Application of Partial Hydrogenation for the Generation of Minor Tocochromanol Homologs and Functional Evaluation of Hydrogenated Tocotrienol-rich Vitamin E Oil in Diabetic Obese Mice

Fumiaki Beppu, Aimi Sakuma, Satoshi Kasatani, Yoshinori Aoki, Naohiro Gotoh

J Oleo Sci . 2021;70(1):103-112. doi: 10.5650/jos.ess20233.

Abstract

Recent research has identified minor homologs of vitamin E with one or two double bonds in the side-chain, namely tocomonoenol (T1) and tocodienol (T2), in natural products. We first explored the effectiveness of partial hydrogenation for generating minor tocochromanols from tocotrienol (T3). During hydrogenation with pure α-T3 as a substrate, the side-chain was partially saturated in a time-dependent manner, and a large amount of α-T1 and α-T2 was obtained. To investigate the beneficial effects of the hydrogenated product, we fed diabetic obese KK-A y mice with a hydrogenated T3 mixture (HT3). Feeding HT3 revealed tissue-specific accumulation of tocochromanols, ameliorated hyperglycemia and improved ratio of high-density lipoprotein cholesterol to total cholesterol in serum, with invariant body weight and fat mass. Hence, we propose that hydrogenation is a useful method for generating T1 and T2 homologs, which can be applied to explore the structure-related function of tocochromanols.

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Mechanisms Mediating Anti-Inflammatory Effects of Delta-Tocotrienol and Tart Cherry Anthocyanins in 3T3-L1 Adipocytes

Lexie Harlan, London T Mena, Latha Ramalingam, Shasika Jayarathne, Chwan-Li Shen, Naima Moustaid-Moussa

Nutrients . 2020 Oct 30;12(11):3356. doi: 10.3390/nu12113356.

Abstract

Chronic low-grade inflammation is a primary characteristic of obesity and can lead to other metabolic complications including insulin resistance and type 2 diabetes (T2D). Several anti-inflammatory dietary bioactives decrease inflammation that accompanies metabolic diseases. We are specifically interested in delta-tocotrienol, (DT3) an isomer of vitamin E, and tart cherry anthocyanins (TCA), both of which possess individual anti-inflammatory properties. We have previously demonstrated that DT3 and TCA, individually, reduced systemic and adipose tissue inflammation in rodent models of obesity. However, whether these compounds have combinatorial effects has not been determined yet. Hence, we hypothesize that a combined treatment of DT3 and TCA will have great effects in reducing inflammation in adipocytes, and that these effects are mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), a major inflammatory transcription factor. We used 3T3-L1 adipocytes and treated them with 1-5 µM doses of DT3 along with tart cherry containing 18-36 µg anthocyanin/mL, to assess effects on inflammation. Neither DT3 nor TCA, nor their combinations had toxic effects on adipocytes. Furthermore, pro-inflammatory markers interleukin-6 (IL-6) and p-65 (subunit of NFkB) were reduced at the protein level in media collected from adipocytes with both individual and combined treatments. Additionally, other downstream targets of NFkB including macrophage inflammatory protein 2 (Mip2), and Cyclooxygenase-2 (Cox2) were also significantly downregulated (p ≤ 0.05) when treated with individual and combined doses of DT3 and TCA with no additional combinatorial effects. In summary, DT3 and TCA individually, are beneficial in reducing inflammation with no additional combinatorial effects.

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Negative Correlation Between Vitamin A and Positive Correlation Between Vitamin E and Inflammation Among Healthy Adults in Korea: Based on the Korea National Health and Nutrition Examination Survey (KNHANES) 2016-2018 7th Edition

Ki-Hong Hong, Young Lee

J Inflamm Res . 2020 Oct 29;13:799-811. doi: 10.2147/JIR.S265856. eCollection 2020.

Abstract

Purpose: Vitamins exert its effect through different isoforms. The isoform conversion phases involved are affected outside factors. Here, we investigated the correlation between serum retinol, α-tocopherol, and serum inflammatory markers using stratified data acquired from 2016 to 2018 Korea National Health and Nutrition Examination Survey (KNHANES).

Materials and methods: This study was based on data acquired from the 7th edition (2016-2018) of the Korea National Health and Nutrition Examination Survey, consisting of survey data on smoking and alcohol drinking, serum retinol level, serum α-tocopherol level, high-sensitivity C-reactive protein (hs-CRP), and baseline characteristics.

Results: There was a negative correlation between serum retinol and hs-CRP in alcohol drinking men. There was a negative correlation between serum retinol and hs-CRP in the alcohol-nonsmoking female group. There was a positive correlation between α-tocopherol and hs-CRP in the nonsmoking and alcohol-drinking group. There was a positive correlation between α-tocopherol and hs-CRP in the nonsmoking and alcohol-drinking female group. There was positive correlation between vitamin A and E and metabolic syndrome. The lowest vitamin A level was observed in subjects with all five metabolic syndrome criteria matched.

Conclusion: There was a negative correlation between serum retinol and hs-CRP and positive correlation between α-tocopherol and hs-CRP. Absorption and secretion of serum retinol are affected by inflammation status through retinol-binding protein. Alcohol acts as a competitive inhibitor of vitamin A oxidation through alcohol dehydrogenase and ALDH activity. Smoking causes inflammation and induces reactive oxygen species scavenging system and increases cytochrome p450 levels. These factors may have contributed to the observed findings. Metabolic syndrome subjects increased as the levels of vitamin A and vitamin E increased. Since obesity is inversely related to ALDH activity, we postulate that patients with metabolic syndrome may also have low ALDH activity, especially in the Asian population. Future studies are warranted to study the efficacy of ALDH or ALDH inducers in patients with vitamin A deficiency or metabolic syndrome.

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Supplementation with Resveratrol, Piperine and Alpha-Tocopherol Decreases Chronic Inflammation in a Cluster of Older Adults with Metabolic Syndrome

Raúl Francisco Pastor, Marisa Gabriela Repetto, Fabiana Lairion, Alberto Lazarowski, Amalia Merelli, Zulma Manfredi Carabetti, Isabel Pastor, Elena Pastor, Laura Valeria Iermoli, Carlos Amadeo Bavasso, Roberto Héctor Iermoli

Nutrients . 2020 Oct 15;12(10):E3149. doi: 10.3390/nu12103149.

Abstract

Metabolic Syndrome (MetS) is increasing worldwide regardless of culture, genetic, gender, and geographic differences. While multiple individual risk factors, such as obesity, hypertension, diabetes, and hyperlipidemia, can cause cardiovascular disease (CVD), it is the intercurrence of these risk factors that defines MetS as a cluster that creates an environment for atherosclerosis and other manifestations of CVD. Despite the advances in the knowledge and management of each of the components of MetS, there are two molecular biology processes, chronic inflammation and oxidative stress, which are still underdiagnosed and undertreated. In order to assess the effect of a dietary supplement on chronic inflammation in MetS, we conducted a clinical trial with volunteers receiving a formula composed of resveratrol, piperine and alpha tocopherol (FRAMINTROL®), together with their habitual treatment, for three months. The inflammatory state was evaluated by ultrasensitive C reactive protein (US CRP) and ferritin in plasma, and oxygen consumption and chemiluminescence in neutrophils. The results showed that ferritin decreased by 10% (p < 0.05), US-CRP by 33% (p < 0.0001), oxygen consumption by 55% (p < 0.0001), and spontaneous chemiluminiscence was by 25% (p < 0.005) after treatment. As far as we know, this is the first study showing a chronic inflammation decrease in MetS patients due to the administration of a biopower Resveratrol-piperine and alpha tocopherol dietary supplement together with conventional therapy.

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The effects of royal jelly and tocotrienol-rich fraction on impaired glycemic control and inflammation through irisin in obese rats

Pardis Irandoost, Naimeh Mesri Alamdari, Atoosa Saidpour, Farzad Shidfar, Neda Roshanravan, Mohammad Asghari Jafarabadi, Farnaz Farsi, Nazanin Asghari Hanjani, Mohammadreza Vafa

J Food Biochem . 2020 Oct 5;e13493. doi: 10.1111/jfbc.13493. Online ahead of print.

Abstract

The effects of royal jelly (RJ) and tocotrienol-rich fraction (TRF) on obesity-induced glucose intolerance and inflammation were assessed in the current study. Regarding irisin as an important adipomyokine that attenuates obesity-induced disorders, we evaluated whether RJ and TRF could exert their metabolism regulatory effects through irisin. Obese rats were fed a high-fat diet (HFD) with or without supplementation of RJ, TRF, or both, for 8 weeks. At the end of the intervention, weight, irisin, glycemic, and inflammatory indices were measured. The weight of the rats did not remarkably reduce in any of the groups. Glucose homeostasis and inflammation were improved when we added RJ and TRF to HFD. RJ elevated irisin concentration, but the effect of TRF on irisin was not noticeable. Our results indicated that, despite the lack of significant weight loss, RJ and TRF promoted healthy obesity. This improvement was mediated by irisin in RJ consuming rats. PRACTICAL APPLICATIONS: Obesity is a public health concern associated with several chronic disorders. The beneficial effects of irisin on obesity-related disorders are well-established. It is the first study assessing the effect of RJ and TRF as functional foods, with pharmacological and nutritional activities on obesity complications, through irisin mediation. Our study demonstrated that RJ exerts its metabolic regulatory effects by irisin as a mediator. Our investigation makes a remarkable contribution to the literature, because it suggests a new mechanism for the anti-obesity properties of RJ and TRF.

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Cardiovascular and Metabolic Protection by Vitamin E: A Matter of Treatment Strategy?

Melanie Ziegler, Maria Wallert, Stefan Lorkowski, Karlheinz Peter

Antioxidants (Basel) . 2020 Sep 29;9(10):935. doi: 10.3390/antiox9100935.

Abstract

Cardiovascular diseases (CVD) cause about 1/3 of global deaths. Therefore, new strategies for the prevention and treatment of cardiovascular events are highly sought-after. Vitamin E is known for significant antioxidative and anti-inflammatory properties, and has been studied in the prevention of CVD, supported by findings that vitamin E deficiency is associated with increased risk of cardiovascular events. However, randomized controlled trials in humans reveal conflicting and ultimately disappointing results regarding the reduction of cardiovascular events with vitamin E supplementation. As we discuss in detail, this outcome is strongly affected by study design, cohort selection, co-morbidities, genetic variations, age, and gender. For effective chronic primary and secondary prevention by vitamin E, oxidative and inflammatory status might not have been sufficiently antagonized. In contrast, acute administration of vitamin E may be more translatable into positive clinical outcomes. In patients with myocardial infarction (MI), which is associated with severe oxidative and inflammatory reactions, decreased plasma levels of vitamin E have been found. The offsetting of this acute vitamin E deficiency via short-term treatment in MI has shown promising results, and, thus, acute medication, rather than chronic supplementation, with vitamin E might revitalize vitamin E therapy and even provide positive clinical outcomes.

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Effect of vitamin E on low density lipoprotein oxidation at lysosomal pH

Hadeel K M Alboaklah, David S Leake

Free Radic Res . 2020 Sep 16;1-11. doi: 10.1080/10715762.2020.1817912. Online ahead of print.

Abstract

Many cholesterol-laden foam cells in atherosclerotic lesions are macrophages and much of their cholesterol is present in their lysosomes and derived from low density lipoprotein (LDL). LDL oxidation has been proposed to be involved in the pathogenesis of atherosclerosis. We have shown previously that LDL can be oxidised in the lysosomes of macrophages. α-Tocopherol has been shown to inhibit LDL oxidation in vitro, but did not protect against cardiovascular disease in large clinical trials. We have therefore investigated the effect of α-tocopherol on LDL oxidation at lysosomal pH (about pH 4.5). LDL was enriched with α-tocopherol by incubating human plasma with α-tocopherol followed by LDL isolation by ultracentrifugation. The α-tocopherol content of LDL was increased from 14.4 ± 0.2 to 24.3 ± 0.3 nmol/mg protein. LDL oxidation was assessed by measuring the formation of conjugated dienes at 234 nm and oxidised lipids (cholesteryl linoleate hydroperoxide and 7-ketocholesterol) by HPLC. As expected, LDL enriched with α-tocopherol was oxidised more slowly than control LDL by Cu2+ at pH 7.4, but was not protected against oxidation by Cu2+ or Fe3+ or a low concentration of Fe2+ at pH 4.5 (it was sometimes oxidised faster by α-tocopherol with Cu2+ or Fe3+ at pH 4.5). α-Tocopherol-enriched LDL reduced Cu2+ and Fe3+ into the more pro-oxidant Cu+ and Fe2+ faster than did control LDL at pH 4.5. These findings might help to explain why the large clinical trials of α-tocopherol did not protect against cardiovascular disease.

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The effect of royal jelly and tocotrienol-rich fraction along with calorie restriction on hypothalamic endoplasmic reticulum stress and adipose tissue inflammation in diet-induced obese rats

Pardis Irandoost, Naimeh Mesri Alamdari, Atoosa Saidpour, Farzad Shidfar, Farnaz Farsi, Mohammad Asghari Jafarabadi, Mohammad Reza Alivand, Mohammadreza Vafa

BMC Res Notes . 2020 Aug 31;13(1):409. doi: 10.1186/s13104-020-05258-0.

Abstract

Objectives: Endoplasmic reticulum (ER) stress causes adipose tissue dysfunction and chronic inflammation in obesity. Royal jelly (RJ) and tocotrienol-rich fraction (TRF) are reported to ameliorate inflammation. However, the improving effects of RJ and TRF on inflammation from ER stress modulating view have not been assessed so far. Hence, we investigated the effect of RJ and TRF on ER stress and some adipose tissue-derived inflammatory markers in the high-fat diet (HFD)-induced obesity. Wistar obese rats randomly allocated into 5 groups: HFD, calorie restriction diet (CRD), RJ + CRD, TRF + CRD, RJ + TRF + CRD. After 8-week intervention, adipose tissues and hypothalamus were dissected and serum was collected.

Results: RJ reduced glucose-regulated protein-78 (GRP78) expression as ER stress indicator in WAT and hypothalamus compared to CRD. Besides, RJ diminished the expression of inflammatory markers in white adipose tissue (WAT) and also decreased the serum concentration of them. TRF reduced inflammatory markers in the serum without remarkable effects on ER stress. Overall, RJ has protective effect against adipose tissue dysfunction and inflammation then suggested as a therapeutic approach to reduce some obesity-related complications. The impact of TRF in this regard is lower than RJ and limited to systemic inflammation improvement without remarkable changes in adipose tissue inflammation.

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The effect of royal jelly and tocotrienol-rich fraction along with calorie restriction on hypothalamic

Pardis Irandoost, Naimeh Mesri Alamdari, Atoosa Saidpour, Farzad Shidfar, Farnaz Farsi, Mohammad Asghari Jafarabadi, Mohammad Reza Alivand, Mohammadreza Vafa

BMC Res Notes . 2020 Aug 31;13(1):409. doi: 10.1186/s13104-020-05258-0.

Abstract

Objectives: Endoplasmic reticulum (ER) stress causes adipose tissue dysfunction and chronic inflammation in obesity. Royal jelly (RJ) and tocotrienol-rich fraction (TRF) are reported to ameliorate inflammation. However, the improving effects of RJ and TRF on inflammation from ER stress modulating view have not been assessed so far. Hence, we investigated the effect of RJ and TRF on ER stress and some adipose tissue-derived inflammatory markers in the high-fat diet (HFD)-induced obesity. Wistar obese rats randomly allocated into 5 groups: HFD, calorie restriction diet (CRD), RJ + CRD, TRF + CRD, RJ + TRF + CRD. After 8-week intervention, adipose tissues and hypothalamus were dissected and serum was collected.

Results: RJ reduced glucose-regulated protein-78 (GRP78) expression as ER stress indicator in WAT and hypothalamus compared to CRD. Besides, RJ diminished the expression of inflammatory markers in white adipose tissue (WAT) and also decreased the serum concentration of them. TRF reduced inflammatory markers in the serum without remarkable effects on ER stress. Overall, RJ has protective effect against adipose tissue dysfunction and inflammation then suggested as a therapeutic approach to reduce some obesity-related complications. The impact of TRF in this regard is lower than RJ and limited to systemic inflammation improvement without remarkable changes in adipose tissue inflammation.

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The effects of tocotrienol supplementation on lipid profile: A meta-analysis of randomized controlled trials

Shuping Zuo, Guiping Wang, QuanLe Han, Hongling Xiao, Heitor O Santos, David Avelar Rodriguez, Vahid Khani, Jianlei Tang

Complement Ther Med . 2020 Aug;52:102450. doi: 10.1016/j.ctim.2020.102450. Epub 2020 May 25.

Abstract

Background & objective: Tocotrienol supplementation has been emerged as a potent candidate for the treatment of dyslipidemia. In the present study, a systematic review and meta-analysis of randomized controlled trials was performed with the aim of examining the effects of tocotrienol supplementation on the lipid profile.

Methods: Four databases (Scopus, PubMed/Medline, Web of Science and Embase) were used to accomplish the literature search up to November 2019. Clinical trials encompassing the impact of tocotrienol supplementation on lipid profile were extracted regardless of clinical condition, with studies included involving only adults patients.

Results: A total of 15 articles with 20 arms were eligible and included in the meta-analysis to estimate the pooled effect size. Overall results showed a significant effect of tocotrienol supplementation on increasing high-density lipoprotein cholesterol (HDL-C) levels (weight mean difference (WMD): 0.146 mmol/L, I2 = 85.9%) and a non-significant influence on total cholesterol (TC) (WMD: 0.010 mmol/L, I2 = 64.5%), low-density lipoprotein cholesterol (LDL-C) (WMD: 0.095 mmol/L, I2 = 87.4%), and triglycerides (TG) (WMD: -0.112 mmol/L, I2 = 67.4%) levels. Increment in HDL-C levels was significant greater for the tocotrienol dosage ≥ 200 mg/d (WMD: 0.202 mmol/L) and ≤8 weeks (WMD: 0.278 mmol/L). Moreover, studies that investigated tocotrienol dose ≥200 mg had no heterogeneity, while showing a significant decrease in TG levels (WMD: -0.177 mmol/L).

Conclusion: The present meta-analysis demonstrated that supplementing with tocotrienols does not decrease the concentrations of LDL-C, TC and TG. However, tocotrienol supplementation was considered a candidate for increasing HDL-C levels.

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