Monthly Archives: August 2019

Vitamin E D-alpha-tocopheryl polyethylene glycol 1000 succinate-conjugated liposomal docetaxel reverses multidrug resistance in breast cancer cells

Li N, Fu T, Fei W, Han T, Gu X, Hou Y, Liu Y, Yang J

J Pharm Pharmacol. 2019 Aug;71(8):1243-1254. doi: 10.1111/jphp.13126. Epub 2019 Jun 18.

Abstract

OBJECTIVES:

Multidrug resistance (MDR) remains a primary challenge in breast cancer treatment. In the present study, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS)-coated docetaxel-loaded liposomes were developed as a novel drug delivery system to reverse MDR and enhance breast cancer therapy compared with the traditional liposomes, DSPE-mPEG-coated liposomes (stealth liposomes) and commercial Taxotere® .

KEY FINDINGS:

Liposomes were prepared by thin – film dispersion method. Evaluations were performed using human breast cancer MCF-7 and resistant MCF-7/ADR cells. The reversal multidrug-resistant effect was assessed by P-gp inhibition assay, cytotoxicity, cellular uptake and apoptosis assay.

RESULTS:

The TPGS-chol-liposomes were of an appropriate particle size (140.0 ± 6.0 nm), zeta potential (-0.196 ± 0.08 mv), high encapsulation efficiency (99.0 ± 0.9) and favourable in vitro sustained release. The TPGS-coated liposomes significantly improved cytotoxicity and increased the intracellular accumulation of docetaxel in both types of breast cancer cells. The TPGS-coated liposomes were confirmed to induce apoptosis via a synergistic effect between docetaxel and TPGS. It was demonstrated that TPGS enhanced the intracellular accumulation of drug by inhibiting overexpressed P-glycoprotein.

CONCLUSIONS:

The TPGS-conjugated liposomes showed significant advantages in vitro compared with the PEG-conjugated liposomes. The TPGS-conjugated liposomes could reverse the MDR and enhance breast cancer therapy.

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Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial

Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J, Tio F, Suman A, Orsak BK, Hecht J, Cusi K

Diabetes Care. 2019 Aug;42(8):1481-1488. doi: 10.2337/dc19-0167. Epub 2019 May 21.

Abstract

OBJECTIVE:

While vitamin E has shown to improve nonalcoholic steatohepatitis (NASH) in patients without diabetes, information on patients with type 2 diabetes mellitus (T2DM) is lacking. The aim of this study was to determine whether vitamin E, alone or combined with pioglitazone, improves histology in patients with T2DM and NASH.

RESEARCH DESIGN AND METHODS:

This was a proof-of-concept, randomized, double-blind, placebo-controlled trial conducted from 2010 to 2016. Patients with T2DM and biopsy-proven NASH (n = 105) were randomized to vitamin E 400 IU b.i.d., vitamin E 400 IU b.i.d. plus pioglitazone 45 mg/day, or placebo. Eighty-six patients completed the 18-month study. The primary end point was a two-point reduction in the nonalcoholic fatty liver disease activity score from two different parameters, without worsening of fibrosis. Secondary outcomes were resolution of NASH without worsening of fibrosis, individual histological scores, and metabolic parameters.

RESULTS:

More patients on combination therapy achieved the primary outcome versus placebo (54% vs. 19%, P = 0.003) but not with vitamin E alone (31% vs. 19%, P = 0.26). Both groups showed improvements in resolution of NASH compared with placebo (combination group: 43% vs. 12%, P = 0.005; vitamin E alone: 33% vs. 12%, P = 0.04). While steatosis assessed by histology improved with combination therapy (P < 0.001) and vitamin E alone (P = 0.018), inflammation (P = 0.018) and ballooning (P = 0.022) only improved with combination therapy. No improvement in fibrosis was observed in any group.

CONCLUSIONS:

In this proof-of-concept study, combination therapy was better than placebo in improving liver histology in patients with NASH and T2DM. Vitamin E alone did not significantly change the primary histological outcome.

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Bi-layered α-tocopherol acetate loaded membranes for potential wound healing and skin regeneration

Zahid S, Khalid H, Ikram F, Iqbal H, Samie M, Shahzadi L, Shah AT, Yar M, Chaudhry AA, Awan SJ, Khan AF, Rehman IU

Mater Sci Eng C Mater Biol Appl. 2019 Aug;101:438-447. doi: 10.1016/j.msec.2019.03.080. Epub 2019 Mar 23.

Abstract

With an increase in the demand for skin regeneration products, there is a noticeable increase in developing materials that encourage, wound healing and skin regeneration. It has been reported that antioxidants play an important role in anti-inflammatory reactions, cellular proliferation and remodeling phase of wound healing. While consideration all these factors, a novel α-tocopherol acetate (vitamin E) (VE) loaded bi-layered electrospun membrane, based on lower polycaprolactone (PCL) layer and upper polylactic acid (PLA) layer, was fabricated through electrospinning. Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), in-vitro degradation studies, swelling studies and VE release studies were performed to evaluate structural, physical and in-vitro behavior of membranes. Biological properties of membranes were evaluated through cell proliferation assay, cell adhesion studies, live/dead cell assay and CAM assay. SEM images showed that the average diameter of nanofibers ranged from 1 to 6 μm, while addition of VE changed the diameter and morphology of fibers. Bi-layered membranes showed significant swelling behavior through water uptake, membranes loaded with 30% VE showed 8.7% and 6.8% degradation in lysozyme and H2O2 respectively. 20% and 30% VE loaded membranes followed Korsmeyer-Peppas and first order drug release kinetics followed by non-fickian drug release kinetics. Membranes showed non-toxic behavior and supported cell proliferation via alamar blue assay, cell adhesion via SEM, cell viability via live/dead assay and wound healing by scratch assay. CAM assay showed that membranes having VE supported angiogenesis and showed significant formation of blood vessels making it suitable for skin regeneration and wound healing. Results showed that large surface area of nanofibers, porous structure and biocompatible nature are suitable for targeted clinical applications.

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Effect of dietary vitamin E on oxidative stress-related gene-mediated differences in anxiety-like behavior in inbred strains of mice

Matsuo K, Watanabe T, Takenaka A

Physiol Behav. 2019 Aug 1;207:64-72. doi: 10.1016/j.physbeh.2019.04.026. Epub 2019 May 4.

Abstract

It has been reported that the degree of anxiety-like behavior differs between inbred strains of mice, and that this phenomenon was linked to the expression levels of the oxidative stress-related genes glyoxalase 1 (Glo1) and glutathione reductase 1 (Gsr) in the brain. Therefore, we investigated whether antioxidative activity in the brain affects the Glo1 and Gsr mRNA expressions and strain-dependent anxiety-like behavior using mice fed different amounts of vitamin E. First, we measured brain Glo1 and Gsr mRNA levels and evaluated the anxiety-like behaviors presented by C57BL/6J (B6) and DBA/2C (D2) mice. We demonstrated that D2 mice presented both significantly elevated Glo1 and Gsr mRNA levels as well as more prominent anxiety-like behavior in elevated plus-maze and open field tests. Next, we fed mice from these two strains either a control, vitamin E-free, or vitamin E-supplemented diet for four weeks. Plasma, liver, and brain α-tocopherolconcentrations changed in a dose-dependent manner. However, neither brain Glo1 and Gsr mRNA levels nor anxiety-like behavior were affected by dietary vitamin E intake. These results demonstrated that while strain-dependent anxiety-like behavior in mice was related to oxidative stress-related gene expression, the regulatory mechanisms for these genes and anxiety-like behaviors were independent of antioxidative activity in the brain. Strain-dependent differences of the anxiety in mice are probably related to the anxiolytic effects of methylglyoxal, a substrate for Glo1 and Gsr.

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A five-year follow-up study of antioxidants, oxidative stress and polyunsaturated fatty acids in schizophrenia

Solberg DK, Refsum H, Andreassen OA, Bentsen H

Acta Neuropsychiatr. 2019 Aug;31(4):202-212. doi: 10.1017/neu.2019.14. Epub 2019 Jun 10.

Abstract

OBJECTIVE:

Oxidative stress and dysregulated antioxidant defence may be involved in the pathophysiology of schizophrenia. In the present study, we investigated changes in antioxidants and oxidative stress from an acute to a later stable phase. We hypothesised that the levels of oxidative markers are increased in schizophrenia compared with healthy controls; change from the acute to the stable phase; and are associated with the levels of membrane polyunsaturated fatty acids (PUFAs) and symptom severity.

METHODS:

Fifty-five patients with schizophrenia spectrum disorders, assessed during an acute phase and 5 years later during a stable phase, and 51 healthy controls were included. We measured antioxidants (α-tocopherol, uric acid, albumin and bilirubin), markers of oxidative stress (F2-isoprostane and reactive oxygen metabolites) and membrane fatty acids. Antioxidants and oxidative stress markers were compared in schizophrenia versus healthy controls, adjusting for differences in sex, age and smoking, and changes over time. Associations between symptoms and PUFA were also investigated.

RESULTS:

In the acute phase, α-tocopherol was significantly higher (p &lt; 0.001), while albumin was lower (p &lt; 0.001) compared with the stable phase. Changes in α-tocopherol were associated with PUFA levels in the acute phase. In the stable phase, schizophrenia patients had higher uric acid (p = 0.009) and lower bilirubin (p = 0.046) than healthy controls. CRP was higher in patients in the stable phase (p &lt; 0.001), and there was no significant change from the acute phase.

CONCLUSION:

The present findings of change in antioxidant levels in the acute versus stable phase of schizophrenia the present findings suggest that redox regulation is dynamic and changes during different phases of the disorder.

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Preventative Effects of Vitamin E on Testicular Damage and Sperm Parameters in the First-Generation Mice Pups due to Pre- and Postnatal Mancozeb Exposure

Saddein E, Haghpanah T, Nematollahi-Mahani SN, Seyedi F, Ezzatabadipour M

J Toxicol. 2019 Aug 1;2019:4763684. doi: 10.1155/2019/4763684. eCollection 2019.

Abstract

The present study aimed to evaluate the effects of vitamin E on mancozeb-induced testis damage of the first-generation pups during intrauterine and lactating periods. Two groups of pregnant NMRI mice received 500 mg/kg mancozeb (MNZ) as MNZ group and 200 mg/kg vitamin E as MNZ+vit.E group before receiving MNZ. In addition, a vehicle and a control group were designed every other day in gestation and lactation periods. The male pups from each group were maintained until adulthood (8-10 W). The left testes and epididymides were removed following the sacrifice of the pups. Then, they were weighed, and sperm parameters including number, viability, motility, and morphology and testis structure were evaluated. A significant decrease occurred in sperm parameters of the mancozeb-treated pups compared to the control and vehicle groups. Treatment with vitamin E reversed the deleterious effects of MNZ to a nearly normal condition. Testis parameters including the weight, gonadosomatic index, seminiferous tubule diameters, and Johnsen’s score, as well as the number of germ cells such as spermatogonia, spermatocyte, spermatid, and Sertoli, decreased significantly in the MNZ group, compared to the amount in the control and vehicle groups. Interestingly, the treatment with vitamin E was reversed in most of these parameters. Based on the results, the exposure of pups to mancozeb during pregnancy and lactating periods negatively affects the reproductive system of male pups. However, the coadministration of vitamin E could prevent the deleterious effects of mancozeb on sperm and testis parameters.

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