γ-Tocotrienol Suppression of the Warburg Effect Is Mediated by AMPK Activation in Human Breast Cancer Cells

Dronamraju V, Ibrahim BA, Briski KP, Sylvester PW

Nutr Cancer. 2019 Apr 6:1-15. doi: 10.1080/01635581.2019.1599969. [Epub ahead of print]

Abstract

Cancer cell metabolism is characterized by aerobic glycolysis or the “Warburg effect”. Enhanced Akt signaling is associated with activation of various downstream enzymes involved in the glycolytic process, whereas activation of 5′-AMP-activated kinase (AMPK) acts to terminate energy expending mechanisms and decrease glycolytic enzyme expression. Studies were conducted to determine if the anticancer effects of γ-tocotrienol, are mediated through a suppression in aerobic glycolysis. Results show that treatment with 0-7 μM γ-tocotrienol throughout a 4-day culture period resulted in a dose-responsive increase in AMPK activation, and corresponding decrease in Akt activity in human MCF-7 and MDA-MB-231 breast cancer cells. γ-Tocotrienol treatment was also found to induce a dose-responsive decrease in phosphorylated-Fox03 (inactivated), a transcription factor that acts to inhibit in the levels of glycolytic enzyme, and this decrease was associated with a reduction in glycolytic enzyme levels and activity, as well as glucose consumption in these cells. PCR microarray analysis shows that γ-tocotrienol treatment decreases the expression of genes associate with metabolic signaling and glycolysis in MCF-7 and MDA-MB-231 breast cancer cells. In summary, these findings demonstrate that the anticancer effects of γ-tocotrienol are mediated, at least in part, by a suppression in the Warburg effect.

Massaccesi L, Ragone V, Papini N, Goi G, Corsi Romanelli MM, Galliera E

Front Endocrinol (Lausanne). 2019 Apr 3;10:203. doi: 10.3389/fendo.2019.00203. eCollection 2019.

Abstract

High Crosslink process was introduced in the development of joint prosthetic devices, in order to decrease the wear rate of ultrahigh molecular weight polyethylene (UHMWPE), but it also triggers the formation of free radicals and oxidative stress, which affects the physiological bone remodeling, leading to osteolysis. Vitamin E stabilization of UHMWPE was proposed to provide oxidation resistance without affecting mechanical properties and fatigue strength. The aim of this study is to evaluate the antioxidant effect of vitamin E added to UHMWPE on oxidative stress induced osteolysis, focusing in particular on the oxidative stress response in correlation with the production of osteoimmunological markers, Sclerostin and DKK-1, and the RANKL/OPG ratio compared to conventional UHMWPE wear debris. Human osteoblastic cell line SaOS2 were incubated for 96 h with wear particles derived from crosslinked and not crosslinked Vitamin E-stabilized, UHMWPE without Vitamin E, and growth medium as control. Cellular response to oxidative stress, compared to not treat cells, was evaluated in terms of proteins O-GlcNAcylation, cellular levels of OGA, and OGT proteins by immunoblotting. O-GlcNAcylation and its positive regulator OGT levels are increased in the presence of Vitamin E blended UHMWPE, in particular with not crosslinked Vit E stabilized UHMWPE. Conversely, the negative regulator OGA increased in the presence of UHMWPE not blended with Vitamin E. Vitamin E-stabilized UHMWPE induced a decrease of RANKL/OPG ratio compared to UHMWPE without Vitamin E, and the same effect was observed for Sclerostin, while DKK-1 was not significantly affected. In conclusion, Vitamin E stabilization of UHMWPE increased osteoblast response to oxidative stress, inducing a cellular mechanism aimed at cell survival. Vitamin E antioxidant effect influences the secretion of osteoimmunological factors, shifting the bone turnover balance toward bone protection stimuli. This suggests that Vitamin E-Stabilization of UHMWPE could contribute to reduction of oxidation-induced osteolysis and the consequent loosening of the prosthetic devices, therefore improving the longevity of total joint replacements.

Husain K, Zhang A, Shivers SC, Davis-Yadley AH, Coppola D, Yang CS, Malafa MP

Cancer Prev Res (Phila). 2019 Apr 2. pii: canprevres.0290.2018. doi: 10.1158/1940-6207.CAPR-18-0290. [Epub ahead of print]

Abstract

This study evaluated the preclinical activity of δ-tocotrienol (DT3), a bioactive form of vitamin E, in the inhibition of colorectal cancer growth and development in vitro and in vivo. DT3 is the most bioactive isomer of vitamin E in inhibiting growth of colorectal cancer cells. However, it had little effect on the proliferation of normal colon mucosal cells NCM460. In HCT-116 and SW-620 colorectal cancer cells, DT3 (50 µM) significantly inhibited malignant transformation (P < .02, P < .001), cell migration (P < .02, P < .05) and invasion (P < .05, P < .01) compared to vehicle. DT3 inhibited markers for epithelial (E-cadherin) to mesenchymal (vimentin) transition, metastasis (matrix metalloproteinase 9), angiogenesis vascular endothelial growth factor (VEGF), inflammation (NF-kB), and Wnt signaling (β-catenin) compared to vehicle in colorectal cancer cells. DT3 induced apoptosis selectively in colorectal cancer cells (SW-620 cells, HCT-116 cells, and HT-29) without affecting the normal colon cells. In the Azoxymethane-induced colorectal carcinogenesis model in rats, DT3 (200 mg/kg orally twice a day) for 20 weeks significantly inhibited colorectal polyps by 70% and colorectal cancer by almost 99% compared to the vehicle treatment group (P < .02, P < .001), and the cancer inhibition effect was more potent than sulindac (50%). Taken together, these data demonstrate that DT3 is a potential chemopreventive agent in colorectal cancer, warranting further investigation into its clinical use in the prevention and treatment of colorectal cancer.

Abdel-Daim MM, Aleya L, El-Bialy BE, Abushouk AI, Alkahtani S, Alarifi S, Alkahtane AA, AlBasher G, Ali D, Almeer RS, Al-Sultan NK, Alghamdi J, Alahmari A, Bungau SG

Environ Sci Pollut Res Int. 2019 Mar 30. doi: 10.1007/s11356-019-04801-2. [Epub ahead of print]

Abstract

Nephrotoxicity is a common adverse effect of treatment with cisplatin (CDDP). This study was performed to evaluate the antioxidant and nephroprotective efficacy of ceftriaxone (CTX) and vitamin E (Vit.E), alone and in combination against CDDP-induced acute renal injury. Fifty-six male albino rats were equally divided into seven groups, receiving (I) normal saline, (II) CTX (100 mg/kg, intraperitoneal [i.p] injection), (III) Vit.E (100 mg/kg orally), (IV) CDDP (5 mg/kg i.p injection), (V) CDDP plus CTX, (VI) CDDP plus Vit.E, and (VII) CDDP plus CTX in combination with Vit.E. All treatments were administered daily for 10 days except CDDP, which was given as a single dose at the sixth day of the study. Compared to normal control rats, CDDP-injected rats showed significantly (p < 0.05) higher serum levels of renal injury biomarkers (uric acid, urea, and creatinine) and tumor necrosis factor-α (TNF-α), as well as increased renal tissue concentrations of malondialdehyde, nitric oxide, and TNF-α. Moreover, CDDP administration was associated with significantly lower (p < 0.05) renal tissue levels of reduced glutathione and activities of endogenous antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) and total antioxidant capacity. All these alterations were significantly ameliorated in CDDP-injected rats, receiving CTX and/or Vit.E, compared to rats receiving CDDP alone. Interestingly, the antioxidant and anti-inflammatory effects were more marked in the CTX-Vit.E combination group, compared to groups receiving either drug alone. In conclusion, CTX and Vit.E (especially in combination) could counteract the nephrotoxic effect of CDDP, probably through their antioxidant activities.

Wang W, Li J, Zhang H, Wang X, Zhang X

Nutr Neurosci. 2019 Mar 22:1-10. doi: 10.1080/1028415X.2019.1585506. [Epub ahead of print]

Abstract

OBJECTIVE:

The association between vitamin E supplementation and Alzheimer’s disease (AD) was controversial because of conflicting data in the literature. This study was designed to systematically evaluate evidence about the efficacy of vitamin E supplementation not only on the risk but also on the progression of AD.

DESIGN:

Five electronic databases were searched for studies published up to June 2017. Articles reporting vitamin E supplementation and AD were included, and the random-effect model was performed for the meta-analysis about the relationship between vitamin Esupplementation and AD.

RESULTS:

Five cohort studies and three randomized controlled trial (RCT) studies (total n = 14,262) involving 1313 cases about vitamin Eeffects on the risk of AD and 244 cases about effects on progression of AD. The pooled RR for vitamin E supplemental and risk of AD was 0.81 [95% CI: 0.50-1.33, I² = 69.2%]. Suitable data could not be extracted to do meta-analysis as there was no unified standard of outcome measure for studies on AD progression. We carefully analyzed and evaluated the authenticity and accuracy of every single trial, while reliable evidence could not be obtained.

CONCLUSIONS:

From what we do, neither the synthetic data on risk of AD nor the critical review on progression of AD could provide enough evidence on our research. Thus, we cannot draw a specific conclusion on the association or correlation between Vitamin E and AD.

Wong SK, Mohamad NV, Ibrahim N', Chin KY, Shuid AN, Ima-Nirwana S

Int J Mol Sci. 2019 Mar 22;20(6). pii: E1453. doi: 10.3390/ijms20061453.

Abstract

Bone remodelling is a tightly-coordinated and lifelong process of replacing old damaged bone with newly-synthesized healthy bone. In the bone remodelling cycle, bone resorption is coupled with bone formation to maintain the bone volume and microarchitecture. This process is a result of communication between bone cells (osteoclasts, osteoblasts, and osteocytes) with paracrine and endocrine regulators, such as cytokines, reactive oxygen species, growth factors, and hormones. The essential signalling pathways responsible for osteoclastic bone resorption and osteoblastic bone formation include the receptor activator of nuclear factor kappa-B (RANK)/receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG), Wnt/β-catenin, and oxidative stress signalling. The imbalance between bone formation and degradation, in favour of resorption, leads to the occurrence of osteoporosis. Intriguingly, vitamin E has been extensively reported for its anti-osteoporotic properties using various male and female animal models. Thus, understanding the underlying cellular and molecular mechanisms contributing to the skeletal action of vitamin E is vital to promote its use as a potential bone-protecting agent. This review aims to summarize the current evidence elucidating the molecular actions of vitamin E in regulating the bone remodelling cycle.

Jian H, Ai-Min L

Hepatology. 2019 Mar 18. doi: 10.1002/hep.30603. [Epub ahead of print]

Abstract

According to the article conducted by Eduardo et al.(1), the non-transplant survival rate of nonalcoholic steatohepatitis (NASH) patients with bridging necrosis and cirrhosis, which is a subtype of non-alcoholic fatty liver disease (NAFLD), was found to be improved by vitamin E, who will reduce the occurrence of liver decompensation. However, combined with the literature we have reviewed and the clinical experience we have achieved, two important factors that may affect the study results will be proposed in the article. This article is protected by copyright. All rights reserved.

Chin KY, Ima-Nirwana S

Int J Mol Sci. 2019 Mar 18;20(6). pii: E1355. doi: 10.3390/ijms20061355.

Abstract

Male osteoporosis is a significant but undetermined healthcare problem. Men suffer from a higher mortality rate post-fracture than women and they are marginalized in osteoporosis treatment. The current prophylactic agents for osteoporosis are limited. Functional food components such as tocotrienol may be an alternative option for osteoporosis prevention in men. This paper aims to review the current evidence regarding the skeletal effects of tocotrienol in animal models of male osteoporosis and its potential antiosteoporotic mechanism. The efficacy of tocotrienol of various sources (single isoform, palm and annatto vitamin E mixture) had been tested in animal models of bone loss induced by testosterone deficiency (orchidectomy and buserelin), metabolic syndrome, nicotine, alcoholism, and glucocorticoid. The treated animals showed improvements ranging from bone microstructural indices, histomorphometric indices, calcium content, and mechanical strength. The bone-sparing effects of tocotrienol may be exerted through its antioxidant, anti-inflammatory, and mevalonate-suppressive pathways. However, information pertaining to its mechanism of actions is superficial and warrants further studies. As a conclusion, tocotrienol could serve as a functional food component to prevent male osteoporosis, but its application requires validation from a clinical trial in men.

Sekar P, Chauhan A

J Colloid Interface Sci. 2019 Mar 15;539:457-467. doi: 10.1016/j.jcis.2018.12.036. Epub 2018 Dec 17.

Abstract

HYPOTHESIS:

Glaucoma is effectively treated by prostaglandin analogs. Low corneal bioavailability (<5%) of daily-instilled prostaglandin drops complemented by frequent application results in low patient compliance (<50%). One alternative route is ocular delivery via commercial hydrogel contact lens. Commercial lenses, however, release prostaglandins rapidly in a few hours owing to their small molecular size, resulting in toxic side-effects. Here, the feasibility of sustained prostaglandin, namely bimatoprost and latanoprost delivery by vitamin-Eintegrated polymeric hydrogels is explored. Inclusion of these barriers is expected to augment transport resistance and influence delivery rates.

EXPERIMENTS:

Lens immersion in vitamin-E concentrated ethanol is done to enable formation of nano-barrier depots.

FINDINGS:

Pilot in vitro studies indicate that ACUVUE® OASYS® and ACUVUE® TruEye™ lenses loaded with ∼0.2 g of vitamin-E/g of hydrogel effectively prolong bimatoprost dynamics by 10-40-fold, delivering therapeutic dosages for >10 days. Incorporation of vitamin-E into the lenses retains visible light transmission and other properties. Further, vitamin-E integration does not influence latanoprost transport. An in vivo model involving coupled mass transport in the lens and post-lens tear film (POLTF) domains predicts >50% corneal bioavailability of bimatoprost delivered via modified lenses.

Takahashi K, Yanai S, Takisawa S, Kono N, Arai H, Nishida Y, Yokota T, Endo S, Ishigami A

Arch Biochem Biophys. 2019 Mar 15;663:120-128. doi: 10.1016/j.abb.2019.01.003. Epub 2019 Jan 8.

Abstract

BACKGROUND:

Vitamin C (l-ascorbic acid, VC) and vitamin E (α-tocopherol, VE) play important physiological roles as endogenous antioxidants in many tissues and organs. However, their roles in the brain remain entirely elusive. We established senescence marker protein 30 (SMP30)/α-tocopherol transfer protein (αTTP) double knockout (DKO) mice as a novel VC and VE double-deficiency model and examined the effect of VC and VE double-deficiency on brain functions.

METHODS:

DKO and wild-type (WT) mice were divided into the following two groups: mice in the CE (+) group were supplied with sufficient amounts of VC and VE and mice in the CE (-) group were deficient in both VC and VE. After 8 weeks of CE (+) or CE (-) treatments, a battery of behavioral experiments was conducted to analyze cognitive functions, including memory, through the Morris water maze and Pavlovian fear conditioning tasks.

RESULTS:

The plasma VC and VE levels in DKO-CE (-) mice and VE level in WT-CE (-) mice were almost completely depleted after 8 weeks of the deficient treatment. The behavioral study revealed that the general behaviors, including locomotor activity and anxiety level, were not influenced by the CE (-) treatment in DKO and WT mice. However, in the Pavlovian fear conditioning task, DKO-CE (-) mice showed impaired conditioned fear memory compared with that of DKO-CE (+) mice. Furthermore, increased mRNA expression was observed in inflammatory-related genes, such as IL-6, TNFα, F4/80, and Mcp-1, in the hippocampus of DKO-CE (-) mice.

CONCLUSIONS:

The findings of this study provide evidence that VC and VE deficiency led to impaired conditioned fear memory possibly caused by neuroinflammation in the brain.