Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus.

Dnmt3a2, a de novo DNA methyltransferase, is induced by neuronal activity and participates in long-term memory formation with the increased expression of synaptic plasticity genes. We wanted to determine if Dnmt3a2 with its partner Dnmt3L may influence motor behavior via the dopaminergic system. To this end, we generated a mouse line, Dnmt3a2/3LDat/wt, with dopamine transporter (DAT) promotor driven Dnmt3a2/3L overexpression. The mice were studied with behavioral paradigms (e.g., cylinder test, open field, and treadmill), brain slice patch clamp recordings, ex vivo metabolite analysis, and in vivo positron emission tomography (PET) using the dopaminergic tracer 6-[18F]FMT. The results showed that spontaneous activity and exercise performance were enhanced in Dnmt3a2/3LDat/wt mice compared to Dnmt3a2/3Lwt/wt controls. Dopaminergic substantia nigra pars compacta neurons of Dnmt3a2/3LDat/wt animals displayed a higher fire frequency and excitability. However, dopamine concentration was not increased in the striatum, and dopamine metabolite concentration was even significantly decreased. Striatal 6-[18F]FMT uptake, reflecting aromatic L-amino acid decarboxylase activity, was the same in Dnmt3a2/3LDat/wt mice and controls. [18F]FDG PET showed that hypothalamic metabolic activity was tightly linked to motor behavior in Dnmt3a2/3LDat/wt mice. Furthermore, dopamine biosynthesis and motor-related metabolic activity were correlated in the hypothalamus. Our findings suggest that Dnmt3a2/3L, when overexpressed in dopaminergic neurons, modulates motor performance via activation of the nigrostriatal pathway. This does not involve increased dopamine synthesis.

Vitamin E: Regulatory Redox Interactions.

Vitamin E is an essential nutrient that was discovered in the 1920s. Many of the physiological functions of vitamin E, including its antioxidative effects, have been studied for nearly 100 years. Changes in redox balance induced by both endogenously and exogenously generated reactive oxygen species (ROS) are involved in various diseases, and are also a phenomenon that is considered essential for survival. Vitamin E is known to regulate redox balance in the body due to its high concentration among the lipid soluble vitamin groups, and exists ubiquitously in the whole body, including cell membranes and lipoproteins. However, it has been reported that the beneficial properties of vitamin E, including its antioxidative effects, are only displayed in vitro, and not in vivo. Therefore, there exists an ongoing debate regarding the biological functions of vitamin E and its relationship with redox balance. In this review, we introduce the relationship between vitamin E and redox interactions with (i) absorption, distribution, metabolism, and excretion of vitamin E, (ii) oxidative stress and ROS in the body, (iii) mechanism of antioxidative effects, (iv) non-antioxidant functions of vitamin E, and (v) recent recognition of the field of oxidative stress research. Understanding the recent findings of the redox interaction of vitamin E may help to elucidate the different antioxidative phenomena observed for vitamin E in vitro and in vivo. © 2019 IUBMB Life, 71(4):430-441, 2019.

Biological Functions of Antioxidant Dipeptides.

In the history of modern nutritional science, understanding antioxidants is one of the major topics. In many cases, food-derived antioxidants have π conjugate or thiol group in their molecular structures because π conjugate stabilizes radical by its delocalization and two thiol groups form a disulfide bond in its antioxidative process. In recent years, antioxidant peptides have received much attention because for their ability to scavenge free radicals, inhibition of lipid peroxidation, chelation of transition metal ions, as well as their additional nutritional value. Among them, dipeptides are attracting much interest as post-amino acids, which have residues in common with amino acids, but also have different physiological properties and functions from those of amino acids. Especially, dipeptides containing moieties of several amino acid (tryptophan, tyrosine, histidine, cysteine, and methionine) possess potent antioxidant activity. This review summarizes previous details of structural property, radical scavenging activity, and biological activity of antioxidant dipeptide. Hopefully, this review will help provide a new insight into the study of the biological functions of antioxidant dipeptides.

Antioxidant effect of astaxanthin on phospholipid peroxidation in human erythrocytes.

Phospholipid hydroperoxides (PLOOH) accumulate abnormally in the erythrocytes of dementia patients, and dietary xanthophylls (polar carotenoids such as astaxanthin) are hypothesised to prevent the accumulation. In the present study, we conducted a randomised, double-blind, placebo-controlled human trial to assess the efficacy of 12-week astaxanthin supplementation (6 or 12 mg/d) on both astaxanthin and PLOOH levels in the erythrocytes of thirty middle-aged and senior subjects. After 12 weeks of treatment, erythrocyte astaxanthin concentrations were higher in both the 6 and 12 mg astaxanthin groups than in the placebo group. In contrast, erythrocyte PLOOH concentrations were lower in the astaxanthin groups than in the placebo group. In the plasma, somewhat lower PLOOH levels were found after astaxanthin treatment. These results suggest that astaxanthin supplementation results in improved erythrocyte antioxidant status and decreased PLOOH levels, which may contribute to the prevention of dementia.

A Critical Review of the Use of Surfactant-Coated Nanoparticles in Nanomedicine and Food Nanotechnology.

Surfactants, whose existence has been recognized as early as 2800 BC, have had a long history with the development of human civilization. With the rapid development of nanotechnology in the latter half of the 20th century, breakthroughs in nanomedicine and food nanotechnology using nanoparticles have been remarkable, and new applications have been developed. The technology of surfactant-coated nanoparticles, which provides new functions to nanoparticles for use in the fields of nanomedicine and food nanotechnology, is attracting a lot of attention in the fields of basic research and industry. This review systematically describes these "surfactant-coated nanoparticles" through various sections in order: 1) surfactants, 2) surfactant-coated nanoparticles, application of surfactant-coated nanoparticles to 3) nanomedicine, and 4) food nanotechnology. Furthermore, current progress and problems of the technology using surfactant-coated nanoparticles through recent research reports have been discussed.

Influence of quercetin on the global DNA methylation pattern in pigs.

The plant flavonol quercetin causes multiple health-promoting effects in human and animals. In this study, we investigated the possible effects of quercetin on global DNA methylation in growing pigs after 7 weeks of feeding a quercetin-enriched diet. The results indicated that a trend for an improved feed conversion was observed in the quercetin fed group compared to the control group. Furthermore, quercetin influenced global DNA methylation by upregulating DNA methyltransferase 1 (DNMT1) in both mRNA and protein expressions in a tissue specific manner. The observed bioactivity of quercetin against the global methylation marker in pigs indicates that quercetin could be a potential inducer of DNA methylation which might be of economic significance for effective nutritional interventions affecting the health and productivity of animals.

δ and γ tocotrienols suppress human hepatocellular carcinoma cell proliferation via regulation of Ras-Raf-MEK-ERK pathway-associated upstream signaling.

Tocotrienol (T3) has recently gained increasing interest due to its anti-cancer effect. Here, we investigated the modulating effect of δ and γ T3 on the Ras-Raf-MEK-ERK oncogenic upstream signaling pathway in human hepatocellular carcinoma HepG2 cells. The results indicated that T3 regulated the upstream signaling cascades of this pathway.

Young persimmon ingestion suppresses lipid oxidation in rats.

Persimmon is widely eaten in Asia and the nutritional components of young and mature persimmons differ. Although raw young persimmon has a strong bitter taste and is difficult to eat, the beneficial health effects of young persimmon powder have attracted attention in recent years. Young persimmon has been suggested to have hypolipidemic activity as well as other biological effects. However, there has been little investigation of the beneficial effects of young persimmon. In the present study, we investigated the antioxidative effects of persimmon in an animal study and compared the effects of young persimmon and mature persimmon. Six-week-old male F344 rats were divided into three groups and fed a standard diet, young persimmon diet, or mature persimmon diet for 4 wk. The young persimmon and mature persimmon groups were fed a diet containing 5% (w/w) freeze-dried young or mature persimmon. We analyzed phosphatidylcholine hydroperoxide (PCOOH) levels in the rats as a biomarker of membrane lipid peroxidation. Our study showed that plasma PCOOH levels were significantly lower in the young persimmon group (36.1 ± 28.5 pmol/mL plasma) than in the control group (120 ± 66 pmol/mL plasma). No significant difference was observed between the mature persimmon group (57.3 ± 15.6 pmol/mL plasma) and the control group. It is possible that ascorbic acid and soluble tannin contribute to the difference in the antioxidant effects of young and mature persimmons. These results indicated that intake of young persimmon contributes to the reduction of plasma phospholipid hydroperoxide levels in rats.

Tocotrienol modulates crucial lipid metabolism-related genes in differentiated 3T3-L1 preadipocytes.

Obesity and other lipid metabolism-related diseases have become more prevalent in recent years due to drastic lifestyle changes and dietary patterns. Unsaturated vitamin E, tocotrienol (T3), represents one of the most fascinating naturally occurring compounds that has the potential to influence a broad range of mechanisms underlying abnormal lipid metabolism processes. However, its efficacy and mechanism have been uncertain due to scarcity of data concerning the effect of T3 on lipid metabolism. In this study, we report a series of fascinating experimental findings on how T3 affects lipid metabolism in differentiated 3T3-L1 preadipocytes. Treatment with T3 (25 µM), especially δ and γ isomers, inhibited the accumulation of triglyceride and lipid droplets in differentiated 3T3-L1 cells. This manifestation was supported by mRNA and protein expression of crucial lipid metabolism-related genes. The present study provides a novel set of data pertaining to the possibility of T3 as an anti-metabolic disorder agent.

γ-Tocotrienol attenuates triglyceride through effect on lipogenic gene expressions in mouse hepatocellular carcinoma Hepa 1-6.

Vitamin E is the generic name for tocopherol (Toc) and tocotrienol (T3), which have saturated and unsaturated side chains, respectively. Such differences allow T3 to be different from Toc in terms of their functions. T3 has been known to attenuate cholesterol (Cho) level by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR). Recent reports also showed the efficacy of T3 in improving triglyceride (TG) profiles in both in vivo and in vitro studies. However the mechanism involved in this biological activity is still unclear and needs to be further investigated. In the present study, we elucidated the effect of γ-T3 on lipid levels and lipogenic gene expressions in mouse hepatocellular carcinoma Hepa 1-6. γ-T3 showed attenuation of TG through effect on fatty acid synthase, sterol regulatory element-binding transcription factor 1, stearoyl CoA desaturase 1, and carnitine palmitoyl transferase 1A gene expression in Hepa 1-6. In contrast, the Cho level remained unchanged. These results expanded our previous finding of lipid-lowering effects of T3, especially for TG. Therefore, T3 is a potential lipid-lowering compound candidate with realistic prospects for its use as a therapy for lipid-related diseases in humans.

Tocotrienol attenuates triglyceride accumulation in HepG2 cells and F344 rats.

Tocotrienol (T3) is an important phytonutrient found in rice bran and palm oil. T3 has gained much interest for lipid lowering effects, especially for cholesterol (Cho) by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Also, usefulness of T3 in improving triglyceride (TG) profiles has been suggested, but its efficacy and mechanism have been unclear. We investigated how T3 decreases TG concentration in cultured cells and animals. In a cell culture study, human hepatoma cells (HepG2) were incubated in a control or a fat (1 mM oleic acid)-loaded medium containing γ-T3 for 24 h. We found that 10-15 µM γ-T3 inhibited cellular TG accumulation significantly, especially in the fat-loaded medium. This manifestation was supported by mRNA and protein expressions of fatty acid synthase, carnitine palmitoyltransferase 1, and cytochrome P450 3A4. In concordance with these results, rice bran T3 supplementation to F344 rats (5 or 10 mg T3/day/rat) receiving a high fat diet for 3 weeks significantly reduced TG and the oxidative stress marker (phospholipid hydroperoxides, PLOOH) in the liver and blood plasma. T3 supplementation did not show changes in the Cho level. These results provided new information and the mechanism of the TG-lowering effect of T3. The lipid lowering effects of dietary T3 might be mediated by the reduction of TG synthesis.