Mechanisms of vanadium action: insulin-mimetic or insulin-enhancing agent?

The demonstration that the trace element vanadium has insulin-like properties in isolated cells and tissues and in vivo has generated considerable enthusiasm for its potential therapeutic value in human diabetes. However, the mechanisms by which vanadium induces its metabolic effects in vivo remain poorly understood, and whether vanadium directly mimics or rather enhances insulin effects is considered in this review. It is clear that vanadium treatment results in the correction of several diabetes-related abnormalities in carbohydrate and lipid metabolism, and in gene expression. However, many of these in vivo insulin-like effects can be ascribed to the reversal of defects that are secondary to hyperglycemia. The observations that the glucose-lowering effect of vanadium depends on the presence of endogenous insulin whereas metabolic homeostasis in control animals appears not to be affected, suggest that vanadium does not act completely independently in vivo, but augments tissue sensitivity to low levels of plasma insulin. Another crucial consideration is one of dose-dependency in that insulin-like effects of vanadium in isolated cells are often demonstrated at high concentrations that are not normally achieved by chronic treatment in vivo and may induce toxic side effects. In addition, vanadium appears to be selective for specific actions of insulin in some tissues while failing to influence others. As the intracellular active forms of vanadium are not precisely defined, the site(s) of action of vanadium in metabolic and signal transduction pathways is still unknown. In this review, we therefore examine the evidence for and against the concept that vanadium is truly an insulin-mimetic agent at low concentrations in vivo. In considering the effects of vanadium on carbohydrate and lipid metabolism, we conclude that vanadium acts not globally, but selectively and by enhancing, rather than by mimicking the effects of insulin in vivo.     

Mechanisms of heat protection by cycloheximide or puromycin: Involvement of polyamines?

1. 1.|When Chinese hamster ovary cells are treated with cycloheximide (10 μg/ml) or puromycin (100 μg/ml) for 2 h before and during heating at 43°C for 3 h, there is protection from hyperthermic killing; i.e. the plating efficiency increases 2000-fold from 3.7 × 10⁻⁵ to (6–9) × 10⁻².

2. 2.|The total intracellular levels of spermidine and spermine are not altered by the hyperthermic or drug treatments.

3. 3.|The small 30% decrease in intracellular putrescine observed after heating is not altered by drug treatment.

4. 4.|Heat protection by treatment with cycloheximide or puromycin cannot be attributed to changes in levels of total intracellular polyamines.

Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals?

The reactive oxygen species that are generated by mitochondrial respiration, including hydrogen peroxide (H2O2), are potent inducers of oxidative damage and mediators of ageing. It is not clear, however, whether oxidative stress is the result of a genetic programme or the by-product of physiological processes. Recent findings demonstrate that a fraction of mitochondrial H2O2, produced by a specialized enzyme as a signalling molecule in the pathway of apoptosis, induces intracellular oxidative stress and accelerates ageing. We propose that genes that control H2O2 production are selected determinants of lifespan.     

Mechanisms in macroecology: AWOL or purloined letter? Towards a pragmatic view of mechanism

Ecologists often believe the discovery of mechanism to be the central goal of scientific research. While many macroecologists have inherited this view, to date they have been much more efficient at producing patterns than identifying their underlying processes. We discuss several possible attitudes for macroecologists to adopt in this context while also arguing that in fact macroecology already has many mechanisms that are ignored. We briefly describe six of these: central limit theorem, fractals, random sampling and placement, neutral theory (and descendents), concordance of forces, and maximum entropy. We explore why these mechanisms are overlooked and discuss whether they should be. We conclude that macroecology needs to take a more pragmatic, less ideological approach to mechanism. We apply this viewpoint to the recent controversy over maximum entropy and suggest that maximum entropy needs to be viewed more pragmatically and less ideologically.     

Mechanisms of social reciprocity in three primate species: Symmetrical relationship characteristics or cognition?

Agonistic intervention behavior was observed in captive groups of chimpanzees (Pan troglodytes), rhesus monkeys (Macaca mulatta), and stumptail monkeys (M. arctoides). Reciprocity correlations of interventions were determined while removing from the data the effects of several symmetrical relationship characteristics, that is, matrillineal kinship, proximity relations, and same-sex combination. It was considered likely that if significant reciprocity persisted after controlling for these characteristics, the reciprocity was based on cognitive mechanisms. Statistical significance was tested by means of recently developed matrix permutation procedures. All three species exhibited significant reciprocity with regard to beneficial interventions, even after controlling for symmetrical traits. Harmful interventions were, however, reciprocal among chimpanzees only. This species showed a “revenge system”, that is, if A often intervened against B, B did the same to A. In contrast, both macaque species showed significantly inversed reciprocity in their harmful interventions: if A often intervened against B, B rarely intervened against A. Further analysis indicates that the strict hierarchy of macaques prevents them from achieving complete reciprocity. Compared to chimpanzees, macaques rarely intervene against higher ranking group members. The observed contrast can be partially explained on the basis of differences in available space, as indicated by a comparison of indoor and outdoor living conditions for the chimpanzee colony. Yet, even when such spatial factors are taken into account, substantial behavior differences between chimpanzees and macaques remain.     

What happens with ageing: decline or remodeling of opsonin‐independent phagocyte oxidative activity?

Changes that occur with age in the opsonin‐independent oxidative activity of peripheral phagocytes in whole blood were examined by means of luminol chemiluminescence (LCL). The chemiluminescence was registered simultaneously by non‐stimulated and stimulated cells and the age‐related alterations of total and extracellular generation of reactive oxygen species (ROS) were studied using model systems. It was found that the rate of phagocyte activation by the glass surface of the measuring chambers, assessed by the time of the peak appearance after the start of LCL response, increased. However, the maximum oxidative activity and the integral oxidative capacity of the cells during adhesion, evaluated by the maximum LCL intensity and the area under the LCL curve, respectively, declined. No age‐dependence of formyl‐methionyl‐leucyl‐phenylalanine (fMLP)‐stimulated oxidative cellular activity for total ROS generation was detected. The maximum oxidative activity and the integral oxidative capacity of peripheral phagocytes to generate extracellular superoxide in response to fMLP was decreased. The likely causes for the observed alterations in phagocyte function are discussed and an analysis of the obtained results is given on the background of the contradictory data published on phagocyte oxidative activity age‐related changes. Copyright © 2009 John Wiley & Sons, Ltd.     

DNA damage, cellular senescence and organismal ageing: causal or correlative?

Cellular senescence has long been used as a cellular model for understanding mechanisms underlying the ageing process. Compelling evidence obtained in recent years demonstrate that DNA damage is a common mediator for both replicative senescence, which is triggered by telomere shortening, and premature cellular senescence induced by various stressors such as oncogenic stress and oxidative stress. Extensive observations suggest that DNA damage accumulates with age and that this may be due to an increase in production of reactive oxygen species (ROS) and a decline in DNA repair capacity with age. Mutation or disrupted expression of genes that increase DNA damage often result in premature ageing. In contrast, interventions that enhance resistance to oxidative stress and attenuate DNA damage contribute towards longevity. This evidence suggests that genomic instability plays a causative role in the ageing process. However, conflicting findings exist which indicate that ROS production and oxidative damage levels of macromolecules including DNA do not always correlate with lifespan in model animals. Here we review the recent advances in addressing the role of DNA damage in cellular senescence and organismal ageing.     

Patient and public involvement: Two sides of the same coin or different coins altogether?

Patient and public involvement (PPI) has gained widespread support in health research and health policy circles, but there is little consensus on the precise meaning or justifications of PPI. We argue that an important step towards clarifying the meaning and justification for PPI is to split apart the familiar acronym and draw a distinction between patient and public involvement. Specifically, we argue that patient involvement should refer to the practice of involving individuals in health research or policy on the basis of their experience with a particular condition, while public involvement should refer to the practice of involving individuals in health policy or research based on their status as members of a relevant population. Analyzing cases from the UK, Australia, and the USA, we show how our proposed distinction can deliver much needed clarity to conversations on PPI, while guiding the development and evaluation of future PPI‐based policies.     

Oxidative stress and ageing: is ageing a cysteine deficiency syndrome?

Reactive oxygen species (ROS) are constantly produced in biological tissues and play a role in various signalling pathways. Abnormally high ROS concentrations cause oxidative stress associated with tissue damage and dysregulation of physiological signals. There is growing evidence that oxidative stress increases with age. It has also been shown that the life span of worms, flies and mice can be significantly increased by mutations which impede the insulin receptor signalling cascade. Molecular studies revealed that the insulin-independent basal activity of the insulin receptor is increased by ROS and downregulated by certain antioxidants. Complementary clinical studies confirmed that supplementation of the glutathione precursor cysteine decreases insulin responsiveness in the fasted state. In several clinical trials, cysteine supplementation improved skeletal muscle functions, decreased the body fat/lean body mass ratio, decreased plasma levels of the inflammatory cytokine tumour necrosis factor alpha (TNF-alpha), improved immune functions, and increased plasma albumin levels. As all these parameters degenerate with age, these findings suggest: (i) that loss of youth, health and quality of life may be partly explained by a deficit in cysteine and (ii) that the dietary consumption of cysteine is generally suboptimal and everybody is likely to have a cysteine deficiency sooner or later.     

p53 and ageing: too much of a good thing?

A recent report by Tyner et al.(1) suggests that p53 is bad for longevity. Heterozygotic mice carrying a p53 mutation that apparently enhances the stability of the wild-type protein showed shorter lifespans and faster ageing while also developing fewer tumours. This fits with the idea that cellular ageing is the price paid for better protection against unlimited proliferation of cancer cells. But other work shows that there is a strong positive association between DNA repair-mediated protection against cancer and ageing. So what are we to make of the new data with regard to overall understanding of the mechanisms of ageing?     

Mechanisms of chlorophyll fluorescence revisited: Prompt or delayed emission from photosystem II with closed reaction centers?

This paper proposes a model which correlates the exciton decay kinetics observed in picosecond fluorescence studies with the primary processes of charge separation in the reaction center of photosystem II. We conclude that the experimental results from green algae and chloroplasts from higher plants are inconsistent with the concept that delayed luminescence after charge recombination should account for the long-lived (approx. 2 ns) fluorescence decay component of closed photosystem II centers. Instead, we show that the experimental data are in agreement with a model in which the long-lived fluorescence is also prompt fluorescence. The model suggests furthermore that the rate constant of primary charge separation is regulated by the oxidation state of the quinone acceptor Q_A.     

The actin cytoskeleton: a key regulator of apoptosis and ageing?

Evidence from many organisms has shown that the accumulation of reactive oxygen species (ROS) has a detrimental effect on cell well-being. High levels of ROS have been linked to programmed cell death pathways and to ageing. Recent reports have implicated changes to the dynamics of the actin cytoskeleton in the release of ROS from mitochondria and subsequent cell death.     

Knowlesi malaria: newly emergent and of public health importance?

Several questions on public health impact have arisen from the discovery of a large focus of the simian malaria parasite, Plasmodium knowlesi, in the human population. P. knowlesi malaria is not newly emergent and was overlooked until molecular tools to distinguish between P. knowlesi and the morphologically similar Plasmodium malariae became available. Knowlesi malaria is a zoonosis that is widely distributed in Southeast Asia and can be fatal. Information on knowlesi malaria should be included in medical and public health guidelines to encourage the accurate diagnosis and treatment of patients, and monitor the incidence and distribution of cases. A complete emergence of P. knowlesi into the human population could be overwhelming and, although challenging, the prevention of this situation deserves serious consideration.