The gut microbiota and lipid metabolism: implications for human health and coronary heart disease

Coronary heart disease (CHD) is the leading cause of mortality in Western societies, affecting about one third of the population before their seventieth year. Over the past decades modifiable risk factors of CHD have been identified, including smoking and diet. These factors when altered can have a significant impact on an individuals' risk of developing CHD, their overall health and quality of life. There is strong evidence suggesting that dietary intake of plant foods rich in fibre and polyphenolic compounds, effectively lowers the risk of developing CHD. However, the efficacy of these foods often appears to be greater than the sum of their recognised biologically active parts. Here we discuss the hypothesis that beneficial metabolic and vascular effects of dietary fibre and plant polyphenols are due to an up regulation of the colon-systemic metabolic axis by these compounds. Fibres and many polyphenols are converted into biologically active compounds by the colonic microbiota. This microbiota imparts great metabolic versatility and dynamism, with many of their reductive or hydrolytic activities appearing complementary to oxidative or conjugative human metabolism. Understanding these microbial activities is central to determining the role of different dietary components in preventing or beneficially impacting on the impaired lipid metabolism and vascular dysfunction that typifies CHD and type 11 diabetes. This approach lays the foundation for rational selection of health promoting foods, rational target driven design of functional foods, and provides an essential thus-far, overlooked, dynamic to our understanding of how foods recognised as "healthy" impact on the human metabonome.

Ataxia telangiectasia mutated (ATM) inhibition transforms human mammary gland epithelial cells.

Carriers of mutations in the cell cycle checkpoint protein kinase ataxia telangiectasia mutated (ATM), which represent 1-2% of the general population, have an increased risk of breast cancer. However, experimental evidence that ATM deficiency contributes to human breast carcinogenesis is lacking. We report here that in MCF-10A and MCF-12A cells, which are well established normal human mammary gland epithelial cell models, partial or almost complete stable ATM silencing or pharmacological inhibition resulted in cellular transformation, genomic instability, and formation of dysplastic lesions in NOD/SCID mice. These effects did not require the activity of exogenous DNA-damaging agents and were preceded by an unsuspected and striking increase in cell proliferation also observed in primary human mammary gland epithelial cells. Increased proliferation correlated with a dramatic, transient, and proteasome-dependent reduction of p21(WAF1/CIP1) and p27(KIP1) protein levels, whereas little or no effect was observed on p21(WAF1/CIP1) or p27(KIP1) mRNAs. p21(WAF1/CIP1) silencing also increased MCF-10A cell proliferation, thus identifying p21(WAF1/CIP1) down-regulation as a mediator of the proliferative effect of ATM inhibition. Our findings provide the first experimental evidence that ATM is a human breast tumor suppressor. In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells.

The antibiotics roseoflavin and 8-demethyl-8-amino-riboflavin from Streptomyces davawensis are metabolized by human flavokinase and human FAD synthetase

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Silibinin attenuates oxidative metabolism and cytokine production by monocytes from preeclamptic women.

Silibinin is a polyphenolic plant flavonoid with anti-inflammatory properties. The present study investigated the effect of silibinin on oxidative metabolism and cytokine production - tumor necrosis factor-alpha (TNF-α), interleukin (IL)12, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, IL-10, and transforming growth factor beta (TGF-β1) - by peripheral blood monocytes (PBM) from preeclamptic pregnant women. It is a case-controlled study involving women with preeclampsia (PE, n = 30) compared with normotensive pregnant (NT, n = 30) and with non-pregnant (NP, n = 30) women. Monocytes were obtained and cultured with or without silibinin (5 μM or 50 μM) for 18 h. Superoxide anion (O2-) and hydrogen peroxide (H2O2) release were determined by specific assays, and cytokine levels were determined by immunoenzymatic assays (ELISA). Monocytes from preeclamptic women cultured without stimulus released higher levels of O22, H2O2 and TNF-α, and lower levels of IL-10 and TGF-β1 than did monocytes from NT and NP women. Treatment in vitro with silibinin significantly inhibited spontaneous O2- and H2O2 release and TNF-α production by monocytes from preeclamptic women. The main effect of silibinin was obtained at 50 μM concentration. Thus, silibinin exerts anti-oxidative and anti-inflammatory effects on monocytes from preeclamptic pregnant women by inhibiting the in vitro endogenous release of reactive oxygen species and TNF-α production.

Expression of glucocorticoid and progesterone nuclear receptor genes in archival breast cancer tissue.

BACKGROUND: Previous studies in our laboratory have shown associations of specific nuclear receptor gene variants with sporadic breast cancer. In order to investigate these findings further, we conducted the present study to determine whether expression levels of the progesterone and glucocorticoid nuclear receptor genes vary in different breast cancer grades. METHODS: RNA was extracted from paraffin-embedded archival breast tumour tissue and converted into cDNA. Sample cDNA underwent PCR using labelled primers to enable quantitation of mRNA expression. Expression data were normalized against the 18S ribosomal gene multiplex and analyzed using analysis of variance. RESULTS: Analysis of variance indicated a variable level of expression of both genes with regard to breast cancer grade (P = 0.00033 for glucocorticoid receptor and P = 0.023 for progesterone receptor). CONCLUSION: Statistical analysis indicated that expression of the progesterone nuclear receptor is elevated in late grade breast cancer tissue.

Targeting histone deacetylases for the treatment of disease : Epigenetics Review Series

The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular 'code' recognized and used by non-histone proteins to regulate specific chromatin functions. One modification, which has received significant attention, is that of histone acetylation. The enzymes that regulate this modification are described as lysine acetyltransferases or KATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The pro-inflammatory environment is increasingly being recognized as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential and current development of histone deacetylases for the treatment of diseases for which a pro-inflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the pro-inflammatory environment. © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Irisin - a myth rather than an exercise-inducible myokine.

The myokine irisin is supposed to be cleaved from a transmembrane precursor, FNDC5 (fibronectin type III domain containing 5), and to mediate beneficial effects of exercise on human metabolism. However, evidence for irisin circulating in blood is largely based on commercial ELISA kits which are based on polyclonal antibodies (pAbs) not previously tested for cross-reacting serum proteins. We have analyzed four commercial pAbs by Western blotting, which revealed prominent cross-reactivity with non-specific proteins in human and animal sera. Using recombinant glycosylated and non-glycosylated irisin as positive controls, we found no immune-reactive bands of the expected size in any biological samples. A FNDC5 signature was identified at ~20 kDa by mass spectrometry in human serum but was not detected by the commercial pAbs tested. Our results call into question all previous data obtained with commercial ELISA kits for irisin, and provide evidence against a physiological role for irisin in humans and other species.

High-resolution (space, time) anthropogenic heat emissions: London 1970-2025

The anthropogenic heat emissions generated by human activities in London are analysed in detail for 2005–2008 and considered in context of long-term past and future trends (1970–2025). Emissions from buildings, road traffic and human metabolism are finely resolved in space (30 min) and time (200 × 200 m2). Software to compute and visualize the results is provided. The annual mean anthropogenic heat flux for Greater London is 10.9 W m−2 for 2005–2008, with the highest peaks in the central activities zone (CAZ) associated with extensive service industry activities. Towards the outskirts of the city, emissions from the domestic sector and road traffic dominate. Anthropogenic heat is mostly emitted as sensible heat, with a latent heat fraction of 7.3% and a heat-to-wastewater fraction of 12%; the implications related to the use of evaporative cooling towers are briefly addressed. Projections indicate a further increase of heat emissions within the CAZ in the next two decades related to further intensification of activities within this area.

Anthropogenic heat in the city of So Paulo, Brazil

The main goal of this work is to describe the anthropogenic energy flux (Q (F)) in the city of So Paulo, Brazil. The hourly, monthly, and annual values of the anthropogenic energy flux are estimated using the inventory method, and the contributions of vehicular, stationary, and human metabolism sources from 2004 to 2007 are considered. The vehicular and stationary sources are evaluated using the primary consumption of energy based on fossil fuel, bio fuel, and electricity usage by the population. The diurnal evolution of the anthropogenic energy flux shows three relative maxima, with the largest maxima occurring early in the morning (similar to 19.9 Wm(-2)) and in the late afternoon (similar to 20.3 Wm(-2)). The relative maximum that occurs around noontime (similar to 19.6 Wm(-2)) reflects the diurnal pattern of vehicle traffic that seems to be specific to So Paulo. With respect to diurnal evolution, the energy flux released by vehicular sources (Q (FV)) contributes approximately 50% of the total anthropogenic energy flux. Stationary sources (Q (FS)) and human metabolism (Q (FM)) represent about 41% and 9% of the anthropogenic energy flux, respectively. For 2007, the monthly values of Q (FV), Q (FS), Q (FM), and Q (F) are, respectively, 16.8 +/- 0.25, 14.3 +/- 0.16, 3.5 +/- 0.03, and 34.6 +/- 0.41 MJ m(-2) month(-1). The seasonal evolution monthly values of Q (FV), Q (FS), Q (FM), and Q (F) show a relative minimum during the summer and winter vacations and a systematic and progressive increase associated with the seasonal evolution of the economic activity in So Paulo. The annual evolution of Q (F) indicates that the city of So Paulo released 355.2 MJ m(-2) year(-1) in 2004 and 415.5 MJ m(-2) year(-1) in 2007 in association with an annual rate of increase of 19.6 MJ m(-2) year(-1) (from 2004 to 2006) and 30.5 MJ m(-2) year(-1) (from 2006 to 2007). The anthropogenic energy flux corresponds to about 9% of the net radiation at the surface in the summer and 15% in the winter. The amplitude of seasonal variation of the maximum hourly value of the diurnal variation increases exponentially with latitude.

Zinc deficiency and its inherited disorders - A review

Zinc is an essential trace element required by all living organisms because of its critical roles both as a structural component of proteins and as a cofactor in enzyme catalysis. The importance of zinc in human metabolism is illustrated by the effects of zinc deficiency, which include a diminished immune response, reduced healing and neurological disorders. Furthermore, nutritional zinc deficiency can be fatal in newborn or growing animals. While zinc deficiency is commonly caused by dietary factors, several inherited defects of zinc deficiency have been identified. Acrodermatitis enteropathica is the most commonly described inherited condition found in humans. In several of the few cases that have been reported, this disorder is associated with mutations in the hZIP4 gene, a member of the SLC39 family, whose members encode membranebound putative zinc transporters. Mutations in other members of this family or in different genes may account for other cases of acrodermatitis in which defects in hZIP4 have not been detected. Another inherited form of zinc deficiency occurs in the lethal milk mouse, where a mutation in ZnT4 gene, a member of the SLC30 family of transmembrane proteins results in impaired secretion of zinc into milk from the mammary gland. A similar disorder to the lethal milk mouse occurs in humans. In the few cases studied, no changes in ZnT4 orthologue, hZnT4, were detected. This, and the presence of several minor phenotypic differences between the zinc deficiency in humans and mice, suggests that the human condition is caused by defects in genes that are yet to be identified. Taking into account the fact that there are no definitive tests for zinc deficiency and that this disorder can go undiagnosed, plus the recent identification of multiple members of the SCL30 and SLC39, it is likely that mutations in other genes may underlie additional inherited disorders of zinc deficiency.

Jumping on the omega-3 bandwagon : distinguishing the role of long-chain and short-chain omega-3 fatty acids

Omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) are almost unanimously recognized for their health benefits, while only limited evidence of any health benefit is currently available specifically for the main precursor of these fatty acids, namely α-linolenic acid (ALA, 18:3n-3). However, both the n-3 LC-PUFA and the short-chain C18 PUFA (i.e., ALA) are commonly referred to as “omega-3” fatty acids, and it is difficult for consumers to recognize this difference. A current gap of many food labelling legislations worldwide allow products containing only ALA and without n-3 LC-PUFA to be marketed as “omega-3 source” and this misleading information can negatively impact the ability of consumers to choose more healthy diets. Within the context of the documented nutritional and health promoting roles of omega-3 fatty acids, we briefly review the different metabolic fates of dietary ALA and n-3 LC-PUFA. We also review food sources rich in n-3 LC-PUFA, some characteristics of LC-PUFA and current industry and regulatory trends. A further objective is to present a case for regulatory bodies to clearly distinguish food products containing only ALA from foods containing n-3 LC-PUFA. Such information, when available, would then avoid misleading information and empower consumers to make a more informed choice in their food purchasing behavior.

Electrochemical Reduction as a Powerful Tool to Highlight the Possible Formation of By-Products More Toxic Than Sudan III Dye

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

ENDOCRINE INTERACTION BETWEEN ZINC AND PROLACTIN - AN INTERPRETATIVE REVIEW

Zinc plays a very important role in animal and human metabolism. Nowadays, it is one of the most extensively studied trace element, since its sphere of action has been demonstrated to be very broad. From the biochemical standpoint, it controls more than 300 different enzymes, many of them involved with intermediary metabolism, DNA and RNA synthesis, gene expression, and immunocompetence. It also plays a significant role in hormonal homeostasis, since it can interact with almost all hormones. Zn2+ is closely related to the thyroid and steroid hormones, insulin, parathormone, and pituitary hormones, particularly prolactin (PRL). Zn2+ can inhibit PRL secretion within a range of physiologically and pharmacologically relevant concentrations. This property has raised the possibility of clinical applications of zinc. In this article, we review the Literature on the subject in an attempt to provide a comprehensible general view.