Thomas Prates Ong

Nutritional status of selenium in Alzheimer's disease patients

Studies have shown that various antioxidants are decreased in different age-related degenerative diseases and thus, oxidative stress would have a central role in the pathogenesis of many disorders that involve neuronal degeneration, including Alzheimers disease (AD). The present study aimed to assess the nutritional status of Se in AD patients and to compare with control subjects with normal cognitive function. The case-control study was carried out on a group of elderly with AD (n 28) and compared with a control group (n 29), both aged between 60 and 89 years. Se intake was evaluated by using a 3-d dietary food record. Se was evaluated in plasma, erythrocytes and nails by using the method of hydride generation atomic absorption spectroscopy. Deficient Se intake was largely observed in the AD group. AD patients showed significantly lower Se levels in plasma, erythrocytes and nails (32.59 microg/l, 43.74 microg/l and 0.302 microg/g) when compared with the control group (50.99 microg/l, 79.16 microg/l and 0.400 microg/g). The results allowed us to suggest that AD has an important relation with Se deficiency.

Targeting the epigenome with bioactive food components for cancer prevention.

Epigenetic processes participate in cancer development and likely influence cancer prevention. Global DNA hypomethylation, gene promoter hypermethylation and aberrant histone post-translational modifications are hallmarks of neoplastic cells which have been associated with genomic instability and altered gene expression. Because epigenetic deregulation occurs early in carcinogenesis and is potentially reversible, intervention strategies targeting the epigenome have been proposed for cancer prevention. Bioactive food components (BFCs) with anticancer potential, including folate, polyphenols, selenium, retinoids, fatty acids, isothiocyanates and allyl compounds, influence DNA methylation and histone modification processes. Such activities have been shown to affect the expression of genes involved in cell proliferation, death and differentiation that are frequently altered in cancer. Although the epigenome represents a promising target for cancer prevention with BFCs, few studies have addressed the influence of dietary components on these mechanisms in vivo, particularly on the phenotype of humans, and thus the exact mechanisms whereby diet mediates an effect on cancer prevention remains unclear. Primary factors that should be elucidated include the effective doses and dose timing of BFCs to attain epigenetic effects. Because diet-epigenome interactions are likely to occur in utero, the impact of early-life nutrition on cancer risk programming should be further investigated.

Associations between glutathione peroxidase-1 Pro198Leu polymorphism, selenium status, and DNA damage levels in obese women after consumption of Brazil nuts

OBJECTIVE Alterations in selenium (Se) status may result in suboptimal amounts of selenoproteins, which have been associated with increased oxidative stress levels. The Pro198Leu polymorphism at the glutathione peroxidase-1 (GPx1) gene is supposed to be functional. The response of Se status, GPx activity, and levels of DNA damage to a Se supplementation trial between the genotypes related to that polymorphism was investigated. METHODS A randomized trial was conducted with 37 morbidly obese women. Participants consumed one Brazil nut, which provided approximately 290 μg of Se a day, for 8 wk. Blood Se concentrations, erythrocyte GPx activity, and DNA damage levels were measured at baseline and at 8 wk. The results were compared by genotypes. RESULTS The genotype frequencies were 0.487, 0.378, and 0.135 for Pro/Pro (the wild-type genotype), Pro/Leu, and Leu/Leu, respectively. At baseline, 100% of the subjects were Se deficient, and after the supplementation, there was an improvement in plasma Se (P < 0.001 for Pro/Pro and Pro/Leu, P < 0.05 for Leu/Leu), erythrocyte Se (P = 0.00 for Pro/Pro and Pro/Leu, P < 0.05 for Leu/Leu), and GPx activity (P = 0.00 for Pro/Pro, P < 0.00001 for Pro/Leu, P < 0.001 for Leu/Leu). In addition, the Pro/Pro group showed a decrease in DNA damage after Brazil nut consumption compared with baseline (P < 0.005), and those levels were higher in Leu/Leu subjects compared with those with the wild-type genotype (P < 0.05). CONCLUSION Consumption of one unit of Brazil nuts daily effectively increases Se status and increases GPx activity in obese women, regardless of GPx1 Pro198Leu polymorphism. However, the evaluated biomarkers showed distinct results in response to the supplementation when the polymorphism was considered.

Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: Efficacy of tributyrin, a butyric acid prodrug

Hepatocellular carcinoma (HCC) ranks in prevalence and mortality among top 10 cancers worldwide. Butyric acid (BA), a member of histone deacetylase inhibitors (HDACi) has been proposed as an anticarcinogenic agent. However, its short half‐life is a therapeutical limitation. This problem could be circumvented with tributyrin (TB), a proposed BA prodrug. To investigate TB effectiveness for chemoprevention, rats were treated with the compound during initial phases of “resistant hepatocyte” model of hepatocarcinogenesis, and cellular and molecular parameters were evaluated. TB inhibited (p < 0.05) development of hepatic preneoplastic lesions (PNL) including persistent ones considered HCC progression sites. TB increased (p < 0.05) PNL remodeling, a process whereby they tend to disappear. TB did not inhibit cell proliferation in PNL, but induced (p < 0.05) apoptosis in remodeling ones. Compared to controls, rats treated with TB presented increased (p < 0.05) hepatic levels of BA indicating its effectiveness as a prodrug. Molecular mechanisms of TB‐induced hepatocarcinogenesis chemoprevention were investigated. TB increased (p < 0.05) hepatic nuclear histone H3K9 hyperacetylation specifically in PNL and p21 protein expression, which could be associated with inhibitory HDAC effects. Moreover, it reduced (p < 0.05) the frequency of persistent PNL with aberrant cytoplasmic p53 accumulation, an alteration associated with increased malignancy. Original data observed in our study support the effectiveness of TB as a prodrug of BA and as an HDACi in hepatocarcinogenesis chemoprevention. Besides histone acetylation and p21 restored expression, molecular mechanisms involved with TB anticarcinogenic actions could also be related to modulation of p53 pathways.

Chemopreventive effects of β-ionone and geraniol during rat hepatocarcinogenesis promotion: distinct actions on cell proliferation, apoptosis, HMGCoA reductase, and RhoA

Chemopreventive activities of the dietary isoprenoids β-ionone (βI) and geraniol (GOH) were evaluated during the promotion phase of hepatocarcinogenesis. Over 5 consecutive weeks, rats received daily 16 mg/100 g body weight (b.w.) of βI (βI group), 25 mg/100 g b.w. of GOH (GOH group), or only corn oil (CO group, controls). Compared to the CO group, the following was observed: only the βI group showed a decrease in the mean number of visible hepatocyte nodules (P<.05); βI and GOH groups had reduced mean number of persistent preneoplastic lesions (pPNLs) (P<.05), but no differences regarding number of remodeling PNL (rPNLs) were observed; only the βI group exhibited smaller rPNL size and percentage of liver sections occupied by pPNLs (P<.05), whereas the GOH group displayed a smaller percentage of liver sections occupied by rPNLs (P<.05); a trend was observed in the βI group, which showed reduced cell proliferation of pPNLs (P<.10), and the GOH group had increased apoptosis in pPNLs and rPNLs (P<.05); only the βI group displayed reduced total plasma cholesterol concentrations (P<.05) and increased hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase mRNA levels (P<.05); only the GOH group had lower hepatic membrane RhoA protein levels (P<.05); both the βI- and GOH-treated groups had higher hepatic concentrations of βI and GOH, respectively (P<.05). Given these data, βI and GOH show promising chemopreventive effects during promotion of hepatocarcinogenesis by acting through distinct mechanism of actions: βI may inhibit cell proliferation and modulate HMGCoA reductase, and GOH can induce apoptosis and inhibit RhoA activation.

Anti-atherogenic and anti-angiogenic activities of polyphenols from propolis.

Propolis is a polyphenol-rich resinous substance extensively used to improve health and prevent diseases. The effects of polyphenols from different sources of propolis on atherosclerotic lesions and inflammatory and angiogenic factors were investigated in LDL receptor gene (LDLr-/-) knockout mice. The animals received a cholesterol-enriched diet to induce the initial atherosclerotic lesions (IALs) or advanced atherosclerotic lesions (AALs). The IAL or AAL animals were divided into three groups, each receiving polyphenols from either the green, red or brown propolis (250 mg/kg per day) by gavage. After 4 weeks of polyphenol treatment, the animals were sacrificed and their blood was collected for lipid profile analysis. The atheromatous lesions at the aortic root were also analyzed for gene expression of inflammatory and angiogenic factors by quantitative real-time polymerase chain reaction and immunohistochemistry. All three polyphenol extracts improved the lipid profile and decreased the atherosclerotic lesion area in IAL animals. However, only polyphenols from the red propolis induced favorable changes in the lipid profiles and reduced the lesion areas in AAL mice. In IAL groups, VCAM, MCP-1, FGF, PDGF, VEGF, PECAM and MMP-9 gene expression was down-regulated, while the metalloproteinase inhibitor TIMP-1 gene was up-regulated by all polyphenol extracts. In contrast, for advanced lesions, only the polyphenols from red propolis induced the down-regulation of CD36 and the up-regulation of HO-1 and TIMP-1 when compared to polyphenols from the other two types of propolis. In conclusion, polyphenols from propolis, particularly red propolis, are able to reduce atherosclerotic lesions through mechanisms including the modulation of inflammatory and angiogenic factors.

Inhibitory Effects of Lutein and Lycopene on Placental Glutathione S-Transferase-Positive Preneoplastic Lesions and DNA Strand Breakage Induced in Wistar Rats by the Resistant Hepatocyte Model of Hepatocarcinogenesis

Inhibitory effects of lutein (LUT) and lycopene (LYC) on hepatic preneoplastic lesions (PNLs) and DNA strand breakage induced in Wistar rats by the resistant hepatocyte (RH) model of hepatocarcinogenesis were investigated. Animals received by gavage during 8 consecutive weeks on alternate days 70 mg/kg body weight of LUT or LYC. Rats treated with only corn oil and submitted to this model were used as controls. At the end of the experiment, treatment of the animals with LUT or LYC resulted in an increase in the respective liver carotenoid concentrations (P < 0.05). Moreover, it tended to reduce the incidence, total number, and multiplicity of hepatocyte nodules compared with the control group, although the differences did not reach statistical significance. Animals treated with LUT or LYC presented also a lower number of hepatic placental glutathione S-transferase-positive (GST-P) PNLs (P < 0.05), which were smaller (P < 0.05) and occupied a smaller area of the liver section (P < 0.05). Finally, hepatic DNA strand breakage evaluated by the comet assay was lower (P < 0.05) in carotenoid-treated animals when compared with the control group. Therefore, the results indicate that LUT and LYC represent promising chemopreventive agents during hepatocarcinogenesis and whose anticarcinogenic actions could be related to a protection against DNA instability.

Inhibitory effects of β-carotene and vitamin A during the progression phase of hepatocarcinogenesis involve inhibition of cell proliferation but not alterations in DNA methylation

The inhibitory effects of β-Carotene and vitamin A administered to rats in the progression phase of the resistant hepatocyte model of hepatocarcinogenesis were investigated. β-Carotene- and vitamin A-treated animals tended to present with a lower incidence of hepatic cancers than controls at sacrifice. Vitamin A, but not β-Carotene, administration also tended to reduce the total number of persistent hepatocyte nodules. Histological examination of sections stained with hematoxylin and eosin confirmed these results. This suggests that both compounds exhibit inhibitory effects during conversion of persistent nodules to cancers, whereas only the retinoid is also capable of inhibiting the evolution of persistent nodules or causing them to regress. Moreover, β-carotene- and vitamin A-treated animals showed lower hepatic bromodeoxyuridine labeling indexes in neoplastic lesions as well as in adjacent normal tissues than controls, suggesting an inhibitory action of these substances on cell proliferation. However, neither β-carotene nor vitamin A administration resulted in substantial alterations in the CCGG sequence methylation pattern of hydroxymethylglutaryl coenzyme A reductase, c-myc, and c-Ha-ras genes, the products of which are related to cell proliferation and carcinogenesis. Therefore, these inhibitory effects of β-carotene and vitamin A on progression of hepatocarcinogenesis do not seem to be related to DNA methylation.

Developmental programming of type 2 diabetes: early nutrition and epigenetic mechanisms.

Purpose of reviewThe environment experienced during critical windows of development can ‘programme’ long-term health and risk of metabolic diseases such as type 2 diabetes in the offspring. The purpose of this review is to discuss potential epigenetic mechanisms involved in the developmental programming of type 2 diabetes by early nutrition. Recent findingsMaternal and more recently paternal nutrition have been shown to play key roles in metabolic programming of the offspring. Although the exact mechanisms are still not clear, epigenetic processes have emerged as playing a plausible role. Epigenetic dysregulation is associated with several components that contribute to type 2 diabetes risk, including altered feeding behaviour, insulin secretion and insulin action. It may also contribute to transgenerational risk transmission. SummaryEpigenetic processes may represent a central underlying mechanism of developmental programming of type 2 diabetes. During embryonic and foetal development, extensive epigenetic remodelling takes place not only in somatic but also in primordial germ cells. Therefore, concerns have been raised that epigenetic dysregulation induced by a suboptimal early environment could programme altered phenotypes not only in the first generation but also in the subsequent ones. Characterizing these altered epigenetic marks has great implications for identifying individuals at an increased disease risk as well as potentially leading to novel preventive and treatment strategies.

Effects of selenium compounds on proliferation and epigenetic marks of breast cancer cells

Breast cancer is a global public health problem and the most frequent cause of cancer death among women. Mammary carcinogenesis is driven not only by genetic alterations but also by epigenetic disturbances. Because epigenetic marks are potentially reversible they represent promising molecular targets for breast cancer prevention interventions. Selenium is a promising anti-breast cancer trace element that has shown the modulation of DNA methylation and histone post-translational modifications in other malignancies. This study aimed to evaluate the effects of selenium compounds [methylseleninic acid (MSA) and selenite] on cell proliferation and death, expression of the tumor suppressor gene RASSF1A and epigenetic marks in MCF-7 human breast adenocarcinoma cells. Treatment with MSA or selenite markedly inhibited (P<0.05) in a dose-dependent manner the proliferation of MCF-7 cells. MSA induced (P<0.05) G2/M cell arrest while selenite presented the opposite effect. Regarding cell death induction, MSA acted mainly by inducing apoptosis (P<0.05), while selenite only induced necrosis (P<0.05). Furthermore selenite, but not MSA, markedly induced (P<0.05) cytotoxicity and increased (P<0.05) RASSF1A expression. Both selenium compounds inhibited (P<0.05) DNMT1 expression. MSA decreased (P<0.05) H3K9me3 and increased (P<0.05) H4K16ac, while selenite decreased (P<0.05) this latter histone mark. To the best of our knowledge this is the first report showing that selenite and MSA modulate epigenetic marks specifically in breast cancer cells. Our data reinforce the anti-breast cancer potential of selenium that is dependent on its chemical form. Furthermore the data show that epigenetic mechanisms represent relevant molecular targets involved in selenium inhibitory effects in breast cancer cells.