Antioxidants: Molecules, medicines, and myths

There is an industry-driven public obsession with antioxidants, which are equated to safe, health-giving molecules to be swallowed as mega-dose supplements or in fortified foods. Sometimes they are good for you, but sometimes they may not be, and pro-oxidants can be better for you in some circumstances. This article re-examines and challenges some basic assumptions in the nutritional antioxidant field.     

PharmEcology: A pharmacological approach to understanding plant-herbivore interactions: an introduction to the symposium

A central goal in understanding the ecology and evolution of animals is to identify factors that constrain or expand breadth of diet. Selection of diet in many animals is often constrained by chemical deterrents (i.e., secondary metabolites) in available food items. The integration of chemistry and ecology has led to a significant understanding of the chemical complexity of prey (e.g., animals, plants, and algae) and the resultant foraging behavior of consumers. However, most of the literature on chemical defenses of marine and terrestrial prey lacks a mechanistic understanding of how consumers tolerate, or avoid, chemically-defended foods. In order to understand ecological patterns of foraging and co-evolutionary relationships between prey and consumers, we must advance our understanding of the physiological mechanisms responsible for chemical interactions. Such mechanistic studies require the integration of the discipline of pharmacology with ecology, which we call "PharmEcology." Pharmacology provides the tools and insight to investigate the fate (what the body does to a chemical) and action (what a chemical does to the body) of chemicals in living organisms, whereas ecology provides the insight into the interactions between organisms (e.g., herbivores) and their environment (e.g., plants). Although, the general concepts of pharmacology were introduced to ecologists studying plant-herbivore interactions over 30 years ago, the empirical use of pharmacology to understand mechanisms of chemical interactions has remained limited. Moreover, many of the recent biochemical, molecular and technical advances in pharmacology have yet to be utilized by ecologists. The PharmEcology symposium held at a meeting of the Society for Integrative and Comparative Biology in January of 2009 was developed to define novel research directions at the interface of pharmacology and ecology.     

Thiol-dependent cytolytic bacterial toxins: streptolysin O and prominent toxins

Streptolysin O is the prototype of fifteen bacterial cytolytic protein toxins elaborated by gram-positive bacteria of species Streptococcus, Clostridium, Bacillus and Listeria. These toxins share a number of common properties: they are antigenically related as shown by cross-neutralization and immunoprecipitation; their cytolytic and other reducing agents; these toxins are inactivated by cholesterol and certain related sterols. This group of oxygen-labile cytolytic toxins has been named sulfyhdryl-activated toxins or thiol-activated cytolysins. The mechanism of action of these toxins is very likely identical or at least closely similar.     

Pathogens, toxins, and lipid rafts

Summary The plasma membrane is not a uniform two-dimensional space but includes various types of specialized regions containing specific lipids and proteins. These include clathrin-coated pits and caveolae. The existence of other cholesterol- and glycosphingolipid-rich microdomains has also been proposed. The aim of this review is to illustrate that these latter domains, also called lipid rafts, may be the preferential interaction sites between a variety of toxins, bacteria, and viruses and the target cell. These pathogens and toxins have hijacked components that are preferentially found in rafts, such as glycosylphosphatidylinositol-anchored proteins, sphingomyelin, and cholesterol. These molecules not only allow binding of the pathogen or toxin to the proper target cell but also appear to potentiate the toxic action. We briefly review the structure and proposed functions of cholesterol- and glycosphingolipid-rich microdomains and then describe the toxins and pathogens that interact with them. When possible the advantage conferred by the interaction with microdomains will be discussed.Abbreviation GPI glycosylphosphatidylinositol     

芦芽山鬼箭锦鸡儿灌丛营养特征及土壤养分分布规律

研究了芦芽山自然保护区亚高山草甸带鬼箭锦鸡儿（Caragana jubata）灌丛营养成分季节性变化和土壤养分分布规律．结果表明,鬼箭锦鸡儿具有很高的营养价值,粗蛋白含量达20．27％,粗纤维含量33．83％,灰分5．12％,同时含有丰富的Ca、Fe、Mn等中微量元素,是亚高山草场家畜的优质饲料来源．鬼箭锦鸡儿营养成分呈明显的季节性变化规律：从5月开始,随着灌丛生长发育,体内粗蛋白、灰分和矿质元素含量呈上升趋势,7月（开花期）达到最高,然后逐步降低．为适应海拔高、气温低、土层薄的亚高山草甸带生境,鬼箭锦鸡儿灌丛周围的土壤养分向灌丛中心聚集,灌丛中心的土壤电导率、有机质、全氮、速效磷和有效钾分别较灌丛边缘高18．8％、16．4％、18．7％、16．6％和8．4％,形成了明显的”肥岛效应”．鬼箭锦鸡儿灌丛根际土壤有机质、全氮出现富集,有效磷、速效钾和速效铁、锰在根际周围出现明显亏缺,表明鬼箭锦鸡儿具有高效固氮和吸收利用土壤养分的能力．     

Voltage-gated sodium channel toxins: poisons,probes, and future promise

Neurotoxins have served as invaluable agents for identification, purification, and functional characterization of voltage-gated ion channels. Multiple classes of these toxins, which target voltage- gated Na+ channels via high-affinity binding to distinct but allosterically coupled sites, have been identified. The toxins are chemically diverse, including guanidinium heterocycles, a variety of structurally unrelated alkaloids, and multiple families of nonhomologous polypeptides having either related or distinct functions. This review describes the biochemistry and pharmacology of these agents, and summarizes the structure-function relationships underlying their interaction with molecular targets. In addition, we explore recent advances in the use of these toxins as molecular scaffolding agents, drugs, and insecticides.     

Productivity of clear and humic lakes: nutrients,phytoplankton, bacteria

The relationships between long-term surface average concentrations of humic acids measured as water colour, dissolved organic carbon (DOC) or Secchi disk transparency and trophic state variables were studied with literature data from more than 600 freshwater lakes. The geometric means of summer surface average nutrient (phosphorus and nitrogen) concentration, phytoplankton biomass (chlorophyll concentration), and hypolimnetic anoxia (anoxic factor) were significantly higher in coloured than in clear lakes. The regressions of colour or DOC on these trophic state variables were positive and significant throughout a range of three orders of magnitude. Phytoplankton or primary productivity was higher in coloured lakes, when expressed per volume of epilimnion. Annual integral primary productivity expressed on an areal basis was smaller in coloured lakes, probably a reflection of shallower phototrophic depths in these lakes. There is evidence that annual integral bacteria productivity is much higher in coloured lakes for two reasons: first, epilimnetic bacteria production was ca. four times higher in coloured lakes, second, other studies have shown that hypolimnetic bacteria production is commonly higher than epilimnetic production, especially in anoxic hypolimnia that are frequent in coloured lakes. All volumetrically expressed variables indicated higher productivity in coloured lakes. In addition, high bacteria productivity reflects a different food chain involving mixotrophs, possibly compensating for low light conditions. Our analyses indicate that primary and secondary productivity is as high as or higher than in clear lakes. This revised version was published online in July 2006 with corrections to the Cover Date.     

Metformin and cancer: Doses,mechanisms and the dandelion and hormetic phenomena

In the early 1970s, Professor Vladimir Dilman originally developed the idea that antidiabetic biguanides may be promising as geroprotectors and anticancer drugs ("metabolic rehabilitation"). In the early 2000s, Anisimov´s experiments revealed that chronic treatment of female transgenic HER2-/neu mice with metformin significantly reduced the incidence and size of mammary adenocarcinomas and increased the mean latency of the tumors. Epidemiological studies have confirmed that metformin, but not other anti-diabetic drugs, significantly reduces cancer incidence and improves cancer patients' survival in type 2 diabetics. At present, pioneer work by Dilman & Anisimov at the Petrov Institute of Oncology (St. Petersburg, Russia) is rapidly evolving due to ever-growing preclinical studies using human tumor-derived cultured cancer cells and animal models. We herein critically review how the antidiabetic drug metformin is getting reset to metabolically fight cancer. Our current perception is that metformin may constitute a novel "hybrid anti-cancer pill" physically combining both the long-lasting effects of antibodies -by persistently lowering levels of blood insulin and glucose- and the immediate potency of a cancer cell-targeting molecular agent -by suppressing the pivotal AMPK/mTOR/S6K1 axis and several protein kinases at once, including tyrosine kinase receptors such as HER1 and HER2-. In this scenario, we discuss the relevance of metformin doses in pre-clinical models regarding metformin's mechanisms of action in clinical settings. We examine recent landmark studies demonstrating metformin's ability to specifically target the cancer-initiating stem cells from which tumor cells develop, thereby preventing cancer relapse when used in combination with cytotoxic chemotherapy (dandelion hypothesis). We present the notion that, by acting as an efficient caloric restriction mimetic, metformin enhanced intrinsic capacity of mitotically competent cells to self-maintenance and repair (hormesis) might trigger counterintuitive detrimental effects. Ongoing chemopreventive, neoadjuvant and adjuvant trials should definitely establish whether metformin's ability to kill the "dandelion root" beneath the "cancer soil" likely exceeds metformin-related dangers of hormesis.     

Changes in toxins, intracellular and dissolved free amino acids of the toxic dinoflagellate Gymnodinium catenatum in response to changes in inorganic nutrients and salinity

The paralytic shellfish poison prducing dinoflagellate Gymnodiniuncatemrum was subjected to changes in salinity, phosphate, ammoniumand nitrate using continuous culture and batch culture methods.In contrast with other algae, this species showed very slowchanges in the concentration of intracellular amino acids, inthe Gln:Glu ratio, and, in contrast with Alrsandnum spp., onlyslow changes in toxin content, during such events as N-feedingof Ndeprived cells or during nutrient deprivation. This organismwas found to be very susceptible to disturbance; maximum growthrates around 0.25–0.3 day^–1 with a minimum C:N massratio of 5.5, were attained when cultures were only disturbedby sampling once a day. P-deprived cells were larger (twicethe usual C content of 4 ng C cell^–1 and volume of 20pl). The content of free amino acids was always low (5% of cell-N),with low contributions made by arginine (the precursor for paralyticshellfish toxins). Cells growing using ammonium had the lowestC:N ratios and the highest proportion of intracellular aminoacids as arginine. The toxin profile (equal mole ratios of dcSTX,GTX₅, dcGT_2/3 C₁ and C₂, and half those values for C₃ and C₄)was stable and the toxin concentration varied between 0.2 and1 mM STX equivalents (highest when ammonium was not limiting,lowest in P-deprived cells, though as the latter were largertoxin per cell was not so variable). Decreased salinity didnot result in increases in toxin content. Significant amountsof amino acids (mainly serine and glycine, with a total oftenexceeding 4 µM) accumulated in the growth medium duringbatch growth even though the cultures were not bacteria free. ⁴Present address: Instituto Español de Oceanografia,Apdo 1552, 36280, Vigo, Spain     

Nutritional requirements of Plasmodium falciparum in culture. III. Further observations on essential nutrients and antimetabolites

In a semi-defined minimal medium for cultivation of Plasmodium falciparum, ribose, mannose, fructose, galactose, and maltose could not replace glucose. Hypoxanthine was the preferred purine source for the parasite over adenine, guanine, inosine, adenosine and guanosine although all supported growth equally. Inhibitors of nucleoside uptake had low potency in killing the parasites but depressed incorporation of [3H]adenosine more than [3H]hypoxanthine. Glutamate could not be replaced by 5-oxoproline, indicating that the gamma-glutamyl transferase pathway for amino acid uptake is probably not found in this organism. Adenine, nicotinamide, and orotic acid could not supplement glutamine-deficient medium. The pyridoxine antagonists isoniazid and 4-deoxypyridoxine were reversed by amino acid supplementation, suggesting that transaminases may be targets of these drugs. Orotic acid, but not glutathione or its amino acid components, partially reversed the effects of 8-methylamino-8-desmethyl riboflavin. Thus, the flavin enzyme, dihydroorotic acid dehydrogenase, but not glutathione reductase, appears to be a target of this riboflavin antagonist. Five biotin antagonists had no significant activity. The choline antagonist 2-(tert-butylamino)ethanol and thiamin uptake inhibitors had nonspecific inhibitory effects, which were not reversed by the respective target vitamin. Buthionine sulfoximine and methionine sulfoximine, inhibitors of glutathione synthesis, had significant oxygen-dependent toxicity. Six sulfonamides showed marked variation in potency and efficacy. Sulfathiazole and sulfadoxine were reversed differentially by p-aminobenzoic acid, folic acid, and folinic acid. Folinic acid was more effective than folic acid at reversing the toxicity of the dihydrofolate reductase inhibitors aminopterin and pyrimethamine; p-amino-benzoic acid had no effect.     

Nutritional management of hypertension: past, present, and future

A succinct overview of the nutritional management of hypertension, past, present, and future is presented. Prior to 1945, the low sodium diet and the rice-fruit diet were shown to be effective in reducing the blood pressure to normal levels in 35-40% of hypertensive patients. Between 1945 and the present, many studies were made on the effects of alcohol, water hardness, obesity, moderate restriction of sodium with increased potassium intake, increased dietary calcium, low animal and high unsaturated fat intake, and increased amounts of fiber in the diet. Criticisms are made of the very small magnitude, even if statistically significant, of blood pressure decreases and the too-short control periods in many instances, and also concerning the assumption of use of 24-h urinary sodium as an accurate index of the sodium intake, and of urinary creatinine as a physiological reference standard against the excretion of sodium. The author mentions, for possible future research, long-term studies of the effects of diets moderately restricted in sodium and high in potassium, of reducing weight and increasing physical activity in obese hypertensives, and of low animal and high polyunsaturated fat diets in patients with mild essential hypertension.     

Longevity nutrients resveratrol, wines and grapes

A mild-to-moderate wine drinking has been linked with reduced cardiovascular, cerebrovascular, and peripheral vascular risk as well as reduced risk due to cancer. The reduced risk of cardiovascular disease associated with wine drinking is popularly known as French Paradox. A large number of reports exist in the literature indicating that resveratrol present in wine is primarily responsible for the cardioprotection associated with wine. Recently, resveratrol was shown to extend life span in yeast through the activation of longevity gene SirT1, which is also responsible for the longevity mediated by calorie restriction. This review summarizes the reports available on the functional and molecular biological aspects of resveratrol, wine and grapes in potentiating the longevity genes.