was more efficient than F+TC+T except for TAC and high density lipoprotein cholesterol which were more improved on addition of TC and T. Conclusion: Borage and fish oil with or without antioxidants protect from cardiovascular and fatty liver diseases with variable degrees.

Anti-oxidative and anti-inflammatory effects of Rosa Mosqueta oil supplementation in rat liver ischemia-reperfusion.

Ischemia-reperfusion (IR) is a deleterious condition associated with liver transplantation or resection that involves pro-oxidant and pro-inflammatory mechanisms. Considering that Rosa Mosqueta (RM) oil composition is rich in protective components such as α-linolenic acid (ALA) and tocopherols, we studied the effects of RM oil supplementation given prior to an IR protocol. Male Sprague-Dawley rats receiving RM oil (0.4 mL d-1) for 21 days were subjected to 1 h of ischemia followed by 20 h reperfusion. Parameters of liver injury (serum transaminases, histology), oxidative stress [liver contents of protein carbonyls, thiobarbituric acid reactants, Nrf2 activity and its target mRNA expression of heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1)] and inflammation [nuclear factor-κB (NF-κB) and its target mRNA expression of tumor necrosis factor-α (TNF-α) and interleukine-1ß (IL-1ß)] were studied. RM oil increased liver ALA and its derived EPA and DHA fatty acids' contents, with enhancement in those of α- and γ-tocopherols. IR induced inflammatory liver injury, with enhancement in serum transaminases, oxidative stress-related parameters with reduced Nrf2 signaling, and higher pro-inflammatory cytokines, indexes that were attenuated or abrogated by RM oil pretreatment. It is concluded that RM oil supplementation represents a novel non-invasive preconditioning strategy against liver injury induced by IR that has potential clinical applications in metabolic stress conditions.

Vitamin B12 and Homocysteine Levels Predict Different Outcomes in Early Parkinson's Disease.

BACKGROUND: In moderately advanced Parkinson's disease (PD), low serum vitamin B12 levels are common and are associated with neuropathy and cognitive impairment. However, little is known about B12 in early PD. OBJECTIVE: To determine the prevalence of low vitamin B12 status in early PD and whether it is associated with clinical progression. METHODS: We measured vitamin B12 and other B12 status determinants (methylmalonic acid, homocysteine, and holotranscobalamin) in 680 baseline and 456 follow-up serum samples collected from DATATOP participants with early, untreated PD. Borderline low B12 status was defined as serum B12 <184 pmol/L (250 pg/mL), and elevated homocysteine was defined as >15 µmol/L. Outcomes included the UPDRS, ambulatory capacity score (sum of UPDRS items 13-15, 29&30), and MMSE, calculated as annualized rates of change. RESULTS: At baseline, 13% had borderline low B12 levels, 7% had elevated homocysteine, whereas 2% had both. Elevated homocysteine at baseline was associated with worse scores on the baseline MMSE. Analysis of study outcomes showed that compared with the other tertiles, participants in the low B12 tertile (<234 pmol/L; 317 pg/mL) developed greater morbidity as assessed by greater annualized worsening of the ambulatory capacity score. Elevated homocysteine was associated with greater annualized decline in MMSE (-1.96 vs. 0.06; P = 0001). Blood count indices were not associated with B12 or homocysteine status. CONCLUSIONS: In this study of early PD, low B12 status was common. Low B12 at baseline predicted greater worsening of mobility whereas elevated homocysteine predicted greater cognitive decline. Given that low B12 and elevated homocysteine can improve with vitamin supplementation, future studies should test whether prevention or early correction of these nutritionally modifiable conditions slows development of disability. © 2018 International Parkinson and Movement Disorder Society.

Serum Metabolomic Profiling of All-Cause Mortality: A Prospective Analysis in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study Cohort.

Tobacco use, hypertension, hyperglycemia, overweight, and inactivity are leading causes of overall and cardiovascular disease (CVD) mortality worldwide, yet the relevant metabolic alterations responsible are largely unknown. We conducted a serum metabolomic analysis of 620 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985-2013). During 28 years of follow-up, there were 435 deaths (197 CVD and 107 cancer). The analysis included 406 known metabolites measured with ultra-high-performance liquid chromatography/mass spectrometry-gas chromatography/mass spectrometry. We used Cox regression to estimate mortality hazard ratios for a 1-standard-deviation difference in metabolite signals. The strongest associations with overall mortality were N-acetylvaline (hazard ratio (HR) = 1.28; P < 4.1 × 10-5, below Bonferroni statistical threshold) and dimethylglycine, 7-methylguanine, C-glycosyltryptophan, taurocholate, and N-acetyltryptophan (1.23 ≤ HR ≤ 1.32; 5 × 10-5 ≤ P ≤ 1 × 10-4). C-Glycosyltryptophan, 7-methylguanine, and 4-androsten-3ß,17ß-diol disulfate were statistically significantly associated with CVD mortality (1.49 ≤ HR ≤ 1.62, P < 4.1 × 10-5). No metabolite was associated with cancer mortality, at a false discovery rate of <0.1. Individuals with a 1-standard-deviation higher metabolite risk score had increased all-cause and CVD mortality in the test set (HR = 1.4, P = 0.05; HR = 1.8, P = 0.003, respectively). The several serum metabolites and their composite risk score independently associated with all-cause and CVD mortality may provide potential leads regarding the molecular basis of mortality.

Rutin hydrate ameliorates cadmium chloride-induced spatial memory loss and neural apoptosis in rats by enhancing levels of acetylcholine, inhibiting JNK and ERK1/2 activation and activating mTOR signalling.

This study aimed at studying the potential neuroprotective effect of Rutin hydrate (RH) alone or in conjugation with α-tocopherol against cadmium chloride (CdCl2)-induced neurotoxicity and cognitive impairment in rats and to investigate the mechanisms of action. Rats intoxicated with CdCl2 were treated with the vehicle, RH, α-tocopherol or combined treatment were examined, and compared to control rats received vehicle or individual doses of either drug. Data confirmed that RH improves spatial memory function by increasing acetylcholine availability, boosting endogenous antioxidant potential, activating cell survival and inhibiting apoptotic pathways, an effect that is more effective when RH was conjugated with α-tocopherol. Mechanism of RH action includes activation of PP2A mediated inhibiting of ERK1/2 and JNK apoptotic pathways and inhibition of PTEN mediated activation of mTOR survival pathway. In conclusion, RH affords a potent neuroprotection against CdCl2-induced brain damage and memory dysfunction and co-administration of α-tocopherol enhances its activity.

Phytoestrogen-Rich Natural Preparation for Treatment of Climacteric Syndrome and Atherosclerosis Prevention in Perimenopausal Women.

The present study evaluated the risks and benefits of phytoestrogen treatment in healthy perimenopausal women in relation to the dynamics of climacteric syndrome and progression of atherosclerosis. Study participants were treated with placebo or phytoestrogen-rich natural preparation Karinat based on grape (Vitis vinifera) seeds, green tea (Camellia sinensis) leaves, hop (Hunulus lupulus) cone powder and garlic (Allium sativum) powder. The dynamics of climacteric syndrome was evaluated by Kupperman Index and Utian Quality of Life Scale. Atherosclerosis progression was evaluated by measuring carotid intima-media thickness. Significant changes of climacteric syndrome's severity in both Karinat and placebo groups (p = 0.005 and p = 0.001) were obtained after 24 months of follow-up. Detailed analysis of Kupperman Index suggested that Karinat possessed a significant effect on nervousness (p = 0.010), weakness (p = 0.020) and formication (p = 0.010). A significant improvement of medical (p = 0.070) and emotional (p = 0.060) components of Kupperman Index and Utian Quality of Life Scale was also observed in Karinat group. However, difference in carotid intima-media thickness between the two groups was not statistically significant at follow-up. A slight positive effect of phytoestrogens on climacteric syndrome manifestations was demonstrated in this study. Karinat can be used for alleviation of climacteric syndrome and cardiovascular disease prevention in perimenopausal women. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of feeding two RRR-α-tocopherol formulations on serum, cerebrospinal fluid and muscle α-tocopherol concentrations in horses with subclinical vitamin E deficiency.

BACKGROUND: Alpha-tocopherol (α-TP) supplementation is recommended for the prevention of various equine neuromuscular disorders. Formulations available include RRR-α-TP acetate powder and a more expensive but rapidly water-dispersible liquid RRR-α-TP (WD RRR-α-TP). No cost-effective means of rapidly increasing serum and cerebrospinal fluid (CSF) α-TP with WD RRR-α-TP and then sustaining concentrations with RRR-α-TP acetate has yet been reported. OBJECTIVES: To evaluate serum, CSF and muscle α-TP concentrations in an 8-week dosing regimen in which horses were transitioned from WD RRR-α-TP to RRR-α-TP acetate. STUDY DESIGN: Non-randomised controlled trial. METHODS: Healthy horses with serum α-TP of <2 µg/mL were divided into three groups and followed for 8 weeks. In the control group (n = 5), no α-TP was administered. In the second group (Group A; n = 7), 5000 IU/day RRR-α-TP acetate was administered. In the third group (Group WD-A; n = 7), doses of 5000 IU/day of WD RRR-α-TP were administered over 3 weeks, followed by a 4-week transition from WD RRR-α-TP to RRR-α-TP acetate, and a final 1 week of treatment with RRR-α-TP acetate. Serum samples were obtained weekly; muscle biopsies were obtained before, at 2.5 weeks and after supplementation. CSF samples were obtained before and after the 8-week period of supplementation. RESULTS: Serum α-TP increased significantly in Group WD-A at week 1 and remained significantly higher than in Group A and the control group throughout the transition, with inter-individual variation in response. Serum α-TP increased significantly by week 7 in Group A. CSF α-TP increased significantly in Group WD-A only. Muscle α-TP concentrations did not differ significantly across groups. Serum and CSF α-TP were closely correlated (r = 0.675), whereas serum and muscle-α-TP concentrations were not correlated. MAIN LIMITATIONS: The study duration was short and data on pre-transition CSF was lacking. CONCLUSIONS: The administration of 5000 IU/day of water-dispersible RRR-α-TP rapidly increases serum α-TP. Serum and CSF α-TP concentrations are sustained with a gradual transition to 5000 IU/day of RRR-α-TP acetate. Periodic evaluation of serum α-TP concentrations is recommended because responses vary among individuals.

Vitamin E for Alzheimer's dementia and mild cognitive impairment.

BACKGROUND: Vitamin E occurs naturally in the diet. It has several biological activities, including functioning as an antioxidant to scavenge toxic free radicals. Evidence that free radicals may contribute to the pathological processes behind cognitive impairment has led to interest in the use of vitamin E supplements to treat mild cognitive impairment (MCI) and Alzheimer's disease (AD). This is an update of a Cochrane Review first published in 2000, and previously updated in 2006 and 2012. OBJECTIVES: To assess the efficacy of vitamin E in the treatment of MCI and dementia due to AD. SEARCH METHODS: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS as well as many trials databases and grey literature sources on 22 April 2016 using the terms: "Vitamin E", vitamin-E, alpha-tocopherol. SELECTION CRITERIA: We included all double-blind, randomised trials in which treatment with any dose of vitamin E was compared with placebo in people with AD or MCI. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of the evidence using the GRADE approach. Where appropriate we attempted to contact authors to obtain missing information. MAIN RESULTS: Four trials met the inclusion criteria, but we could only extract outcome data in accordance with our protocol from two trials, one in an AD population (n = 304) and one in an MCI population (n = 516). Both trials had an overall low to unclear risk of bias. It was not possible to pool data across studies owing to a lack of comparable outcome measures.In people with AD, we found no evidence of any clinically important effect of vitamin E on cognition, measured with change from baseline in the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) over six to 48 months (mean difference (MD) -1.81, 95% confidence interval (CI) -3.75 to 0.13, P = 0.07, 1 study, n = 272; moderate quality evidence). There was no evidence of a difference between vitamin E and placebo groups in the risk of experiencing at least one serious adverse event over six to 48 months (risk ratio (RR) 0.86, 95% CI 0.71 to 1.05, P = 0.13, 1 study, n = 304; moderate quality evidence), or in the risk of death (RR 0.84, 95% CI 0.52 to 1.34, P = 0.46, 1 study, n = 304; moderate quality evidence). People with AD receiving vitamin E showed less functional decline on the Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory than people receiving placebo at six to 48 months (mean difference (MD) 3.15, 95% CI 0.07 to 6.23, P = 0.04, 1 study, n = 280; moderate quality evidence). There was no evidence of any clinically important effect on neuropsychiatric symptoms measured with the Neuropsychiatric Inventory (MD -1.47, 95% CI -4.26 to 1.32, P = 0.30, 1 study, n = 280; moderate quality evidence).We found no evidence that vitamin E affected the probability of progression from MCI to probable dementia due to AD over 36 months (RR 1.03, 95% CI 0.79 to 1.35, P = 0.81, 1 study, n = 516; moderate quality evidence). Five deaths occurred in each of the vitamin E and placebo groups over the 36 months (RR 1.01, 95% CI 0.30 to 3.44, P = 0.99, 1 study, n = 516; moderate quality evidence). We were unable to extract data in accordance with the review protocol for other outcomes. However, the study authors found no evidence that vitamin E differed from placebo in its effect on cognitive function, global severity or activities of daily living . There was also no evidence of a difference between groups in the more commonly reported adverse events. AUTHORS' CONCLUSIONS: We found no evidence that the alpha-tocopherol form of vitamin E given to people with MCI prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD. However, there is moderate quality evidence from a single study that it may slow functional decline in AD. Vitamin E was not associated with an increased risk of serious adverse events or mortality in the trials in this review. These conclusions have changed since the previous update, however they are still based on small numbers of trials and participants and further research is quite likely to affect the results.

Vitamin E for Alzheimer's dementia and mild cognitive impairment.

BACKGROUND: Vitamin E occurs naturally in the diet. It has several biological activities, including functioning as an antioxidant to scavenge toxic free radicals. Evidence that free radicals may contribute to the pathological processes behind cognitive impairment has led to interest in the use of vitamin E supplements to treat mild cognitive impairment (MCI) and Alzheimer's disease (AD). This is an update of a Cochrane Review first published in 2000, and previously updated in 2006 and 2012. OBJECTIVES: To assess the efficacy of vitamin E in the treatment of MCI and dementia due to AD. SEARCH METHODS: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS as well as many trials databases and grey literature sources on 22 April 2016 using the terms: "Vitamin E", vitamin-E, alpha-tocopherol. SELECTION CRITERIA: We included all double-blind, randomised trials in which treatment with any dose of vitamin E was compared with placebo in people with AD or MCI. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of the evidence using the GRADE approach. Where appropriate we attempted to contact authors to obtain missing information. MAIN RESULTS: Four trials met the inclusion criteria, but we could only extract outcome data in accordance with our protocol from two trials, one in an AD population (n = 304) and one in an MCI population (n = 516). Both trials had an overall low to unclear risk of bias. It was not possible to pool data across studies owing to a lack of comparable outcome measures.In people with AD, we found no evidence of any clinically important effect of vitamin E on cognition, measured with change from baseline in the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) over six to 48 months (mean difference (MD) -1.81, 95% confidence interval (CI) -3.75 to 0.13, P = 0.07, 1 study, n = 272; moderate quality evidence). There was no evidence of a difference between vitamin E and placebo groups in the risk of experiencing at least one serious adverse event over six to 48 months (risk ratio (RR) 0.86, 95% CI 0.71 to 1.05, P = 0.13, 1 study, n = 304; moderate quality evidence), or in the risk of death (RR 0.84, 95% CI 0.52 to 1.34, P = 0.46, 1 study, n = 304; moderate quality evidence). People with AD receiving vitamin E showed less functional decline on the Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory than people receiving placebo at six to 48 months (mean difference (MD) 3.15, 95% CI 0.07 to 6.23, P = 0.04, 1 study, n = 280; moderate quality evidence). There was no evidence of any clinically important effect on neuropsychiatric symptoms measured with the Neuropsychiatric Inventory (MD -1.47, 95% CI -4.26 to 1.32, P = 0.30, 1 study, n = 280; moderate quality evidence).We found no evidence that vitamin E affected the probability of progression from MCI to probable dementia due to AD over 36 months (RR 1.03, 95% CI 0.79 to 1.35, P = 0.81, 1 study, n = 516; moderate quality evidence). Five deaths occurred in each of the vitamin E and placebo groups over the 36 months (RR 1.01, 95% CI 0.30 to 3.44, P = 0.99, 1 study, n = 516; moderate quality evidence). We were unable to extract data in accordance with the review protocol for other outcomes. However, the study authors found no evidence that vitamin E differed from placebo in its effect on cognitive function, global severity or activities of daily living . There was also no evidence of a difference between groups in the more commonly reported adverse events. AUTHORS' CONCLUSIONS: We found no evidence that the alpha-tocopherol form of vitamin E given to people with MCI prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD. However, there is moderate quality evidence from a single study that it may slow functional decline in AD. Vitamin E was not associated with an increased risk of serious adverse events or mortality in the trials in this review. These conclusions have changed since the previous update, however they are still based on small numbers of trials and participants and further research is quite likely to affect the results.