Blog Archives

Involvement of miR-190b in Xbp1 mRNA Splicing upon Tocotrienol Treatment

Roberto Ambra, Sonia Manca, Guido Leoni, Barbara Guantario, Raffaella Canali, Raffaella Comitato

Molecules . 2020 Dec 31;26(1):163. doi: 10.3390/molecules26010163.

Abstract

We previously demonstrated that apoptosis induced by tocotrienols (γ and δT3) in HeLa cells is preceded by Ca2+ release from the endoplasmic reticulum. This event is eventually followed by the induction of specific calcium-dependent signals, leading to the expression and activation of the gene encoding for the IRE1α protein and, in turn, to the alternative splicing of the pro-apoptotic protein sXbp1 and other molecules involved in the unfolded protein response, the core pathway coping with EndoR stress. Here, we showed that treatment with T3s induces the expression of a specific set of miRNAs in HeLa cells. Data interrogation based on the intersection of this set of miRNAs with a set of genes previously differentially expressed after γT3 treatment provided a few miRNA candidates to be the effectors of EndoR-stress-induced apoptosis. To identify the best candidate to act as the effector of the Xbp1-mediated apoptotic response to γT3, we performed in silico analysis based on the evaluation of the highest ∆ in Gibbs energy of different mRNA-miRNA-Argonaute (AGO) protein complexes. The involvement of the best candidate identified in silico, miR-190b, in Xbp1 splicing was confirmed in vitro using T3-treated cells pre-incubated with the specific miRNA inhibitor, providing a preliminary indication of its role as an effector of EndoR-stress-induced apoptosis.

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Pharmacology and Pharmacokinetics of Vitamin E: Nanoformulations to Enhance Bioavailability

Anis Syauqina Mohd Zaffarin, Shiow-Fern Ng, Min Hwei Ng, Haniza Hassan, Ekram Alias

Int J Nanomedicine . 2020 Dec 8;15:9961-9974. doi: 10.2147/IJN.S276355. eCollection 2020.

Abstract

Vitamin E belongs to the family of lipid-soluble vitamins and can be divided into two groups, tocopherols and tocotrienols, with four isomers (alpha, beta, gamma and delta). Although vitamin E is widely known as a potent antioxidant, studies have also revealed that vitamin E possesses anti-inflammatory properties. These crucial properties of vitamin E are beneficial in various aspects of health, especially in neuroprotection and cardiovascular, skin and bone health. However, the poor bioavailability of vitamin E, especially tocotrienols, remains a great limitation for clinical applications. Recently, nanoformulations that include nanovesicles, solid-lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and polymeric nanoparticles have shown promising outcomes in improving the efficacy and bioavailability of vitamin E. This review focuses on the pharmacological properties and pharmacokinetics of vitamin E and current advances in vitamin E nanoformulations for future clinical applications. The limitations and future recommendations are also discussed in this review.

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Synthesis of [ 18 F]F-γ-T-3, a Redox-Silent γ-Tocotrienol (γ-T-3) Vitamin E Analogue for Image-Based In Vivo Studies of Vitamin E Biodistribution and Dynamics

Peter Roselt, Carleen Cullinane, Wayne Noonan, Hassan Elsaidi, Peter Eu, Leonard I Wiebe

Molecules . 2020 Dec 3;25(23):5700. doi: 10.3390/molecules25235700.

Abstract

Vitamin E, a natural antioxidant, is of interest to scientists, health care pundits and faddists; its nutritional and biomedical attributes may be validated, anecdotal or fantasy. Vitamin E is a mixture of tocopherols (TPs) and tocotrienols (T-3s), each class having four substitutional isomers (α-, β-, γ-, δ-). Vitamin E analogues attain only low concentrations in most tissues, necessitating exacting invasive techniques for analytical research. Quantitative positron emission tomography (PET) with an F-18-labeled molecular probe would expedite access to Vitamin E’s biodistributions and pharmacokinetics via non-invasive temporal imaging. (R)-6-(3-[18F]Fluoropropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane ([18F]F-γ-T-3) was prepared for this purpose. [18F]F-γ-T-3 was synthesized from γ-T-3 in two steps: (i) 1,3-di-O-tosylpropane was introduced at C6-O to form TsO-γ-T-3, and (ii) reaction of this tosylate with [18F]fluoride in DMF/K222. Non-radioactive F-γ-T-3 was synthesized by reaction of γ-T-3 with 3-fluoropropyl methanesulfonate. [18F]F-γ-T-3 biodistribution in a murine tumor model was imaged using a small-animal PET scanner. F-γ-T-3 was prepared in 61% chemical yield. [18F]F-γ-T-3 was synthesized in acceptable radiochemical yield (RCY 12%) with high radiochemical purity (>99% RCP) in 45 min. Preliminary F-18 PET images in mice showed upper abdominal accumulation with evidence of renal clearance, only low concentrations in the thorax (lung/heart) and head, and rapid clearance from blood. [18F]F-γ-T-3 shows promise as an F-18 PET tracer for detailed in vivo studies of Vitamin E. The labeling procedure provides acceptable RCY, high RCP and pertinence to all eight Vitamin E analogues.

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Stereological and histopathological evaluation of doxorubicin-induced toxicity in female rats’ ovary and uterus and palliative effects of quercetin and vitamin E

M Samare-Najaf, F Zal, S Safari, F Koohpeyma, N Jamali

Hum Exp Toxicol . 2020 Dec;39(12):1710-1724. doi: 10.1177/0960327120937329. Epub 2020 Jul 15.

Abstract

Doxorubicin (DOX) is a widely used chemotherapeutic agent with demonstrated reproductive toxicity. This study sought to determine the DOX-induced toxicity in the ovary and uterus and the preventive effects of quercetin (QCT) and vitamin E (Vit.E). Female rats were divided into six groups as follows: control, QCT (20 mg/kg), Vit.E (200 mg/kg), DOX (accumulative 15 mg/kg), DOX/QCT, and DOX/Vit.E. After 3 weeks, the toxicity of DOX in ovarian and uterine tissues and the potential palliative effects of QCT and Vit.E were evaluated by histopathological-stereological methods. The findings indicate a dramatic decline in the number of ovarian follicles (p < 0.001), ovarian and its associated structures volume, the volume of the uterus, its layers, and related structures (p < 0.05). Coadministration of QCT and Vit.E with DOX-treated rats demonstrated an alleviative effect on most of the studied parameters. Nevertheless, few adverse effects were recognized concerning these antioxidants administration (p < 0.05). In conclusion, the findings of this study support the protective role of these dietary supplements in the prevention of DOX-induced toxicity in uterine and ovarian tissues.

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Epidermal Growth Factor and Tocotrienol-Rich Fraction Cream Formulation Accelerates Burn Healing Process Based on Its Gene Expression Pattern in Deep Partial-Thickness Burn Wound Model

Hui-Fang Guo, Razana Mohd Ali, Roslida Abd Hamid, Sui Kiat Chang, Mohammed Habibur Rahman, Zaida Zainal, Huzwah Khaza'ai

Int J Low Extrem Wounds . 2020 Nov 26;1534734620971066. doi: 10.1177/1534734620971066. Online ahead of print.

Abstract

Our previous study has demonstrated that epidermal growth factor (EGF) with tocotrienol-rich fraction (TRF) cream formulation accelerating postburn wound healing with deep partial-thickness burn in rats. Current study was conducted to determine the gene expression levels related to burn wound healing process. A total of 180 Sprague-Dawley rats were randomly divided into 6 groups: untreated control, treated with Silverdin cream, base cream, base cream with 0.00075% EGF, base cream with 3% TRF or base cream with 0.00075% EGF, and 3% TRF, respectively. Burn wounds were created and the above-mentioned creams were applied once daily. Six animals from each group were sacrificed on days 3, 7, 11, 14, and 21 postburn. RNA was extracted from wound tissues and quantitative real-time polymerase chain reaction was performed to analyze the 9 wound healing-related genes against time postburn. Results demonstrated that topically applied EGF + TRF formulation downregulated the expression levels of IL-6 (interluekin-6), TNF-α (tumor necrosis factor-α) and iNOS (inducible nitric oxide synthase) throughout the whole healing process. TGF-β1 (transforming growth factor-β) and VEGF-A (vascular endothelial growth factor-A) were reduced on day 14 postburn. On the contrary, increased expression of Collagen-1 in the early stage of wound healing was observed with no effects on epidemal growth factor receptor (EGFR). The results showed beneficial application of EGF + TRF cream in the treatment of burn wound since it accelerated wound healing by relieving oxidative stress, decreasing inflammation, and promoting proper tissue modelling in the burn wound.

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Analysis of expression of vitamin E-binding proteins in H2O2 induced SK-N-SH neuronal cells supplemented with α-tocopherol and tocotrienol-rich fraction

Aishatu Ali Chiroma, Huzwah Khaza'ai, Roslida Abd Hamid, Sui Kiat Chang, Zainul Amiruddin Zakaria, Zaida Zainal

PLoS One . 2020 Nov 24;15(11):e0241112. doi: 10.1371/journal.pone.0241112. eCollection 2020.

Abstract

Natural α-tocopherol (α-TCP), but not tocotrienol, is preferentially retained in the human body. α-Tocopherol transfer protein (α-TTP) is responsible for binding α-TCP for cellular uptake and has high affinity and specificity for α-TCP but not α-tocotrienol. The purpose of this study was to examine the modification of α-TTP together with other related vitamin E-binding genes (i.e., TTPA, SEC14L2, and PI-TPNA) in regulating vitamin E uptake in neuronal cells at rest and under oxidative stress. Oxidative stress was induced with H2O2 for an hour which was followed by supplementation with different ratios of α-TCP and tocotrienol-rich fraction (TRF) for four hours. The cellular levels of vitamin E were quantified to determine bioavailability at cellular levels. The expression levels of TTPA, SEC14L2, and PI-TPNA genes in 0% α-TCP were found to be positively correlated with the levels of vitamin E in resting neuronal cells. In addition, the regulation of all the above-mentioned genes affect the distribution of vitamin E in the neuronal cells. It was observed that, increased levels of α-TCP secretion occur under oxidative stress. Thus, our results showed that in conclusion vitamin E-binding proteins may be modified in the absence of α-TCP to produce tocotrienols (TCT), as a source of vitamin E. The current study suggests that the expression levels of vitamin E transport proteins may influence the cellular concentrations of vitamin E levels in the neuronal cells.

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Gamma Tocotrienol Protects Mice From Targeted Thoracic Radiation Injury

Vidya P Kumar, Sasha Stone, Shukla Biswas, Neel Sharma, Sanchita P Ghosh

Front Pharmacol . 2020 Nov 12;11:587970. doi: 10.3389/fphar.2020.587970. eCollection 2020.

Abstract

Radiation injury will result in multiorgan dysfuntion leading to multiorgan failure. In addition to many factors such as radiation dose, dose rate, the severity of the injury will also depend on organ systems which are exposed. Here, we report the protective property of gamma tocotrienol (GT3) in total as well as partial body irradiation (PBI) model in C3H/HeN male mice. We have carried out PBI by targeting thoracic region (lung-PBI) using Small Animal Radiation Research Platform, an X-ray irradiator with capabilities of an image guided irradiation with a variable collimator with minimized exposure to non-targeted tissues and organs. Precise and accurate irradiation of lungs was carried out at either 14 or 16 Gy at an approximate dose rate of 2.6 Gy/min. Though a low throughput model, it is amenable to change the field size on the spot. No damage to other non-targeted organs was observed in histopathological evaluation. There was no significant change in peripheral blood counts of irradiated mice in comparison to naïve mice. Femoral bone marrow cells had no damage in irradiated mice. As expected, damage to the targeted tissue was observed in the histopathological evaluation and non-targeted tissue was found normal. Regeneration and increase of cellularity and megakaryocytes on GT3 treatment was compared to significant loss of cellularity in saline group. Peak alveolitis was observed on day 14 post-PBI and protection from alveolitis by GT3 was noted. In irradiated lung tissue, thirty proteins were found to be differentially expressed but modulated by GT3 to reverse the effects of irradiation. We propose that possible mode of action of GT3 could be Angiopoietin 2-Tie2 pathway leading to AKT/ERK pathways resulting in disruption in cell survival/angiogenesis.

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Cognitive function improvement with astaxanthin and tocotrienol intake: a randomized, double-blind, placebo-controlled study

Takahiro Sekikawa, Yuki Kizawa, Yanmei Li, Tsuyoshi Takara

J Clin Biochem Nutr . 2020 Nov;67(3):307-316. doi: 10.3164/jcbn.19-116. Epub 2020 Jun 19.

Abstract

We examined the effects of the mixed ingestion of astaxanthin derived from Haematococcus pluvialis and tocotrienols on the cognitive function of healthy Japanese adults who feel a memory decline. Forty-four subjects were randomly but equally assigned to the astaxanthin-tocotrienols or placebo group. An astaxanthin-tocotrienols or placebo capsule was taken once daily before or after breakfast for a 12-week intervention period. The primary outcome was composite memory from the Cognitrax cognitive test, and the secondary outcomes were other cognitive functions and subjective symptoms for memory. Each group included 18 subjects in the efficacy analysis (astaxanthin-tocotrienols group, 55.4 ± 7.9 years; placebo group, 54.6 ± 6.9 years). The astaxanthin-tocotrienols group showed a significant improvement in composite memory and verbal memory in Cognitrax at Δ12 weeks compared with the placebo group. Additionally, the astaxanthin-tocotrienols group showed a significant improvement in the subjective symptom of “During the last week, have you had trouble remembering people’s names or the names of things?” compared with the placebo group after 12 weeks. No adverse events were observed in this study. The results demonstrated that taking an astaxanthin-tocotrienols combination improves the composite memory and verbal memory of Japanese adults who feel a memory decline (UMIN 000031758).

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Vitamin E as promising adjunct treatment option in the combat of infectious diseases caused by bacterial including multi-drug resistant pathogens – Results from a comprehensive literature survey

Minnja S Hartmann, Soraya Mousavi, Stefan Bereswill, Markus M Heimesaat

Eur J Microbiol Immunol (Bp) . 2020 Nov 5. doi: 10.1556/1886.2020.00020. Online ahead of print.

Abstract

The use of antibiotics has provoked an emergence of various multidrug-resistant (MDR) bacteria. Infectious diseases that cannot be treated sufficiently with conventional antibiotic intervention strategies anymore constitue serious threats to human health. Therefore, current research focus has shifted to alternative, antibiotic-independent therapeutic approaches. In this context, vitamin E constitutes a promising candidate molecule due to its multi-faceted modes of action. Therefore, we used the PubMed database to perform a comprehensive literature survey reviewing studies addressing the antimicrobial properties of vitamin E against bacterial pathogens including MDR bacteria. The included studies published between 2010 and 2020 revealed that given its potent synergistic antimicrobial effects in combination with distinct antibiotic compounds, vitamin E constitutes a promising adjunct antibiotic treatment option directed against infectious diseases caused by MDR bacteria such as Pseudomonas aeruginosa, Burkholderia cenocepacia and methicillin-resistant Staphylococcus aureus (MRSA). In conclusion, the therapeutic value of vitamin E for the treatment of bacterial infections should therefore be investigated in future clinical studies.

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