The Effect of Alpha-Tocopherol on Morphine Tolerance-induced Expression of c-fos Proto-oncogene from a Biotechnological Perspective

Mehrabi S, Nasirinezhad F, Barati M, Abutaleb N, Barati S, Dereshky BT, Amini N, Milan PB, Jahanmahin A, Sarveazad A, Samadikuchaksaraei A, Mozafari M

Recent Pat Biotechnol. 2019;13(2):137-148. doi: 10.2174/1872208312666181120105333.

Abstract

BACKGROUND:

The increase of oxidant compounds is the most well-known reasons for the tolerance to the analgesic properties of Morphine. Additionally, the production of proxy-nitrite impairs receptors, proteins and enzymes involved in the signaling pathways of analgesia, apoptosis and necrosis. Also, we revised all patents relating to opioid tolerance control methods.

OBJECTIVE:

The aim of this study was to assess the effects of Alpha-tocopherol as an anti-oxidant agent to reduce Morphine tolerance.

METHOD:

Forty male rats randomly divided into four groups. 10 mg/kg of morphine was injected subcutaneously to create the desired level of tolerance. After modeling, 70 mg/kg Alpha- Tocopherol was injected intraperitoneal. Also, the hot plate recorded pain threshold alterations was used to evaluate the behavioral test. All tissue samples were extracted from the spinal cord, thalamus and frontal cortex for molecular and gene expression evaluations. Also, the effect of Alpha- Tocopherol on the apoptosis and necrosis parameters was analyzed using nissl staining and tunel test.

RESULTS:

The time latency results showed that there were no significant differences in the different days in groups treated with Morphine plus Alpha-Tocopherol. However, our data highlighted that the pain threshold and their time latency in respond to it had substantially increased in comparison with the control group. Furthermore, we found that the Alpha-Tocopherol obviously decreased c-fos gene expression, especially in the spinal cord.

CONCLUSION:

Thus, co-administration of Alpha-Tocopherol with Morphine can decrease the adverse effects of nitrite proxy, which is released due to repeated injections of Morphine.

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Alpha-tocopherol in intravenous lipid emulsions imparts hepatic protection in a murine model of hepatosteatosis induced by the enteral administration of a parenteral nutrition solution

Fell GL, Anez-Bustillos L, Dao DT, Baker MA, Nandivada P, Cho BS, Pan A, O'Loughlin AA, Nose V, Gura KM, Puder M

PLoS One. 2019 Jul 11;14(7):e0217155. doi: 10.1371/journal.pone.0217155. eCollection 2019.

Abstract

Intestinal failure-associated liver disease (IFALD) is a risk of parenteral nutrition (PN)-dependence. Intravenous soybean oil-based parenteral fat can exacerbate the risk of IFALD while intravenous fish oil can minimize its progression, yet the mechanisms by which soybean oil harms and fish oil protects the liver are uncertain. Properties that differentiate soybean and fish oils include α-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little α-tocopherol. Fish oil contains abundant α-tocopherol and little phytosterols. This study tested whether α-tocopherol confers hepatoprotective properties while phytosterols confer hepatotoxicity to intravenous fat emulsions. Utilizing emulsions formulated in the laboratory, a soybean oil emulsion (SO) failed to protect from hepatosteatosis in mice administered a PN solution enterally. An emulsion of soybean oil containing α-tocopherol (SO+AT) preserved normal hepatic architecture. A fish oil emulsion (FO) and an emulsion of fish oil containing phytosterols (FO+P) protected from steatosis in this model. Expression of hepatic acetyl CoA carboxylase (ACC) and peroxisome proliferator-activated receptor gamma (PPARγ), was increased in animals administered SO. ACC and PPARγ levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for α-tocopherol in liver injury induced by the enteral administration of a parenteral nutrition solution. Phytosterols do not appear to compromise the hepatoprotective effects of fish oil.

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Combination Effect of Bowman-Birk Inhibitor and α-Tocopheryl Succinate on Prostate Cancer Stem-Like Cells

Kaneko S, Yamazaki T, Kohno K, Sato A, Kato K, Yano T

J Nutr Sci Vitaminol (Tokyo). 2019;65(3):272-277. doi: 10.3177/jnsv.65.272.

Abstract

The reoccurrence of androgen-dependent prostate cancer after anti-androgen therapy mainly depends on prostate cancer stem-like cells. To reduce the risk, it is important to delete the cancer stem-like cells. Furthermore, to induce differentiation of cancer stem-like cells is critical to abrogate stemness of the cells. Therefore, we tried to investigate a possibility on the establishment of a new effective therapy to eradicate the cancer stem-like cells via the induction of differentiation in this study. Prostate cancer stem-like cells from an androgen-dependent prostate cancer cell line (LNCaP cell) had severe resistance against an anti-androgen therapeutic agent. We selected Bowman-Birk inhibitor (BBI) from soybeans reported as a chemopreventive agent in prostate cancer to differentiate the caner stem-like cells and α-tocopheryl succinate (TOS) known as a mitocan to induce effectively cytotoxic effect against the cancer stem-like cells. In fact, only TOS treatment had cytotoxic effect against the cancer stem-like cells, but the addition of BBI treatment to the cells treated with TOS reinforced TOS-mediated cytotoxicity in the cancer stem-like cells. This reinforcement coincided with the combination-enhanced apoptosis in the stem-like cells. Also, we confirmed caspase9-caspase3 cascade mainly contributed to the enhancement of the cytotoxicity in the stem-like cells caused by the combination, indicating that the reinforcement of BBI on TOS-mediated apoptosis via mitochondria related to the enhancing cytotoxic effect of the combination on the prostate cancer stem-like cells. Overall, it seems that the combination is an effective new approach to reduce the reoccurrence of prostate cancer targeting prostate cancer stem cells.

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Vitamin E and Alzheimer’s disease: what do we know so far?

Browne D, McGuinness B, Woodside JV, McKay GJ

Clin Interv Aging. 2019 Jul 18;14:1303-1317. doi: 10.2147/CIA.S186760. eCollection 2019.

Abstract

Vitamin E has been proposed as a potential clinical intervention for Alzheimer’s disease (AD) given the plausibility of its various biological functions in influencing the neurodegenerative processes associated with the condition. The tocopherol and tocotrienol isoforms of vitamin Ehave multiple properties including potent antioxidant and anti-inflammatory characteristics, in addition to influences on immune function, cellular signalling and lowering cholesterol. Several of these roles offer a theoretical rationale for providing benefit for the treatment of AD-associated pathology. Diminished circulating concentrations of vitamin E have been demonstrated in individuals with AD. Reduced plasma levels have furthermore been associated with an increased risk of AD development while intake, particularly from dietary sources, may limit or reduce the rate of disease progression. This benefit may be linked to synergistic actions between vitamin E isoforms and other micronutrients. Nevertheless, randomised trials have found limited and inconsistent evidence of vitamin E supplementation as an effective clinical intervention. Thus, despite a strong rationale in support of a beneficial role for vitamin E for the treatment of AD, the evidence remains inconclusive. Several factors may partly explain this discrepancy and represent the difficulties of translating complex laboratory evidence and dietary interactions into clinical interventions. Methodological design limitations of existing randomised trials and restrictions to supplementation with a single vitamin E isoform may also limit the influence of effect. Moreover, several factors influence individual responsiveness to vitamin E intake and recent findings suggest variation in the underlying genetic architecture attenuates vitamin E biological availability and activity which likely contributes to the variation in clinical responsiveness and the failure of randomised trials to date. Importantly, the clinical safety of vitamin E remains controversial and warrants further investigation.

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Antioxidant vitamin supplementation prevents oxidative stress but does not enhance performance in young football athletes

de Oliveira DCX, Rosa FT, Simões-Ambrósio L, Jordao AA, Deminice R

Nutrition. 2019 Jul - Aug;63-64:29-35. doi: 10.1016/j.nut.2019.01.007. Epub 2019 Jan 24.

Abstract

OBJECTIVES:

The aim of this study was to verify the effects of supplementation with antioxidants (vitamins C and E) on oxidative stress, delayed-onset muscle soreness (DOMS), and performance in football players during a recovery period after an exercise-induced oxidative stress protocol.

METHODS:

Twenty-one football athletes were randomly assigned to two groups: placebo and antioxidant-supplemented. Supplementation was performed in a double-blind, controlled manner using vitamin C (500 mg/d) and E (400 UI/d) for 15 d. After 7 d of supplementation, athletes were submitted to an exercise-induced oxidative stress protocol consisting of plyometric jumping and strength resistance sets to exhaustion. Blood samples, performance tests, and DOMS were determined before and 24, 48, and 72 h after exercise.

RESULTS:

Antioxidant supplementation was continued during the recuperation week and for a total of 15 d. Antioxidant supplementation caused a significant increase in plasma vitamins C and E. The antioxidant supplementation could inhibit oxidative stress characterized by elevated lipid peroxidation markers malondialdehyde and total lipid peroxidation as well as reduced ratio of glutathione to oxidized glutathione promoted by exercise. Antioxidant supplementation, however, did not significantly reduce the plasma creatine kinesis concentration or DOMS during the recovery days. Likewise, supplementation with vitamin C and E did not improve lower body power, agility, or anaerobic power, nor did it provide any indication of faster muscle recovery.

CONCLUSION:

Antioxidant supplementation does not attenuate elevated markers of muscle damage or muscle soreness promoted by acute exercise and do not exert any ergogenic effect on football performance of young athletes, although it reduced oxidative stress.

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Effect of atherosclerosis and the protective effect of the antioxidant vitamin E on the rabbit cerebellum

Elbeltagy MAF, Elkholy WB, Salman AS

Microscopy (Oxf). 2019 Jul 15. pii: dfz023. doi: 10.1093/jmicro/dfz023. [Epub ahead of print]

Abstract

BACKGROUND:

Atherosclerosis is a major cardiovascular disease and one of the commonest causes of mortality in the world. Speech, balance, fine motor control and cognition are affected by atherosclerosis of cerebellar arteries. This study investigated the protective role of vitamin E against induced atherosclerosis in the rabbit cerebellum.

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Development of α-tocopherol surface-modified targeted delivery of 5-fluorouracil-loaded poly-D, L-lactic-co-glycolic acid nanoparticles against oral squamous cell carcinoma

Srivastava S, Gupta S, Mohammad S, Ahmad I

J Cancer Res Ther. 2019 Jul-Sep;15(3):480-490. doi: 10.4103/jcrt.JCRT_263_18.

Abstract

OBJECTIVE:

The aim of the study to develop surface modified targeted moiety α-tocopherol (α-t) encapsulated with 5-fluorouracil (5-FU)-poly-D, L-lactic-co-glycolic acid nanoparticles (PLGA NPs) toward the anticancer activity against oral squamous cell carcinoma (OSCC).

MATERIALS AND METHODS:

5-FU was conjugated with the polymer, PLGA by ionic cross-linking and α-tocopherol use as a functionalized surface moiety. Characterization, drug entrapment efficiency, and in-vitro drug release system were optimized at different pH 7.4 and pH 4.5. The in-vitro cell was performed to optimize the anticancer activity through MTT assay and apoptotic staining assay was also performed by flow cytometry to evaluate the cellular apoptotic activity and cellular uptake.

RESULTS:

The particle size was distributed within an average range of 145-162 nm, the polydispersity index values lie 0.16-0.30, and the surface charge was at the negative side, -17mV to -23mV. The in vitro drug release system showed more sympathetic situation at pH 7.4 as compared to pH 4.5, for targeted NPs, approximately 86% and 69%, respectively. The non-targeted 5-FU-PLGA NPs showed drug release of 83% and 64% at pH 7.4 and 4.5 subsequently. In vitro anticancer activity confirmed the intense inhibition by α-t-FU-PLGA NPs of 79.98% after 96 h treatment of SCC15 cells and confirmed the steady-state inhibition of 83.74% after 160 h incubation in comparison to 5-FU-PLGA NPs. Subsequently, the early apoptosis, 27.98%, and 16.45%, and late apoptosis, 47.29%, and 32.57%, suggested the higher apoptosis rate in targeted NPs against OSCC.

CONCLUSIONS:

The surface modified α-t-FU-PLGA NP was treated over SCC15 cells, and the oral cancer cells have shown the high intensity of cellular uptake, which confirmed that the target moiety has successfully invaded over the surface of cancer cells and shown advanced targeted delivery against OSCC.

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Tocotrienols and Cancer: From the State of the Art to Promising Novel Patents

Fontana F, Raimondi M, Marzagalli M, Moretti RM, Marelli MM, Limonta P

Recent Pat Anticancer Drug Discov. 2019;14(1):5-18. doi: 10.2174/1574892814666190116111827.

Abstract

BACKGROUND:

Tocotrienols (TTs) are vitamin E derivatives naturally occurring in several plants and vegetable oils. Like Tocopherols (TPs), they comprise four isoforms, α, β, γ and δ, but unlike TPs, they present an unsaturated isoprenoid chain. Recent studies indicate that TTs provide important health benefits, including neuroprotective, anti-inflammatory, anti-oxidant, cholesterol lowering and immunomodulatory effects. Moreover, they have been found to possess unique anti-cancer properties.

OBJECTIVE:

The purpose of this review is to present an overview of the state of the art of TTs role in cancer prevention and treatment, as well as to describe recent patents proposing new methods for TTs isolation, chemical modification and use in cancer prevention and/or therapy.

METHODS:

Recent literature and patents focusing on TTs anti-cancer applications have been identified and reviewed, with special regard to their scientific impact and novelty.

RESULTS:

TTs have demonstrated significant anti-cancer activity in multiple tumor types, both in vitro and in vivo. Furthermore, they have shown synergistic effects when given in combination with standard anti-cancer agents or other anti-tumor natural compounds. Finally, new purification processes and transgenic sources have been designed in order to improve TTs production, and novel TTs formulations and synthetic derivatives have been developed to enhance their solubility and bioavailability.

CONCLUSION:

The promising anti-cancer effects shown by TTs in several preclinical studies may open new opportunities for therapeutic interventions in different tumors. Thus, clinical trials aimed at confirming TTs chemopreventive and tumor-suppressing activity, particularly in combination with standard therapies, are urgently needed.

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A Redox-Inactive Derivative of Tocotrienol Suppresses Tumor Growth of Mesothelioma Cells in a Xenograft Model

Sato A, Arai T, Fusegi M, Ando A, Yano T

Biol Pharm Bull. 2019;42(6):1034-1037. doi: 10.1248/bpb.b18-00924.

Abstract

Malignant mesothelioma (MM) is an aggressive cancer with poor prognosis. We focused on the anticancer activity of tocotrienol (T3) and have reported that a new redox-inactive T3 derivative (6-O-carboxypropyl-α-tocotrienol; T3E) exerts stronger inhibitory effects on MM cell growth than that of T3 in vitro. Furthermore, we have revealed some mechanisms of T3E that are involved in anti-MM effects. However, the effect of T3E in vivo remains unclear. In this study, we compared the plasma concentrations of T3E to that of T3 using mice to clarify differences in pharmacokinetics. Blood was sequentially collected after oral administration of T3 or T3E, and plasma concentrations were analyzed by HPLC. The area under the plasma T3 and T3E concentration-time curve from 0 to 24 h (AUC0-24 h) of T3E was two times higher than that of T3. In addition, we evaluated the effect of T3E oral administration on tumor growth using a xenograft model of mice that were transplanted with human MM cells (H2052 cell line). Tumor volume was significantly reduced without body weight loss in mice orally administered 150 mg/kg T3E once per 2 d for 10 d, which suggests that T3E has potential anti-MM effects.

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Vitamin E (α-tocopherol) consumption influences gut microbiota composition

Choi Y, Lee S, Kim S, Lee J, Ha J, Oh H, Lee Y, Kim Y, Yoon Y

Int J Food Sci Nutr. 2019 Jul 12:1-5. doi: 10.1080/09637486.2019.1639637. [Epub ahead of print]

Abstract

This study evaluated if vitamin E consumption affects gut microbiota. Mice were grouped into control, low vitamin E (LV), and high vitamin E (HV). LV and HV were fed DL-α-tocopherol at 0.06 mg/20 g and 0.18 mg/20 g of body weight per day, respectively, for 34 days. Body weight of mice was measured before and after vitamin E treatment. Animals were sacrificed, liver, spleen, small intestine and large intestine collected, and weight and length were measured. Composition of gut microbiota was determined by microbiome analysis. Spleen weight index of LV was the highest. However, liver weight indices and intestinal lengths were not different. Body weights of LV group were higher than those of control. Ratio of Firmicutes to Bacteroidetes was different in LV compared to control and HV. These results indicate that low-level consumption of vitamin E increases spleen and body weight, and changes gut microbiota.

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