Hormesis and Cellular Quality Control: A Possible Explanation for the Molecular Mechanisms that Underlie the Benefits of Mild Stress.

In contrast to the detrimental action of severe stress conditions, the beneficial effects of mild stress, known as hormesis, is increasingly discussed and studied. A variety of applications for hormesis in risk assessment processes, anti-ageing strategies and clinical therapies have been proposed. The molecular mechanisms underlying the phenomenon of hormesis, however, are not yet fully understood. A possible mechanism that has been proposed for hormesis, the homoeostasis overshoot hypothesis, assumes that an overshoot of repair- and self-recovery mechanisms in response to mild damage can be held responsible for the beneficial effects of hormesis. The present paper proposes 'cellular quality control' as a further explanation of the molecular mechanisms underlying the benefits observed after exposure to mild stress. The most important quality control mechanisms are outlined and their known and hypothesised actions in hormesis are discussed. As an example, different aspects of protein quality control will be described in more detail, which includes the reaction of the cell upon stress-induced protein damage and -aggregation. The regulation of Heat Shock Proteins and components from the ubiquitin proteasome system as part of cellular quality control is described in relation to its beneficial role in hormesis.

Postconditioning hormesis put in perspective: an overview of experimental and clinical studies.

A beneficial effect of applying mild stress to cells or organisms, that were initially exposed to a high dose of stress, has been referred to as 'postconditioning hormesis'. The initial high dose of stress activates intrinsic self-recovery mechanisms. Modulation of these endogenous adaptation strategies by administration of a subsequent low dose of stress can confer effects that are beneficial to the biological system. Owing to its potentially therapeutic applications, postconditioning hormesis is subject to research in various scientific disciplines. This paper presents an overview of the dynamics of postconditioning hormesis and illustrates this phenomenon with a number of examples in experimental and clinical research.

Postconditioning hormesis and the homeopathic Similia principle: molecular aspects.

Postexposure conditioning, as a part of hormesis, involves the application of a low dose of stress following exposure to a severe stress condition. Depending on whether the low-dose stress is of the same type of stress or is different from the initial high-dose stress causing the diseased state, postconditioning can be classified as homologous or heterologous, respectively. In clinical homeopathy, the same distinction is found between isopathic and homeopathic application of low-dose substances. Homeopathy is unique for its Similia principle, which implies that substances causing symptoms in healthy biological systems can be used to treat similar symptoms in diseased biological systems. The evaluation of the Similia principle in an experimental set-up requires the analysis of a complex sequence of 'damage-disease-treatment-effect' events. The process of recovery from an insult is then monitored and a possible beneficial effect on this recovery process, upon application of a range of substances in low dose, can subsequently be analyzed using molecular and functional parameters. It is then possible to compare the effect of treatment with the degree of similarity between the diseased state and the effects caused by homologous and/or different heterologous substances. Beneficial effects of postconditioning mild stress conditions have been described in terms of an increase of the synthesis of stress proteins. In this commentary paper, we present additional information on this aspect. The experimental data suggest that the beneficial effect of the low-dose stress condition used as heterologous postconditioning is related to similarity in molecular stress response.

The influence of adaptogens on ultraweak biophoton emission: a pilot-experiment.

In the present study, the effect of plant adaptogens (Rhodiola rosea and ADAPT-232) on human photon emission has been determined. In a randomized double blind placebo-controlled study, 30 subjects were randomly assigned to three groups: one group (n = 10) taking placebo pills, one group (n = 10) taking Rhodiola rosea (SHR-5) pills and one group (n = 10) taking ADAPT-232 supplements (the latter being a fixed combination of the following three adaptogens: Eleutherococcus senticosus, Rhodiola rosea and Schisandra chinensis). All subjects underwent measurements to determine ultra-weak photon emission (UPE) of the dorsal side of their hands using a photon-counting device, both before and after a week of taking the supplements. In addition, the experienced levels of stress and fatigue (tiredness) were evaluated. After 1 week of supplementation, the Rhodiola group showed a significant decrease (p = 0.027) in photon emission in comparison with the placebo group. Furthermore, after supplementation, a significant decrease (p = 0.049) concerning the experienced level of fatigue in the Rhodiola group was observed compared with the placebo group. No significant changes were observed between the ADAPT-232 and the placebo group.

Plant adaptogens increase lifespan and stress resistance in C. elegans.

Extracts of plant adaptogens such as Eleutherococcus senticosus (or Acanthopanax senticosus) and Rhodiola rosea can increase stress resistance in several model systems. We now show that both extracts also increase the mean lifespan of the nematode C. elegans in a dose-dependent way. In at least four independent experiments, 250 microg/ml Eleutherococcus (SHE-3) and 10-25 microg/ml Rhodiola (SHR-5) significantly increased life span between 10 and 20% (P < 0.001), increased the maximum lifespan with 2-3 days and postponed the moment when the first individuals in a population die, suggesting a modulation of the ageing process. With higher concentrations, less effect was observed, whereas at the highest concentrations tested (2500 microg/ml Eleutherococcus and 250 microg/ml Rhodiola) a lifespan shortening effect was observed of 15-25% (P < 0.001). Both adaptogen extracts were also able to increase stress resistance in C. elegans: against a relatively short heat shock (35 degrees C during 3 h) as well as chronic heat treatment at 26 degrees C. An increase against chronic oxidative stress conditions was observed in mev-1 mutants, and during exposure of the wild type nematode to paraquat (10 mM) or UV stress, be it less efficiently. Concerning the mode of action: both adaptogens induce translocation of the DAF-16 transcription factor from the cytoplasm into the nucleus, suggesting a reprogramming of transcriptional activities favoring the synthesis of proteins involved in stress resistance (such as the chaperone HSP-16) and longevity. Based on these observations, it is suggested that adaptogens are experienced as mild stressors at the lifespan-enhancing concentrations and thereby induce increased stress resistance and a longer lifespan.

Histamine dilutions modulate basophil activation.

BACKGROUND: In order to demonstrate that high dilutions of histamine are able to inhibit basophil activation in a reproducible fashion, several techniques were used in different research laboratories. OBJECTIVE: The aim of the study was to investigate the action of histamine dilutions on basophil activation. METHODS: Basophil activation was assessed by alcian blue staining, measurement of histamine release and CD63 expression. Study 1 used a blinded multi-centre approach in 4 centres. Study 2, related to the confirmation of the multi-centre study by flow cytometry, was performed independently in 3 laboratories. Study 3 examined the histamine release (one laboratory) and the activity of H(2) receptor antagonists and structural analogues (two laboratories). RESULTS: High dilutions of histamine (10(-30)-10(-38) M) influence the activation of human basophils measured by alcian blue staining. The degree of inhibition depends on the initial level of anti-IgE induced stimulation, with the greatest inhibitory effects seen at lower levels of stimulation. This multicentre study was confirmed in the three laboratories by using flow cytometry and in one laboratory by histamine release. Inhibition of CD63 expression by histamine high dilutions was reversed by cimetidine (effect observed in two laboratories) and not by ranitidine (one laboratory). Histidine tested in parallel with histamine showed no activity on this model. CONCLUSIONS: In 3 different types of experiment, it has been shown that high dilutions of histamine may indeed exert an effect on basophil activity. This activity observed by staining basophils with alcian blue was confirmed by flow cytometry. Inhibition by histamine was reversed by anti-H2 and was not observed with histidine these results being in favour of the specificity of this effect We are however unable to explain our findings and are reporting them to encourage others to investigate this phenomenon.

Climbing activity in frogs and the effect of highly diluted sucussed thyroxine

The experiments investigate the influence of extremely dilute thyroxine (T4) in special "homoeopathic" preparation (dilution T4.30x) on the spontaneous tendency of juvenile frogs to leave the water and climb on land. Climbing activity was suppressed by dilution T4.30x, with statistical significance both in comparison to the effect of the "potentized" preparation of the solvent (dilution H2O.30x) as well as in comparison to the control observations before the start of the treatment. Finally, in the search for optimal treatment duration, it was shown that exposure to the dilutions for even a few minutes sufficed to cause significant effects