Palm Tocotrienol-Adjuvanted Dendritic Cells Decrease Expression of the SATB1 Gene in Murine Breast Cancer Cells and Tissues

Abdul Hafid SR, Radhakrishnan AK

Vaccines (Basel). 2019 Nov 27;7(4). pii: E198. doi: 10.3390/vaccines7040198.

Abstract

The aim of this study was to evaluate the effectiveness of immunotherapy using dendritic cells (DC) pulsed with tumor lysate (a DC vaccine) in combination with daily supplementation of tocotrienol-rich fraction (TRF) to potentiate anti-tumor immune responses. We had previously reported that DC-vaccine immunotherapy together with TRF supplementation induced protective immunity to tumor challenge. Breast cancer was induced in female BALB/c mice. The mice were randomly assigned into the treatment groups. At autopsy, peripheral blood was collected in heparinized tube and the expression of cell surface molecules (CD40, CD80, CD83, and CD86) that are crucial for T-cell activation and survival were analyzed by flow cytometry. Tumor was excised from each animal and snap-frozen. Total RNA was extracted from each tumor tissue for microarray and gene expression analysis. Total protein was extracted from tumor tissue for protein expression studies using Western blotting. The results show that systemic administration of 1 mg TRF daily in combination with DC-vaccine immunotherapy (DC + TL + TRF) caused a marked reduction (p < 0.05) of tumor size and increased (p < 0.05) the survival rates of the tumor-inoculated mice. The expression of CD40, CD80, CD83, and CD86 were upregulated in peripheral blood from the DC + TL + TRF group compared to other groups. In addition, there was higher expression of FasL in tumor-excised mice from the DC + TL + TRF group compared to other groups. FasL plays an important role in maintaining immune privilege and is required for cytotoxic T-lymphocyte (CTL) activity. Microarray analysis identified several genes involved in the regulation of cancer. In this study, we focused on the special AT rich binding protein 1 (SATB1) gene, which was reported to have dual functions, one of which was to induce aggressive growth in breast cancer cells. Tumors from DC + TL + TRF mice showed lower (p < 0.05) expression of SATB1 gene. Further study will be conducted to investigate the molecular functions of and the role of SATB1 in 4T1 mammary cancer cells and DC. In conclusion, TRF supplementation can potentiate the effectiveness of DC-vaccine immunotherapy.

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Association of vitamin E on the risk of ovarian cancer: A meta-analysis

Leng Y, Zhou H, Meng F, Tian T, Xu J, Yan F

Biosci Rep. 2019 Nov 27. pii: BSR20193311. doi: 10.1042/BSR20193311.

Abstract

Many researches were conducted to assess the association of vitamin E intake on the risk of ovarian cancer, with conflict results. The current meta-analysis of published observational studies aimed to investigate the effect of vitamin E intake on ovarian cancer risk. The summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were calculated to measure the effectiveness of vitamin E intake on ovarian cancer risk using a random-effects model. As a result, fourteen studies including 4597 patients were identified. Eleven studies reported about total vitamin E intake, eight studies about vitamin E intake from food only and five studies about vitamin E intake from supplement only on the risk of ovarian cancer. Overall, the summary RRs on ovarian cancer risk was 0.95 (95%CIs= 0.78-1.16) in total vitamin E intake, 0.99 (95%CIs= 0.77-1.27) in vitamin E intake from food only and 0.82 (95%CIs= 0.54-1.25) in vitamin E intake from supplement only. Results in subgroup analyses by study design and geographic location were consistent with overall result. In conclusions, the findings of this meta-analysis suggested that high intake of vitamin E from food or vitamin E supplement had no significant effect on the risk of ovarian cancer.

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Palm Tocotrienol-Adjuvanted Dendritic Cells Decrease Expression of the SATB1 Gene in Murine Breast Cancer Cells and Tissues

Abdul Hafid SR, Radhakrishnan AK

Vaccines (Basel). 2019 Nov 27;7(4). pii: E198. doi: 10.3390/vaccines7040198.

Abstract

The aim of this study was to evaluate the effectiveness of immunotherapy using dendritic cells (DC) pulsed with tumor lysate (a DC vaccine) in combination with daily supplementation of tocotrienol-rich fraction (TRF) to potentiate anti-tumor immune responses. We had previously reported that DC-vaccine immunotherapy together with TRF supplementation induced protective immunity to tumor challenge. Breast cancer was induced in female BALB/c mice. The mice were randomly assigned into the treatment groups. At autopsy, peripheral blood was collected in heparinized tube and the expression of cell surface molecules (CD40, CD80, CD83, and CD86) that are crucial for T-cell activation and survival were analyzed by flow cytometry. Tumor was excised from each animal and snap-frozen. Total RNA was extracted from each tumor tissue for microarray and gene expression analysis. Total protein was extracted from tumor tissue for protein expression studies using Western blotting. The results show that systemic administration of 1 mg TRF daily in combination with DC-vaccine immunotherapy (DC + TL + TRF) caused a marked reduction (p < 0.05) of tumor size and increased (p < 0.05) the survival rates of the tumor-inoculated mice. The expression of CD40, CD80, CD83, and CD86 were upregulated in peripheral blood from the DC + TL + TRF group compared to other groups. In addition, there was higher expression of FasL in tumor-excised mice from the DC + TL + TRF group compared to other groups. FasL plays an important role in maintaining immune privilege and is required for cytotoxic T-lymphocyte (CTL) activity. Microarray analysis identified several genes involved in the regulation of cancer. In this study, we focused on the special AT rich binding protein 1 (SATB1) gene, which was reported to have dual functions, one of which was to induce aggressive growth in breast cancer cells. Tumors from DC + TL + TRF mice showed lower (p < 0.05) expression of SATB1 gene. Further study will be conducted to investigate the molecular functions of and the role of SATB1 in 4T1 mammary cancer cells and DC. In conclusion, TRF supplementation can potentiate the effectiveness of DC-vaccine immunotherapy.

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Synthesis, DFT Calculations, and In Vitro Antioxidant Study on Novel Carba-Analogs of Vitamin E

Baj A, Cedrowski J, Olchowik-Grabarek E, Ratkiewicz A, Witkowski S

Antioxidants (Basel). 2019 Nov 26;8(12). pii: E589. doi: 10.3390/antiox8120589.

Abstract

Vitamin E is the most active natural lipophilic antioxidant with a broad spectrum of biological activity. α-Tocopherol (α-T), the main representative of the vitamin E family, is a strong inhibitor of lipid peroxidation as a chain-breaking antioxidant. Antioxidant and antiradical properties of vitamin E result from the presence of a phenolic hydroxyl group at the C-6 position. Due to stereoelectronic effects in the dihydropyranyl ring, the dissociation enthalpy for phenolic O-H bond (BDEOH) is reduced. The high chain-breaking reactivity of α-T is mainly attributed to orbital overlapping of the 2p-type lone pair on the oxygen atom (O1) in para position to the phenolic group, and the aromatic π-electron system. The influence of the O1 atom on the antioxidant activity of vitamin E was estimated quantitatively. The all-rac-1-carba-α-tocopherol was synthesized for the first time. Along with model compounds, 1-carba-analog of Trolox and its methyl ester were screened for their in vitro antioxidant activity by inhibition of styrene oxidation, and for the radical-reducing properties by means of 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) scavenging assay. To study the antioxidant activity, density functional theory (DFT) was also applied. Reaction enthalpies related to HAT (hydrogen atom transfer), SET-PT (sequential electron transfer-proton transfer), and SPLET (sequential proton loss-electron transfer) mechanisms were calculated.

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Development of a Novel Pharmaceutical Formula of Nanoparticle Lipid Carriers of Gentamicin/α-Tocopherol and In Vivo Assessment of the Antioxidant Protective Effect of α-Tocopherol in Gentamicin-Induced Nephrotoxicity

Elfaky MA, Thabit AK, Sirwi A, Fahmy UA, Bahabri RM, Al-Awad EA, Basaeed LF

Antibiotics (Basel). 2019 Nov 25;8(4). pii: E234. doi: 10.3390/antibiotics8040234.

Abstract

Gentamicin is a potent antibiotic with a nephrotoxicity drawback which limits its use. D-α-tocopherol polyethylene glycol succinate (α-tocopherol) is widely used as a surfactant and have potent antioxidant properties. This study aimed to assess the protective effect of α-tocopherol on gentamicin-induced nephrotoxicity by loading gentamicin on nanostructured lipid carriers (NLC). In vivo, the product was administered intravenously to three groups of rabbits (control, gentamicin and gentamicin/α-tocopherol NLC) for 10 consecutive days. Blood was collected on days 1, 5 and 10 to assess renal function. A significant difference in all plasma parameters related to kidney function were observed in the gentamicin group compared to the control by day 5 and 10, confirming the nephrotoxicity effect. On the other hand, the same parameter levels of the NLC group were significantly different compared to the gentamicin group, confirming the protective effect on kidney function. Gentamicin also caused significant decreases in plasma levels of glutathione sulfhydryl (GSH) and superoxide dismutase (SOD) activity. However, gentamicin-α-tocopherol NLC significantly elevates both plasma levels of GSH as well as SOD activity. The present work indicates that, loading of gentamicin on NLC by using α-tocopherol, is an innovative strategy to protect against aminoglycoside-induced nephrotoxicity due to its antioxidant activity.

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Antioxidant status following postprandial challenge of two different doses of tocopherols and tocotrienols

Fairus S, Cheng HM, Sundram K

J Integr Med. 2019 Nov 23. pii: S2095-4964(19)30113-X. doi: 10.1016/j.joim.2019.11.005.

Abstract

OBJECTIVE:

Tocotrienols (T3s) have been hypothesized to have greater antioxidant capacity than tocopherols (Ts) due to differences in biokinetics that affect their absorption and function. The present trial compares the antioxidant effectiveness following postprandial challenge of two different doses of α-T or palm T3-rich fraction (TRF) treatments and evaluates their dose-response effects on antioxidant status.

METHODS:

Ten healthy volunteers were given four different doses of vitamin E formulations (268 mg α-T, 537 mg α-T, 263 mg TRF or 526 mg TRF) in a cross-over postprandial trial. Blood was sampled at 0, 2, 4, 5, 6 and 8 hours after meal consumption and plasma antioxidant status including total glutathione, superoxide dismutase, malondialdehyde (MDA), ferric reducing antioxidant potential and trolox-equivalent antioxidant capacity, was analyzed.

RESULTS:

Supplementation with the different doses of either α-T or TRF did not significantly improve overall antioxidant status. There was no significant difference in overall antioxidant status among treatments at the different doses compared. However, a significant dose-response effect was observed for plasma MDA throughout the 8-hour postprandial period. MDA was significantly lower after the 537 mg α-T treatment, compared to the 268 mg α-T treatment; it was also lower after the 526 mg TRF treatment compared to the 263 mg TRF treatment (P < 0.05).

CONCLUSION:

T3 and α-T demonstrated similar antioxidant capacity, despite markedly lower levels of T3 in blood and lipoproteins, compared to α-T.

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Single-Cell RNA-seq Reveals Profound Alterations in Mechanosensitive Dorsal Root Ganglion Neurons with Vitamin E Deficiency

Finno CJ, Peterson J, Kang M, Park S, Bordbari MH, Durbin-Johnson B, Settles M, Perez-Flores MC, Lee JH, Yamoah EN

iScience. 2019 Nov 22;21:720-735. doi: 10.1016/j.isci.2019.10.064.

Abstract

Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa-/- mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa-/- DRGNs showed marked upregulation of voltage-gated Ca2+ and K+ channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa-/- DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation.

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Bioactive Compounds: Natural Defense Against Cancer?

Subramaniam S, Selvaduray KR, Radhakrishnan AK

Biomolecules. 2019 Nov 21;9(12). pii: E758. doi: 10.3390/biom9120758.

Abstract

Cancer is a devastating disease that has claimed many lives. Natural bioactive agents from plants are gaining wide attention for their anticancer activities. Several studies have found that natural plant-based bioactive compounds can enhance the efficacy of chemotherapy, and in some cases ameliorate some of the side-effects of drugs used as chemotherapeutic agents. In this paper, we have reviewed the literature on the anticancer effects of four plant-based bioactive compounds namely, curcumin, myricetin, geraniin and tocotrienols (T3) to provide an overview on some of the key findings that are related to this effect. The molecular mechanisms through which the active compounds may exert their anticancer properties in cell and animal-based studies also discussed.

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Tocotrienol-rich fraction from annatto ameliorates expression of lysyl oxidase in human osteoblastic MG-63 cells

Kohno K, Yamada W, Ishitsuka A, Sekine M, Virgona N, Ota M, Yano T

Biosci Biotechnol Biochem. 2019 Nov 19:1-10. doi: 10.1080/09168451.2019.1693252.

Abstract

Lysyl oxidase (LOX) is required for the formation of bone collagen cross-links. Inactivation of the LOX gene in osteoblasts by DNA methylation and JAK signaling has been reported to cause loss of cross-links and an increased risk of fractures. Tocotrienols (T3s) have proven benefits on bone strength, but their potential effects on LOX remain largely unknown. Thus, the present study investigates the in vitro effects of T3s on LOX expression in human osteoblastic MG-63 cells. Results indicated that Tocotrienol-Rich Fraction (TRF), the δ-T3 rich oil extracted from Annatto was the most effective and significantly increased LOX expression. TRF treatment decreased de-novo methyltransferases (DNMTs), DNMT3A and DNMT3B levels. In addition, TRF significantly inhibited JAK2 activation and decreased expression of Fli1, a transcription factor of DNMTs. We conclude that TRF induced an increase in LOX expression via inhibition of de-novo methylation and reduction of Fli1 expression by the inactivation of JAK2.

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Plasma versus Erythrocyte Vitamin E in Renal Transplant Recipients, and Duality of Tocopherol Species

Sotomayor CG, Rodrigo R, Gomes-Neto AW, Gormaz JG, Pol RA, Minović I, Eggersdorfer ML, Vos M, Riphagen IJ, de Borst MH, Nolte IM, Berger SP, Navis GJ, Bakker SJL

Nutrients. 2019 Nov 19;11(11). pii: E2821. doi: 10.3390/nu11112821.

Abstract

Redox imbalance is an adverse on-going phenomenon in renal transplant recipients (RTR). Vitamin E has important antioxidant properties that counterbalance its deleterious effects. However, plasma vitamin E affinity with lipids challenges interpretation of its levels. To test the hypothesis that erythrocyte membranes represent a lipids-independent specimen to estimate vitamin E status, we performed a cross-sectional study in a cohort of adult RTR (n = 113) recruited in a university setting (2015-2018). We compared crude and total lipids-standardized linear regression-derived coefficients of plasma and erythrocyte tocopherol species in relation to clinical and laboratory parameters. Strongly positive associations of fasting lipids with plasma tocopherol became inverse, rather than absent, in total lipids-standardized analyses, indicating potential overadjustment. Whilst, no variables from the lipids domain were associated with the tocopherol species measured from erythrocyte specimens. In relation to inflammatory status and clinical parameters with antioxidant activity, we found associations in directions that are consistent with either beneficial or adverse effects concerning α- or γ-tocopherol, respectively. In conclusion, erythrocytes offer a lipids-independent alternative to estimate vitamin E status and investigate its relationship with parameters over other biological domains. In RTR, α- and γ-tocopherol may serve as biomarkers of relatively lower or higher vulnerability to oxidative stress and inflammation, noticeably in opposite directions.

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