O melanoma é uma neoplasia maligna derivada de melanócitos, o qual tem uma letalidade elevada devido a sua característica altamente invasiva e agressiva. O caule da E. tirucalli produz um látex de coloração branca usado na medicina popular para o tratamento de neoplasias, que possui diversos constituintes ativos, incluindo o eufol, euforbol e isoeuforal. O objetivo do trabalho foi estudar os efeitos antineoplásicos in vitro e in vivo do látex da Euphorbia tirucalli em alguns modelos experimentais in vitro e in vivo. Células de melanoma B16/F10 foram tratadas com as seguintes diluições seriadas do látex a partir de uma concentração inicial de 0,1037ug/uL: 1/2, 1/4, 1/8, 1/16, 1/32, 1/64, 1/128, 1/256, 1/512, 1/1024, 1/2048, 1/5096, 1/11192. A viabilidade celular foi avaliada por MTT às 24, 48 e 72 horas. No experimento primeiro in vivo, células de melanoma foram inoculadas no tecido subcutâneo dorsal lombar de camundongos BALB/c e 10 dias após tratados, ou não, com 0,467ug/25g em volume de 200uL de látex de E. tirucalli por gavagem durante 14 dias. No segundo experimento, camundongos C57BL/6 foram inoculados com células de melanoma B16/F10 na veia da cauda para colonização pulmonar. No experimento in vitro, observou-se uma diminuição da viabilidade celular nas diluições de 1/1024 e 1/11192 no tempo de 24h e ás 48h houve uma diminuição da viabilidade celular nas diluições de 1/128, 1/256, 1/2048 e 1/11192. No experimento in vivo, observou-se que o látex da E. tirucalli foi capaz de reduzir o volume dos tumores subcutâneos em 53,5%, enquanto que o grupo não tratado o volume aumentou em 818,1%. No experimento de inoculação na veia da cauda com melanoma B16/F10 a administração de látex da E. tirucalli foi capaz de reduzir a fração de área pulmonar ocupada pelas colônias para 10,5% enquanto que no grupo não tratado, a fração de área pulmonar com colônias de melanoma aumentou para 35%. Não foram observadas alterações histopatológicas em nenhum dos grupos experimentais em outros órgãos. Os efeitos de redução de tumor, redução das colônias pulmonares e da viabilidade celular podem ser devidos à ação dos constituintes do látex que já demonstraram ter atividade antiproliferativa e citotóxica em outros experimentos, como o eufol e o euforbol. Embora o látex seja uma substância tóxica, ela pode ter tido, nas maiores diluições utilizadas, um efeito positivo para o tratamento do tipo hormesis / Melanoma is a malignant neoplasm derived from melanocytes, which has a high lethality due to its highly invasive and aggressive trait. The E. tirucalli stem produces a white latex used in folk medicine for the treatment of cancer, this product has several active constituents, including euphol, euphorbol and isoeuphoral. The objective of this work was to study the antineoplastic effects of Euphorbia tirucalli latex in experimental models in vitro and in vivo. B16/F10 melanoma cells were treated with the following serial dilutions of the latex from an initial concentration of 0.1037ug/?l: 1/2, 1/4, 1/8, 1/16, 1/32, 1/64, 1/128, 1/256, 1/512, 1/1024, 1/2048, 1/5096, 1/11192. Cell viability was assessed by MTT at 24, 48 and 72 hours. In the first in vivo experiment, melanoma cells were inoculated into the lumbar dorsal subcutaneous tissue of BALB/c mice and 10 days later they were treated or not treated with 0.467ug/25g of body weight in of 200?L of E. tirucalli latex by gavage for 14 days. In the second experiment, C57BL/ 6 mice were inoculated with B16/F10 melanoma cells into the tail vein for lung colonization. In the in vitro experiment, a decrease in cell viability at 1/1024 and 1/11192 dilutions was observed at 24h, and at 48h there was a decrease in cell viability at the dilutions of 1/128, 1/256, 1/2048 and 1/11192. In the in vivo experiment it was observed that the latex of E. tirucalli could reduce the volume of the subcutaneous tumors in 53.5% while in the untreated group the volume increased 818.1%. In the experiment of inoculation into the tail vein with B16/F10 melanoma cells, E. tirucalli latex administration was able to reduce the fraction of lung area occupied by the colonies to 10.5% whereas in the untreated group, the fraction of lung area with colonies was 35%. No histopathological changes were observed in any of the experimental groups in other organs. The effects of tumor reduction, reduction of lung colonies and cell viability may be due to the action of latex constituents that have already demonstrated antiproliferative and cytotoxic activity in other experiments, such as euphol and euphorbol. Although latex is a toxic substance, it may have developed, at the low dilutions used, a positive effect for the treatment of the hormesis type

A sinalização retrógrada mitocondrial é uma via de comunicação entre a mitocôndria e o núcleo que regula a expressão de uma série de genes nucleares que codificam proteínas mitocondriais, em resposta a disfunções mitocondriais. Em Saccharomyces cerevisiae, a via depende de Rtg1p e Rtg3p, que juntos formam o fator de transcrição que regula a expressão gênica, e de Rtg2p, um ativador da via. Aqui, nós mostramos novos estudos direcionados à investigação do impacto da sinalização retrógrada RTG-dependente na fisiologia mitocondrial. Verificamos que mutantes incapazes de realizar sinalização retrógrada RTG-dependente apresentam consumo de oxigênio mais elevado e menor produção de peróxido de hidrogênio em fase estacionária quando comparados a células selvagens. Interessantemente, mutantes RTG são menos capazes de decompor peróxido de hidrogênio assim como manter-se viáveis quando desafiados com peróxido. Nossos resultados indicam que a sinalização por RTG está envolvida na indução hormética de defesas antioxidantes e de resistência a estresse, função ainda não descrita para este sistema. / Mitochondrial retrograde signaling is a communication pathway between the mitochondrion and the nucleus which regulates the expression of a subset of nuclear genes that codify mitochondrial proteins, mediating cell response to mitochondrial dysfunction. In Saccharomyces cerevisiae, the pathway depends on Rtg1p and Rtg3p, which together form the transcription factor that regulates gene expression, and Rtg2p, an activator of the pathway. Here, we provide novel studies aimed at assessing the functional impact of the lack of RTG-dependent signaling on mitochondrial activity. We show that mutants defective in RTG-dependent retrograde signaling present higher oxygen consumption and reduced hydrogen peroxide release in the stationary phase when compared to wild type cells. Interestingly, RTG mutants are less able to decompose hydrogen peroxide as well as maintain viability when challenged with hydrogen peroxide. Overall, our results indicate that RTG signaling is involved in the hormetic induction of antioxidant defenses and stress resistance, a function of this system not yet described.

Potential long-term (~7months) sub-lethal impacts of soil-applied low levels of Roundup herbicide formulation were investigated in a greenhouse environment using the vegetative clones of succulent non-crop plant model, Bryophyllum pinnatum (Lam.) Oken. An eleven day LC50 (concentration that killed 50% of the plants) was found to be 6.25% (~1.25mg glyphosate/mL and 1.25mg pelargonic acid/mL combined), and complete mortality occurred at 12.5%, of the field application rate (i.e., ~20mg glyphosate/mL and 20mg pelargonic acid/mL as active ingredients). While sub-lethal Roundup (1-5%) exposures led to hormesis-characterized by a significant increase in biomass and vegetative reproduction, higher concentrations (≥6.25%) were toxic. A significant interaction between Roundup concentrations and leaf biomass was found to influence the F1 plantlets' biomass. Biomass asymmetry generally increased with increasing Roundup concentrations, indicating that plants were more stressed at higher Roundup treatments but within the low-dose regime (≤5% of the as-supplied formulation). While leaf apex region demonstrated higher reproduction with lower biomass increase, leaf basal area showed lower reproduction with greater biomass increase, in plantlets. The results suggest long-term exposures to drifted low levels of Roundup in soil may promote biomass and reproduction in B. pinnatum.

Hormesis is a nonlinear dose-response characterized by biological responses at low doses that are opposite to those observed at higher doses. Studies and review articles on hormesis are being published at an increasing rate by researchers from diverse disciplines and debate has emerged over the role hormesis in risk assessment. As a result, a survey was conducted to assess toxicologists and risk assessors knowledge and attitudes about the hormesis dose response. Study goals were to: 1) ascertain attitudes towards hormesis and other dose-response models, 2) identify whether acceptance or rejection of hormesis is based on knowledge of hormesis, predisposing values, or demographic characteristics, and 3) evaluate potential for response bias. The survey consisted of 44 questions pre-tested by 25 toxicologists and risk assessors. The survey was distributed via email to the membership of the Society of Toxicology and the Society for Risk Analysis, 9,500 potential respondents. The overall response rate was 17% (n= 1,463) with a completion rate over 87%. Major findings were that 50% of respondents indicated sufficient data exist to support the view hormesis occurs across a wide range of species and endpoints, 59% indicated evaluating potential benefits due to hormesis should be included in risk assessments, and 65% are in favor of modifying hazard assessment protocols to identify the presence of hormesis. Respondent characteristics such as: years of experience, society membership, education, residence, employment (excluding government and pharmaceutical companies), and political, economic or social views had little influence on opinion. One of the largest positive influences was experience with hormesis based on actual research; 79% of subjects who reported observing hormesis commonly in their studies agreed hormesis is broadly generalizable. The influence of non-response bias was evaluated through several internal and external measures. Despite a lower than hoped for response rate, but because of robust external validity measures, it is concluded that respondents’ opinions are likely a reasonable representation of the societies of which they are members. Because this is a baseline survey, a follow-up survey is in order. Future survey design should separately evaluate the science of dose-response from the regulatory approach to risk assessment.

L'exposition à des niveaux faibles de radiation ionisante est connue pour déclencher une réponse adaptative qui inclut la stimulation immunitaire et l'augmentation des effets protecteurs à long terme incluant l’amélioration de la détection et la réparation de dégâts causés à l’ADN, la croissance renforcée et la longévité. Tandis que les aspects hormetique de la réponse adaptative augmentent clairement la santé physique en présence de stress environnementaux, ils doivent la diminuer dans des conditions environnementales normales parce que les mécanismes biologiques responsables ne sont pas maintenus dans un état amélioré, mais exigent plutôt une certaine forme d'exposition sensibilisante. Il a été suggéré que la stimulation de la réponse adaptative pourrait être métaboliquement coûteuse cependant aucune mesure directe du coût métabolique de la croissance stimulée de radiation a été précédemment essayée. Cette thèse a évalué si la croissance stimulée de radiation du grand corégone (Coregonus clupeaformis) est accompagnée par un compromis dans l'efficacité métabolique ou par une augmentation durable de demandes énergiques. L'exposition à un régime fractionné de radiation ionisante d'une source de 137Cs s’est avéré stimuler considérablement la croissance dans des embryons du grand corégone comparés aux contrôles avec une augmentation correspondante de la consommation de jaune. Cependant, les mesures d'efficacité métabolique utilisant une série de temps de poids secs non préservés ont montré que la croissance stimulée était non-accompagnée par une réduction de l'efficacité métabolique. Une température moyenne exponentiellement transformée a été utilisée comme un point de référence quantitative pour évaluer la vulnérabilité du développement des embryons du grand corégone à la disparité phénologique. Le temps d’éclosion différait des prédictions de références sous des régimes thermiques asymétriquement variables. Les écarts ont été attribués aux embryons grandissant à dans un stade plus avancée de développement sous des températures basses. Le terme heterograde est proposé pour décrire la dépendance thermique dans l'étape d’éclosion qui peut avoir évolué comme un mécanisme pour synchroniser l’éclosion de larves viables pour l'augmentation de la densité de zooplancton qui accompagne le débâcle printanière Un modèle de prédiction incorporant l’éclosion heterograde a permis une amélioration significative dans l’exactitude des prédictions comparé aux modèles précédents. L'efficacité énergique a une importance particulière pour le grand corégone comme il a une des périodes d'incubation naturelles les plus longues pour un poisson d'eau douce, avec des températures d'incubation les plus basses et avec des œufs seulement 10 % de la taille de la plupart des salmonidés non-coregonine. L'évolution de mécanismes pour synchroniser l’éclosion au démantèlement de couverture de glace hivernale met en évidence la vulnérabilité du grand corégone à la disparité phénologique et ce par le développement accéléré qui cause l’éclosion asynchrone des embryons avec le démantèlement de la couverture de glace d'hiver ou par une augmentation durable de demandes énergiques qui augmentent leur vulnérabilité à la famine. L'absence de compromis mesurable dans l'efficacité métabolique indique ce dernier comme un coût général plausible de hormesis. / Exposure to low levels of ionizing radiation is known to trigger an adaptive response that includes immune stimulation and the up-regulation of long-lasting protective effects including improved detection and repair of DNA damage, enhanced growth, and longevity. While the hormetic aspects of the adaptive response clearly increase fitness in the presence of environmental stresses, they must decrease fitness under normal environmental conditions because the responsible biological mechanisms are not maintained in an upregulated state but rather require some form of sensitizing exposure. It has been suggested that stimulation of the adaptive response could be metabolically costly however no direct measurement of the metabolic cost of radiation stimulated growth has been previously attempted. This thesis assessed whether radiation-stimulated growth in the lake whitefish (Coregonus clupeaformis) is accompanied by a trade-off in metabolic efficiency, or by a sustained increase in energetic demands. Exposure to a fractionated regime of ionizing radiation from a 137Cs source was found to significantly stimulate growth in lake whitefish embryos compared to controls with a corresponding increase in yolk consumption. However, measurements of metabolic efficiency using a time series of unpreserved dry weights showed that the stimulated growth was unaccompanied by a reduction in metabolic efficiency. An exponentially transformed mean temperature was used as a quantitative baseline to assess the vulnerability of developing whitefish embryos to phenological mismatch. Hatch timing was found to deviate from baseline predictions under asymmetrically variable thermal regimes. The deviations were attributed to the embryos growing to a more advanced stage of development at low temperatures. The term heterograde is proposed to describe the thermal dependency of hatching stage which may have evolved as a mechanism to synchronize the hatching of viable larvae to the increase of zooplankton density that accompanies spring break-up. A predictive model incorporating heterograde hatching yielded a significant improvement in predictive accuracy over previous models. Energetic efficiency is of particular importance to the lake whitefish as it has one of the longest natural incubation periods of any freshwater fish, at some of the lowest incubation temperatures, and with eggs only 10% the size of most non-coregonine salmonids. The evolution of mechanisms to synchronize hatching to the break-up of winter ice cover highlights the vulnerability of the lake whitefish to phenological mismatch whether through accelerated development that causes embryos to hatch asynchronously with the break-up of winter ice cover, or through a sustained increase in energetic demands that increases their vulnerability to starvation. The absence of any measurable trade-off in metabolic efficiency points to the latter as a plausible general cost of hormesis. / Dissertation / Doctor of Philosophy (PhD)

No description available.

<p>Radiation is a prominent source of environmental oxidative stress that can have deleterious consequences for health. Despite its well-known negative effects, radiation is commonly employed clinically for disease treatment and diagnosis. Bone marrow transplantation (BMT), used in the treatment of a variety of diseases, is preceded by a myeloablative regimen that usually involves radiation. Mortality associated with BMT is quite high and the aggressive radiation pre-treatment regimen contributes to these high rates of mortality. Interventions that inhibit the negative consequences of irradiation and promote BMT success would have significant implications for public health. Exercise-induced adaptations in numerous body tissues have been associated with amelioration of a variety of pathologies, particularly those associated with oxidative stress, and an overall improvement in health. Whether these adaptations can protect from damage induced by an external source of oxidative stress, such as a high dose of radiation, or promote BMT success is unknown. The purpose of this thesis was to determine if the adaptive response to exercise training could inhibit the negative effects of irradiation in skeletal muscle and bone marrow, and promote BMT success. To apply these adaptations to BMT, we examined the response of hematopoietic stem cells (HSC) and their niche to exercise. We report that muscle from exercise trained mice exhibits an enhanced response to radiation characterized by increased antioxidant and mitochondrial metabolic enzyme activity. Extending these findings to cells in the bone marrow, we demonstrated that exercise training inhibited radiation-induced genotoxicity and cytotoxicity. With respect to BMT, exercise training increased HSC quantity with no effects on HSC function; however, preconditioning BMT recipients with exercise training resulted in improved probability of survival and enhanced hematopoietic regeneration. Collectively, results from the studies presented herein suggest that exercise training may be a successful therapeutic intervention to inhibit the damaging effects of radiation and improve BMT outcomes.</p> / Doctor of Philosophy (PhD)

Tannine sind pflanzliche, polyphenolische Sekundärmetabolite mit Protein-präzipitierenden und –bindenden Kapazitäten, welche offenbar für die antinutritiven und gesundheitsschädlichen Wirkungen der Tannine verantwortlich sind. Jedoch dominieren in der Literatur die gesundheitsfördernden Beschreibungen, für die meist die antioxidative Kapazität verantwortlich gemacht wurde. Der etablierte Modelorganismus Caenorhabditis elegans wurde zur Analyse dieses Kontrastes ausgewählt. Zunächst wurden Lebensdauer und Stressresistenz der mit Tanninsäure und den Tanninbausteinen Gallussäure, Ellagsäure und Catechin behandelten Nematoden ermittelt. Das vermutete Vorliegen eines „Calorie Restriction“ (CR)-Effektes als auch einer hormetischen Dosis-Wirkungs-Beziehung wurde überprüft. Weiterhin wurden antimikrobielle und antioxidative Eigenschaften als potentielle Ursachen der Langlebigkeit untersucht und die Auswirkungen auf die Fitness und Genexpression analysiert. Die Einbeziehung verschiedener Alterungs-Theorien rundete die Analyse der Tanninwirkung ab. Alle Tannin-Substanzen konnten eine Lebensverlängerung erwirken, doch erstaunlicherweise erwiesen sich Langlebigkeit und Stressresistenz als individuelle, nicht zwangsläufig gekoppelte Parameter. Hormesis, CR-nachahmende Eigenschaften, antimikrobielle Kapazitäten als auch verschiedene stressrelevante Gene sind teilweise für die Lebensverlängerung verantwortlich. Die antioxidative Kapazität scheint jedoch irrelevant zu sein. Die differentielle Expression mehrerer hundert Gene durch Tanninsäure unterstreicht zudem die Komplexität der Wirkweise. Hinweise zur Bestätigung der „Disposable Soma Theory“, der „Mitohormesis“-Theorie und der „Green Theory of Ageing“ konnten zum Teil gefunden werden. Diese Arbeit zeigt die individuelle und kontrastreiche Wirksamkeit der Tannine auf. Sie unterstreicht, dass Tannine molekulare Regulatoren sind, welche nicht nur auf ihre antioxidative und antinutritive Kapazität reduziert werden sollten. / The polyphenolic tannins are plant-produced secondary metabolites with protein precipitating and binding capacities. This characteristic is seemingly responsible for antinutritional and harmful effects. However, health benefits have also been extensively described in the literature. Indeed, antioxidant properties are believed to be the reason for these beneficial effects. The established model organism Caenorhabditis elegans was chosen to examine this apparent contradiction. The nematodes were exposed to tannic acid and to the tannin building blocks gallic acid, ellagic acid, and catechin and the lifespan and stress resistance were determined. The presence of a calorie restriction (CR) effect and a hormetic dose-response-relationship was verified. Furthermore, antimicrobial and antioxidative capacities were assessed as possible causes of longevity and the impact on fitness parameters and gene expressions was analysed. The consideration of different ageing theories completed the analysis of the tannin action. All tannin-substances were able to prolong the lifespan but against all expectations, longevity and stress resistance were shown to be independent entities, which are not necessarily linked. Hormesis, CR-mimetic properties, antimicrobial capacities as well as several stress relevant genes are partly responsible for the life-extension. The antioxidant capacities, however, appeared to be irrelevant. The regulation of several hundred gene expressions by tannic acid underlined the complexity of the mode of action. Furthermore, the results partly confirm the “Disposable Soma Theory”, the “Mitohormesis Theory” and the “Green Theory of Ageing”. This work dissects the contrasting efficiency of the tannin family and underlines in particular, that tannins are molecular regulators, which should not be reduced to their antioxidative and antinutritional capacities

Die mittlere Lebenserwartung des Menschen ist über die letzten 200 Jahre kontinuierlich gestiegen. Da Langlebigkeit ohne Gesundheit wenig Wert besitzt, ist es ein zentrales Anliegen, das Auftreten altersbedingter Krankheiten zu mindern. Besonders pflanzliche Phytochemikalien, im speziellen Polyphenole (PPs), sollen erheblich an der Gesundheitsförderung mitwirken. Die exakten Mechanismen jedoch, welche die Wirkvielfalt erklären könnten, sind nicht im Detail bekannt. Diese Fragen können nur durch in vivo Studien an Modelorganismen beantwortet werden, die sowohl die Lebensdauer, sowie physiologische und genetische Parameter einschließen. In dieser Studie wurden drei PPs mit lebensverlängernden Eigenschaften in C. elegans identifiziert: Quercetin (Q), Kaffeesäure (CA) und Rosmarinsäure (RA). Für alle drei PPs wurden hormetische Konzentration-Wirkungs-Kurven gefunden, dennoch war die Hormetin-typische Aktivierung einer Stressantwort (gemessen als Geneexpressions-Level von Hitzeschock-Proteinen) auf Q und RA beschränkt. Eine Umverteilung von Ressourcen nach dem Prinzip der „Disposable Soma Theorie“ konnte anhand von Abweichungen in der Größe, verändertem Lipid-Metabolismus und verzögerter Reproduktion (bei gleichbleibender Anzahl der Nachkommen), für alle drei PPs gezeigt werden. Während direkte CR-Effekte ausgeschlossen wurden, ist dies nicht möglich für durch CA und RA ausgelöste indirekte CR-Effekte, da beide die Lebensspanne von sir-2.1 Mutanten nicht verlängern konnten. Alle drei PPs verlängerten die Lebensspanne von mev-1 Mutanten, jedoch wurde eine erhöhte TAC in vivo und eine reduzierte oxidative Schädigung, nur durch Q- und CA- Gabe erreicht. Die genetischen Wirkwege der PPs wurden durch Lebensdauer- und Thermotoleranztests mit in alters-relevanten Genen mutierten Nematoden definiert. Die gesundheitsfördernden Eigenschaften von CA und RA konnten so osr-1, sek-1, sir-2.1 and unc-43, sowie daf-16 im Falle von CA, zugeschrieben werden. Die Mechanismen von Q wurden in größerem Umfang, durch die Integration von durchgeführten Lebensdauertests und Microarray-Studien einerseits und einer umfassenden Meta-Analyse von veröffentlichten, alters-relevanten Genexpressions-Profilen andererseits, analysiert. Q wirkt vermutlich durch ein komplexes Zusammenspiel von konservierten genetischen Signalwegen, im Speziellen dem Insulin-ähnlichen (ILS), TGF-beta, p38 MAPK, CAMKII und möglicherweise auch über eine von der Keimbahn und somatischen Gonade ausgehenden Signalwirkung. Zusammenfassend lässt sich sagen, dass sowohl in vivo antioxidative und prooxidative Eigenschaften, die Modulation auf Genebene, sowie eine Umverteilung von Ressourcen zu gewissen Teilen (abhängig vom PP) zur Lebensverlängerung beitragen. / The mean life expectancy of humans has increased continuously over the last 200 years. Since longevity is of little value in the absence of health, it is a central request to prevent the increasing burden of age-related diseases. It is suggested that phytochemicals in plants, specifically the polyphenols (PPs), are important factors to support the overall well-being. However, the precise mechanisms that can explain, in full, the magnitude of impact remains elusive. This knowledge gap can only be plugged by in vivo model organism approaches that integrate lifespan assays with physiological, and genetic parameters following the ingestion of PPs. In this study, three PPs with life-extending properties in C. elegans were identified: Quercetin (Q), Caffeic acid (CA) and Rosmarinic acid (RA). The underlying mechanisms were systematically studied by a broad spectrum of functional and genetic investigations. For all three compounds, life extension was characterized by hormetic concentration-response curves, but stress-response induction, a hallmark of hormetin action, was restricted to Q and RA, at least when assessed at the level of gene expression of heat shock proteins. A reallocation of resources in a disposable soma-like pattern could be shown for all three PPs, because the exposure to Q, CA and RA resulted in variations in body size, altered lipid-metabolism and a tendency towards a delay in reproductive timing. However, the total number of offspring was unaltered. While direct CR effects arising from reduced food uptake could be rejected, an indirect CR effect cannot be excluded for CA and RA, as these PPs failed to provoke longevity in sir-2.1 mutants. Furthermore, the in vitro versus in vivo antioxidative properties were evaluated. While all three PPs could prolong mev-1 lifespan, only Q and CA were shown to increase the TAC in vivo and reduce oxidative damage in the nematodes. To define the genetic pathways of PP action, lifespan and thermotolerance assays were performed in mutant animals devoid of aging-relevant genetic players. These experiments revealed that the health gaining properties of CA and RA both rely on osr-1, sek-1, sir-2.1 and unc-43, plus daf-16 in the case of CA. The mechanisms of Q action are partly distinct and were analyzed in more detail by integrating own mutant lifespan assays and microarray studies with an extensive meta-analysis of published gene expression profiles obtained under aging-relevant conditions. Quercetin is proposed to act through a complex interplay of conserved genetic pathways, for example Insulin-like signaling (ILS), TGF-beta signaling, p38 MAPK, CaMKII, and possibly also due to germline and somatic gonad signaling. Taken together, hormesis, in vivo antioxidative/prooxidative properties, modulation of genetic players, as well as the re-allocation of resources all contribute (to some extent and dependent on the polyphenol) to life extension. Summary 1

BACKGROUND:This paper proposes a novel model for homeopathic remedy action on living systems. Research indicates that homeopathic remedies (a) contain measurable source and silica nanoparticles heterogeneously dispersed in colloidal solution / (b) act by modulating biological function of the allostatic stress response network (c) evoke biphasic actions on living systems via organism-dependent adaptive and endogenously amplified effects / (d) improve systemic resilience.DISCUSSION:The proposed active components of homeopathic remedies are nanoparticles of source substance in water-based colloidal solution, not bulk-form drugs. Nanoparticles have unique biological and physico-chemical properties, including increased catalytic reactivity, protein and DNA adsorption, bioavailability, dose-sparing, electromagnetic, and quantum effects different from bulk-form materials. Trituration and/or liquid succussions during classical remedy preparation create "top-down" nanostructures. Plants can biosynthesize remedy-templated silica nanostructures. Nanoparticles stimulate hormesis, a beneficial low-dose adaptive response. Homeopathic remedies prescribed in low doses spaced intermittently over time act as biological signals that stimulate the organism's allostatic biological stress response network, evoking nonlinear modulatory, self-organizing change. Potential mechanisms include time-dependent sensitization (TDS), a type of adaptive plasticity/metaplasticity involving progressive amplification of host responses, which reverse direction and oscillate at physiological limits. To mobilize hormesis and TDS, the remedy must be appraised as a salient, but low level, novel threat, stressor, or homeostatic disruption for the whole organism. Silica nanoparticles adsorb remedy source and amplify effects. Properly-timed remedy dosing elicits disease-primed compensatory reversal in direction of maladaptive dynamics of the allostatic network, thus promoting resilience and recovery from disease.SUMMARY:Homeopathic remedies are proposed as source nanoparticles that mobilize hormesis and time-dependent sensitization via non-pharmacological effects on specific biological adaptive and amplification mechanisms. The nanoparticle nature of remedies would distinguish them from conventional bulk drugs in structure, morphology, and functional properties. Outcomes would depend upon the ability of the organism to respond to the remedy as a novel stressor or heterotypic biological threat, initiating reversals of cumulative, cross-adapted biological maladaptations underlying disease in the allostatic stress response network. Systemic resilience would improve. This model provides a foundation for theory-driven research on the role of nanomaterials in living systems, mechanisms of homeopathic remedy actions and translational uses in nanomedicine.