Chemical Pathology of Homocysteine VIII. Effects of Tocotrienol, Geranylgeraniol, and Squalene on Thioretinaco Ozonide, Mitochondrial Permeability, and Oxidative Phosphorylation in Arteriosclerosis, Cancer, Neurodegeneration and Aging

Kilmer S McCully

Ann Clin Lab Sci . 2020 Sep;50(5):567-577.


A century ago a fat-soluble vitamin from leafy vegetables, later named vitamin E, was discovered to enhance fertility in animals. Vitamin E consists of 8 isomers of tocopherols and tocotrienols, each containing chromanol groups that confer antioxidant properties and differ only in the 15-carbon saturated phytyl poly-isoprenoid side chain of tocopherols and the 15-carbon unsaturated farnesyl poly-isoprenoid side chain of tocotrienols. Although tocotrienol was first isolated from rubber plants in 1964, its importance in multiple disease processes was not recognized until two decades later, when the cholesterol-lowering and anti-cancer effects were first reported. Tocotrienol (T3) protects against radiation injury and mitochondrial dysfunction by preventing opening of the mitochondrial permeability transition pore, thereby inhibiting loss of the active site for oxidative phosphorylation, thioretinaco ozonide oxygen ATP, from mitochondria by complex formation with the active site, TR2CoO3O2NAD+H2PO4 T3. The preventive effects of tocotrienol on vascular disease, cancer, neurodegeneration and aging are attributed to its effects on cellular apoptosis and senescence. Geranylgeraniol is an important intermediate in the biosynthesis of cholesterol, and cholesterol auxotrophy of lymphoma cell lines and primary tumors is attributed to loss of squalene monooxygenase and accumulation of intracellular squalene. Geranylgeraniol and tocotrienol have synergistic inhibitory effects on growth and HMG CoA reductase activity, accompanied by reduction of membrane KRAS protein of cultured human prostate carcinoma cells. Since cholesterol inhibits opening of the mPTP pore of mitochondria, inhibition of cholesterol biosynthesis by these effects of tocotrienol and geranylgeraniol produces increased mitochondrial dysfunction and apoptosis from loss of the active site of oxidative phosphorylation from mitochondria.

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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.


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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Systemic treatment with alpha-tocopherol and/or sodium selenite decreases the progression of experimental periodontitis

Nurgül Bas, Nezahat Arzu Kayar, Z Füsun Baba, Mustafa Cihat Avunduk, Seyfullah Haliloğlu, Nilgün Özlem Alptekin

Clin Oral Investig . 2020 Sep 28. doi: 10.1007/s00784-020-03579-9. Online ahead of print.


Objective: To investigate the effects of sodium selenite (Se) and/or α-tocopherol (αT) applications on the alveolar bone loss (ABL), the number of gingival collagen fibers, inducible nitric oxide synthase (iNOS)+ and CD95+ cell numbers, and serum cytokine concentrations in experimental periodontitis in rats.

Materials and methods: Forty Sprague Dawley rats were divided into four groups of ten as follows: group A: Se group, group B: αT group, group C: Se and αT combined group, and group D: control group (intraperitoneal (IP) saline injection applied). Using the image analysis method in the connective tissue under the connective epithelium, the numbers of iNOS, CD95 positive cells, and collagen fibers were counted. ELISA kits were used to test the concentrations of serum interleukin (IL)-1β, IL-6, and IL-4.

Results: The combination of Se and αT (group C) suppressed ABL compared with the control group (group D) (P < 0.05). In group A (Se), the number of iNOS+ cells was smaller than in group D (P < 0.05).

Conclusion: Se has been concluded to inhibit inflammation of the gum due to iNOS. Se and αT can have a remarkable important role in preventing alveolar bone loss, and particularly in combination.

Clinical relevance: Se and/or αT application may be useful in preventing the destruction of periodontal tissue and treatment of periodontal disease.

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Evaluation of the effects of vitamins C and E on experimental orthodontic tooth movement

Esra Bolat, Elçin Esenlik, Meral Öncü, Meltem Özgöçmen, Mustafa Cihat Avunduk, Özlem Yüksel

J Dent Res Dent Clin Dent Prospects . Spring 2020;14(2):131-137. doi: 10.34172/joddd.2020.0027. Epub 2020 Jun 17.


Background. This experimental study aimed to assess the effects of Vitamins C and E on orthodontic tooth movement. Methods. Fifty-one male Wistar albino rats were divided into six groups: five appliance groups and one control group. The appliance groups had an orthodontic appliance consisting of a closed-coil spring ligated between the maxillary incisor and maxillary first molar (50 g). Vitamin E and C (150 mg/kg) were injected intraperitoneally per day in the first and second groups, respectively. Vitamins E and C (20 μL) were locally injected into the periodontal gap of the moving teeth in the third and fourth groups, respectively, once every three days. No vitamin was injected in the last (fifth) appliance group.The experimental period was 18 days. Histological and biochemical (alkaline phosphatase, osteocalcin, and NTx levels) evaluations of the samples were performed, and maxillary incisor‒molar distance was measured before and after the experiment. Results. The amount of tooth movement was similar in the appliance groups. All the vitamin groups showed significantly increased osteoblastic activity, while those treated with systemic vitamins exhibited significantly increased numbers of collagen fibers on the tension side compared to the appliance control group (P<0.05). Conclusion. Vitamin C and E supplements positively affected bone formation on the tension side of the teeth during experimental orthodontic tooth movement.

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Effect of vitamin E on stroke-associated pneumonia

Hongwei Shen, Bingyan Zhan

J Int Med Res . 2020 Sep;48(9):300060520949657. doi: 10.1177/0300060520949657.


Objective: To study the role of vitamin E in stroke-associated pneumonia.

Methods: We selected 183 patients with stroke-related pneumonia who were divided into different nutrition groups according to the Mini Nutritional Assessment score. Patients were then administered different doses of vitamin E.

Results: CD55 and CD47 levels in patients taking vitamin E across different nutrition score groups were better than those in patients who did not use vitamin E. The levels of CD55 and CD47 and the duration of hospitalization were better in the high-dose vitamin E group than in the low-dose vitamin E group.

Conclusion: Vitamin E may have an auxiliary therapeutic effect in patients with stroke-associated pneumonia.

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Tocotrienols activate Nrf2 nuclear translocation and increase the antioxidant-related hepatoprotective mechanism in mice liver

Ahmed Atia, Nadia Salem Al-Rawaiq, Azman Abdullah

Curr Pharm Biotechnol . 2020 Sep 27. doi: 10.2174/1389201021666200928095950. Online ahead of print.


Background: The most common preparation of tocotrienols is the tocotrienol-rich fraction (TRF). This study aimed to investigate whether TRF induced liver Nrf2 nuclear translocation and influenced the expression of Nrf2-regulated genes.

Methods: In the Nrf2 induction study, mice were divided into control, 2000 mg/kg TRF and diethyl maleate treated groups. After acute treatment, mice were sacrificed at specific time points. Liver nuclear extracts were prepared and Nrf2 nuclear translocation was detected through Western blotting. To determine the effect of increasing doses of TRF on the extent of liver nuclear Nrf2 translocation and its implication on the expression levels of several Nrf2-regulated genes, mice were divided into 5 groups (control, 200, 500 and 1000 mg/kg TRF, and butylated hydroxyanisole-treated groups). After 14 days, mice were sacrificed and liver RNA extracted for qPCR assay.

Results: 2000 mg/kg TRF administration initiated Nrf2 nuclear translocation within 30 min, reached maximum level around 1 h and dropped to half-maximal levels by 24 h. Incremental doses of TRF resulted in dose-dependent increases in liver Nrf2 nuclear levels, along with concomitant dose-dependent increases in the expressions of Nrf2-regulated genes.

Conclusion: TRF activated the liver Nrf2 pathway resulting in increased expression of Nrf2-regulated cytoprotective genes.

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A first description of ataxia with vitamin E deficiency associated with MT-TG gene mutation

Marwa Maalej, Fatma Kammoun, Marwa Kharrat, Wafa Bouchaala, Marwa Ammar, Emna Mkaouar-Rebai, Chahnez Triki, Faiza Fakhfakh

Acta Neurol Belg . 2020 Sep 26. doi: 10.1007/s13760-020-01490-4. Online ahead of print.


Ataxia with isolated vitamin E deficiency (AVED) is a rare autosomal recessive cerebellar ataxia disorder that is caused by a mutation in the alpha-tocopherol transfer protein gene TTPA, leading to a lower level of serum vitamin E. Although it is almost clinically similar to Friedreich’s ataxia, its devastating neurological features can be prevented with appropriate treatment. In this study, we present a patient who was initially diagnosed with Friedreich’s ataxia, but was later found to have AVED. Frataxin gene screening revealed the absence of GAA expansion in homozygous or heterozygous state. However, TTPAgene sequencing showed the presence of the c.744delA mutation, leading to a premature stop codon (p.E249fx). In addition, the result of mutational analysis of MT-DNA genes revealed the presence of several variants, including the m.10044A>G mutation in MT-TG gene. Here, we report for the first time the coexistence of both mitochondrial and nuclear genes mutations in AVED.

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Interrelation between Plasma Concentrations of Vitamins C and E along the Trajectory of Ageing in Consideration of Lifestyle and Body Composition: A Longitudinal Study over Two Decades

Alexandra Jungert, Monika Neuhäuser-Berthold

Nutrients . 2020 Sep 25;12(10):E2944. doi: 10.3390/nu12102944.


Although the interrelation between vitamins C and E has been demonstrated on an experimental level, its impact on biomarkers in community-dwelling subjects along the trajectory of ageing has not yet been shown. The present longitudinal study investigates the determinants and interrelation of vitamins C and E plasma concentrations in 399 subjects aged ≥60 years with a median follow-up time of 12 years. Linear mixed-effects models were used to analyze the influence of age, sex, body composition, dietary intake, physical activity, smoking and supplement/drug use on plasma vitamin C, plasma α-tocopherol and α-tocopherol/total cholesterol ratio. At baseline, median plasma concentrations of vitamin C and α-tocopherol were 74 and 35 µmol/L. Absolute fat-free mass, physical activity, use of supplements, and plasma α-tocopherol were main determinants of plasma vitamin C in the course of ageing. For the α-tocopherol/total cholesterol ratio, age, use of supplements, use of lipid-modifying drugs, and plasma vitamin C were main determinants. The results reveal a stable positive interrelation between plasma concentrations of vitamins C and E along the trajectory of ageing independent of the other identified determinants. The possible regulatory mechanisms that could explain this robust positive interrelation remain to be elucidated.

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Isotretinoin and α-tocopherol acetate-loaded solid lipid nanoparticle topical gel for the treatment of acne

Shivani Gupta, Sarika Wairkar, Lokesh Kumar Bhatt

J Microencapsul . 2020 Sep 24;1-9. doi: 10.1080/02652048.2020.1823499. Online ahead of print.


Aims: This study was aimed to develop Isotretinoin (ITN) and α-tocopherol acetate (α-TA) loaded solid lipid nanoparticle topical gel for better skin sensitivity and potentiation of efficacy.

Methods: ITN and α-TA-loaded solid lipid nanoparticles (AE-SLN) were prepared by microemulsion method with glyceryl mono-stearate as lipid and tween 80: butanol as surfactantmix and characterised. AE-SLN gel was evaluated for physicochemical characteristics, drug release, skin irritation and anti-acne activity in rats.

Results: AE-SLNs had mean particle size of 193.4 nm (zeta-potential -29 mV) and entrapment efficiency of 84%w/w for ITN and 77.4%w/w for α-TA. AE-SLN gel showed sustained drug release for 24 h with a final cumulative release of 95.8% w/w and 89.1%w/w for ITN and α-TA. AE-SLN gel showed no erythema or edoema in rabbits and potent efficacy in rat model of acne.

Conclusion: In conclusion, AE-SLN gel has the potential to use as a non-irritant topical formulation for the treatment of acne.

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