Nonalcoholic steatohepatitis, obesity, and cardiac dysfunction

Mathews SE, Kumar RB, Shukla AP

Curr Opin Endocrinol Diabetes Obes. 2018 Oct;25(5):315-320. doi: 10.1097/MED.0000000000000432.



Obesity and nonalcoholic steatohepatitis (NASH) are epidemiologically and pathophysiologically linked disorders. Here, we summarize the effect of obesity on NASH and how it has a cascading effect on cardiovascular dysfunction. We also review the current and emerging treatment options for NASH.


The link between NASH and cardiac dysfunction has been further delineated in recent studies demonstrating endothelial dysfunction, diastolic dysfunction, and increased coronary artery calcification in patients with known NASH. Standard treatment of obesity with lifestyle interventions including diet, exercise, and behavioral modification has been shown to improve NASH as well as reduce cardiovascular dysfunction. In addition to FDA-approved drugs like vitamin E and pioglitazone, several agents including NGM282, obeticholic acid, elafibranor, and liraglutide are currently being investigated for their therapeutic potential in NASH. Recent studies show that bariatric surgery results in significant improvement or resolution of NASH.


Obesity is a major factor in the development of nonalcoholic fatty liver disease (NAFLD) and its progression to steatohepatitis. Patients with NAFLD have a significant increase in cardiovascular disease risk. For biopsy-proven NASH, vitamin E and pioglitazone are the recommended medical treatments in addition to lifestyle modification.

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Optimizing microencapsulation of α-tocopherol with pectin and sodium alginate

Singh J, Kaur K, Kumar P

J Food Sci Technol. 2018 Sep;55(9):3625-3631. doi: 10.1007/s13197-018-3288-6. Epub 2018 Jul 11.


αTocopherol is a well-known fat-soluble antioxidant and is widely used in the food industry for stabilizing free radicals. Incorporation and stability of it into food is another challenge as directly added αtocopherol is prone to inactivation by food constituents. This study was aimed at optimizing conditions for encapsulation of αtocopherol using combination of sodium alginate (0.5, 1.0, 1.5 and 2.0%) as primary wall material and pectin (2.0%) as filler. The optimum conditions were selected on the basis of encapsulation efficiency, shape, size, bulk density, yield and swelling index with syringe method. The encapsulation efficiency of αtocopherol in microencapsules produced under optimal conditions was 52.91% using sodium alginate 1.5% w/v and pectin 2.0% w/v. αTocopherol was encapsulated with encapsulator using standard conditions and was compared with syringe method. The encapsulation efficiency was found more (55.97%) in microencapsules prepared with encapsulator and 52.11% in microencapsules prepared with syringe.

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Dietary L-carnitine and vitamin-E; a strategy to combat ochratoxin-A induced immunosuppression.

Bhatti SA, Khan MZ, Hassan ZU, Saleemi MK, Khatoon A, Abidin ZU, Hameed MR

Toxicon. 2018 Aug 29. pii: S0041-0101(18)30358-1. doi: 10.1016/j.toxicon.2018.08.012. [Epub ahead of print]


This study aimed to evaluate the effect of dietary ochratoxin A (OA), in the presence and absence of L-carnitine (LC) and vitamin E (VE), on the humoral immune responses of White Leghorn cockerels (WLC). One-day old white male Leghorn chicks were divided into 12 groups, having 20 birds each and were offered ration contaminated with OA (1.0 or 2.0 mg/kg feed) alone and concurrently with LC (1.0 g/kg) and/or VE (0.2 g/kg), for 42 days. The humoral immune responses were accessed by lymphoproliferative response to avian tuberculin, in-vivo phagosomes activity to carbon particles and antibody response to the sheep red blood cells (SRBCs). The dietary addition of OA alone suppressed the humoral immune responses, however, the exposure of birds to 1.0 mg/kg OA in the presence of LC and/or VE showed a significant reduction in OA induced immunotoxicity. This protective response was absent in the birds fed 2.0 mg/kg OA in the presence and absence of LC and/or VE. Histopathological and morphometric examination of the bursa of Fabricius exhibited a decrease in the severity and frequency of OA induced lesions in the presence of dietary LC and/or VE. The use of LC and VE as dietary supplement, can effectively overcome OA (≤1.0 mg/kg) induced immunosuppression.

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Measurements of Singlet Oxygen-Quenching Activity of Vitamin E Homologs and Palm Oil and Soybean Extracts in a Micellar Solution

Mukai K, Ishikawa E, Ouchi A, Nagaoka SI, Abe K, Suzuki T, Izumisawa K

Lipids. 2018 Aug 28. doi: 10.1002/lipd.12053. [Epub ahead of print]


Recently, a new assay method that can quantify the singlet oxygen-absorption capacity (SOAC) of antioxidants (AO) and food extracts in homogeneous organic solvents has been proposed. In the present study, second-order rate constants (kQ ) for the reaction of singlet oxygen (1 O2 ) with vitamin E homologs (α-, β-, γ-, and δ-tocopherols [Toc] and α-, β-, γ-, and δ-tocotrienols [Toc-3]) were measured in an aqueous Triton X-100 (5.0 wt%) micellar solution (pH 7.4). Toc-3 showed kQ values larger than those of Toc in a micellar solution, although Toc and Toc-3 showed the same kQ values in a homogeneous solution. Similar measurements were performed for 5 palm oil extracts 1-5 and one soybean extract 6, which contained different concentrations of Toc, Toc-3, and carotenoids. It has been clarified that the 1 O2 -quenching rates (kQ ) (that is, the relative SOAC value) obtained for extracts 3-6 may be explained as the sum of the product ΣkQAO-iAO-i/100 of the rate constant (kQAO-i) and the concentration ([AO-i]/100) of AO-i contained. The UV-vis absorption spectra of Toc and Toc-3 were measured in a micellar solution and chloroform. The results obtained demonstrated that the kQ values of AO in homogeneous and heterogeneous solutions vary notably depending on (1) polarity (dielectric constant [ε]) of the reaction field between 1 O2 and AO, (2) the local concentration of AO, and (3) the mobility of AO in solution. The results suggest that the SOAC method is applicable to the measurement of 1 O2 -quenching activity of general food extracts in a heterogeneous micellar solution.

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DNA-loaded nano-adjuvant formed with a vitamin E-scaffold intracellular environmentally-responsive lipid-like material for cancer immunotherapy

Kawai M, Nakamura T, Miura N, Maeta M, Tanaka H, Ueda K, Higashi K, Moribe K, Tange K, Nakai Y, Yoshioka H, Harashima H, Akita H

Nanomedicine. 2018 Aug 28. pii: S1549-9634(18)30510-0. doi: 10.1016/j.nano.2018.08.006. [Epub ahead of print


Cytoplasmic DNA triggers cellular immunity via activating the stimulator of interferon genes pathway. Since DNA is degradable and membrane impermeable, delivery system would permit cytoplasmic delivery by destabilizing the endosomal membrane for the use as an adjuvant. Herein, we report on the development of a plasmid DNA (pDNA)-encapsulating lipid nanoparticle (LNP). The structural components include an SS-cleavable and pH-activated lipid-like material that mounts vitamin E as a hydrophobic scaffold, and dual sensing motifs that are responsive to the intracellular environment (ssPalmE). The pDNA-encapsulating LNP (ssPalmE-LNP) induced a high interferon-β production in Raw 264.7 cells. The subcutaneous injection of ssPalmE-LNP strongly enhanced antigen-specific cytotoxic T cell activity. The ssPalmE-LNP treatment efficiently induced antitumor effects against E.G7-OVA tumor and B16-F10 melanoma metastasis. Furthermore, when combined with an anti-programmed death 1 antibody, an extensive therapeutic antitumor effect was observed. Therefore, the ssPalmE-LNP is a promising carrier of adjuvants for cancer immunotherapy.

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Low intake of vitamin E accelerates cellular aging in patients with established cardiovascular disease: The CORDIOPREV study

Corina A, Rangel-Zúñiga OA, Jiménez-Lucena R, Alcalá-Díaz JF, Quintana-Navarro G, Yubero-Serrano EM, López-Moreno J, Delgado-Lista J, Tinahones F, Ordovás JM, López-Miranda J, Pérez-Martínez P

J Gerontol A Biol Sci Med Sci. 2018 Aug 27. doi: 10.1093/gerona/gly195. [Epub ahead of print]


Leukocyte telomere length (LTL) shortening is a biomarker of cellular aging that can be decelerated by diet. We aimed to investigate the effect of dietary intake of vitamin E on biomarkers of cellular senescence in patients with established cardiovascular disease. To this end, DNA from 1002 participants of the CORDIOPREV study (NCT00924937) was isolated and LTL wa s measured by real-time PCR. Dietary information was collected using a 146-item food frequency questionnaire, and several oxidative stress and damage biomarkers were determined. We found that patients with an inadequate intake of vitamin E according to the European Food Safety Authority, U.S. Food and Nutrition Board, and Spanish dietary recommendation had shorter LTL than those with an adequate intake (p=0.004, p=0.015 and p=0.005, respectively). Moreover, we observed a positive correlation between olive oil, fish consumption and LTL (r2=0.083, p=0.010; r2=0.090, p=0.006, respectively). Subjects who consumed more than 30 mL olive oil/day had longer LTL than subjects with lower consumption (p=0.013). Furthermore, we observed higher glutathione peroxidase activity in subjects consuming less vitamin E (p=0.031). Our findings support the importance of an adequate consumption of the antioxidant vitamin E, and the value of the diet as a modulating tool of the senescence process.Read More

Electrophilic nitroalkene-tocopherol derivatives: synthesis, physicochemical characterization and evaluation of anti-inflammatory signaling responses

Rodriguez-Duarte J, Dapueto R, Galliussi G, Turell L, Kamaid A, Khoo NKH, Schopfer FJ, Freeman BA, Escande C, Batthyány C, Ferrer-Sueta G, López GV

Sci Rep. 2018 Aug 24;8(1):12784. doi: 10.1038/s41598-018-31218-7.


Inflammation plays a major role in the onset and development of chronic non-communicable diseases like obesity, cardiovascular diseases and cancer. Combined, these diseases represent the most common causes of death worldwide, thus development of novel pharmacological approaches is crucial. Electrophilic nitroalkenes derived from fatty acids are formed endogenously and exert anti-inflammatory actions by the modification of proteins involved in inflammation signaling cascades. We have developed novel nitroalkenes derived from α-tocopherolaiming to increase its salutary actions by adding anti-inflammatory properties to a well-known nutraceutical. We synthesized and characterized an α-tocopherol-nitroalkene (NATOH) and two hydrosoluble analogues derived from Trolox (NATxME and NATx0). We analyzed the kinetics of the Michael addition reaction of these compounds with thiols in micellar systems aiming to understand the effect of hydrophobic partition on the reactivity of nitroalkenes. We studied NATxME in vitro showing it exerts non-conventional anti-inflammatory responses by inducing Nrf2-Keap1-dependent gene expression and inhibiting the secretion of NF-κB dependent pro-inflammatory cytokines. NATxME was also effective in vivo, inhibiting neutrophil recruitment in a zebrafish model of inflammation. This work lays the foundation for the rational design of a new therapeutic strategy for the prevention and treatment of metabolic and inflammation-related diseases.

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The Effects of Vitamin E from Elaeis guineensis (Oil Palm) in a Rat Model of Bone Loss Due to Metabolic Syndrome

Wong SK, Chin KY, Suhaimi FH, Ahmad F, Ima-Nirwana S

Int J Environ Res Public Health. 2018 Aug 24;15(9). pii: E1828. doi: 10.3390/ijerph15091828.


The beneficial effects of vitamin E in improving components of MetS or bone loss have been established. This study aimed to investigate the potential of palm vitamin E (PVE) as a single agent, targeting MetS and bone loss concurrently, using a MetS animal model. Twelve-week-old male Wistar rats were divided into five groups. The baseline group was sacrificed upon arrival. The normal group was given standard rat chow. The remaining three groups were fed with high-carbohydrate high-fat (HCHF) diet and treated with tocopherol-stripped corn oil (vehicle), 60 mg/kg or 100 mg/kg PVE. At the end of the study, the rats were evaluated for MetS parameters and bone density. After euthanasia, blood and femurs were harvested for the evaluation of lipid profile, bone histomorphometric analysis, and remodeling markers. PVE improved blood pressure, glycemic status, and lipid profile; increased osteoblast surface, osteoid surface, bone volume, and trabecular thickness, as well as decreased eroded surface and single-labeled surface. Administration of PVE also significantly reduced leptin level in the HCHF rats. PVE is a potential agent in concurrently preventing MetS and protecting bone loss. This may be, in part, achieved by reducing the leptin level and modulating the bone remodeling activity in male rats.

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Astaxanthin-alpha tocopherol nanoemulsion formulation by emulsification methods: Investigation on anticancer, wound healing, and antibacterial effects

Shanmugapriya K, Kim H, Saravana PS, Chun BS, Kang HW

Colloids Surf B Biointerfaces. 2018 Aug 20;172:170-179. doi: 10.1016/j.colsurfb.2018.08.042. [Epub ahead of print]


Emulsion-based delivery systems have been fabricated and developed to increase the bioavailability of astaxanthin and alpha-tocopherol as active compounds for various biomedical applications. Astaxanthin-alpha tocopherol nanoemulsion (ATNE) is well known for its potential 6.-6.30 effect. The current study investigated ATNE by spontaneous (SENE) and ultrasonication emulsification (USNE) methods to optimally fabricate oil/water nanoemulsion characterized for biomedical applications. The two methods were compared by using a response surface method of 3-level Box-Behnken design (BBD) with significant factors. Transmission electron microscopy (TEM) confirmed spherical-shaped nanoemulsion from SENE and USNE methods and dynamic light scattering (DLS) proved the good stability of the fabricated nanoemulsion. Cytotoxicity studies on three different cancer cells confirmed that the nanoemulsion at higher concentrations was more toxic than one at lower concentrations by accompanying a significant decrease in the cellular viability after 24 and 48 h of exposure. The wound-healing potential using scratch assay evidenced faster healing effect of the nanoemulsion. Both minimal inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC) methods confirmed significant antibacterial activity to disrupt the integrity of the bacterial cell membrane. The current results suggested that ATNE act as effectively targeted drug delivery vehicles in the future for cancer treatment applications due to its significant results of anticancer, wound healing, and antimicrobial effects.

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γ-tocotrienol inhibits the invasion and migration of human gastric cancer cells through downregulation of cyclooxygenase-2 expression.

Zhang YH, Ma K, Liu JR, Wang HX, Tian WX, Tu YH, Sun WG

Oncol Rep. 2018 Aug;40(2):999-1007. doi: 10.3892/or.2018.6497. Epub 2018 Jun 14.


γ-tocotrienol (γ-T3), a tocotrienol isoform belonging to the vitamin E family, has been revealed to exert inhibitory effects on proliferation, migration and invasion in human gastric cancer cells. However, its precise mechanism of action is still unclear and needs to be further tested. Cyclooxygenase-2 (COX-2) is well known for its key role in promoting the migration and invasion abilities of human gastric cancer cells. In light of these data, our study aimed to validate whether the inhibitory actions of γ-T3 could be achieved by downregulation of COX-2 activity in vitro. In the present study, a Cell Counting Kit-8 (CCK-8) assay was performed to observe proliferation in human gastric cancer cells (SGC-7901 and MGC-803 cells), and wound healing and Transwell chamber assays were performed to detect migration and invasion. Western blot analyses were performed to analyse the relative expression of COX-2, matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) proteins, and enzyme-linked immunosorbent assays (ELISA) were used to determine the exocrine roles of MMP-2 and MMP-9. The results revealed that γ-T3 exerted significant inhibitory effects on proliferation, migration, invasion and COX-2 protein expression, as well as on exocrine functions of MMP-2 and MMP-9 in SGC-7901 and MGC-803 cells. Therefore, our results indicated that γ-T3 exerts inhibitory effects on migration and invasion, which may be mediated through downregulation of COX-2 expression in SGC-7901 and MGC-803 cells.

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